{"gname":"COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv","grp_id":"181","rels":[{"rel_title":"MarkerScout: A Disease-Agnostic Machine Learning Framework for Biomarker Prediction from Multi-Scale Mechanistic Models","rel_doi":"10.64898\/2026.05.30.727266","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.30.727266","rel_abs":"Identifying robust biomarkers from high-dimensional biomedical data is a central challenge in translational research, but candidate rankings produced by any single feature-selection or classification method depend on algorithmic choices and rarely reproduce across pipelines. We present a disease-agnostic machine-learning framework that addresses this dependence by systematically benchmarking 25 (feature-selection x classifier) pipelines under five-fold stratified cross-validation, aggregating per-feature evidence by two independent methods (a weighted-selection consensus score and Robust Rank Aggregation), and characterizing the direction of each candidate using Cohen's d. We demonstrate the framework on immune-response measurements from two clinical phases: SARS-CoV-2 hospitalization and intensive-care admission; obtaining cross-validated mean F1 above 0.99 with balanced classification errors and producing tiered, direction-aware biomarker lists per phase. Interleukin-18 (IL-18) reached the strongest tier in both phases with consistent direction. The framework generalizes to any binary clinical classification problem and supports principled, reproducible biomarker prioritization.","rel_num_authors":6,"rel_authors":[{"author_name":"Robert Bristow Moore II","author_inst":"University of Nebraska - Lincoln"},{"author_name":"Frank Agayie-Ntim","author_inst":"University of Nebraska-Lincoln"},{"author_name":"Lindsey B Crawford","author_inst":"University of Nebraska-Lincoln"},{"author_name":"Prakash Packrisamy","author_inst":"University of Nebraska-Lincoln"},{"author_name":"Ahmed Abdeen Hamed","author_inst":"University of Nebraska-Lincoln"},{"author_name":"Tomas Helikar","author_inst":"University of Nebraska - Lincoln"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Meningitis vaccination campaign in the context of COVID-19 in Cameroon","rel_doi":"10.64898\/2026.06.02.26354702","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.06.02.26354702","rel_abs":"Objective: The study aimed to describe the challenges, best practices, and lessons learned during meningitis vaccination campaigns conducted in the context of COVID-19 in Cameroon in 2020. Results: During the prevention campaigns, 3,460 individuals were selected. All were tested before the campaign (100%). Eight cases were positive, representing a positivity rate of 0.23% (8\/3,460). The campaign was carried out using a fixed strategy in health facilities and prisons and a fixed-temporary strategy in communities. Most health areas received sufficient quantities of COVID-19 equipment for some items and insufficient quantities for others. No screening was done during or after the campaign. The main difficulties encountered were compliance with social distancing and the continuous wearing of gowns. The challenges faced were the screening of actors and the use of personal protective equipment. Lessons learned: aspects related to COVID-19 impacted the speed of the campaign. Vaccination coverage ranged from 91% to 140% in prisons on the one hand, and from 35% to 112% in the health areas surrounding prisons on the other. The campaign in the context of COVID-19 was effective. Compliance with barrier measures was not optimal due to difficulties encountered with aspects such as social distancing, continuous wearing of gowns, screening of participants during and after the campaign, and insufficient personal protective equipment.","rel_num_authors":6,"rel_authors":[{"author_name":"Marie Angele Mbang","author_inst":"Sub-Directorate of Vaccination, Department of Family Health, Ministry of Public Health, Yaounde, Cameroon"},{"author_name":"Fabrice Zobel Lekeumo Cheuyem","author_inst":"Department of Public Health, Faculty of Medicine and Biomedical Sciences, The University of Yaounde 1, Yaounde, Cameroon"},{"author_name":"Rick Tchamani","author_inst":"Central Africa University Institute of Excellence, Yaounde, Cameroon"},{"author_name":"Jeudi Debnet","author_inst":"Sub-Directorate of Vaccination, Department of Family Health, Ministry of Public Health, Yaounde, Cameroon"},{"author_name":"Zacheus Nanje Ebongo","author_inst":"Department of Family Health, Ministry of Public Health, Yaounde, Cameroon"},{"author_name":"Andre Arsene Bita Fouda","author_inst":"Faculty of Medicine and Pharmaceutical Sciences of Douala, Douala, Cameroon"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Shared epigenetic regulation acting on neuroimmune pathways contributes to the comorbidity between generalized anxiety disorder and COVID-19","rel_doi":"10.64898\/2026.06.03.26354830","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.06.03.26354830","rel_abs":"Background: The biological mechanisms linking generalized anxiety disorder (GAD) and COVID-19 remain poorly understood, despite substantial evidence of their comorbidity. To address this gap, we examined genetic and epigenetic factors underlying their co-occurrence. Methods: In a multi-ancestry sample of 893 participants, we conducted genome-wide and epigenome-wide analyses of GAD and COVID-19 severity. Integrating large-scale genome-wide datasets and information regarding methylation quantitative trait loci, complementary analytic approaches were used to identify regional methylation patterns, assess genetically regulated DNA methylation in blood and brain tissue, and evaluate causal loci shared between GAD and COVID-19. Results: GAD was associated with epigenome-wide significant variation in loci involved in chromatin regulation and synaptic signaling. Conversely, COVID-19-related epigenetic signals were enriched in immune-inflammatory and host-response pathways. Mild COVID-19 was epigenetically related to endothelial-inflammatory signals, while severe COVID-19 was linked to epigenetic changes implicated in myeloid and thrombo-inflammatory pathways. Epigenetic signals shared between GAD and COVID-19 implicated processes related to stress adaptation and tissue homeostasis. Genetically informed analyses identified 60 shared loci, including MAPT, ZFP57, and FBXL18, indicating pleiotropy between GAD and COVID-19 in genetically regulated DNA methylation variation. Brain-specific analyses further highlighted convergence in additional loci (i.e., MICB and HLA-DPB1), suggesting neuroimmune mechanisms underlying GAD-COVID-19 shared methylation patterns. Conclusions: These findings support that GAD and COVID-19 share epigenetic and genetic architecture involving pathways related to vascular integrity, immune function, and cellular adaptation, highlighting a potential neuroimmune basis for their co-occurrence.","rel_num_authors":11,"rel_authors":[{"author_name":"Sefayet Karaca","author_inst":"Yale University"},{"author_name":"Brenda Cabrera Mendoza","author_inst":"Yale University"},{"author_name":"Jun He","author_inst":"Yale University"},{"author_name":"Dan Qiu","author_inst":"Yale University"},{"author_name":"David Davtian","author_inst":"Yale University"},{"author_name":"AnnMarie Lacobelle","author_inst":"Yale University"},{"author_name":"Yaira Z Nunez","author_inst":"Yale University"},{"author_name":"John H Krystal","author_inst":"Yale University"},{"author_name":"Robert H Pietrzak","author_inst":"Yale University"},{"author_name":"Joel Gelernter","author_inst":"Yale Univ. School of Medicine"},{"author_name":"Renato Polimanti","author_inst":"Yale University"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Pooled testing for SARS-CoV-2 surveillance in schools: real-world evaluation of transmission control, testing resources, and educational disruption","rel_doi":"10.64898\/2026.06.03.26354821","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.06.03.26354821","rel_abs":"Pooled testing programs were introduced during the COVID-19 pandemic to expand surveillance capacity while preserving testing resources, but evidence on their epidemiological impact in schools under real-world conditions remains limited. We analyzed data from the pooled testing program implemented in public primary schools of the canton of Basel-Landschaft, Switzerland, during the Fall-Winter 2021 Delta wave. We used an agent-based transmission model informed by pooled and individual testing results, school characteristics, contact networks, and community incidence. The model was fitted to pooled positivity ratios in four clusters of administrative areas with similar epidemic trajectories. We compared pooled testing with alternative protocols in terms of school transmission, testing volume, and student-days lost. During the study period, pooled testing was offered to 21'187 students across 62 public primary schools, with high and stable participation across clusters (mean 71-79%). The fitted model reproduced observed pool positivity trends well. Compared with pooled testing, reactive class closure, reactive screening, and symptomatic testing were associated with higher in-school transmission, with excess ranging from 50% to 87%, 63% to 104%, and 72% to 133% across clusters. Weekly individual screening achieved similar reductions in transmission but required 15-25 times more tests. Relaxing class closure after depooling substantially reduced student-days lost without increasing transmission. Under real-world conditions, pooled testing provided an effective and resource-efficient strategy to reduce SARS-CoV-2 transmission in primary schools. Combining early detection of asymptomatic infections with low testing demands, pooled testing offers a scalable approach to school surveillance and control for pandemic response in educational settings.","rel_num_authors":6,"rel_authors":[{"author_name":"Elisabetta Colosi","author_inst":"Bocconi University, Dondena Research Centre for Social Dynamics and Public Policy, Milan, Italy"},{"author_name":"Lucille Calmon","author_inst":"ISI Foundation, Turin, Italy"},{"author_name":"Montserrat F\u00e4ssli","author_inst":"Paediatric Research Centre, University Children's Hospital of both Basel (UKBB), Basel, Switzerland"},{"author_name":"Katrin Koch","author_inst":"Cantonal Office of Public Health, Economics and Health Directorate, Canton of Basel-Landschaft, Switzerland"},{"author_name":"Julia Anna Bielicki","author_inst":"Paediatric Research Centre, University Children's Hospital of both Basel (UKBB), Basel, Switzerland"},{"author_name":"Vittoria Colizza","author_inst":"Sorbonne Universit\u00e9, INSERM, Pierre Louis Institute of Epidemiology and Public Health, Paris, France"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Insights from Wastewater Surveillance of SARS-CoV-2 in Skilled Nursing Facilities: Comparing Virus Concentration Methods for Wastewater and Correlating Wastewater Virus Concentrations with Clinical Infections, Georgia, USA, 2022","rel_doi":"10.64898\/2026.06.01.26354622","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.06.01.26354622","rel_abs":"To understand the utility of healthcare facility-level wastewater surveillance (WWS) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is important to correlate wastewater SARS-CoV-2 RNA detection with the number of clinical infections. WWS for SARS-CoV-2 was performed at three skilled nursing facilities (SNFs) over 25 weeks. Electronegative membrane filtration (enMF) and Nanotrap(R) Magnetic Virus Particles (NP) virus concentration methods were compared. Extracts were tested by droplet digital polymerase chain reaction. Spearman's correlations ({rho}) between wastewater virus RNA concentrations and infection counts were calculated. From split wastewater samples, enMF recovered higher SARS-CoV-2 RNA concentrations than NP. Combining data from all facilities, the median concentrations were 53.0 versus 38.6 gc\/100 mL for enMF and NP, respectively (p=0.001). Using enMF, correlations were moderate to strong at SNF A ({rho} ranged 0.67 to 0.86, all p-values <0.001). Weak to moderate correlations can be explained by the sampled manhole not representing the entire facility (SNF B, {rho} ranged 0.47 to 0.72, p-values ranged <0.001 to 0.12) and longitudinal data gaps from summer heat and equipment maintenance (SNF C, {rho} ranged 0.14 to 0.59, p-values ranged 0.52 to <0.01). WWS can be a valuable tool for tracking dynamics of SARS-CoV-2 infections in healthcare facilities.","rel_num_authors":25,"rel_authors":[{"author_name":"Florence Whitehill","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Amanda K. Lyons","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Bethelhem Abera","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Colin Adler","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Maria Burgos-Garay","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Mariya Campbell","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Ariel J. Santiago","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Christine Ganim","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Jamari Moore","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Yimu Cahela","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Susanna Lenz","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Paige Gable","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Magdalena Medrzycki","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Maroya Spalding Walters","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Amelia Keaton","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Peter W. Cook","author_inst":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 "},{"author_name":"Yan Li","author_inst":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 "},{"author_name":"Ying Tao","author_inst":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 "},{"author_name":"Jing Zhang","author_inst":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 "},{"author_name":"Lakshmi Malapati","author_inst":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 "},{"author_name":"Adam C. Retchless","author_inst":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 "},{"author_name":"Suxiang Tong","author_inst":"Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 "},{"author_name":"Margaret Williams","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Rodney Donlan","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"},{"author_name":"Angela Coulliette-Salmond","author_inst":"Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifto"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Interferon-gamma induced RNF213 targets nascent double membrane vesicles to inhibit coronavirus primary translation","rel_doi":"10.64898\/2026.06.02.729663","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.02.729663","rel_abs":"Innate immune systems employ many mechanisms to inhibit the replication of viruses that profoundly affect host range and pathogenicity. To identify proteins that restrict human respiratory virus replication, we executed CRISPR screens targeting both type-I and type-II interferon stimulated genes. Among the candidate antiviral genes identified, the giant ring finger protein 213 (RNF213) was a key mediator of antiviral activity of interferon gamma (IFN{gamma}) against the human betacoronavirus HCoV-OC43. RNF213 has ATPase and ubiquitin ligase activities, both of which were required for anti-HCoV-OC43 activity. Using newly designed reporter viruses, we demonstrate that RNF213 acts by a previously undescribed mechanism, inhibiting the translation of incoming viral genomes. RNF213 colocalized and coimmunoprecipitated with the primary viral translation product, NSP3, that orchestrates the formation coronavirus replication compartments. Notably, RNF213 restricted genetically diverse common human coronaviruses, but SARS-CoV-2 apparently evades interaction with and inhibition by RNF213.","rel_num_authors":10,"rel_authors":[{"author_name":"Michael A Tartell","author_inst":"Rockefeller University"},{"author_name":"Randa Tissawak","author_inst":"The Hebrew University of Jerusalem"},{"author_name":"Lennard Voss","author_inst":"Friedrich-Alexander-Universitat Erlangen-Nurnberg"},{"author_name":"Manivel Lodha","author_inst":"The Rockefeller University"},{"author_name":"Christopher Bianco","author_inst":"The Rockefeller University"},{"author_name":"Masashi Iwamoto","author_inst":"The Rockefeller University"},{"author_name":"Daniel Poston","author_inst":"The Rockefeller University"},{"author_name":"Theodora Hatziioannou","author_inst":"Rockefeller University"},{"author_name":"Yiska Weisblum","author_inst":"The Rockefeller University"},{"author_name":"Paul D Bieniasz","author_inst":"The Rockefeller University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"A designed overlapping variant immunogen pool elicits broad sarbecovirus neutralization","rel_doi":"10.64898\/2026.06.03.729821","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.03.729821","rel_abs":"A central problem in achieving vaccine-based protection against viral infections is eliciting antibodies that are resilient to viral variation. Successive waves of SARS-CoV-2 infection during the COVID19 pandemic were driven by variants that acquired resistance to neutralizing antibodies elicited by prior SARS-CoV-2 variants. To the extent that serum neutralization breadth occurs in individuals with multiple exposures to SARS-CoV-2 antigens, we and others find that it is largely comprised of antibodies that target the variable receptor binding domain (RBD), rather than more conserved spike protein domains. By designing synthetic dimeric RBD immunogens we show that limiting divergence in heterodimeric components favors the generation of cross-reactive B cells and antibodies. We thus devised a vaccine approach based on a two-dose immunization with a pool of five overlapping heterodimeric synthetic RBD variants. Collectively, the RBD heterodimer pool was designed to cover 10% sequence variation and elicited greater antibody cross-reactivity and neutralization breadth than homodimers or heterodimers with highly divergent components. Using an unconventional prospective challenge model in mice, we demonstrate the effectiveness of the RBD heterodimer pool in inducing antibody responses that attenuate infection by future SARS-CoV-2 variants, as well as protection in a challenge model based on a chimeric vesicular stomatitis virus bearing a spike protein from SARS-CoV-1.","rel_num_authors":15,"rel_authors":[{"author_name":"Trinity Zang","author_inst":"The Rockefeller University"},{"author_name":"Viren A Baharani","author_inst":"The Rockefeller University"},{"author_name":"Miranda Aldis","author_inst":"The Rockefeller University"},{"author_name":"Marie Canis","author_inst":"The Rockefeller University"},{"author_name":"Rachel Patejak","author_inst":"The Rockefeller University"},{"author_name":"Edmund Osei Kuffour","author_inst":"The Rockefeller University"},{"author_name":"Hans Heinrich Hoffman","author_inst":"The Rockefeller University"},{"author_name":"Harm van Bakel","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Emilia M Sordillo","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Viviana Simon","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Margaret R MacDonald","author_inst":"The Rockefeller University"},{"author_name":"Charles M Rice","author_inst":"The Rockefeller University"},{"author_name":"Michel C Nussenzweig","author_inst":"The Rockefeller University"},{"author_name":"Theodora Haziionannou","author_inst":"The Rockefeller University"},{"author_name":"Paul D Bieniasz","author_inst":"The Rockefeller University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Systems-Scale Structural Modeling Reveals the Germline Architecture of Immunodominance","rel_doi":"10.64898\/2026.06.02.729678","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.02.729678","rel_abs":"The adaptive immune system generates diverse antibodies to protect against infection, yet responses often focus on a limited number of antigenic sites, a phenomenon called immunodominance. Using the SARS-CoV-2 receptor-binding domain as a model, this study combines large-scale antibody sequencing, deep mutational scanning, and AlphaFold 3 structural modeling to investigate the basis of immunodominant epitope selection. The results show that germline-encoded antibody features are a primary driver of immunodominance. Specifically, 76% of RBD-targeting antibodies display conserved gene segment usage and\/or germline-encoded HCDR3 motifs. Structural analyses identified recurrent germline-encoded residues within these regions that interact with immunodominant epitopes, and mutating these residues eliminated binding. Mutations in SARS-CoV-2 variants frequently disrupt these interactions and are associated with immune escape; other mutations enable germline-mediated recognition and generate new immunodominant epitopes. These findings indicate that innate features, rather than diverse somatic mutations, determine binding specificity for the large majority of the antibody response and underlie antibody immunodominance.","rel_num_authors":12,"rel_authors":[{"author_name":"Ellen L. Shrock","author_inst":"Institute for Protein Design, University of Washington, Seattle, WA 98195, USA"},{"author_name":"Eric Sun","author_inst":"Institute for Protein Design, University of Washington, Seattle, WA 98195, USA"},{"author_name":"Amrita Dhindsa","author_inst":"The Hospital for Sick Children"},{"author_name":"Max H. Witwer","author_inst":"Institute for Protein Design, University of Washington, Seattle, WA 98195, USA"},{"author_name":"Zhou Yu","author_inst":"Brigham and Women's Hospital"},{"author_name":"Danton Ivanochko","author_inst":"The Hospital for Sick Children"},{"author_name":"I-Hsiu Lee","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA 02115, USA"},{"author_name":"Brian Coventry","author_inst":"University of Washington"},{"author_name":"Maria Borras Gonzalez","author_inst":"University of Washington"},{"author_name":"Jean-Philippe Julien","author_inst":"Hospital for Sick Children"},{"author_name":"Stephen J. Elledge","author_inst":"Howard Hughes Medical Institute, Department of Genetics, Harvard University Medical School"},{"author_name":"David Baker","author_inst":"University of Washington"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"No objective evidence of neuropsychological deficits in people with subjective cognitive changes following COVID-19 infection","rel_doi":"10.64898\/2026.06.03.723612","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.03.723612","rel_abs":"Background: Among those who develop Long COVID, many experience persistent cognitive 'brain fog'. The degree to which these subjective complaints reflect measurable neuropsychological deficits remains unclear. Prior work suggests that subjective cognitive impairment may be more closely associated with affective symptoms than objective performance. This study examines the relationship between subjective and objective cognitive function in adults with post-COVID cognitive complaints, and assesses the association between self-reported deficits and biological markers of dementia risk and inflammation. Methods: Eighty-six adults with prior COVID-19 infection (mean age 41.5 years) completed neuropsychological testing (MATRICS; CVLT-III) and self-report measures of depression and anxiety (Beck Inventories). Participants were classified as Cases (n=47) if they endorsed worsening memory or concentration since infection or Controls (n=38) if they did not. Objective cognitive impairment was defined as performance <1 SD below normative means on at least one test. APOE-e4 status and soluble CD14 (sCD14) levels were assessed. Results: Cases reported higher depression and anxiety symptoms than Controls (both p<0.001), but groups did not differ on objective cognitive performance (p=0.39). Cases were more likely to be APOE-e4 carriers (p=0.01) and had higher sCD14 levels (p=0.01). Neither marker was associated with objective performance. Conclusions: Subjective cognitive complaints following COVID-19 were not accompanied by measurable neuropsychological deficits but were linked to elevated affective symptoms and biological risk markers. Findings highlight a dissociation between perceived and objective cognition and suggest that inflammatory, genetic, and affective factors may shape self-perceived decline. Longitudinal studies are needed to determine whether these markers confer vulnerability to cognitive decline. Keywords: COVID-19; subjective cognitive decline; APOE-e4; neuropsychological assessment, depression\/anxiety, inflammation","rel_num_authors":9,"rel_authors":[{"author_name":"Samantha Abram","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Kaitlyn Dal Bon","author_inst":"Carnegie Mellon University; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Daniel H Mathalon","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Susanna L Fryer","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Sara Song","author_inst":"University of California, San Francisco"},{"author_name":"Zanib Naeem","author_inst":"Veterans Affairs San Francisco Healthcare System"},{"author_name":"Norina Tang","author_inst":"Veterans Affairs San Francisco Healthcare System"},{"author_name":"Lynn Pulliam","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Judith M Ford","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Hierarchical classification of immune cell transcriptomes at population-scale","rel_doi":"10.64898\/2026.05.30.728980","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.30.728980","rel_abs":"Accurate immune cell classification is essential for interpreting single-cell RNA sequencing (scRNA-seq) data. However, progress is constrained by the lack of independent, high-resolution benchmarks, as the routine integration of datasets introduces statistical dependencies that artificially inflate model generalizability. Here, we present the single-cell universal classification omnibus (Suco), a resource of independent, uniform expert annotations, and Compocyte, a modular hierarchical classifier. Together, they establish a framework designed for the scale of human population immunology. This approach substantially outperforms existing classifiers while facilitating expert review of ambiguous annotations. Applying Compocyte across 50 studies, including three newly generated datasets, we classified 15.6 million leukocytes from 3,965 patients. Within this expansive cohort, we identified a new tumor-associated resorptive macrophage phenotype, a non-canonical monocyte subtype in subclinical cytokine release syndrome, and the programmatic erosion of T cell memory stemness across metastatic sites. Suco and Compocyte thus provide a generalizable architecture and benchmark capable of sustaining high-resolution annotation across massive clinical cohorts.","rel_num_authors":42,"rel_authors":[{"author_name":"Christopher Beltz","author_inst":"Computational Cancer Biomedicine, Institut dInvestigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain"},{"author_name":"Zekai Qiu","author_inst":"Department of Radiooncology and Radiotherapy, Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Germany"},{"author_name":"Leon Sadowski","author_inst":"German Cancer Research Center, Clinical Cooperation Unit Molecular Radiooncology, Heidelberg, Germany"},{"author_name":"Joscha A. Kraske","author_inst":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) & Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Ge"},{"author_name":"Anmol Aggarwal","author_inst":"German Cancer Research Center, Clinical Cooperation Unit Virotherapy, Heidelberg, Germany"},{"author_name":"Alvaro Quintanal-Villalonga","author_inst":"Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"},{"author_name":"Parvathy Manoj","author_inst":"Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"},{"author_name":"Andrea Littbarski","author_inst":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) & Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Ge"},{"author_name":"Sunanjay Bajaj","author_inst":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) & Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Ge"},{"author_name":"Brigita Meskauskaite","author_inst":"Single Cell Analytics Innovation Lab, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Shigeaki Umeda","author_inst":"The David M Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY"},{"author_name":"Linas Mazutis","author_inst":"Institute of Biotechnology, Vilnius University, Vilnius, Lithuania"},{"author_name":"Samuel A. Rose","author_inst":"Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Joseph M. Chan","author_inst":"Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Tal Nawy","author_inst":"Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Juozas Nainys","author_inst":"Atrandi Biosciences, Vilnius, Lithuania"},{"author_name":"Ronan Chaligne","author_inst":"Single Cell Analytics Innovation Lab, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Elisa de Stanchina","author_inst":"Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Katharina A. Kaelber","author_inst":"Department of Dermatology, Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Germany"},{"author_name":"Christiane S. Cussigh","author_inst":"Department of Dermatology, Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Germany"},{"author_name":"Stefan M. Kallenberger","author_inst":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) & Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Ge"},{"author_name":"Anja Williams","author_inst":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) & Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Ge"},{"author_name":"Maximilian Jenzer","author_inst":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) & Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Ge"},{"author_name":"Tillmann Pompecki","author_inst":"Department of Gastroenterology, Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Germany"},{"author_name":"Steffen Kahle","author_inst":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) & Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Ge"},{"author_name":"Nicolas Hohmann","author_inst":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) & Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Ge"},{"author_name":"Daniel P. Nussbaum","author_inst":"Department of Surgery, Duke University, Durham, NC 27708, USA"},{"author_name":"Nelson S. Moss","author_inst":"Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"},{"author_name":"Etay Ziv","author_inst":"Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"},{"author_name":"Anne K. Berger","author_inst":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) & Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Ge"},{"author_name":"Christoph Springfeld","author_inst":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) & Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Ge"},{"author_name":"Stefanie Zschaebitz","author_inst":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) & Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Ge"},{"author_name":"Jessica C. Hassel","author_inst":"Department of Dermatology, Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Germany"},{"author_name":"Juergen Debus","author_inst":"Department of Radiooncology and Radiotherapy, Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Germany"},{"author_name":"Dirk Jaeger","author_inst":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) & Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Ge"},{"author_name":"Christine A. Iacobuzio-Donahue","author_inst":"The David M Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY"},{"author_name":"Karuna Ganesh","author_inst":"Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Dana Peer","author_inst":"Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Guy Ungerechts","author_inst":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) & Heidelberg University Hospital, Medical Faculty Heidelberg, Heidelberg University, Ge"},{"author_name":"Charles M. Rudin","author_inst":"Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"},{"author_name":"Peter E. Huber","author_inst":"German Cancer Research Center, Clinical Cooperation Unit Molecular Radiooncology, Heidelberg, Germany"},{"author_name":"Thomas Walle","author_inst":"Computational Cancer Biomedicine, Institut dInvestigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Rationale and Design of RECOVER-ENERGIZE: A Platform Clinical Trial of Interventions for Exercise Intolerance With and Without Post-exertional Malaise in Long COVID","rel_doi":"10.64898\/2026.06.02.26354455","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.06.02.26354455","rel_abs":"IntroductionA prominent symptom of post-acute sequelae of SARS-CoV-2 infection (i.e., Long COVID) is exercise intolerance with or without post-exertional malaise (PEM). PEM is characterized by the worsening of both symptoms and function following even minor physical or mental exertion, with symptoms typically worsening 12 to 48 hours after activity and lasting for days or even weeks. Individualized, supervised cardiopulmonary rehabilitation is considered a safe and effective intervention for many cardiac and pulmonary conditions, and has been effective in gradually improving function in previously hospitalized and nonhospitalized patients with severe COVID-19. While traditional cardiopulmonary rehabilitation approaches appear helpful in some situations, the exercise intolerance symptoms experienced by many individuals with Long COVID may require a different approach, especially when attempts to increase physical activity result in PEM. No clear consensus exists on the optimal treatment of PEM, and no major studies have evaluated the efficacy in individuals with Long COVID of either carefully supervised, individualized cardiopulmonary rehabilitation programs for exercise intolerance without significant PEM or activity pacing interventions designed to treat or prevent PEM.\n\nMethods and AnalysisThe Researching COVID to Enhance Recovery Clinical Trials (RECOVER-CT) initiative funded by the National Institutes of Health (NIH) included a prospective, multicenter, randomized controlled platform trial (RECOVER-ENERGIZE) designed to assess two interventions in patients with Long COVID and exercise intolerance: (1) cardiopulmonary rehabilitation for patients without significant PEM and (2) structured activity pacing to prevent or reduce PEM in participants who experience the symptom. The intervention duration will be 12 weeks. The primary endpoints for the trial include the Endurance Shuttle Walk Test as a measure of endurance capacity for the cardiopulmonary rehabilitation intervention and a modified version of the DePaul Symptom Questionnaire-Post-Exertional Malaise for the pacing intervention. Assessments will be completed at baseline, middle of intervention, end of intervention, and 12 weeks after completion of the intervention, and include physical performance measures and patient-reported surveys.\n\nEthics and DisseminationThe RECOVER-ENERGIZE trial protocol has been approved by an institutional review board (Advarra), and written informed consent will be obtained from all participants prior to enrollment. The trial is registered on ClinicalTrials.gov (NCT06404047). Formally assessing PEM and developing a structured activity pacing intervention delivered by local pacing coaches are novel features of this trial. Results will be disseminated through peer-reviewed publications, presentations at scientific conferences, and communication with participants, patient advocacy organizations, and the broader Long COVID community. De-identified participant data will be made available through the NIH RECOVER data repository in accordance with NIH data-sharing policies. If successful, this protocol will provide accessible tools that clinicians can use to address exercise intolerance and PEM in patients with Long COVID.\n\nTrial registrationClinicalTrials.gov - Platform: NCT06404047; Appendix A: NCT06404060; Appendix B: NCT06404073. Registered on May 6, 2024.\n\nStrengths and limitations of this studyO_LIRECOVER-ENERGIZE is a large, multicenter, randomized controlled platform trial that stratifies participants by PEM status, separately evaluating cardiopulmonary rehabilitation in those without significant PEM and structured activity pacing in those with PEM, while mitigating the risk of exertional harm.\nC_LIO_LIThe structured activity pacing intervention is novel and has not previously been tested in a randomized trial in Long COVID. Its coach-delivered, video-conference format is designed to be easily implemented and scalable across diverse clinical settings.\nC_LIO_LIPatient, caregiver, and community representatives were integrally involved throughout protocol development, shaping eligibility criteria, intervention design, and selection of outcome measures, which strengthens the relevance of the trial to the Long COVID community.\nC_LIO_LIThe trial combines a performance-based measure of endurance capacity (the Endurance Shuttle Walk Test) with a modified, PEM-specific patient-reported instrument (mDSQ-PEM). However, the nature of the interventions precludes blinding of participants and providers, and several key outcomes rely on self-report, which may introduce bias.\nC_LI","rel_num_authors":18,"rel_authors":[{"author_name":"Janna Friedly","author_inst":"University of Washington"},{"author_name":"Lucinda Bateman","author_inst":"Bateman Horne Center"},{"author_name":"Lisa G. Berdan","author_inst":"National Institutes of Health"},{"author_name":"Richard Casaburi","author_inst":"The Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center"},{"author_name":"Nathaniel Erdmann","author_inst":"University of Alabama at Birmingham"},{"author_name":"G. Michael Felker","author_inst":"Duke University School of Medicine"},{"author_name":"Nilda Itchon-Ramos","author_inst":"Duke University School of Medicine"},{"author_name":"Steven J. Keteyian","author_inst":"Henry Ford Health"},{"author_name":"Neil R. MacIntyre","author_inst":"Duke University School of Medicine"},{"author_name":"Lisa O\u2019Brien","author_inst":"RECOVER Patient, Caregiver, or Community Representative"},{"author_name":"Craig Reist","author_inst":"RTI International"},{"author_name":"Harry B. Rossiter","author_inst":"The Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center"},{"author_name":"Adam P Silverstein","author_inst":"Duke Clinical Research Institute"},{"author_name":"Emily Taylor","author_inst":"RECOVER Patient, Caregiver, or Community Representative"},{"author_name":"Helena Pike Welch","author_inst":"Duke University School of Medicine"},{"author_name":"N. David Yanez","author_inst":"Duke University School of Medicine"},{"author_name":"Kanecia O. Zimmerman","author_inst":"Duke University School of Medicine"},{"author_name":"Barry Make","author_inst":"National Jewish Health"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Simple cumulative weighting of routine surveillance data identifies epidemic wave origins more accurately than a large language model: evidence from eight COVID-19 waves in Japan","rel_doi":"10.64898\/2026.06.02.26354691","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.06.02.26354691","rel_abs":"Identifying the origin of an emerging epidemic wave within days of onset could enable targeted response before national spread, yet current methods rely on genomic sequencing that lags clinical detection by 2-4 weeks. We analysed daily COVID-19 cases from Japan's 47 prefectures across eight waves (2020-2023), aggregated into 11 regional blocks. Wave onset was defined by the first difference of the K-value (K'). Six surveillance indicators were evaluated with and without cumulative historical weighting ({lambda} = 0.75) and benchmarked against a large language model (Claude Haiku), scored by F1 against genomically confirmed origins. At 14 days after onset, cumulative weighting of peak and cumulative incidence (B1+prior, B3+prior) reached mean F1 = 0.622, exceeding the model (0.524); the gap was largest in Wave 7 (1.000 vs 0.333). Simple cumulative weighting of routine surveillance data identified wave origins more accurately than a language model, without proprietary tools or sequencing.","rel_num_authors":2,"rel_authors":[{"author_name":"Shinichi Nakagawa","author_inst":"Research Institute of Info-Communication Medicine"},{"author_name":"Akira Yamamoto","author_inst":"Faculty of Health Data Science, Juntendo University"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"SARS-CoV-2 BA.3.2.2 is more evasive of neutralization by sera from young children","rel_doi":"10.64898\/2026.06.01.728533","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.01.728533","rel_abs":"Dominant SARS-CoV-2 variants have most prominently displayed greater evasion of serum neutralizing antibodies than predecessor strains. BA.3.2, a descendant of Omicron BA.3, carrying 43 additional spike mutations, emerged in 2024, and over the last several months its subvariant BA.3.2.2 has slowly increased in prevalence globally. BA.3.2.2 continues to circulate at lower frequency than the genetically and antigenically distant dominant JN.1 subvariants NB.1.8.1 and XFG. However, concerningly, epidemiologic analyses have suggested that a larger proportion of COVID-19 cases in children are caused by BA.3.2.2 compared to adults, raising the possibility that susceptibility to BA.3.2.2 differs across age groups. Since immune imprinting shapes variant-specific anti-SARS-CoV-2 antibody profiles and children born after 2021 primarily were first exposed to Omicron subvariants, we hypothesized that young children may have lower circulating neutralizing antibody titers against BA.3.2.2 than adults. Using pseudovirus neutralization assays, we measured titers against BA.3.2.2 and other SARS-CoV-2 variants in serum or plasma samples from a total of 36 adults ([&ge;]18 years old), school-age children (3-10 years old), and infants\/toddlers (6-28 months old) in the US. We found that both cohorts of children had lower geometric mean titers against BA.3.2.2 than adults, even though all tested age groups had similar titers against dominant strains NB.1.8.1 and XFG. Together, these findings suggest that susceptibility to emerging SARS-CoV-2 variants may diverge across age groups, perhaps as a result of their different exposure histories. Furthermore, these results highlight the importance of SARS-CoV-2 surveillance and the monitoring of immunity against viral variants across age ranges.","rel_num_authors":9,"rel_authors":[{"author_name":"Madeline Wu","author_inst":"Columbia University"},{"author_name":"Hsiang Hong","author_inst":"Columbia University"},{"author_name":"Yicheng Guo","author_inst":"Columbia University"},{"author_name":"Kristin Daniel","author_inst":"Columbia University"},{"author_name":"Ryan Hisner","author_inst":"University of Cape Town"},{"author_name":"Marc C Johnson","author_inst":"University of Missouri"},{"author_name":"Aubree Gordon","author_inst":"University of Michigan"},{"author_name":"David D Ho","author_inst":"Columbia University"},{"author_name":"Ian A Mellis","author_inst":"Columbia University"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Chronic cocaine exposure negatively impacts Long-COVID-like outcomes produced by the SARS-CoV-2 spike protein in the rat","rel_doi":"10.64898\/2026.06.02.729575","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.02.729575","rel_abs":"Acute COVID-19 outcomes are exacerbated by substance use, however, the impact of substance use on Long-COVID is unknown. Here, we investigated the impact of chronic cocaine administration on spike-induced Long-COVID-like outcomes in the rat. Rats received intermittent chronic cocaine administration and a single intravenous injection of the SARS-CoV-2 spike protein. Two months following spike administration, Long-COVID-like outcomes were assessed. Exposure to spike protein in the presence of cocaine produced a persistent reduction in weight gain as compared with controls or spike protein alone. Further, cocaine-treated rats exposed to spike had lower withdrawal thresholds compared to control animals as well as their own baseline, suggesting increased pain sensitivity. Spike and\/or cocaine increased the ratio of interleukin-6 (IL-6) to interleukin-10 (IL-10) levels in the hippocampus, indicating a shift towards a proinflammatory state. Paw withdrawal thresholds were positively correlated with IL-10 levels in the hippocampus and prefrontal cortex. Regarding olfaction, rats exposed to spike spent less time sniffing an odor attractant. Cocaine produced an anxiolytic-like phenotype during the elevated plus maze test. Further analysis of behaviors on the maze revealed that the latency to enter the open arms was shorter in rats exposed to spike or cocaine, suggesting a possible impulsive-like phenotype in these animals. These findings demonstrate the negative impact of cocaine on Long-COVID-like outcomes suggesting a need for increased clinical observations of people with co-occurring Long-COVID and cocaine use disorder.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=59 SRC=\"FIGDIR\/small\/729575v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (10K):\norg.highwire.dtl.DTLVardef@12fdc19org.highwire.dtl.DTLVardef@11b1b0dorg.highwire.dtl.DTLVardef@8d1e21org.highwire.dtl.DTLVardef@b53d20_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":9,"rel_authors":[{"author_name":"Sarah E Davis","author_inst":"Lewis Katz School of Medicine, Temple University"},{"author_name":"Danielle R Stern","author_inst":"Lewis Katz School of Medicine, Temple University"},{"author_name":"Saadet Inan","author_inst":"Lewis Katz School of Medicine, Temple University"},{"author_name":"Emily Vu","author_inst":"Lewis Katz School of Medicine, Temple University"},{"author_name":"Daniel Lopez","author_inst":"Lewis Katz School of Medicine, Temple University"},{"author_name":"Flourish Anwuri","author_inst":"Lewis Katz School of Medicine, Temple University"},{"author_name":"Marco G Ghilotti","author_inst":"Lewis Katz School of Medicine, Temple University"},{"author_name":"Joseph J Meissler","author_inst":"Lewis Katz School of Medicine, Temple University"},{"author_name":"Ellen M Unterwald","author_inst":"Lewis Katz School of Medicine, Temple University"}],"rel_date":"2026-06-02","rel_site":"biorxiv"},{"rel_title":"A Viral Mutation Profiling and Discovery Strategy for Sensitive Multiplex Detection of Viruses and Variants in Saliva by Proteomics","rel_doi":"10.64898\/2026.05.30.729008","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.30.729008","rel_abs":"BackgroundDetecting multiple viruses in biofluids such as saliva remains challenging because of rapid mutation and low abundance presenting in the complex matrix. Proteomics analysis provides a complementary method by directly measuring viral peptides and resolving protein-level sequence variation in rapidly evolving viruses such as influenza and SARS-CoV-2. However, the ongoing viral evolution challenges search sensitivity by introducing numerous mutations. Here, we develop a saliva viral proteomics strategy that integrates mutation profiling of clinically relevant viral sequences with single amino acid substitution mutation discovery to enable sensitive detection of both known and emerging variants.\n\nResultsIn silico analysis of SARS-CoV-2 and influenza viral sequences reveals bimodal prevalence distributions of mutated peptides. For mutation profiling of clinically relevant viral sequences, we prioritize high-prevalence peptides, which presumably have higher clinical significance, within a 3-month timespan. Applying a 10% prevalence threshold reduces database size by more than 82.1% for SARS-CoV-2 and 94.5% for influenza. Optimized mutated peptide databases cause <0.8% sensitivity loss compared with searches using viral reference sequences alone, while still covering 97.8% of SARS-CoV-2 and 98.4% of influenza viral populations in the subsequent month. G-PTM-D-based mutation discovery further mitigates the loss of database coverage and enables detection of new variants. In peptide-spiked saliva samples, G-PTM-D detected single-amino-acid variant peptides with femtogram-level sensitivity, outperforming conventional PTM searches and de novo sequencing.\n\nConclusionsThis study provides a scalable framework for mutation profiling and discovery proteomics analysis that enables sensitive detection of both known and emerging viral variants in complex clinical samples.","rel_num_authors":3,"rel_authors":[{"author_name":"Yanjia Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Michael Shortreed","author_inst":"UW-Madison"},{"author_name":"Aaron T. Timperman","author_inst":"University of Pennsylvania"}],"rel_date":"2026-06-02","rel_site":"biorxiv"},{"rel_title":"Structural Basis for Inhibition of the HKU5-CoV Main Protease by Clinical SARS-CoV-2 Protease Inhibitors","rel_doi":"10.64898\/2026.06.01.729201","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.01.729201","rel_abs":"The identification of Pipistrellus bat coronavirus HKU5 lineage 2 (HKU5-CoV-2) as a potential zoonotic threat, owing to its adaptation to the human angiotensin-converting enzyme 2 receptor, highlights the need for antiviral strategies to control emerging HKU5-CoVs. However, despite the importance of the main protease (Mpro) as a key antiviral target, structural and biochemical characterization of HKU5-CoV Mpro in the context of clinical inhibitors has remained limited. In this study, we obtained high-resolution crystal structures of HKU5-CoV-1 Mpro in its apo state and in complex with the clinical inhibitors nirmatrelvir and ensitrelvir. These structures served as a foundation for the characterization of HKU5-CoV-2 Mpro via modeling and molecular dynamics simulations. Biochemical assays revealed that HKU5-CoV-1 and HKU5-CoV-2 Mpro exhibited nearly identical kinetic profiles, with turnover rates approximately two-fold higher than SARS-CoV-2 Mpro. Structural analysis revealed a highly conserved S1 subsite but distinct local environments in the S1', S2, and S4 substrate-binding sites relevant to inhibitor recognition. Despite these variations, nirmatrelvir and ensitrelvir showed potent inhibitory activity, with comparable double-digit nanomolar IC50 values across all three Mpro proteins. Integrated structural modeling and molecular dynamics simulations showed that HKU5-CoV-2 Mpro retains the ligand-induced active-site rearrangements observed in HKU5-CoV-1, supporting a conserved mechanism of inhibitor recognition. These findings provide a structural framework for understanding the susceptibility of emerging Merbecoviruses to clinical Mpro inhibitors and support the development of pan-Coronavirus antivirals.\n\nAuthor summaryAs coronaviruses continue to emerge from wildlife reservoirs, determining whether current clinical antivirals can inhibit divergent viral targets and how they engage these proteins is crucial. This study focuses on Pipistrellus bat coronavirus HKU5, particularly the newly identified lineage 2 (HKU5-CoV-2), which has recently attracted attention as a potential zoonotic coronavirus. We determined high-resolution crystal structures of the HKU5-CoV-1 main protease and used these structures to build and analyze models of the HKU5-CoV-2 protease. Our biochemical and structural analyses show that approved COVID-19 protease inhibitors, including nirmatrelvir (Paxlovid) and ensitrelvir (Xocova), potently inhibit HKU5 Mpro and reveal conserved features of inhibitor recognition. These findings provide a structural foundation for designing coronavirus protease inhibitors with broader activity against emerging coronaviruses.","rel_num_authors":8,"rel_authors":[{"author_name":"Hyojin Kim","author_inst":"Korea Research Institute of Chemical Technology"},{"author_name":"Jinsook Ahn","author_inst":"Korea Advanced Institute of Science and Technology"},{"author_name":"Juyeon Lee","author_inst":"Korea Research Institute of Chemical Technology"},{"author_name":"Seungheon Jung","author_inst":"Korea Research Institute of Chemical Technology"},{"author_name":"Ji Woo Kim","author_inst":"Korea Research Institute of Chemical Technology"},{"author_name":"Byungil Kim","author_inst":"Korea Research Institute of Chemical Technology"},{"author_name":"Nam-Chul Ha","author_inst":"Seoul National University"},{"author_name":"Inseong Jo","author_inst":"Korea Research Institute of Chemical Technology"}],"rel_date":"2026-06-02","rel_site":"biorxiv"},{"rel_title":"Data aggregation and mechanistic modeling enable dose-response analysis of SARS-CoV-1 in non-human primates","rel_doi":"10.64898\/2026.06.01.729195","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.01.729195","rel_abs":"Dose-response modeling provides estimates of infectious and lethal doses, which can be used to inform control and prevention measures. Unfortunately, data from experimental challenge studies, which are needed to perform dose-response modeling, are often sparse. For example, non-human primate (NHP) challenge studies tend to have small samples sizes and little dose variation, often with only one or two dose levels per study. Thus, it is infeasible to apply traditional dose-response modeling approaches to data from single NHP studies. To address this challenge, we developed a mechanistic Bayesian model that aggregates and analyzes NHP pathogen load data across multiple studies. Our model links dose-infectivity to pathogen kinetics, which allows us to estimate the infectious dose and evaluate dose effects on within-host viral kinetics simultaneously. With this model, we obtained the first-ever ID50 estimate for SARS-CoV-1 in NHPs using data compiled from six NHP challenge studies. Our work demonstrates the value in reusing previous data from animal experiments. Our modeling framework can be applied to other pathogens, enabling robust dose-response inference when individual challenge studies are inconclusive.\n\nAuthor summaryDose-response models are used to estimate pathogen doses needed to cause infection in humans, so they are useful for informing outbreak control policies. Unfortunately, performing dose-response modeling can be difficult due to limitations in the available data. If the pathogen causes significant risk of severe disease or death in humans, then controlled human infections cannot be performed. Additionally, experimental challenge studies of relevant animal models, such as non-human primates (NHPs), often have small sample sizes and limited dose ranges, which make dose-response modeling unfeasible using data from single studies. We developed an approach to aggregate data across multiple challenge studies to enable dose-response modeling in the absence of dose-response experiments. We applied our approach to data from six NHP challenge studies to perform the first-ever dose-response analysis of SARS-CoV-1 in NHPs. Our approach also included a mechanistic, mathematical model of within-host pathogen kinetics, which allowed us to assess the effect of SARS-CoV-1 dosage on patterns of viral RNA shedding. The framework we developed can be readily applied to other host-pathogen systems, and the mechanistic components of our model contribute to a growing movement towards understanding dose effects beyond simple infectivity.","rel_num_authors":4,"rel_authors":[{"author_name":"Philip  C Lee","author_inst":"University of California Berkeley"},{"author_name":"Celine  E Snedden","author_inst":"University of California Los Angeles"},{"author_name":"Dylan  H Morris","author_inst":"University of California Los Angeles"},{"author_name":"James Lloyd-Smith","author_inst":"University of California, Los Angeles"}],"rel_date":"2026-06-01","rel_site":"biorxiv"},{"rel_title":"Immune context unmasks regulatory effects of Neanderthal and Denisovan introgression","rel_doi":"10.64898\/2026.05.29.727880","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.29.727880","rel_abs":"Neanderthal and Denisovan introgression have left a pervasive footprint in the human genome, yet its regulatory consequences remain poorly understood. Here we use a massively parallel reporter assay to characterize the cis-regulatory activity of 4,161 high-frequency introgressed variants across respiratory (A549), hepatic (HepG2), and hematopoietic (K562) cells exposed to immune and infectious stimuli. We find that ~18% of variants show differential activity between archaic and modern alleles, including 94 whose effects are revealed or modulated by stimulation, often in a cell type-specific manner. We identify loci, including STAT2, IL23A, and RNF41, where clusters of introgressed alleles exert coordinated regulatory effects consistent with adaptive programs. Finally, we dissect the mechanisms underlying the association between Neanderthal introgression and COVID-19 severity and show that the risk allele rs17713054-A, which displays the strongest effect in our assay, increases activity of a TNF--responsive enhancer in lung epithelial cells, directly upregulating SLC6A20.Together, these findings reveal widespread context-dependent regulatory effects of archaic introgression, with broad evolutionary and biomedical implications.","rel_num_authors":9,"rel_authors":[{"author_name":"Zhi Li","author_inst":"Human Evolutionary Genetics Unit, Institut Pasteur, Universite Paris Cite, CNRS UMR 2000, Paris, France"},{"author_name":"gaspard kerner","author_inst":"Human Evolutionary Genetics Unit, Institut Pasteur, Universite Paris Cite, CNRS UMR 2000, Paris, France"},{"author_name":"Javier Mendoza-Revilla","author_inst":"Human Evolutionary Genetics Unit, Institut Pasteur, Universite Paris Cite, CNRS UMR 2000, Paris, France"},{"author_name":"Fumitaka Inoue","author_inst":"ASHBi, Kyoto University, Japan"},{"author_name":"Simon Fishilevich","author_inst":"Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Etienne Patin","author_inst":"Human Evolutionary Genetics Unit, Institut Pasteur, Universite Paris Cite, CNRS UMR 2000, Paris, France"},{"author_name":"David Gokhman","author_inst":"Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Lluis Quintana-Murci","author_inst":"Human Evolutionary Genetics Unit, Institut Pasteur, Universite Paris Cite, CNRS UMR 2000, Paris, France"},{"author_name":"Maxime Rotival","author_inst":"Human Evolutionary Genetics Unit, Institut Pasteur, Universite Paris Cite, CNRS UMR 2000, Paris, France"}],"rel_date":"2026-06-01","rel_site":"biorxiv"},{"rel_title":"A Monoclonal Antibody Panel to Track Ongoing Antigenic Evolution of SARS-CoV-2 Variants","rel_doi":"10.64898\/2026.05.29.728770","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.29.728770","rel_abs":"SARS-CoV-2 continues to evolve, generating successive variants with enhanced resistance to antibody-mediated neutralization. However, many existing monoclonal antibody (mAb) repertoires were derived from exposures to ancestral or early Omicron strains and thus incompletely capture the antigenic landscape of newly emerging strains. Here, we generated a mAb panel by immunizing naive, unimprinted VelocImmune humanized mice with spike from the KP.3.1.1 variant, and isolated and characterized 11 neutralizing antibodies targeting diverse epitopes of recently evolved antigenic variants. We then integrated these antibodies with previously characterized mAbs to establish an expanded toolbox for profiling antigenic evolution among emerging variants. Application of this panel to currently emerging SARS-CoV-2 variants provided mechanistic insight into recent antigenic evolution, highlighting the potential role of altered receptor-binding domain conformation. Our data also revealed clear differences in antibody-evasion profiles between JN.1-derived lineages and BA.3.2 lineages. Together, our findings establish an updated mAb panel for monitoring SARS-CoV-2 antigenic evolution.","rel_num_authors":10,"rel_authors":[{"author_name":"Madeline Wu","author_inst":"Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Hsiang Hong","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Sue Chong","author_inst":"Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Jian Yu","author_inst":"Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Ian A Mellis","author_inst":"Columbia University"},{"author_name":"Chien-Yu Huang","author_inst":"Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Qian Wang","author_inst":"Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Yaoxing Huang","author_inst":"Columbia University"},{"author_name":"Yicheng Guo","author_inst":"Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"David D Ho","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-06-01","rel_site":"biorxiv"},{"rel_title":"Towards understanding of NK cell antigenic specificity","rel_doi":"10.64898\/2026.05.29.728791","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.29.728791","rel_abs":"NK cells can form clonal populations demonstrating features of adaptive immunity, including long-term memory and at least partial antigenic specificity. Given the limited individual diversity of activating receptors, the nature of NK cell antigenic specificity remains elusive. To explore this riddle, we combined scRNA-Seq of ex vivo FACS-sorted NK cell subsets expressing specific KIR receptors, single-cell cloning and bulk RNA-Seq of in vitro cultured KIR2DS4 NK cell clones, transcriptomic profiling of antigen-stimulated NK cells, and in silico modeling of glycosylated KIR2DS4-peptide-HLA complexes. scRNA-Seq resolved 12-15 clusters per KIR subset with highly heterogeneous KIR, KLRC and NCR expression patterns, consistent with clonal lineages. Notably, those clusters demonstrated over 30 differentially expressed glycosyltransferase genes, potentially involved in post-translational modification of NK cell receptors. Single-cell-derived KIR2DS4 cultures exhibited clone-specific cytotoxic, chemokine and KIR receptor genes, and transcriptional differences in > 40 glycosyltransferases. In peptide culturing autologous assays, SARS-CoV-2 (KTFPPTEPK) and EBV (CRAKFKHLL) peptides elicited NK cell proliferation and distinct transcriptional programs linking cytotoxicity genes, KIR2DS4 and glycosyltransferases. Structural modeling revealed that N-linked glycosyl residues in specific regions of KIR2DS4 may alter its contacts and interaction with MHCI and the presented peptide. We conclude that KIR human NK cells comprise clonally imprinted populations with distinct glycosyltransferase expression profiles, and site-specific KIR2DS4 glycosylation may modulate interaction with peptide-MHCI complexes, suggesting a post-translational layer of clonal NK cell diversification as a clue to their antigenic specificity.","rel_num_authors":8,"rel_authors":[{"author_name":"Maria O Ustiuzhanina","author_inst":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry"},{"author_name":"Irina A Shagina","author_inst":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry"},{"author_name":"Evgeniy Nikitin","author_inst":"Biotech Campus LLC"},{"author_name":"Evgeniy Klimuk","author_inst":"Biotech Campus LLC"},{"author_name":"Olga Britanova","author_inst":"Pirogov Russian National Research Medical University"},{"author_name":"Yendry Ventura-Carmenate","author_inst":"Abu Dhabi Stem Cell Center"},{"author_name":"Elena Kovalenko","author_inst":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry"},{"author_name":"Dmitriy M Chudakov","author_inst":"Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, RAS"}],"rel_date":"2026-06-01","rel_site":"biorxiv"},{"rel_title":"COVID-19 vaccine effectiveness in children under 5 in the USA: a test-negative case-control study","rel_doi":"10.64898\/2026.05.28.26354328","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.28.26354328","rel_abs":"Background and ObjectivesSARS-CoV-2 (COVID-19) continues to mutate, circulate, and adversely impact health and quality of life. While COVID-19 vaccines remain safe and effective, uptake remains low, especially among children, the youngest of whom were not vaccine-eligible until after Omicron and are underrepresented in published research. This study estimated vaccine effectiveness (VE) among under-5-year-olds.\n\nMethodsWe used Virginia Department of Health surveillance data from June 2022 through October 2022 to conduct a test negative case-control study. We estimated VE derived from odds ratios (ORs) of reported infections using logistic regression among children aged 6-months to 5-years.\n\nResultsUsing the earliest positive (cases) or negative (controls) post-vaccine-eligible test results, the VE associated with two doses of a COVID-19 vaccine was 78% (95% CI=45%, 93%; p=0.004) in unadjusted analyses and 70% (95% CI=25%, 91%, p=0.023) when adjusting for age, sex, prior testing behavior, and prior reported infections. The adjusted VE was 74% (95% CI=28%, 94%; p=0.025) among those with no prior positives reported and 45% (95% CI=-302%, 97%; p=0.569) among those with a prior positive reported.\n\nConclusionsThese results show that even though the vaccine was not closely matched to the dominant variants circulating during the time period analyzed, it was effective at reducing the risk of reported infections. This study adds to the body of knowledge on pediatric COVID-19 VE in an underrepresented age-group and in a rural region, illustrates the utility of surveillance data for evaluation, and can inform vaccine decisions to improve vaccine uptake for young children.\n\nWhats Known on This SubjectSARS-CoV-2 (COVID-19) continues to mutate, circulate, and adversely impact health and quality of life. While research continues to show that COVID-19 vaccines remain safe and effective, uptake remains low, especially among young children who were not vaccine-eligible until after Omicron.\n\nWhat This Study AddsChildren under-5 are underrepresented in published COVID-19 vaccine effectiveness research. This test negative case-control study estimates VE in this age-group following vaccine approval after the 2022 Omicron wave, using surveillance data from the Virginian Department of Health in Southwest Virginia.","rel_num_authors":0,"rel_authors":[],"rel_date":"2026-05-30","rel_site":"medrxiv"},{"rel_title":"Pre-pandemic blood profiles predict COVID-19 hospitalization and death a decade later","rel_doi":"10.64898\/2026.05.27.26354230","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.27.26354230","rel_abs":"COVID-19 risk scores developed during the pandemic relied on measurements contemporaneous with infection, leaving unresolved whether the metabolic and inflammatory vulnerability they capture pre-existed as a stable trait or was triggered by acute illness. Here, using 501,946 UK Biobank participants whose blood was drawn between 2006 and 2010--at least ten years before SARS-CoV-2 emerged--we show that baseline proteomic and metabolic profiles predict both COVID-19 hospitalization (2,783 events; C* = 0.676 [0.666-0.686]) and COVID-19 mortality (1,564 deaths; C* = 0.730 [0.701-0.760]) from parsimonious, regularized feature sets. The IL-1 pathway index (xIL1, +0.093) was independently selected for hospitalization but not mortality, while the IL-6 trans-signaling index (xIL6, +0.040) was selected for mortality but not hospitalization--a differential pathway weighting corroborated by independent Light-GBM\/SHAP analysis and mirroring the subsequent success of tocilizumab (anti-IL-6R) and the limited efficacy of anakinra (anti-IL-1R) in reducing COVID-19 mortality in randomized trials conducted years later. The mortality model was additionally characterized by central adiposity (waist-hip ratio, +0.386), a respiratory compromise index (xRSP, +0.149), and prodromal cardiovascular disease (pCVD, +0.246). These findings establish that vulnerability to a novel pathogen is, in substantial part, a pre-existing and measurable prodromal state, with implications for pandemic preparedness and population-level risk stratification.","rel_num_authors":0,"rel_authors":[],"rel_date":"2026-05-29","rel_site":"medrxiv"},{"rel_title":"Preorganized RdRp-Thumb Dynamics Drives SARS-CoV-2 Polymerase Function","rel_doi":"10.64898\/2026.05.29.728794","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.29.728794","rel_abs":"The SARS-CoV-2 RNA-dependent RNA polymerase drives viral genome replication and is a major antiviral target. How intrinsic conformational dynamics organize functional states of the polymerase, however, remains incompletely understood. Here, molecular dynamics (MD) simulations combined with free-energy landscape analysis reveal that the apo polymerase samples preexisting conformational states defined by coordinated thumb-subdomain motions. Projection of experimental structures, representative of the polymerase nucleic acid cycle, onto the conformational landscape identified discrete basins spanning apo-like and elongation-like states and revealed a coherent structural axis coupling global polymerase compaction (radius of gyration, Rg) with thumb-interface separation (center-of-mass distance, COM). These motions connect catalytic motifs, RNA-binding regions, and distal regulatory elements across the polymerase ensemble.\n\nThe observed conformational organization is not apparent from static structures alone and supports a model in which functional transitions arise from intrinsic collective dynamics of the apo enzyme. Intermediate conformational ensembles combine structural stability with retained inter-domain flexibility, identifying mechanically responsive states favorable for allosteric modulation. Together, these findings define structurally coupled regulatory regions within the coronavirus polymerase and support conformational trapping of thumb-subdomain dynamics as a potential strategy for antiviral design targeting RNA virus replication machinery.","rel_num_authors":4,"rel_authors":[{"author_name":"Hannah Gibbs","author_inst":"Saint Joseph's University"},{"author_name":"Artiom Butuc","author_inst":"Saint Joseph's University"},{"author_name":"Preston B Moore","author_inst":"Saint Joseph's University"},{"author_name":"Eleonora Gianti","author_inst":"City University of New York (CUNY) Queens College"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Late induction of IgG4 following SARS-CoV-2 mRNA vaccination in pregnant and non-pregnant individuals includes clonotypes raised early in the response","rel_doi":"10.64898\/2026.05.29.728639","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.29.728639","rel_abs":"To better understand how pregnancy impacts humoral immunity, we conducted an in-depth longitudinal analysis of the kinetics and characteristics of vaccine responses in a prospective cohort of pregnant and non-pregnant women. Humoral immune responses observed among pregnant participants who received the mRNA-delivered SARS-CoV-2 vaccination, including their effector functions, were in some cases marginally lower than those among non-pregnant controls, while prior infection was associated with some potentiation in humoral responses. Importantly, vaccine-induced antibodies were efficiently transferred across the placenta, providing the fetus with passive immunity and underscoring the dual benefit of maternal vaccination for both mother and neonate against COVID-19. Delayed induction of spike-specific IgG4 following the primary two-dose vaccination series was observed in vaccine recipients, independent of pregnancy status. In a subset (n=6) of pregnant women whose spike-specific serum IgG repertoires were extensively profiled at the clonotypic level over time as part of another study, we proteomically identified secreted IgG clonotypes that had class-switched to IgG4. Matching of these clonotypes detected as IgG4 to those defined as SARS-CoV-2 spike-specific revealed that, while a minority of total clonotypes, they were elicited early in the immunization series and tended to be more highly mutated, more prevalent, and more persistent than clonotypes in the serological repertoire that were not detected as IgG4. Consistent with the increase in secreted vaccine-specific IgG4 over time, but its poorer placental transfer, these clonotypes were detected at greater levels in maternal but not cord blood at the time of delivery as compared to 28 days post the second vaccine dose. These findings indicate some impact in the kinetics, characteristics, and functions of the humoral response that may be associated with pregnancy-related immune modulation. Conservation of the late class-switch recombination to IgG4 that has previously been associated with mRNA-based SARS-CoV-2 vaccines raises questions about how different immunological states and vaccine components influence short- and long-term characteristics of the humoral immune response.","rel_num_authors":19,"rel_authors":[{"author_name":"Dhvanir  N Kansara","author_inst":"Dartmouth College Geisel School of Medicine"},{"author_name":"Tae-Geun Yu","author_inst":"Dartmouth College"},{"author_name":"Neel Kansara","author_inst":"Dartmouth College"},{"author_name":"Noor M Taher","author_inst":"Dartmouth College"},{"author_name":"Aisha Yesbalatova","author_inst":"Dartmouth College"},{"author_name":"Larissa DeBrabandere","author_inst":"University of Antwerp: Universiteit Antwerpen"},{"author_name":"Joshua A Weiner","author_inst":"Dartmouth College"},{"author_name":"Gabriela Kovacikova","author_inst":"Dartmouth College"},{"author_name":"Andrew P Hederman","author_inst":"Dartmouth College"},{"author_name":"Pieter Pannus","author_inst":"Universit\u00e9 Libre de Bruxelles"},{"author_name":"Stephanie Depickere","author_inst":"Sciensano"},{"author_name":"Maria E Goosens","author_inst":"Sciensano"},{"author_name":"Anneke Vercoutere","author_inst":"Universite Libre de Bruxelles"},{"author_name":"Nicolas Dauby","author_inst":"Universite Libre de Bruxelles"},{"author_name":"Kevin K Arien","author_inst":"University of Antwerp"},{"author_name":"Kirsten Maertens","author_inst":"University of Antwerp"},{"author_name":"Arnaud Marchant","author_inst":"Universite Libre de Bruxelles"},{"author_name":"Jiwon Lee","author_inst":"Dartmouth College"},{"author_name":"Margaret E Ackerman","author_inst":"Dartmouth College"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"A 667-nucleotide sequence in the SARS-CoV-2 nsp15 coding region promotes genome encapsidation","rel_doi":"10.64898\/2026.05.29.721935","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.29.721935","rel_abs":"Coronavirus genome encapsidation depends on cis-acting RNA elements that interact with viral structural proteins. While such packaging signals have been characterized in several coronaviruses, their definition in SARS-CoV-2 remains incomplete. Using synthetic defective SARS-CoV-2 genomes, we identify a 667-nucleotide region within the nsp15 coding sequence that preferentially binds SARS-CoV-2 nucleoprotein and enhances the accumulation of defective viral genomes both in vitro and in vivo. Sequential and targeted deletion analyses further delineate candidate RNA secondary structures within this region that contribute to this enrichment. These structures show similarity to elements within the putative packaging signal of SARS-CoV but are not conserved across other coronaviruses. Together, these findings support the presence of a structured RNA element within nsp15 that contributes to SARS-CoV-2 genome encapsidation and provide a framework for further structural and functional dissection of coronavirus packaging signals.\n\nIMPORTANCEThis study identifies a 667-nt region within the SARS-CoV-2 nsp15 coding sequence that binds nucleoprotein and promotes accumulation of defective viral genomes, revealing a previously unrecognized contributor to genome encapsidation. Mapping of candidate RNA structures within this region links SARS-CoV-2 packaging activity to conserved structural features observed in SARS-CoV, while highlighting key differences from other coronaviruses. These findings refine understanding of cis-acting packaging signals in SARS-CoV-2 and provide a foundation for further structural and functional analysis of coronavirus genome encapsidation.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC=\"FIGDIR\/small\/721935v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (23K):\norg.highwire.dtl.DTLVardef@1b64611org.highwire.dtl.DTLVardef@1b21b7borg.highwire.dtl.DTLVardef@2a68b5org.highwire.dtl.DTLVardef@405fe1_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO A part of the nsp15 coding sequence of SARS-CoV-2 promotes efficient transmission of defective viral genomes in vitro and in vivo. Using a sequential deletion library and targeted deletions within this region we identify RNA structures that may function as packaging signals.\n\nC_FIG","rel_num_authors":9,"rel_authors":[{"author_name":"Shun Yao","author_inst":"Pennsylvania State University"},{"author_name":"Abhinay Gontu","author_inst":"Pennsylvania State University"},{"author_name":"Jason Atkins","author_inst":"Integrated Research Facility at Fort Detrick, Division of Clinical Research, NIAID, NIH, Fort Detrick"},{"author_name":"Maurice Byukusenge","author_inst":"Pennsylvania State University"},{"author_name":"Padmaja Jakka","author_inst":"Pennsylvania State University"},{"author_name":"Gabriella Worwa","author_inst":"Integrated Research Facility at Fort Detrick, Division of Clinical Research, NIAID, NIH, Fort Detrick"},{"author_name":"Jens Kuhn","author_inst":"Integrated Research Facility at Fort Detrick, Division of Clinical Research, NIAID, NIH, Fort Detrick"},{"author_name":"Suresh Kuchipudi","author_inst":"Pennsylvania State University"},{"author_name":"Marco Archetti","author_inst":"Pennsylvania State University"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Dysregulated dsRNA sensor signaling and viral infection during onset of pediatric autoimmune interferonopathy","rel_doi":"10.64898\/2026.05.27.728148","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.27.728148","rel_abs":"Juvenile dermatomyositis (JDM) is characterized by a type I interferon (IFN-I) signature associated with disease activity. We previously identified a link between SARS-CoV-2 infection and the onset or relapse of JDM. Here, we show that newly diagnosed JDM patients display an overexpression of IFIH1 (encoding MDA5 protein) at baseline, coupled with an altered response to dsRNA stimulation at proteomic and transcriptomic levels, indicating abnormal activation of this antiviral sensing pathway. Single-cell transcriptomic and chromatin accessibility profiling of peripheral blood mononuclear cells (PBMCs) further revealed myeloid-specific enrichment of interferon-stimulated genes (ISGs) and preferential disruption of this pathway at disease onset, supporting a dysregulated IFN-I state in this cell type. We identified SARS-CoV-2 RNA in muscle biopsies of two Covid-19 pandemic-onset JDM patients, strongly implicating viral infection as a potential trigger of the dysregulated MDA5 immune response. To extend these observations beyond SARS-CoV-2, we screened two independent retrospective cohorts for antibodies against 27 common childhood infections. In our discovery cohort JDM patients showed significantly increased exposure to 4 RNA viruses in line with our immunological findings. Increased exposure to RSV B was confirmed in an independent replication cohort supporting a robust association with JDM pathophysiology. Together, these findings integrate systemic, single-cell, and tissue-level analyses implicating RNA viral infection and biased antiviral sensing in shaping IFN-I responses at JDM onset, providing mechanistic insight into environmentally triggered pathogenesis.\n\nOne sentence summaryType I interferon dysregulation at juvenile dermatomyositis onset implicates altered dsRNA sensing and RNA viral exposure as potential disease triggers.","rel_num_authors":40,"rel_authors":[{"author_name":"THOMAS RJ MOREAU","author_inst":"Translational Immunology Unit, Institut Pasteur, Universite Paris-Cite, Paris, France."},{"author_name":"YANN AQUINO","author_inst":"3. Humanevolutionary Genetics Unit, Institut Pasteur, Universite Paris Cite, CNRS UMR2000, Paris, France."},{"author_name":"YIXIANG YJ ZHU","author_inst":"2. Laboratoire de Chimieet Biochimie Pharmacologiqueset Toxicologiques   , CNRS UMR8601, Universite de Paris Cite, FHU INFLAMME Paris, France."},{"author_name":"VINCENT BONDET","author_inst":"1. Translational Immunology Unit, Institut Pasteur, Universite Paris-Cite, Paris, France."},{"author_name":"CHLOE ALBERT-VEGA","author_inst":"1. Translational Immunology Unit, Institut Pasteur, Universite Paris-Cite, Paris, France."},{"author_name":"FRANCOISE DONNADIEU","author_inst":"4. Infectious Disease Analytics andepidemiology Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"FLORIAN DUBOIS","author_inst":"1. Translational Immunology Unit, Institut Pasteur, Universite Paris-Cite, Paris, France."},{"author_name":"BAPTISTE PERIOU","author_inst":"5. Creteil Parisest University, INSERM, IMRB U955, and Reference centre for rare neuromuscular diseases, AP-HP, Henri Mondor Hospital, Creteil, France."},{"author_name":"FARAH RAHAL","author_inst":"1. Translational Immunology Unit, Institut Pasteur, Universite Paris-Cite, Paris, France."},{"author_name":"MINA TIZERARINE","author_inst":"2. Laboratoire de Chimieet Biochimie Pharmacologiqueset Toxicologiques   , CNRS UMR8601, Universite de Paris Cite, FHU INFLAMME Paris, France."},{"author_name":"SASKIA R VELDKAMP","author_inst":"6. Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands."},{"author_name":"ETIENNE VILLAIN","author_inst":"1. Translational Immunology Unit, Institut Pasteur, Universite Paris-Cite, Paris, France."},{"author_name":"ANTHONY BERTRAND","author_inst":"1. Translational Immunology Unit, Institut Pasteur, Universite Paris-Cite, Paris, France."},{"author_name":"CHRISTINE BODEMER","author_inst":"8. Department of Dermatology, Referral Center for Genodermatoses and Rare Skin Diseases, Assistance Publique-Hopitaux de Paris, Hopital Necker-Enfants Malades, "},{"author_name":"CAMILLE BRUNAUD","author_inst":"9. Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR-S-1163, Paris, France."},{"author_name":"MARIE-LOUISE FREMOND","author_inst":"10. Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France."},{"author_name":"BENJAMIN FOURNIER","author_inst":"11. Pediatric Immunology, Hematology and Rheumatology Department, Hopital Necker-Enfants Malades, Assistance Publique-Hopitaux de Paris, Paris, France."},{"author_name":"BENEDICTE HOAREAU","author_inst":"13. Productionet Analyse de donneesen Sciences de la vieeten Sante , Plateforme de Cytometrie de la Pitie-Salpetriere, Unite Mixte de Service (  037, Sorbonne U"},{"author_name":"PIERRE QUARTIER","author_inst":"11. Pediatric Immunology, Hematology and Rheumatology Department, Hopital Necker-Enfants Malades, Assistance Publique-Hopitaux de Paris, Paris, France."},{"author_name":"FRANCOIS-JEROME AUTHIER","author_inst":"5. Creteil Parisest University, INSERM, IMRB U955, and Reference centre for rare neuromuscular diseases, AP-HP, Henri Mondor Hospital 94010, 94010 Creteil, Fran"},{"author_name":"EUGENIE SARDA","author_inst":"14. Department of Clinical Neurophysiology, Reference center for neuromuscular pathologies Paris Nordest, Hopital Necker-Enfants Malades, Universite de Paris Ci"},{"author_name":"ADRIEN SCHVARTZ","author_inst":"15. Department of Pediatric Rheumatology, Reference Center for AutoInflammatory Diseases and Amyloidosis , Hopital Bicetre, AP-HP, Le Kremlin-Bicetre, France."},{"author_name":"ANGELIQUE VINIT","author_inst":"13. Productionet Analyse de donneesen Sciences de la vieeten Sante , Plateforme de Cytometrie de la Pitie-Salpetriere, Unite Mixte de Service (  037, Sorbonne U"},{"author_name":"ANNET VAN ROYEN-KERKHOF","author_inst":"6. Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands."},{"author_name":"FEMKE VAN WIJK","author_inst":"6. Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands."},{"author_name":"ANNE WELFRINGER-MORIN","author_inst":"8. Department of Dermatology, Referral Center for Genodermatoses and Rare Skin Diseases, Assistance Publique-Hopitaux de Paris, Hopital Necker-Enfants Malades, "},{"author_name":"FREDERIC RIEUX-LAUCAT","author_inst":"9. Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, INSERM UMR-S-1163, Paris, France."},{"author_name":"MARC JANSEN","author_inst":"6. Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands."},{"author_name":"DAVID HING","author_inst":"16. Histopathology Platform, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"TATIANA TRABOULSI","author_inst":"17. Cytometry and Biomarkers UTechS, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"CAROLINA MORAES-CABE","author_inst":"17. Cytometry and Biomarkers UTechS, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"MILENA HASAN","author_inst":"17. Cytometry and Biomarkers UTechS, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"DAVID HARDY","author_inst":"16. Histopathology Platform, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"MICHAEL WHITE","author_inst":"4. Infectious Disease Analytics andepidemiology Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"LLUIS QUINTANA-MURCI","author_inst":"3. Humanevolutionary Genetics Unit, Institut Pasteur, Universite Paris Cite, CNRS UMR2000, Paris, France."},{"author_name":"ISABELLE MELKI","author_inst":"12. Reference centre for inflammatory Rheumatism, AutoImmune disease and Systemic interferonopathies in childrEn (RAISE , Paris, France."},{"author_name":"BRIGITTE BADER-MEUNIER","author_inst":"11. Pediatric Immunology, Hematology and Rheumatology Department, Hopital Necker-Enfants Malades, Assistance Publique-Hopitaux de Paris, Paris, France."},{"author_name":"CYRIL GITIAUX","author_inst":"14. Department of Clinical Neurophysiology, Reference center for neuromuscular pathologies Paris Nordest, Hopital Necker-Enfants Malades, Universite de Paris Ci"},{"author_name":"MATHIEU P RODERO","author_inst":"2. Laboratoire de Chimieet Biochimie Pharmacologiqueset Toxicologiques   , CNRS UMR8601, Universite de Paris Cite, FHU INFLAMME Paris, France."},{"author_name":"DARRAGH DUFFY","author_inst":"1. Translational Immunology Unit, Institut Pasteur, Universite Paris-Cite, Paris, France."}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"The biodistribution and effect of post-exposure neutralising monoclonal antibody treatment in a mouse model of SARS-CoV-2 infection with viral spread to the brain","rel_doi":"10.64898\/2026.05.27.728081","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.27.728081","rel_abs":"Ronapreve, a combination of two neutralising monoclonal antibodies, casirivimab and imdevimab, was amongst the authorised treatments against SARS-CoV-2 early in the COVID-19 pandemic. Ronapreve has lost some of its efficiency with the rise of new virus variants, however, it remains a valuable tool for experimental studies to gain insights into the mechanisms and effects of anti-viral drugs. In this study we combined morphological, pharmacokinetic and molecular approaches (including multiomics) to investigate the biodistribution of Ronapreve in the K18-hACE2 murine model of SARS-CoV-2 neuroinvasion, as well as possible consequences for the brain. We also investigated the effect of the treatment on the infection status. Our results showed that after intraperitoneal injection, Ronapreve accumulates in the serum and is unable to cross the blood-brain barrier, thus not reaching the brain parenchyma; treatment has only a minimal effect on the brain transcriptome, with no significant changes in the brain lipidome or metabolome. Nonetheless, post-exposure Ronapreve treatment resulted in reduced viral loads in the lung and, in particular, the brain, with markedly reduced tissue response in the brain, as shown by the transcriptomic analysis. The results suggest a peripheral mode of action of Ronapreve to block brain infection, possibly by lowering viral replication in the nasal epithelium, reducing a subsequent spread to the brain.","rel_num_authors":13,"rel_authors":[{"author_name":"Janine Anja Schlaepfer","author_inst":"University of Zurich"},{"author_name":"Simon De Neck","author_inst":"University of Zurich"},{"author_name":"Rebekah Penrice-Randal","author_inst":"University of Liverpool"},{"author_name":"Parul Sharma","author_inst":"University of Liverpool"},{"author_name":"Adam Kirby","author_inst":"University of Liverpool"},{"author_name":"Lee Tatham","author_inst":"University of Liverpool"},{"author_name":"Eduardo Gallardo Toledo","author_inst":"University of Liverpool"},{"author_name":"Joanna Herriott","author_inst":"University of Liverpool"},{"author_name":"Edyta Kijak","author_inst":"University of Liverpool"},{"author_name":"Jo Sharp","author_inst":"University of Liverpool"},{"author_name":"James P Stewart","author_inst":"University of Liverpool"},{"author_name":"Andrew Owen","author_inst":"University of Liverpool"},{"author_name":"Anja Kipar","author_inst":"University of Zurich"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Increased burden of influenza A\/H1N1pdm09 in older adults following the COVID-19 pandemic","rel_doi":"10.64898\/2026.05.20.26353664","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.20.26353664","rel_abs":"Of the two influenza A virus (IAV) subtypes circulating endemically in humans, A\/H3N2 and A\/H1N1pdm09, A\/H3N2 has historically been the dominant driver of disease burden in older adults. Based on an analysis of publicly available global surveillance data from 2015 to 2025 (>300,000 subtyped, age-stratified infections), we report a substantially increased contribution of A\/H1N1pdm09 to influenza morbidity in older adults since approximately 2022. Birth cohort-stratified analyses suggest elevated A\/H1N1pdm09 burden among individuals born before 1955-1959, consistent with erosion of pre-existing immunity originally generated by exposure to historical A\/H1N1 strains. Pooled estimates across datasets and analytical approaches indicate the increase in A\/H1N1pdm09 burden rises with earlier birth year, ranging from 1.22-fold (95% CI 1.08-1.37) for the 1955-1959 birth cohort to 3.10-fold (95% CI 2.58-3.72) for the 1930-1934 cohort. These findings point to a substantial rise in the overall influenza burden among the most vulnerable age groups, with implications for vaccine policy, clinical management, and public health planning.","rel_num_authors":2,"rel_authors":[{"author_name":"Simon P. J. de Jong","author_inst":"Amsterdam University Medical Centers"},{"author_name":"Colin A Russell","author_inst":"Amsterdam University Medical Center"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"SARS-CoV-2 Antibody Response during Omicron Predominance after COVID-19 Vaccination in People Living with HIV: A Comparative Study in Canada and Burkina Faso","rel_doi":"10.64898\/2026.05.26.26354060","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.26.26354060","rel_abs":"People living with HIV (PLWH) are known to maintain a degree of immune deficiency despite efficient antiretroviral therapy and may exhibit diminished responses to vaccines. In this study, we assessed the immune response to SARS-CoV-2 infection and vaccines in two geographically distinct PLWH populations. PLWH and HIV-negative (HIV-) participants were recruited from Quebec City (QC), Canada, and Bobo-Dioulasso (BD), Burkina Faso, for two visits at 24-week intervals during the predominance of the Omicron variant, from May 2022 to September 2023. Blood samples were collected at each visit for the detection of antibodies against spike (anti-S) and nucleocapsid (anti-N) proteins of SARS-CoV-2 in platelet-free plasma. A total of 360 participants were enrolled. We detected anti-S antibodies in 99% of participants, indicating that nearly all had prior exposure to the SARS-CoV-2 spike antigen, either through vaccination or prior infection. Anti-S titers showed no difference between PLWH and HIV-participants in each location, while significantly higher titers were observed in participants from QC compared to BD. In contrast, anti-N antibodies, indicative of prior infection, were detected in 39% and 86% of the participants in QC and BD, respectively, suggesting that the virus circulated largely in the latter population. No difference in anti-N levels was observed between PLWH and HIV-participants in BD. However, participants in QC had significantly lower titers compared to HIV-participants. Overall, this study shows that PLWH develop robust antibody responses to SARS-CoV-2 vaccination, comparable to those observed in HIV-participants. Significant geographic differences were observed in anti-S titers, irrespective of HIV status, with participants from QC displaying higher titers. In contrast, participants from BD had higher anti-N antibody prevalence and titers, reflecting more SARS-CoV-2 infections in BD than in QC. Finally, analysis of anti-S antibody titers against several circulating variants revealed significantly lower levels in unvaccinated participants and in those vaccinated with monovalent vaccines in BD. No significant difference was observed between monovalent and bivalent vaccines administered in QC.","rel_num_authors":16,"rel_authors":[{"author_name":"Hend Jarras","author_inst":"Universite Laval"},{"author_name":"Wilfried Wenceslas Bazie","author_inst":"Universite Laval"},{"author_name":"Isalie Blais","author_inst":"Universite Laval"},{"author_name":"Arielle Pakenham","author_inst":"Universite Laval"},{"author_name":"justin Valiquette","author_inst":"Universite Laval"},{"author_name":"Mathieu Theriault","author_inst":"Universite Laval"},{"author_name":"Isidore T Traore","author_inst":"Centre Muraz, Institut National de Sante Publique"},{"author_name":"Dramane Kania","author_inst":"Centre MURAZ"},{"author_name":"Aline R Ouoba","author_inst":"Centre Muraz, Institut National de Sante Publique"},{"author_name":"Yvette Zoundi","author_inst":"Centre Muraz, Institut National de Sante Publique"},{"author_name":"Martin Pelletier","author_inst":"Universite Laval"},{"author_name":"Philippe A Tessier","author_inst":"Universite Laval"},{"author_name":"Marc Pouliot","author_inst":"Universite Laval"},{"author_name":"Sylvie Trottier","author_inst":"Universite Laval"},{"author_name":"Marie-Louise Vachon","author_inst":"Universite Laval"},{"author_name":"Caroline Gilbert","author_inst":"Universite Laval"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Dynamic Topic Alignment and Sentiment between Official Health Communication and General Public Discourse during COVID-19: A Comprehensive Infoveillance Framework","rel_doi":"10.64898\/2026.05.23.26353966","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.23.26353966","rel_abs":"Social media has become a critical channel for public health communication during the COVID-19 pandemic, yet how official health messaging aligns with broader public discourse remains insufficiently understood. This study develops an end-to-end infoveillance framework to examine the dynamic relationship between Centers for Disease Control and Prevention (CDC) communications and general public discourse on social media. We analyzed 17,524 CDC tweets and 67,895 public discourse tweets. Biterm Topic Model (BTM) was used to extract topics from each corpus, and a novel topic consistency scoring system integrating cosine similarity with daily public topic prominence was developed to quantify temporal alignment between official health communication and public discourse. Two complementary sentiment measures were incorporated: expected sentiment (average emotional tone) and net sentiment (overall emotional intensity). Temporal relationships were examined using autoregressive integrated moving average with exogenous variables (ARIMAX) models. Results show that topic alignment increased over time across CDC topics, while expected sentiment remained consistently negative. Higher alignment was associated with immediate and delayed changes in expected sentiment and stronger emotional intensity in net sentiment based on ARIMAX results. These findings suggest that topic alignment reflects public attention rather than agreement with official communications and is associated with more negative emotional responses. This framework provides a scalable, generalizable approach to investigate and evaluate public engagement with official health communication.","rel_num_authors":4,"rel_authors":[{"author_name":"Shuhua Yin","author_inst":"University of North Carolina at Charlotte"},{"author_name":"Wangjiaxuan Xin","author_inst":"University of North Carolina at Charlotte"},{"author_name":"Shi Chen","author_inst":"University of North Carolina at Charlotte"},{"author_name":"Yaorong Ge","author_inst":"University of North Carolina at Charlotte"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"Antibody Transcytosis and Neutralizing Activity in Respiratory Epithelial Cells","rel_doi":"10.64898\/2026.05.25.727697","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.25.727697","rel_abs":"The neutralizing activity present in human serum is considered a correlate of protection against SARS-CoV-2 infection and disease but the mechanisms by which serum antibodies are transported into the lumen of the respiratory tract, where they are required to interact with virus particles and infected cells remain incompletely understood. The transcytosis and neutralizing activity of serum-derived IgG and IgA antibodies was investigated using an in vitro SARS-CoV-2 infection model with primary differentiated human nasal and basal epithelial cells (hNECs and hBECs) cultures. Expression of the antibody transport receptors neonatal Fc receptor (FcRn) and polymeric immunoglobulin receptor (pIgR) in hNECs cultures was confirmed by qPCR, immunofluorescence microscopy, and flow cytometry. Both receptors were expressed throughout the epithelial cultures, with enriched expression observed in ciliated cells compared with goblet and basal cells. Purified IgG and IgA isolated from convalescent plasma demonstrated specificity for SARS-CoV-2 spike protein and inhibited ACE2-Spike interactions, although activity was reduced against later variants. Purified IgG contained higher anti-spike antibody titers than purified IgA. Functional neutralization assays showed that transcytosed IgG and IgA significantly reduced SARS-CoV-2 infection compared with untreated controls. However, serial dilution studies demonstrated that IgG-mediated neutralization was more potent than IgA-mediated neutralization. Similar results were determined for influenza A virus H3N2 subtype. The transcytosis of IgG was more efficient in hBEC cultures while IgA transcytosis was higher in hNEC cultures, reflecting the levels of the corresponding transport proteins. Together, these findings demonstrate that serum-derived IgG and IgA can undergo transepithelial transport across human nasal epithelium while retaining SARS-CoV-2 or influenza A virus neutralizing activity in vitro. These results suggest that FcRn- and pIgR-mediated antibody transport may contribute to mucosal protection following vaccination or infection and may help identify antibody responses associated with protection against SARS-CoV-2.\n\nImportanceSerum antibody levels are considered correlates of protection for SARS-CoV-2 and Influenza A virus but its unclear how those antibodies are transported to the apical surface of respiratory epithelial cells, where they must be present for optimal activity. We show that IgG and IgA specific for SARS-CoV-2 or influenza A virus is transcytosed across respiratory epithelial cell cultures, the efficiency of which reflects the level of FcRn or pIgR expression levels, suggesting that cells of the upper and lower respiratory tract transport different antibodies from the blood.","rel_num_authors":7,"rel_authors":[{"author_name":"Eduardo Anaya","author_inst":"johns hopkins bloomberg school of public health"},{"author_name":"Yee Vue","author_inst":"johns hopkins bloomberg school of public health"},{"author_name":"Maggie Li","author_inst":"johns hopkins bloomberg school of public health"},{"author_name":"Jessica Resnick","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Nicholas J Swanson","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"David J Sullivan","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Andrew Pekosz","author_inst":"Johns Hopkins Bloomberg School of Public Health"}],"rel_date":"2026-05-27","rel_site":"biorxiv"},{"rel_title":"Two anti-phase spatial modes and a candidate spatial-persistence regime transition of SARS-CoV-2 in Japan: a 159-week prefecture-level sentinel surveillance study","rel_doi":"10.64898\/2026.05.24.26353972","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.24.26353972","rel_abs":"BackgroundOn 8 May 2023 the Japanese Ministry of Health, Labour and Welfare reclassified COVID-19 under the Infectious Disease Control Law from a designated infectious disease (with case-by-case reporting requirements comparable to those of a Category-2 disease) to a Category-5 (\"Class-5\") notifiable disease, joining the same category as seasonal influenza and most other endemic respiratory infections. Under this regime, COVID-19 case counts are reported weekly from a nationwide network of sentinel medical facilities (initially approximately 5,000, reduced to approximately 3,000 following an April 2025 surveillance reform), and individual case reporting is no longer required. We aimed to characterize the spatial topology of COVID-19 epidemics under this sentinel-surveillance regime and to detect, in a data-driven manner, any structural change in epidemic dynamics over this period.\n\nMethodsWe analyzed weekly per-sentinel-facility COVID-19 case counts in all 47 prefectures of Japan from 2023-W17 to 2026-W19 (159 weeks). For each week we computed the Shannon pseudo-entropy S of the prefecture-share distribution and global, local, and time-lagged Morans I across a 92-edge contiguity-based adjacency matrix. To identify any structural change in a data-driven manner, we adopted a two-stage approach motivated by an empirical regularity established in [&#167;]3: we first verified the wave-amplitude-invariant entropy ceiling (S_max [&ge;] 3.80 in all five pre-transition waves), then restricted change-point detection to the weeks after S(t) last attained this ceiling, applying PELT, CUSUM, and Bai-Perron sup-F within this restricted region. Seasonal structure was characterized by truncated Fourier regression with first-order autoregressive errors (Cochrane-Orcutt) over harmonic orders K [isin] {1, ..., 6}; between-period comparisons used moving block bootstrap as the principal inferential statistic.\n\nResultsThe five epidemic waves during 2023-2025 followed a stereotyped spatial template in which S(t) traced a characteristic U-shape around each peak, with a wave-amplitude-invariant entropy ceiling reaching on average 99.4% of the theoretical maximum ln 47 (range 3.820- 3.836, SD 0.006). The last week in which S(t) attained this entropy ceiling was 2025-W42.\n\nRestricting change-point detection to the 29 subsequent weeks, PELT and CUSUM localised the structural break to late 2025: PELT identified 2025-W48 (robust across penalty values [&ge;] {sigma}2{middle dot}ln(n) and across entropy-ceiling thresholds 3.78-3.82) and CUSUM peaked at 2025-W50 (p < 0.0001), placing the break within a two-week window centred on late November 2025. Bai- Perron sup-F peaked later at 2026-W02 (p = 0.062, with reduced power on n = 29). We adopted 2025-W48 as the principal change-point, defining 135 pre-transition weeks and 24 post-transition weeks. Two anti-phase spatial modes were identified in the pre-transition record: a summer-onset Okinawa-seeded Kyushu cascade (Mode A; annual peak epi week 26) and a winter-onset Tohoku-centred connected-cluster mode (Mode B; annual peak epi week 51), approximately 25 epi weeks out of phase. After the regime transition, this ceiling was not attained, and the spatial-persistence ratio I({tau} = 8 wk)\/I(0) shifted from a highly variable distribution centred near 0.27 (pre-transition, 125 weeks) to a tightly clustered distribution around 0.89 (post-transition, 24 weeks); the mean difference was 0.62 (95% bootstrap CI 0.32 to 0.90; moving block bootstrap p < 0.0001 across block lengths 1-12). The principal finding remained significant under autoregressive-augmented null models and was robust to adjacency-matrix choice, the April 2025 surveillance reform, harmonic order K [isin] {1, ..., 6}, and Okinawa exclusion.\n\nConclusionsData-driven analysis of 159 weeks of Japanese sentinel surveillance identifies a candidate spatial-persistence regime transition emerging in late November 2025, in which the spatial structure of weekly case shares persists for at least 8 weeks rather than dissipating as in pre-transition. The transition coincides with loss of the wave-amplitude-invariant entropy ceiling and with absence of the Mode A signature through the observed post-transition period. The recent uptick in Okinawa case shares (continuing through 2026-W19) leaves open whether the Mode A signature is structurally suppressed or merely deferred; observation through summer 2026 is required to distinguish a sustained shift from a transient anomaly.","rel_num_authors":5,"rel_authors":[{"author_name":"Takashi Nakano","author_inst":"Research Center for Nuclear Physics, The University of Osaka, Osaka, Japan"},{"author_name":"Daisuke Onozuka","author_inst":"Center for Advanced Modalities and DDS (CAMaD), The University of Osaka, Osaka, Japan"},{"author_name":"Yoichi Ikeda","author_inst":"Center for Infectious Disease Education and Research (CiDER), The University of Osaka, Osaka, Japan"},{"author_name":"Kouhei Washiyama","author_inst":"Center for Infectious Disease Education and Research (CiDER), The University of Osaka, Osaka, Japan"},{"author_name":"Yoshihiro Takashima","author_inst":"Center for Advanced Modalities and DDS (CAMaD), The University of Osaka, Osaka, Japan"}],"rel_date":"2026-05-26","rel_site":"medrxiv"},{"rel_title":"Antigenic characterization of SARS-CoV-2 variants BA.3.2.1 and BA.3.2.2 in three animal models","rel_doi":"10.64898\/2026.05.24.727525","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.24.727525","rel_abs":"BA.3.2, a variant of SARS-CoV-2 containing [~]40 mutations in its spike protein compared to its nearest ancestor, has spread globally since its first detection in South Africa in November 2024. Here, we report antigenic characterization of BA.3.2 viruses in three naive animal models, and visualize its antigenic phenotype in the context of SARS-CoV-2 evolution using antigenic cartography. We find that: (1) BA.3.2 is substantially antigenically divergent from existing SARS-CoV-2 variants; (2) infection with BA.3.2 in hamster and mouse animal models produces sera with lower homologous titer than infection with other variants. Both of these results may have implications for the selection of vaccine antigens.","rel_num_authors":17,"rel_authors":[{"author_name":"Samuel A. Turner","author_inst":"University of Cambridge"},{"author_name":"Joey Olivier","author_inst":"University of Cambridge"},{"author_name":"Madison L. Ellis","author_inst":"Emory University"},{"author_name":"Katharine A. Floyd","author_inst":"Emory University"},{"author_name":"Lilin Lai","author_inst":"Emory University Emory National Primate Research Center"},{"author_name":"Suzanne M. Scheaffer","author_inst":"Washington University in St Louis"},{"author_name":"Ionsei Hastings","author_inst":"Washington University in St Louis"},{"author_name":"Tamarand L. Darling","author_inst":"Washington University in St Louis"},{"author_name":"Blake A. Miller","author_inst":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University"},{"author_name":"Charmy J. Patel","author_inst":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University"},{"author_name":"Hannah Peck","author_inst":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University"},{"author_name":"Daryll Vanover","author_inst":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University"},{"author_name":"Philip J. Santangelo","author_inst":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University"},{"author_name":"Michael S. Diamond","author_inst":"Washington University in St Louis"},{"author_name":"Mehul S. Suthar","author_inst":"Emory University"},{"author_name":"Adrianus C. M. Boon","author_inst":"Washington University in St Louis"},{"author_name":"Derek J. Smith","author_inst":"University of Cambridge"}],"rel_date":"2026-05-26","rel_site":"biorxiv"},{"rel_title":"Epistatic evolution drives HLA-dependent CD8+ T Cell escape risk in diverse populations","rel_doi":"10.64898\/2026.05.22.727291","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.22.727291","rel_abs":"Understanding how viral evolution shapes HLA-dependent T cell escape is crucial to identify individuals at risk of reduced cellular immunity to emerging variants. Nevertheless, we lack frameworks to model HLA diversity and the evolutionary feasibility of T cell-evading mutations. Here, we construct an HLA map capturing variation in epitope specificity across HLA-typed cohorts. Enhancing this framework with SARS-CoV-2 CD8 T cell escape reveals heterogeneous escape across HLA-defined groups, with clusters enriched for HLA-B*07:02, HLA-A*03:01 and HLA-A*02:01 showing higher epitope loss. To assess the evolutionary plausibility of escape, we model viral sequence fitness using an epistasis-aware protein language approach trained on coronaviruses to systematically score mutations across viral lineages. We find that the fitness effect of mutations dynamically changes with evolving sequence context, and that T cell-evading mutations become fitter with additional escape mutations. This study links host HLA diversity to viral fitness landscapes for surveillance and vaccine design.","rel_num_authors":10,"rel_authors":[{"author_name":"David Joel Hamelin","author_inst":"University of Montreal"},{"author_name":"Jean-Christophe Grenier","author_inst":"Montreal Heart Institute"},{"author_name":"Raphael Poujol","author_inst":"Montreal Heart Institute"},{"author_name":"Benoite Bourdin","author_inst":"CHU Sainte Justine"},{"author_name":"Bastien Pare","author_inst":"CHU Sainte-Justine"},{"author_name":"Shawn Simpson","author_inst":"CHU Sainte-Justine"},{"author_name":"Martin Smith","author_inst":"UNSW Sydney"},{"author_name":"Helene Decaluwe","author_inst":"Universite de Montreal"},{"author_name":"Etienne Caron","author_inst":"Yale School of Medicine"},{"author_name":"Julie Hussin","author_inst":"Universite de Montreal"}],"rel_date":"2026-05-26","rel_site":"biorxiv"},{"rel_title":"Substrate and target selectivity of 4'-fluoroadenosine against viral and host polymerases","rel_doi":"10.64898\/2026.05.22.727251","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.22.727251","rel_abs":"Developing safe and effective treatments against emerging RNA viruses is an important goal in pandemic preparedness efforts. 4'-fluorouridine (4'-FlU) is a broad-spectrum antiviral that was shown to inhibit viral RNA-dependent RNA polymerases (RdRps). Given its notable range of antiviral activity, this class of nucleoside analogs warrants further investigation. Here, we studied the antiviral activity and underlying mechanism of inhibition of 4'-fluoroadenosine (4'-FlA). Like 4'-FlU, 4'-FlA demonstrates a broad-spectrum of antiviral activity against eight prototypic viruses representing diverse families. Enzyme kinetics show that the triphosphate (4'-FlA-TP) is efficiently incorporated by viral RdRps. A cryo-EM structure of RdRp of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in complex with double-stranded RNA and the incorporated monophosphate (4'-FlA-MP) characterizes interactions at the active site. The incorporated analog elicits heterogeneous inhibition patterns in primer extension reactions. In contrast, templates with embedded 4'-FlA-MP inhibit incorporation of complementary UTP across the viral RdRps. However, incorporation of 4'-FIA-TP is not limited to viral polymerases and likewise includes human mitochondrial RNA polymerase. These results demonstrate the general potential for 4'-fluorinated nucleotides as antiviral drugs and guide the development of more selective derivatives for medical use in appropriate settings.","rel_num_authors":30,"rel_authors":[{"author_name":"Simon M. Walker","author_inst":"University of Alberta"},{"author_name":"Arlo J. Loutan","author_inst":"University of Alberta"},{"author_name":"Egor P. Tchesnokov","author_inst":"University of Alberta"},{"author_name":"Dana Kocincova","author_inst":"University of Alberta"},{"author_name":"Calvin J. Gordon","author_inst":"University of Alberta"},{"author_name":"Ruby A. Escobedo","author_inst":"Texas Biomedical Research Institute"},{"author_name":"Nathaniel Jackson","author_inst":"Texas Biomedical Research Institute"},{"author_name":"Olivia  A. Vogel","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Kim Morsheimer","author_inst":"Boston University"},{"author_name":"Suncheol Park","author_inst":"The Scripps Research Institute"},{"author_name":"Anant Gharpure","author_inst":"The Scripps Research Institute"},{"author_name":"Ixchel Urbano","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute"},{"author_name":"Mina Heacock","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute"},{"author_name":"Zhong Cheng","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute"},{"author_name":"Kushboo Pathak","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute"},{"author_name":"Karen C. Wolff","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute"},{"author_name":"Lauren Huerta","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute"},{"author_name":"Malina A. Bakowski","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute"},{"author_name":"Laura Riva","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute"},{"author_name":"Anil K. Gupta","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute"},{"author_name":"Chenguang Yu","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute"},{"author_name":"Kalyan Das","author_inst":"University of Alberta, Rega Institute for Medical Research"},{"author_name":"Luis Martinez-Sobrido","author_inst":"Texas Biomedical Research Institute"},{"author_name":"Christopher F. Basler","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Robert A. Davey","author_inst":"Boston University"},{"author_name":"Ian A. Wilson","author_inst":"The Scripps Research Institute"},{"author_name":"Andrew B. Ward","author_inst":"The Scripps Research Institute"},{"author_name":"Sumit Chanda","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute"},{"author_name":"Arnab K. Chatterjee","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute"},{"author_name":"Matthias Gotte","author_inst":"University of Alberta"}],"rel_date":"2026-05-26","rel_site":"biorxiv"},{"rel_title":"Low seroprevalence of neutralizing antibodies to gorilla adenovirus 32 (GRAd32) in southern African populations supports evaluation of this vector platform for HIV vaccine development","rel_doi":"10.64898\/2026.05.23.726423","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.23.726423","rel_abs":"Adenoviruses (Ads) are widely used as vaccine vectors. However, pre-existing immunity to commonly used serotypes, like Ad5, can reduce vaccine immunogenicity, with neutralizing antibody titers >200 previously shown to impact vaccine efficacy. Gorilla adenovirus (GRAd) vectors have been developed to evade pre-existing anti-vector responses, but their seroprevalence in southern Africa is poorly defined. Here, we assessed seroprevalence to GRAd32, Ad26 and Ad5 before (baseline) and after COVID-19 vaccination, in cohorts from South Africa and Zimbabwe.\n\nSera from South African participants enrolled in the Sisonke sub-study (n=100, prior to Ad26.COV2.S vaccination) and the follow-up \"Booster after Sisonke\" (BaSiS) study (n=226) were tested for neutralizing antibodies to Ad5, Ad26, and GRAd32. These samples included paired pre\/post boost samples for 27 donors. We also tested sera from the Zimbabwean Mutala cohort (n=131, of which 44 were unvaccinated, and 87 vaccinated with inactivated vaccines). Participants living with HIV (PLWH) comprised 30-50% of each cohort.\n\nIn the pre-vaccination samples from the Sisonke cohort, geometric mean titers (GMT) for anti-GRAd32, Ad26, and Ad5 antibodies were 78, 142, and 459, with neutralization titers >200 observed in 14%, 32%, and 68% of participants, respectively. Similarly, in the unvaccinated participants in the Mutala cohort, GMTs for GRAd32, Ad26, and Ad5 were 117, 245, and 536, with neutralizing titers >200 in 22%, 42%, and 69% of participants. We observed no significant difference in Ad antibody titers between PLWH and those living without HIV. We next assessed the impact of COVID-19 vaccination on titers. Vaccination with inactivated COVID-19 vaccines (Sinopharm\/Sinovac) did not significantly affect Ad5, Ad26 or GRAd32 titers in an unpaired analysis. In contrast, [~]9 months after Ad26.COV2.S vaccination, anti-Ad26 titers for longitudinally sampled participants (n=27) increased 10-fold from a GMT of 141 to 1,426. By comparison, GRAd32 responses were not significantly altered by Ad26.COV2.S vaccination, while anti-Ad5 responses showed a modest <2-fold increase.\n\nOur data support previous findings that, whereas anti-Ad5 neutralizing antibody responses are commonly detected globally, GRAd32 responses are less frequent. Importantly, GRAd32 neutralizing responses remained unchanged after Ad26.COV2.S vaccination. HIV status had no significant effect on antibody titers. These results support the use of the GRAd32 vector in upcoming HIV vaccine trials, including in regions where Ad26-based COVID-19 vaccines were widely deployed.","rel_num_authors":21,"rel_authors":[{"author_name":"Nonhlanhla N Mkhize","author_inst":"NICD: National Institute for Communicable Diseases"},{"author_name":"Anna patjane","author_inst":"NICD: National Institute for Communicable Diseases"},{"author_name":"Nomcebo Shusha","author_inst":"NICD:  National Institute for Communicable Diseases"},{"author_name":"Ashleigh Welsh","author_inst":"NICD: National Institute for Communicable Diseases"},{"author_name":"Tandile Hermanus","author_inst":"NICD:National Institute for Communicable Diseases"},{"author_name":"Prudence Kgagudi","author_inst":"NICD: National Institute for Communicable Diseases"},{"author_name":"Thopisang Motlou","author_inst":"NICD: National Institute for Communicable Diseases"},{"author_name":"Linda-Gail Bekker","author_inst":"University of Cape Town, Desmond Tutu Foundation"},{"author_name":"Glenda Gray","author_inst":"University of the Witwatersrand, SA MRC"},{"author_name":"Nigel Garrett","author_inst":"Desmond Tutu Health Foundation"},{"author_name":"Lee Fairlie","author_inst":"University of the Witwatersrand, Wits RHI"},{"author_name":"Alex Sigal","author_inst":"Africa Health Research Institute, University of KwaZulu-Natal"},{"author_name":"Wendy Burgers","author_inst":"University of Cape Town"},{"author_name":"Takudzwa Mangwaku","author_inst":"African Clinical Research Network, Harare, Zimbabwe"},{"author_name":"Tariro Makadzange","author_inst":"African Clinical Research Network, Harare, Zimbabwe, Mutala Trust"},{"author_name":"Stefano Colloca","author_inst":"ReiThera"},{"author_name":"Antonella Folgori","author_inst":"ReiThera srl"},{"author_name":"Thandeka Moyo-Gwete","author_inst":"NICD: National Institute for Communicable Diseases"},{"author_name":"Michela Gentile","author_inst":"ReiThera srl"},{"author_name":"Stefania Capone","author_inst":"ReiThera srl"},{"author_name":"Penny L Moore","author_inst":"University of the Witwatersrand"}],"rel_date":"2026-05-26","rel_site":"biorxiv"},{"rel_title":"Cumulative In-Context Learning versus Simple Historical Weighting for Real-Time Geographic Origin Identification of Ongoing Epidemic Waves: A Comparative Evaluation Using Eight COVID-19 Waves in Japan","rel_doi":"10.64898\/2026.05.23.26353936","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.23.26353936","rel_abs":"BackgroundIdentifying the geographic origin of epidemic waves early is critical for targeted public health responses. Conventional statistical methods for wave origin estimation rely on fixed algorithms applied to case count time-series data and treat each wave independently. Large language models (LLMs) offer a novel alternative through cumulative learning--the ability to incorporate confirmed epidemiological findings from prior waves into predictions for subsequent waves. Whether this approach outperforms conventional statistical baselines in early detection, and whether the same cumulative learning principle can be implemented in transparent statistical methods, remains unknown.\n\nMethodsWe compared three computational approaches across eight COVID-19 epidemic waves in Japan (Waves 2-8, 2020-2023): (1) non-cumulative statistical baselines (B0-B5) treating each wave independently; (2) a cumulative-learning LLM (Claude Haiku) receiving confirmed origins from all prior waves as in-context historical knowledge; and (3) cumulative calculation statistical baselines implementing the identical historical weighting mechanism as a transparent arithmetic score. We additionally evaluated a non-cumulative LLM condition--receiving only current-wave data--to isolate the contribution of intrinsic LLM geographic reasoning from accumulated historical knowledge. All approaches were evaluated at 7, 14, 21, and 28 days after wave onset and validated against genomically confirmed wave origins.\n\nResultsCumulative calculation statistical baselines (B1, B3) achieved mean F1 = 0.51 at 14 days after wave onset, performing comparably to the cumulative-learning LLM (F1 = 0.52) and outperforming all non-cumulative statistical baselines (F1 = 0.41-0.46). Wave 7 (Omicron BA.5) was correctly identified at 14 days by both methods (F1 = 1.00). Wave 6 (Omicron BA.1) was undetectable by all methods (F1 = 0.00), consistent with an origin outside the domestic surveillance system.\n\nConclusionsThe cumulative historical weighting mechanism--not LLM reasoning per se--drives performance improvement, as transparent arithmetic implementation matches LLM accuracy. However, the non-cumulative LLM achieves F1 = 0.46 without any historical context, suggesting substantial intrinsic geographic reasoning capacity. These findings advance understanding of when and why in-context learning confers advantage, and provide a deployable, spreadsheet-implementable method for real-time epidemic origin identification requiring no AI infrastructure.","rel_num_authors":2,"rel_authors":[{"author_name":"Shinichi Nakagawa","author_inst":"Research Institute of Info-Communication Medicine"},{"author_name":"Akira Yamamoto","author_inst":"Fuculty of Health Data Science, Juntendo University"}],"rel_date":"2026-05-25","rel_site":"medrxiv"},{"rel_title":"Predictors of maternal mental health and coping during the COVID-19 pandemic: A multi-country cross-sectional study","rel_doi":"10.64898\/2026.05.25.26353920","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.25.26353920","rel_abs":"Objectives and studyThis study aimed to examine predictors of post-partum maternal mental health (MMH) and coping during COVID-19 lockdown across seven countries (the UK, China, Japan, Malaysia, Mexico, Argentina, and Thailand).\n\nMethodsAn anonymous questionnaire, developed in the UK in English and translated into local languages, was used in 2021-2022 to collect data on MMH and perceived coping ability from women aged [&ge;]18 years with an infant born before or during lockdowns. Five MMH components (worry, sadness, loneliness, difficulty relaxing, annoyance) and coping were assessed on a 4-point Likert scale, then dichotomised. MMH and coping were compared across countries using Chi-square tests with post-hoc pairwise comparisons conducted via Bonferroni-adjusted z-tests. Predictors of MMH and coping were examined using multivariable logistic regression.\n\nResultsA total of 7,650 women were analysed. Younger infant age, higher income, walking and exercise, and level of support were associated with better MMH and coping, whereas higher education was associated with better coping but poorer MMH. MMH and coping differed across countries (all p<0.001), which remained after adjusting for covariates: mothers in Asian countries reported better MMH, while those in the UK and Thailand reported better coping.\n\nConclusionsPostpartum MMH and coping during lockdown were shaped by both individual and contextual factors. Findings highlight cross-country differences and underscore the need to strengthen maternal support system during future disruptions to perinatal care.\n\nKey messagesO_LIConsistent predictors of better mental health and coping included younger infant age, higher income, regular physical activity, and enough support-factors that are modifiable and relevant in future public health emergencies.\nC_LIO_LICountry of residence remained an independent predictor even after adjusting for individual and social factors, suggesting cultural norms, health service models, and policy responses play important roles.\nC_LIO_LIAlthough the COVID-19 pandemic is largely over, the findings offer important lessons for future crises. Strengthening support systems, promoting physical activity, and ensuring equitable caregiving within households can help protect postpartum mothers wellbeing during any major social disruption.\nC_LI","rel_num_authors":12,"rel_authors":[{"author_name":"Chuwen Liu","author_inst":"University College London"},{"author_name":"Mengyun Liu","author_inst":"Childhood Nutrition Research Group, Population, Policy & Practice Department, UCL Great Ormond Street Institute of Child Health, London, UK."},{"author_name":"Sarah Dib","author_inst":"Childhood Nutrition Research Group, Population, Policy & Practice Department, UCL Great Ormond Street Institute of Child Health, London, UK."},{"author_name":"Milagros Ferrando","author_inst":"Servicio de Nutricion, Hospital Mira y Lopez, Santa Fe, Argentina."},{"author_name":"Masaharu Kagawa","author_inst":"Institute of Nutrition Sciences, Kagawa Nutrition University, Saitama, Japan."},{"author_name":"Krongporn Ongprasert","author_inst":"Department of Community Medicine, Chiang Mai University, Thailand."},{"author_name":"Emeline Rougeaux","author_inst":"University College London"},{"author_name":"Nurul Husna M Shukri","author_inst":"Department of Nutrition, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Malaysia."},{"author_name":"Adriana Vazquez","author_inst":"University College London"},{"author_name":"Jonathan Wells","author_inst":"University College London"},{"author_name":"Mary Fewtrell","author_inst":"UCL Great Ormond Street Institute of Child Health"},{"author_name":"Jinyue Yu","author_inst":"Childhood Nutrition Research Group, Population, Policy & Practice Department, UCL Great Ormond Street Institute of Child Health, London, UK."}],"rel_date":"2026-05-25","rel_site":"medrxiv"},{"rel_title":"Rapid in vitro synthesis of DNA templates via Sidewinder for polyadenylated Hantavirus mRNA vaccine candidates","rel_doi":"10.64898\/2026.05.22.727328","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.22.727328","rel_abs":"As the recent COVID-19 pandemic illustrated, zoonotic viruses and other pathogens pose a credible threat to public health. Recent advancements in vaccine technology, particularly mRNA vaccines, provide key tools for an effective and swift public health response. Although mRNA vaccines can be developed more quickly than traditional vaccines, fast and accurate construction of DNA templates for these vaccines remains a critical bottleneck. Using our novel DNA assembly technology, Sidewinder, we rapidly designed and built multiple mRNA vaccine candidates to guard against a potential outbreak of Hantavirus (ANDV). We successfully constructed the DNA templates from oligo pools and produced the mRNA for three vaccine candidates in just 2 days after delivery of the synthetic DNA oligos.","rel_num_authors":18,"rel_authors":[{"author_name":"Ezri Abraham","author_inst":"California Institute of Technology"},{"author_name":"Joel Andrade","author_inst":"Centivax"},{"author_name":"Alexander Davis","author_inst":"Centivax"},{"author_name":"Tomasz Gawda","author_inst":"California Institute of Technology"},{"author_name":"Jacob Glanville","author_inst":"Centivax"},{"author_name":"Daniel Graves","author_inst":"California Institute of Technology"},{"author_name":"Jianyi Huang","author_inst":"California Institute of Technology"},{"author_name":"Jeongsoo Hur","author_inst":"California Institute of Technology"},{"author_name":"Sangil Kim","author_inst":"Centivax"},{"author_name":"Jean-Sebastien Paul","author_inst":"California Institute of Technology"},{"author_name":"Noah Evan Robinson","author_inst":"California Institute of Technology"},{"author_name":"Charles Sanfiorenzo","author_inst":"California Institute of Technology"},{"author_name":"Sixiang Wang","author_inst":"California Institute of Technology"},{"author_name":"Raymond J Zhang","author_inst":"California Institute of Technology"},{"author_name":"Weilin Zhang","author_inst":"California Institute of Technology"},{"author_name":"Tianhua Zhao","author_inst":"California Institute of Technology"},{"author_name":"Jie Zhou","author_inst":"California Institute of Technology"},{"author_name":"Kaihang Wang","author_inst":"California Institute of Technology"}],"rel_date":"2026-05-25","rel_site":"biorxiv"},{"rel_title":"TRENDS-Thai: decadal trends of dengue, chikungunya, and hand, foot, and mouth disease in Thailand (2016-2025): a multi-disease time-series analysis of COVID-19 disruption","rel_doi":"10.64898\/2026.05.21.26353796","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.21.26353796","rel_abs":"IntroductionDengue, chikungunya, and hand, foot, and mouth disease (HFMD) are priority notifiable infections in Thailand. Whether vector-borne and contact-mediated diseases responded differently to the coronavirus disease 2019 pandemic has not been quantified within a unified national surveillance framework over an extended period.\n\nMethodsWe conducted an ecological interrupted time-series analysis using weekly province-level notifiable disease surveillance data from epidemiological week 1 of 2016 to week 53 of 2025 across all 77 Thai provinces. Incidence per 100,000 population was calculated using year-specific civil registration population denominators. Segmented quasi-Poisson regression with two Fourier harmonics for annual seasonality was fitted, with the primary pandemic onset defined as week 1 of 2020 and two alternative onset definitions prespecified for sensitivity analysis.\n\nResultsThe analysis included 40,579 province-week observations across 527 epidemiological weeks, comprising 790,263 dengue, 32,265 chikungunya, and 713,822 HFMD cases nationally. Immediate incidence rate ratios at pandemic onset were 0.39, 0.54, and 0.51 for dengue, chikungunya, and HFMD, respectively. Sustained post-onset trends diverged across diseases, with declining trajectories for the two vector-borne infections and a positive post-onset slope for hand, foot, and mouth disease. Dengue rebounded above pre-pandemic levels by 2023, chikungunya remained quiescent through 2025, and HFMD exceeded its pre-pandemic baseline by approximately 26%.\n\nConclusionVector-borne and contact-mediated diseases in Thailand followed sharply contrasting decadal trajectories that tracked the transmission ecologies of each pathogen. These findings support transmission-mode-specific pandemic-resilient surveillance, accelerated arboviral and enteroviral vaccine deployment, and integrated vector management.","rel_num_authors":3,"rel_authors":[{"author_name":"Wannarat Pongpirul","author_inst":"Bamrasnaradura Infectious Diseases Institute, Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand"},{"author_name":"Mohamed Mustaf Ahmed","author_inst":"SIMAD University"},{"author_name":"Krit Pongpirul","author_inst":"Chulalongkorn University Faculty of Medicine"}],"rel_date":"2026-05-24","rel_site":"medrxiv"},{"rel_title":"Effect of Antiseptic Mouthwash\/Gargling Solutions on SARS-CoV-2 Viral Load: A Randomized Clinical Trial","rel_doi":"10.64898\/2026.05.20.26353686","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.20.26353686","rel_abs":"BackgroundThe COVID-19 pandemic has caused significant global mortality. Despite declining infection rates, new variants of SARS-CoV-2 continue to emerge, necessitating new prevention strategies.\n\nObjectiveThis study aimed to evaluate the effect of four over-the-counter (OTC) antiseptic mouthwash\/gargling solutions in the U.S., compared with a distilled water control, on SARS-CoV-2 viral load across multiple oral and oropharyngeal sample types.\n\nMethodsThis pilot single-center randomized controlled clinical trial enrolled adults in the San Francisco Bay Area, California, who tested positive for COVID-19. Participants were randomized to distilled water, chlorine dioxide, hydrogen peroxide, cetylpyridinium chloride, and essential oils. Participants were instructed to rinse and gargle four times daily for four weeks using standardized instructions to ensure protocol adherence. Samples were collected on Days 1, 7, and 28 and analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The primary outcome was the change in SARS-CoV-2 viral load from baseline to Day 28, assessed using cycle threshold (Ct) values. Secondary outcomes included self-reported clinical symptoms and hospitalization.\n\nResultsForty-nine participants completed the study. No mouthwash demonstrated a statistically significant reduction in SARS-CoV-2 viral load over time. Cetylpyridinium chloride showed a transient increase in Ct values on Day 7 that was not sustained on Day 28. At baseline, throat swab samples had the lowest Ct values across all sample types. Due to limited subgroup sample sizes for secondary outcome measures, no statistical or moderator analyses were conducted.\n\nConclusionFurther large-scale randomized trials are needed before recommending antiseptic mouthwashes for SARS-CoV-2 prevention or management.\n\nTrial RegistrationClinicalTrials.gov NCT04409873","rel_num_authors":6,"rel_authors":[{"author_name":"Sepideh Banava","author_inst":"University of California San Francisco"},{"author_name":"Allan Radaic","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Kamarajan Pachiyappan","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Nancy  F. Cheng","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Yvonne  L. Hernandez-Kapila","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Stuart  A. Gansky","author_inst":"UCSF: University of California San Francisco"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Caregiving Demands and Depression Symptoms among Caregivers of Individuals with Down Syndrome during the COVID-19 Pandemic","rel_doi":"10.64898\/2026.05.20.26353699","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.20.26353699","rel_abs":"BackgroundThis study examined the association between caregiving demands and depression symptoms among caregivers of individuals with Down syndrome during the COVID-19 pandemic.\n\nMethodWe conducted an online survey of 200 caregivers of children and adults with Down syndrome, including demographic data, the Patient Health Questionnaire-8 (PHQ-8), and questions about lack of childcare and taking over instruction during the pandemic. A multiple linear regression analysis identified predictors of caregiver depression symptoms.\n\nResultsHousehold income (B = -3.45, p < .001) and having to take over instruction (B = 2.24, p < .001) were significant predictors of PHQ-8 scores. Child age, caregiver gender, difficulty paying for health insurance, and lack of childcare were not significant predictors.\n\nConclusionsLower income and instructional caregiving demands were associated with higher depression symptoms among caregivers of individuals with Down syndrome, suggesting potential targets for policy and intervention during future public health emergencies.","rel_num_authors":12,"rel_authors":[{"author_name":"Jennifer Nguyen","author_inst":"Virginia Commonwealth University"},{"author_name":"Carla Wall","author_inst":"Virginia Commonwealth University"},{"author_name":"Ester Jo","author_inst":"Virginia Commonwealth University"},{"author_name":"Lindsay K. Allen","author_inst":"Palm Beach Atlantic University"},{"author_name":"Naomi Wheeler","author_inst":"Virginia Commonwealth University"},{"author_name":"Nicole Baumer","author_inst":"University of Colorado School of Medicine"},{"author_name":"Allison D'Aguilar","author_inst":"Virginia Commonwealth University"},{"author_name":"Timothy P. York","author_inst":"Virginia Commonwealth University"},{"author_name":"George Capone","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Colleen Jackson-Cook","author_inst":"Virginia Commonwealth University"},{"author_name":"Ananda B. Amstadter","author_inst":"Virginia Commonwealth University"},{"author_name":"Ruth C. Brown","author_inst":"Virginia Commonwealth University"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"A longitudinal cohort study comparing clinical trials registered on ClinicalTrials.gov that stopped during the first three years of the SARS-CoV-2 pandemic with trials that stopped in the three years prior","rel_doi":"10.64898\/2026.05.20.26353581","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.20.26353581","rel_abs":"BackgroundThe global SARS-CoV-2 pandemic disrupted healthcare systems worldwide, raising concerns about its impact on clinical research. Early reports suggested reductions in participant enrollment, interruptions to ongoing trials, and challenges to protocol adherence, yet the magnitude and duration of these operational disruptions remain unclear.\n\nMethodsWe conducted a registry-based analysis comparing clinical trials during the COVID-19 pandemic (December 2019 to November 2022) with a matched pre-pandemic cohort (December 2016 to November 2019). Studies were included if they reported any modifications to trial status, enrollment, or protocols during the study periods. Key variables included trial stoppage, enrollment changes, and adoption of remote or hybrid procedures.\n\nResultsThe global SARS-CoV-2 pandemic resulted in widespread disruptions to trial operations with 13,323 clinical trials terminated, suspended or withdrawn over the course of the pandemic, a 38% increase compared to the 9,665 trials that stopped in the 3 years prior to the pandemic. Registries indicated a sharp decline in new participant enrollment across geographic regions and therapeutic areas, with partial recovery in later months. Review findings highlighted barriers including patient inaccessibility, staff redeployment, and supply chain interruptions.\n\nConclusionsThe pandemic caused system-wide operational shocks that compromised trial timelines and may have downstream methodological consequences. Recovery in enrollment does not imply restoration of pre-pandemic protocol fidelity or outcome ascertainment. Standardized reporting of disruptions, proactive contingency planning, and resilient trial designs are needed to maintain data integrity during large-scale disruptions and to support reliable evidence generation.\n\nWhat is newO_LICOVID-19 caused widespread, measurable disruptions to ongoing clinical trials globally, including pauses in enrollment, randomization, and follow-up.\nC_LIO_LIRecovery of trial activity was uneven across regions and therapeutic areas, with some trials still experiencing delayed recruitment and operational challenges months into the pandemic.\nC_LIO_LIStandardized reporting of trial disruptions and flexible, resilient trial designs are needed to maintain reliable evidence generation during future large-scale health emergencies.\nC_LI\n\nPlain language summaryThe COVID-19 pandemic affected the way clinical trials were conducted around the world. Many studies had to stop enrolling new participants, delay treatments, or change how patients were monitored. These interruptions were caused by travel restrictions, social distancing, and limited access to hospitals and research staff. Some studies used phone calls or video visits to continue collecting information, but these changes may have affected the quality of the results. Even as enrollment recovered in some areas, many trials still faced delays and challenges. Understanding these disruptions can help researchers plan better for future emergencies, ensuring that clinical trials remain safe, reliable, and useful for developing new treatments.","rel_num_authors":3,"rel_authors":[{"author_name":"Benjamin Gregory Carlisle","author_inst":"McGill University"},{"author_name":"Nora Hutchinson","author_inst":"Division of Hopsital Medicine, Department of Medicine, University of California, San Francisco"},{"author_name":"Hannah Moyer","author_inst":"Temple University"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Ischemic stroke after bivalent mRNA COVID-19 vaccination and influenza vaccination during the 2022-2023 season: a multi-site self-controlled case series study","rel_doi":"10.64898\/2026.05.20.26353716","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.20.26353716","rel_abs":"BackgroundThe Vaccine Safety Datalink (VSD) detected a statistical signal for ischemic events (ischemic stroke or transient ischemic attack) following bivalent mRNA COVID-19 vaccination through prospective surveillance during 2022-2023. Although multiple studies from other surveillance systems and countries reported no increased risk, important methodological limitations remained. This U.S. study addressed those limitations by evaluating the ischemic stroke risk following bivalent mRNA COVID-19 vaccination, influenza vaccination, and their same-day coadministration using event-dependent self-controlled case series (SCCS) design.\n\nMethodsStudy outcomes included first-ever ischemic stroke (primary outcome), first-in-1-year ischemic stroke (secondary outcome), and ischemic events (exploratory outcomes), identified using ICD-10-CM codes in inpatient and emergency department settings during September 1, 2022-March 31, 2023, among individuals aged [&ge;]12 years across eight VSD sites. Analyses were conducted separately for Pfizer-BioNTech and Moderna bivalent vaccines, with relative incidences (RI) and 95% confidence intervals (CI) estimated for 1-21-day and 1-42-day risk intervals, using person-time outside these intervals as the control period. Subgroup analyses were performed by age group (12-64, >65 years) and history of documented SARS-CoV-2 infection.\n\nResultsA total of 6,510 first-ever ischemic strokes were identified among more than 6.8 million participants. Among recipients of Pfizer-BioNTech bivalent COVID-19 and influenza vaccines, no statistically significant increased risk of first-ever ischemic stroke was observed following bivalent COVID-19 vaccination (RI = 0.94; 95% CI: 0.63-1.41), influenza vaccination (RI = 0.95; 95% CI: 0.82-1.10), or same-day coadministration (RI = 1.15; 95% CI: 0.88-1.49) within 1- 21-day risk intervals; findings were similar for 1-42-day intervals. Comparable null results were observed for Moderna vaccines and across all subgroups, secondary, and exploratory outcomes.\n\nConclusionNo increased risk of ischemic stroke was found following bivalent mRNA COVID-19 vaccination, influenza vaccination, or their coadministration in this multi-site SCCS study. These findings are consistent with previous studies and underscore the importance of continued vaccine safety monitoring.\n\nHighlightsO_LIWe evaluated ischemic stroke risk after bivalent mRNA COVID-19 vaccination, influenza vaccination, and their coadministration.\nC_LIO_LINo increased risk of ischemic stroke was observed within 1-21 or 1-42 days following these vaccination exposures.\nC_LIO_LIFindings were consistent across vaccine type, age group, and prior SARS-CoV-2 infection status.\nC_LIO_LIThese results support the safety of bivalent mRNA COVID-19 vaccines with respect to ischemic stroke.\nC_LI","rel_num_authors":27,"rel_authors":[{"author_name":"Stanley Xu","author_inst":"Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA"},{"author_name":"Lina S Sy","author_inst":"Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA"},{"author_name":"Vennis Hong","author_inst":"Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA"},{"author_name":"Paddy Farrington","author_inst":"School of Mathematics and Statistics, The Open University, Milton Keynes, United Kingdom"},{"author_name":"Sungching C Glenn","author_inst":"Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA"},{"author_name":"Sunhea Kim","author_inst":"Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA"},{"author_name":"Denison S Ryan","author_inst":"Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA"},{"author_name":"Julia E Tubert","author_inst":"Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA"},{"author_name":"Paulina Tong","author_inst":"Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA"},{"author_name":"Bruno J Lewin","author_inst":"Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA"},{"author_name":"Hung Fu Tseng","author_inst":"Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA"},{"author_name":"Alexandra Carbayo","author_inst":"Department of Neurology, Los Angeles Medical Center, Kaiser Permanente Southern California, Los Angeles, CA"},{"author_name":"Cameron Davis","author_inst":"Department of Neurology, Los Angeles Medical Center, Kaiser Permanente Southern California, Los Angeles, CA"},{"author_name":"Navdeep S Sangha","author_inst":"Department of Neurology, Los Angeles Medical Center, Kaiser Permanente Southern California, Los Angeles, CA"},{"author_name":"Edward A Belongia","author_inst":"Marshfield Clinic Research Institute, Marshfield, WI"},{"author_name":"Maria E Sundaram","author_inst":"Marshfield Clinic Research Institute, Marshfield, WI"},{"author_name":"Jennifer C Nelson","author_inst":"Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA"},{"author_name":"Matthew F Daley","author_inst":"Institute for Health Research, Kaiser Permanente Colorado, Denver, CO"},{"author_name":"Nicola P Klein","author_inst":"Kaiser Permanente Vaccine Study Center, Kaiser Permanente Northern California, Oakland, CA"},{"author_name":"Bruce Fireman","author_inst":"Kaiser Permanente Vaccine Study Center, Kaiser Permanente Northern California, Oakland, CA"},{"author_name":"Jacob Haapala","author_inst":"HealthPartners Institute, Minneapolis, MN"},{"author_name":"Laura P Hurley","author_inst":"Division of General Internal Medicine, Denver Health, Denver, CO"},{"author_name":"Stephanie A Irving","author_inst":"Center for Health Research, Kaiser Permanente Northwest, Portland, OR"},{"author_name":"Noelle M Cocoros","author_inst":"Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, MA"},{"author_name":"Eric S Weintraub","author_inst":"Immunization Safety Office, Centers for Disease Control and Prevention, Atlanta, GA"},{"author_name":"Jonathan Duffy","author_inst":"Immunization Safety Office, Centers for Disease Control and Prevention, Atlanta, GA"},{"author_name":"Lei Qian","author_inst":"Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Fronto-limbic and Thalamocortical Network Alterations after COVID-19 Recovery: a Multimodal MRI Study","rel_doi":"10.64898\/2026.05.19.26353613","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.19.26353613","rel_abs":"Persistent neurological and cognitive symptoms following SARS-CoV-2 infection point to long-term alterations in brain structure and function. The thalamus, orbitofrontal cortex, and limbic networks are particularly susceptible to inflammatory and neurovascular stressors. However, the relationship between cortical, white-matter, and thalamocortical alterations in post-COVID syndrome remains unclear. 76 COVID-19 recovered participants (CRPs) and 51 healthy controls (HCs) underwent multimodal MRI comprising structural, diffusion, and resting-state functional acquisitions. Grey-matter morphology was assessed using voxel-based morphometry, white-matter microstructure using tract-based spatial-statistics (TBSS), and thalamocortical functional connectivity (TC-FC) using seed-based analyses from major thalamic nuclei. Results were evaluated both across the groups (HC vs. CRP) and after stratifying CRPs by hospitalisation status (HC vs. Non-hospitalized patients (NHPs) vs. Hospitalized patients (HPs)). No group-level grey-matter differences were observed between HCs and CRPs; however, HPs showed localized volume loss in the orbitofrontal and frontal-pole cortices (pFWE<0.05). TBSS revealed widespread microstructural abnormalities, including reduced fractional anisotropy and mean diffusivity across association and commissural tracts (pcorr<0.05), with regional increases in mode of anisotropy indicating selective loss of crossing fibres (pcorr<0.05). Resting-state analyses revealed increased TC-FC from the mediodorsal thalamic nucleus to anterior cingulate, parietal, and occipital cortices (pcorr<0.05), while differences in pulvinar and ventrolateral nuclei were not significant (pcorr>0.05). Our findings indicate that COVID-19 recovery is associated with enduring alterations in fronto-limbic and thalamo-cortical circuits, most prominently in individuals with severe infection. Convergent structural and functional changes involving the orbitofrontal cortex and mediodorsal thalamus suggest network-specific reorganisation that may underpin persistent cognitive and affective symptoms of post-COVID syndrome.","rel_num_authors":5,"rel_authors":[{"author_name":"Sapna S Mishra","author_inst":"Indian Institute of Technology Delhi"},{"author_name":"Rohit Misra","author_inst":"Indian Institute of Technology Delhi"},{"author_name":"Gwena\u00eblle Douaud","author_inst":"University of Oxford"},{"author_name":"Bharat Biswal","author_inst":"New Jersey Institute of Technology"},{"author_name":"Tapan Gandhi","author_inst":"Indian Institute of Technology Delhi"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"COVID-19 vaccination and the risk of cardiovascular and thromboembolic events after SARS-CoV-2 infection: a systematic review and meta-analysis","rel_doi":"10.64898\/2026.05.21.26353568","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.21.26353568","rel_abs":"Background and AimsSARS-CoV-2 infection is associated with an increased risk of cardiovascular, cerebrovascular and venous thromboembolism events. We aimed to assess the impact of COVID-19 vaccination prior to SARS-CoV-2 infection on the risk of these events post-infection.\n\nMethodsEmbase and MEDLINE were searched from January 2021 to 11 September 2025, supplemented by citation searching. Observational studies were included if they reported risks of cardiovascular, cerebrovascular, or venous thromboembolic events after SARS-CoV-2 infection between different vaccination groups (e.g. unvaccinated, vaccinated, or booster vaccinated), or reported risk of events after SARS-CoV-2 infection compared with no infection, stratified by vaccination status. Random-effects meta-analyses were conducted to estimate pooled hazard ratios (HRs) comparing vaccinated and unvaccinated individuals across prespecified outcomes.\n\nResultsTwenty-three studies were included in the systematic review; most reported an association between vaccination and a reduced risk of post-infection vascular events. Ten studies were included across meta-analyses comparing vaccinated and unvaccinated individuals. Pre-infection vaccination was associated with significantly reduced risks of composite cardiovascular\/cerebrovascular events (HR 0.60, 95% confidence intervals [CI] 0.51-0.69), stroke (HR 0.75, 95% CI 0.64-0.88), acute coronary syndrome (HR 0.70, 95% CI 0.52-0.95), arrhythmias (HR 0.82, 95% CI 0.69-0.98), and venous thromboembolism (HR 0.51, 95% CI 0.36-0.73). No statistically significant reduction was observed for heart failure (HR 0.72 [95% CI 0.47-1.10]).\n\nConclusionsPre-infection COVID-19 vaccination is associated with lower risks of cardiovascular, cerebrovascular and venous thromboembolism events following SARS-CoV-2 infection in the pre- and post-Omicron eras, supporting its role within broader prevention strategies.","rel_num_authors":8,"rel_authors":[{"author_name":"Stephane Heymans","author_inst":"Universiteit Maastricht CARIM School for Cardiovascular Diseases: Universiteit Maastricht Cardiovascular Research Institute Maastricht"},{"author_name":"Bettina Heidecker","author_inst":"Charite Universitatsmedizin Berlin Campus Charite Mitte: Charite Universitatsmedizin Berlin"},{"author_name":"Zoe Marjenberg","author_inst":"Maverex Ltd"},{"author_name":"Rhiannon Green","author_inst":"Maverex Ltd"},{"author_name":"Triantafyllos Pliakas","author_inst":"Impact Epilysis"},{"author_name":"Gregory Y H Lip","author_inst":"University of Liverpool"},{"author_name":"Thomas F L\u00fcscher","author_inst":"Royal Brompton Hospital"},{"author_name":"Sultan Abduljawad","author_inst":"BioNTech UK Ltd"}],"rel_date":"2026-05-22","rel_site":"medrxiv"},{"rel_title":"Mitigation of imprinted antibody responses in elderly COVID-19 highly vaccinated individuals","rel_doi":"10.64898\/2026.05.21.725708","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.21.725708","rel_abs":"SARS-CoV-2 continues to evolve from the Omicron serotype, with BA.2.86 sublineage JN.1 and descendants such as KP.2 predominating in 2025-26. By early 2026, the JN.1-derived NB.1.8.1 and XFG variants had largely replaced other variants globally, with a more recent emergence of the highly divergent BA.3.2 saltation variant. Elderly individuals continue to be at greatest risk of clinical complications from COVID-19, yet contemporary data on kinetics of immune potency and breadth following multiple vaccinations remain very limited in this group. We studied a cohort of forty-three healthy older adults (median age = 85 years, IQR 75-88, 40% female). Using both pseudotyped virus (PV) and surrogate virus neutralisation (SVNT) based assays, we demonstrate that JN.1 and KP.2 vaccinations six months apart elicit high potency neutralisation across all studied variants except BA.3.2.2, which escaped neutralisation almost completely in all individuals. Waning of neutralising activity in serum was observed to be modest in the [~]6 months between vaccine doses, suggesting sustained immunity following multiple vaccines. While absolute neutralisation titres remained highest against ancestral Wu-1 at all timepoints due to multiple historical exposures and accumulation, the recall responses revealed a shift in immunodominance. After the recent KP.2 vaccine dose, neutralisation against full-length Wu-1 spike was not boosted, whereas all tested JN.1 descendants and BA.3.2.2 showed significant boosts, indicating that immune imprinting against ancestral Wu-1 was partially overcome. Interestingly, RBD-specific neutralising responses experienced a boost following KP.2 vaccination, suggesting that RBD responses remain imprinted but that they constitute a small proportion in the overall Wu-1 neutralising response as immune imprinting is alleviated.","rel_num_authors":12,"rel_authors":[{"author_name":"Rebecca B. Morse","author_inst":"University of Cambridge"},{"author_name":"Daniel J.S. Egan","author_inst":"University of Cambridge"},{"author_name":"Mark Tsz Kin Cheng","author_inst":"University of Cambridge"},{"author_name":"Mazharul Altaf","author_inst":"University of Cambridge"},{"author_name":"Kimia Kamelian","author_inst":"University of Cambridge"},{"author_name":"Lourdes Ceron-Gutierrez","author_inst":"University of Cambridge"},{"author_name":"Olga Sokolova","author_inst":"University of Cambridge"},{"author_name":"John Bradley","author_inst":"University of Cambridge"},{"author_name":"Kenneth G. C. Smith","author_inst":"University of Cambridge"},{"author_name":"Rainer Doffinger","author_inst":"University of Cambridge"},{"author_name":"Chee Wah Tan","author_inst":"National University of Singapore"},{"author_name":"Ravindra K Gupta","author_inst":"University of Cambridge"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Force-regulated catch bonds and fusion peptide exposure drive coronavirus entry","rel_doi":"10.64898\/2026.05.21.727024","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.21.727024","rel_abs":"Coronaviruses invade human cells within dynamic mechanical environments through endocytosis and membrane fusion, both mediated by the class I fusion protein spike. In SARS-CoV and SARS-CoV-2, the spike engages the human ACE2 receptor through a catch bond--an interaction whose lifetime increases under tensile force. Concurrently, mechanical pulling facilitates disruption of the S1\/S2 subunits of spike, a critical step for membrane fusion. To elucidate how mechanical cues coordinate these processes, we developed a unified elastic-stochastic model that integrates theoretical analysis and computational simulations to trace viral entry. Our results identify the force-regulated catch bond between spike and ACE2 as a key determinant of successful invasion. This catch bond not only enhances receptor-mediated endocytosis but also increases the probability of S1\/S2 disengagement, thereby promoting membrane fusion. Importantly, under conditions of strong catch bonding, the force-accelerated separation of S1 and S2 fine-tunes the balance between entry pathways. These findings uncover a potential mechanobiological mechanism that mediates viral cell entry by coupling receptor binding strength with spike disassembly under force. By characterizing these mechanical regulations, this work facilitates the assessment of emerging viral threats and inspires the design of drug delivery systems that leverage catch-bond kinetics for enhanced targeting.","rel_num_authors":3,"rel_authors":[{"author_name":"Haiyue Li","author_inst":"Shanghai University"},{"author_name":"Zhenhai Li","author_inst":"Shanghai University"},{"author_name":"Huajian Gao","author_inst":"Tsinghua University"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Antioxidant properties of Rhodiola rosea","rel_doi":"10.64898\/2026.05.21.726678","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.21.726678","rel_abs":"Rhodiola rosea is a traditional medicinal plant often classified as an adaptogen, with reported effects in supporting the bodys response to physical, environmental, and emotional stressors. The present study investigated the antioxidant properties of Rhodiola rosea extract and its major chemical constituents to provide insight into their potential mechanisms of action. Through in vitro biochemical assays, we demonstrated that Rhodiola rosea extract has the capacity to reduce hydrogen peroxide (H2O2) levels. Among its primary chemical components, rosavin significantly decreased H2O2, whereas salidroside had no effect. Neither compound affected superoxide levels. Structural analysis revealed that the intact phenylpropanoid glycoside architecture of rosavin is required for activity, as its individual components, arabinose and rosin, showed no inhibitory effect. Further investigation demonstrated that rosavin attenuates H2O2-mediated oxidation of thiol groups, supporting a role in cellular redox regulation. In cultured human cells, rosavin mitigated reductions in cell viability induced by exposure to H2O2, indicating cytoprotective effects under oxidative stress conditions. Finally, in an in vivo model, administration of SARS-CoV-2 spike protein increased circulating levels of H2O2, which were subsequently reduced following rosavin treatment. Collectively, these findings identify rosavin as a structurally dependent antioxidant component of Rhodiola rosea that modulates H2O2-associated oxidative stress and supports further investigation of phenylpropanoid glycosides as adaptogens.","rel_num_authors":9,"rel_authors":[{"author_name":"Drew F. Brink","author_inst":"Georgetown University Medical Center"},{"author_name":"Tiara L. Sapp","author_inst":"Georgetown University Medical Center"},{"author_name":"Trwska S. Ghafoor","author_inst":"Georgetown University Medical Center"},{"author_name":"Paige A. Boyland","author_inst":"Georgetown University Medical Center"},{"author_name":"Yukako C. Tamazawa","author_inst":"Masaryk University"},{"author_name":"Guneet Kaur","author_inst":"Georgetown University Medical Center"},{"author_name":"Nataliia V. Shults","author_inst":"Georgetown University"},{"author_name":"Robert D. Sullivan","author_inst":"Capitol Anesthesia Associates"},{"author_name":"Yuichiro J. Suzuki","author_inst":"Georgetown University Medical Center"}],"rel_date":"2026-05-22","rel_site":"biorxiv"},{"rel_title":"Sexually Transmitted and Bloodborne Infections, Methamphetamine Use, and COVID-19 Vaccination in Manitoba, Canada: A Retrospective Matched Cohort Analysis Using Population-Based Administrative Healthcare Data (2020-2022)","rel_doi":"10.64898\/2026.05.18.26353507","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.18.26353507","rel_abs":"ObjectivesTo examine COVID-19 vaccine uptake among people diagnosed with sexually transmitted and bloodborne infections (STBBI) and reported methamphetamine users in Manitoba, Canada, during the acute phase of the COVID-19 pandemic.\n\nMethodsWe conducted a retrospective matched-cohort study using linked population-based administrative healthcare, laboratory, and vaccination databases in Manitoba. Individuals aged [&ge;]16 years with laboratory-confirmed chlamydia\/gonorrhea (CT\/NG), syphilis, HIV, and\/or documented methamphetamine use during the four years prior to March 1, 2020 were included in eight exposed cohorts. Each cohort was matched to unexposed comparators on age, sex, geographic region, and income quintile. The primary outcome was receipt of [&ge;]2 COVID-19 vaccine doses between December 1, 2020 and March 31, 2022. Poisson regression models estimated adjusted rate ratios (aRRs) and 95% confidence intervals (95% CIs) for vaccine uptake.\n\nResultsCompared with matched comparators, most exposed cohorts were less likely to complete the COVID-19 primary vaccine series. Individuals in the Syphilis Only (aRR: 0.87, 95% CI: 0.85-0.90), Syphilis Plus (aRR: 0.84, 95% CI: 0.81-0.86), CT\/NG Only (aRR: 0.95, 95% CI: 0.94-0.96), CT\/NG Plus (aRR: 0.82, 95% CI: 0.80-0.85), Methamphetamine Only (aRR: 0.78, 95% CI: 0.76-0.80), and Methamphetamine + STBBI cohorts (aRR: 0.74, 95% CI: 0.72-0.77) had significantly lower vaccine uptake. The HIV Only cohort did not differ significantly from matched comparators (aRR: 0.98, 95% CI: 0.95-1.01). Lower uptake was concentrated among individuals living in lower-income areas.\n\nConclusionsPeople diagnosed with STBBI and methamphetamine users in Manitoba experienced significant inequities in COVID-19 vaccine uptake, particularly those with STBBI co-infections and concurrent substance use. Integrated vaccination approaches linked with HIV, harm reduction, and addiction services may improve vaccine equity during future public health emergencies.\n\nWhat is already known on this topicPrevious studies have shown lower COVID-19 vaccine uptake among marginalized populations, including people who inject drugs, and some people living with HIV, but little research has examined vaccination coverage among people diagnosed with other sexually transmitted or bloodborne infections (STBBI) or those with co-infections and methamphetamine use.\n\nWhat this study addsUsing linked population-based administrative healthcare data from Manitoba, we found that people diagnosed with STBBI and methamphetamine users were generally less likely to complete the COVID-19 primary vaccine series than matched comparators from the general population. The lowest uptake was observed among methamphetamine users with concurrent STBBI, while people living with HIV without evidence of other STBBI had vaccine uptake comparable to matched controls.\n\nHow this study might affect research, practice or policyThese findings demonstrate how intersecting social and structural vulnerabilities contribute to inequities in vaccine uptake during public health emergencies. Integrated vaccination strategies linked with HIV, harm reduction, and addiction services may improve vaccine equity in future pandemics.","rel_num_authors":13,"rel_authors":[{"author_name":"Souradet  Y. Y Shaw","author_inst":"University of Manitoba"},{"author_name":"Alyson Mahar","author_inst":"Queen's University"},{"author_name":"Kim Bailey","author_inst":"Nine Circles Community Health Centre"},{"author_name":"Mike Payne","author_inst":"Nine Circles Community Health Centre"},{"author_name":"Jason Kindrachuk","author_inst":"University of Manitoba"},{"author_name":"Christine Kelly","author_inst":"University of Manitoba"},{"author_name":"Kevin John Friesen","author_inst":"Manitoba Centre for Health Policy"},{"author_name":"Charles N Bernstein","author_inst":"University of Manitoba"},{"author_name":"Joss Reimer","author_inst":"Public Health Agency of Canada"},{"author_name":"Marissa L Becker","author_inst":"University of Manitoba"},{"author_name":"Leigh M McClarty","author_inst":"University of Manitoba"},{"author_name":"Derek Stein","author_inst":"Cadham Provincial Laboratory"},{"author_name":"Nathan C Nickel","author_inst":"University of Manitoba"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"The control gap in long COVID research: a meta-epidemiological analysis","rel_doi":"10.64898\/2026.05.16.26353381","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.16.26353381","rel_abs":"Objectives To quantify the frequency of baseline control-group use in published long COVID prevalence studies and assess their key methodological features. Methods We performed a meta-epidemiological assessment of 440 post-acute COVID-19 prevalence publications from an existing systematic review. To evaluate study design and methodological transparency, we extracted data on the inclusion and classification of comparator groups, the exclusive use of self-reported outcome measures, and whether uncontrolled investigations explicitly recognized the omission of a control group as a limitation. In addition, we surveyed by email the corresponding authors of these articles to determine if any supplementary comparative data existed. The protocol was prospectively registered (DOI: 10.17605\/OSF.IO\/T2UP9). Results Among 440 studies, 372 (84.5%) reported no control group. Healthy or uninfected comparators were reported in 55 studies (12.5%) and other comparator types in 14 (3.2%); 1 study included both categories. Solely self-reported outcomes were used in 279 studies (63.4%). Among 372 uncontrolled studies, 244 (65.6%) did not explicitly acknowledge the absence of a baseline comparator as a limitation. Corresponding authors of 140 studies (31.8%) responded to the survey; 126 (90.0%) reported no additional comparative data, while 14 (10.0%) mentioned some available comparative datasets (19 additional datasets). Almost all that information (10\/14, 17\/19) had been already published in other articles not captured by the index systematic review. Studies with controls had modestly higher citation impact (median 7 versus 4 per year, p=0.002). Conclusions Most published long COVID prevalence studies lacked comparator groups and relied exclusively on self-reported outcomes without acknowledging this limitation. Direct author contact identified little additional comparator information. Much of the long COVID prevalence literature may therefore be poorly suited to estimating burden attributable specifically to SARS-CoV-2.","rel_num_authors":7,"rel_authors":[{"author_name":"Antonios-Periklis Panagiotopoulos","author_inst":"Medical School, National and Kapodistrian University of Athens"},{"author_name":"Alexandros Laskaris","author_inst":"Medical School, National and Kapodistrial University of Athens"},{"author_name":"Deny Tsakri","author_inst":"Medical School, National and Kapodistrian University of Athens"},{"author_name":"Yiannis Manoussopoulos","author_inst":"ELGO-Demeter, Laboratory of Virology, Patras"},{"author_name":"Cleo Anastassopoulou","author_inst":"Medical School, National and Kapodistrian University of Athens"},{"author_name":"Athanasios Tsakris","author_inst":"Medical School, National and Kapodistrian University of Athens"},{"author_name":"John Ioannidis","author_inst":"Stanford University"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Predicting Functional Changes in Down Syndrome During the COVID-19 Pandemic: The Role of Biopsychosocial Determinants of Health","rel_doi":"10.64898\/2026.05.19.26353577","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.19.26353577","rel_abs":"BackgroundBiopsychosocial factors associated with functional changes, including changes in personality, communication, movement, and weight, were evaluated in individuals with Down syndrome (DS) during the COVID-19 pandemic.\n\nMethodCaregivers of individuals with DS (aged [&ge;]12, n = 118) completed an online survey. Elastic net regression with bootstrap resampling assessed 31 candidate predictors.\n\nResultsPandemic-related mental health was most strongly associated with functional changes ({beta} = 0.388). Healthcare access barriers were also reliably selected: inability to access mental health treatment, difficulty affording insurance, difficulty accessing specialists, and residing in a low-income health professional shortage area. The model explained 35.2% of variance.\n\nConclusionsMental health and healthcare access barriers were biopsychosocial correlates of functional changes for people with DS during COVID-19.","rel_num_authors":11,"rel_authors":[{"author_name":"Ester Jo","author_inst":"Virginia Commonwealth University"},{"author_name":"Carla Wall","author_inst":"Virginia Commonwealth University"},{"author_name":"Lindsay K. Allen","author_inst":"Palm Beach Atlantic University"},{"author_name":"Naomi Wheeler","author_inst":"Virginia Commonwealth University"},{"author_name":"Nicole Baumer","author_inst":"University of Colorado School of Medicine"},{"author_name":"Allison D'Aguilar","author_inst":"Virginia Commonwealth University"},{"author_name":"Timothy P. York","author_inst":"Virginia Commonwealth University"},{"author_name":"George Capone","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Colleen Jackson-Cook","author_inst":"Virginia Commonwealth University"},{"author_name":"Ananda B. Amstadter","author_inst":"Virginia Commonwealth University"},{"author_name":"Ruth C. Brown","author_inst":"Virginia Commonwealth University"}],"rel_date":"2026-05-21","rel_site":"medrxiv"},{"rel_title":"Spike antibodies targeting GRP78 predispose to cardiovascular complications compared to Dengue","rel_doi":"10.64898\/2026.05.20.726568","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.20.726568","rel_abs":"One major aftermath of COVID-19 pandemic is cardiovascular consequences. SARS-CoV-2 binds to ACE2 and downregulates vasodilation. Dengue favors hypotension by weakening endothelial glycocalyx leading to plasma leakage. C1q levels, immune complexes (ICs), and proteomic profiles in serum samples from 52 COVID-19 and 19 pre-pandemic Dengue cases were studied. Unlike Dengue, COVID-19 serums showed elevated coagulation proteins promoting vaso-occlusion and peripheral artery diseases.\n\nThe stress-induced chaperone and atherosclerosis marker, GRP78 (gene\/ protein) was found upregulated upon SARS-CoV-2 spike expression in cardiac\/ lung cell lines. Elevated GRP78 levels were also observed in serum samples from COVID-19-diagnosed individuals and subjects with myocardial infarction (MI) in post COVID-era.\n\nSurprisingly, spike antibodies (Abs) showed cross-binding to GRP78 and possibly contributed to the observed higher-level ICs in COVID-19 serums (cardiovascular embolism?). Co-localization studies showed that spike Abs (analogous to pro-atherosclerotic GRP78 auto-Abs) could directly bind to upregulated cellular GRP78 (type II hypersensitivity?). Both pathways could worsen vascular injury and atherosclerosis, leading to cardiac complications in COVID-19 cases with narrowed vessels.","rel_num_authors":9,"rel_authors":[{"author_name":"Supratim Sarker","author_inst":"CSIR-Indian Institute of Chemical Biology, Kolkata"},{"author_name":"Trina Roy","author_inst":"CSIR-Indian Institute of Chemical Biology, Kolkata"},{"author_name":"Abinash Mallick","author_inst":"CSIR-Indian Institute of Chemical Biology, Kolkata"},{"author_name":"Sayantan Das","author_inst":"CSIR-Indian Institute of Chemical Biology, Kolkata"},{"author_name":"Sarakam Dharma Teja","author_inst":"Calcutta National Medical College and Hospital, Kolkata"},{"author_name":"Arun Bandyopadhyay","author_inst":"CSIR-Indian Institute of Chemical Biology, Kolkata"},{"author_name":"Surajit Gorai","author_inst":"Apollo Multispeciality Hospital, Kolkata"},{"author_name":"Abhishek De","author_inst":"Calcutta National Medical College and Hospital, Kolkata"},{"author_name":"Subhajit Biswas","author_inst":"CSIR-Indian Institute of Chemical Biology, Kolkata"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Ribophorin-1 Governs Spike Abundance of Highly Pathogenic Coronaviruses by ER-associated degradation","rel_doi":"10.64898\/2026.05.20.726704","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.20.726704","rel_abs":"The spike protein of highly pathogenic coronaviruses is indispensable for viral entry, pathogenesis, and immune evasion. However, specific host factors governing spike protein degradation and abundance on progeny virions remain largely uncharacterized. Here, we identify Ribophorin-1 (RPN1), a non-catalytic subunit of the oligosaccharyltransferase (OST) complex, as an ER-localized host restriction factor that selectively depletes spike to inhibit coronavirus infection. Conditional knockout of Rpn1 in mouse lung markedly exacerbates SARS-CoV-2 pathogenesis, increasing viral load, immune cell infiltration, and syncytium formation. In cells, RPN1 knockdown enhances susceptibility to diverse variants, whereas its overexpression attenuates infection. Nano-flow cytometry, cryo-EM and LSCM show that RPN1 reduces spike abundance on progeny virions, resulting in reduction in subsequent syncytium formation across SARS-CoV, SARS-CoV-2, and MERS-CoV. Mechanistically, RPN1 promotes VCP\/p97-dependent retrotranslocation and AMFR-mediated ubiquitination of spike protein. Heterologous expression of RPN1s functional domain (residues 180-307) confers significant protection against SARS-CoV-2 both in vitro and in vivo. Collectively, our findings define an RPN1-initiated ERAD pathway that selectively targets coronavirus spike for proteasomal destruction, and provide proof-of-concept evidence that targeting this RPN1-dependent pathway represents a promising broad-spectrum antiviral strategy.","rel_num_authors":14,"rel_authors":[{"author_name":"Yi-Jiao Huang","author_inst":"State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences"},{"author_name":"Lu Lv","author_inst":"State Key Laboratory of Pathogen and Biosecurity"},{"author_name":"Wei Ran","author_inst":"The First Affiliated Hospital of Guangzhou Medical University"},{"author_name":"Hui Zhao","author_inst":"Beijing Institute of Microbiology and Epidemiology"},{"author_name":"Yong-Qiang Deng","author_inst":"Beijing Institute of Microbiology and Epidemiology"},{"author_name":"Qing Ye","author_inst":"State Key Laboratory of Pathogen and Biosecurity"},{"author_name":"Lin Li","author_inst":"State Key Laboratory of Pathogen and Biosecurity"},{"author_name":"Xiao-Yan Wu","author_inst":"State Key Laboratory of Pathogen and Biosecurity,"},{"author_name":"Qi Chen","author_inst":"Institute of Microbiology and Epidemiology"},{"author_name":"Yi Hu","author_inst":"State Key Laboratory of Pathogen and Biosecurity"},{"author_name":"Bei Sun","author_inst":"State Key Laboratory of Pathogen and Biosecurity"},{"author_name":"Jian-Jun Zhao","author_inst":"State Key Laboratory of Pathogen and Biosecurity"},{"author_name":"Jincun Zhao","author_inst":"GIRH"},{"author_name":"Chengfeng Qin","author_inst":"Beijing Institute of Microbiology and Epidemiology"}],"rel_date":"2026-05-21","rel_site":"biorxiv"},{"rel_title":"Occupational hierarchy, racialization, and COVID-19 health outcomes among meat processing plant workers in Alberta: a community-engaged mixed-methods study","rel_doi":"10.64898\/2026.05.14.26353257","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.14.26353257","rel_abs":"BackgroundMeat processing plants in Alberta, Canada experienced among North Americas largest COVID-19 outbreaks. We examined health impacts among workers by occupational hierarchy and equity-relevant characteristics.\n\nMethodsThis exploratory sequential mixed-methods study was guided by community-based participatory research and the PROGRESS-Plus framework. Multilingual qualitative interviews and surveys using validated instruments were conducted among meat plant workers who experienced outbreaks. Interviews were analysed using inductive-deductive thematic analysis. Multivariable logistic regression and linear regression estimated associations between occupational group, racialization, facility, and self-reported COVID-19 diagnosis, physical and mental health, and mean Everyday Discrimination Scale score. We integrated findings using joint displays.\n\nFindingsQualitative and integrated analysis of thirty-six interviews described occupational hierarchy shaping unequal protection, limited communication, constrained agency, and psychosocial harms, amplified by income insecurity and family separation. Among 187 survey respondents, compared with general labour, skilled labour (aOR 0{middle dot}38; 95% CI 0{middle dot}15-0{middle dot}89) and management (aOR 0{middle dot}13; 95% CI 0{middle dot}01-0{middle dot}75) had lower odds of reported COVID-19 diagnosis. Compared with Black workers, other racialized workers had lower odds of reporting fair or poor mental (aOR 0{middle dot}24; 95% CI 0{middle dot}09-0{middle dot}58) and physical health (aOR 0{middle dot}20; 95% CI 0{middle dot}06-0{middle dot}54). Compared with workers from the primary facility, others reported lower mean everyday discrimination scores ({beta} = -0{middle dot}54; 95% CI -0{middle dot}96 to -0{middle dot}12).\n\nInterpretationCOVID-19 harms followed workplace social hierarchies. Pandemic preparedness should combine infection-control measures with paid sick leave and income protection, multilingual communication, enforceable anti-discrimination standards, and independent reporting mechanisms.\n\nFundingCanadian Institutes for Health Research (CIHR Application no. 469206).\n\nResearch in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed\/MEDLINE, Scopus, and Web of Science from June 2020 to December 2025, using terms for COVID-19, meat processing, meatpacking, occupation, and workers including migrants, racialized workers, refugees or immigrants for empirical studies published without language restrictions. Existing studies showed that meat processing plants were sites of occupational COVID-19 outbreaks and that immigrant and racialized workers experienced disproportionate infections and adverse health outcomes. The literature described pre-existing structural vulnerabilities in these settings including crowded working conditions, inadequate occupational protections, and barriers related to language, job security, and access to health information. These inequities intensified during the pandemic, leading to disproportionate infection rates, morbidity, mortality, and psychosocial stress.\n\nAdded value of this studyThis exploratory sequential mixed-methods study used the PROGRESS-Plus framework and a community-based participatory research approach to examine COVID-19-related health impacts after large outbreaks among meat processing plant workers in Alberta, Canada. By integrating multilingual qualitative interviews with quantitative survey data, the study identified how occupational hierarchy, racialization, and processing plant shaped self-reported COVID-19 diagnosis, physical and mental health, and experiences of discrimination. The study also centres workers perspectives to show how workplace hierarchy, unequal communication, and limited agency contributed to health inequities during the pandemic.\n\nImplications of all the available evidencePrevious and current findings suggest that COVID-19 harms in meat processing plants were shaped by pre-existing structural and workplace inequities rather than by exposure alone. Working conditions in large meat processing plants were already difficult for immigrant and racialized workers, particularly those in labour-intensive roles, and the COVID-19 pandemic exacerbated existing health inequities. Preparedness and response in high-risk industrial settings should therefore combine infection-control measures with multilingual communication, stronger worker protections, explicit anti-discrimination safeguards addressing ethnicity, language, and gender, and material supports that reduce the need to work while ill.","rel_num_authors":16,"rel_authors":[{"author_name":"Mohammad Yasir Essar","author_inst":"University of Calgary"},{"author_name":"Eric Norrie","author_inst":"University of Calgary"},{"author_name":"Edna Ramirez Cerino","author_inst":"University of Calgary"},{"author_name":"Minnella Antonio","author_inst":"University of Calgary"},{"author_name":"Ammar Saad","author_inst":"University of Ottawa"},{"author_name":"Mussie Yemane","author_inst":"University of Calgary"},{"author_name":"Linda Holdbrook","author_inst":"University of Calgary"},{"author_name":"Adanech Sahilie","author_inst":"University of Calgary"},{"author_name":"Michael Youssef","author_inst":"University of Calgary"},{"author_name":"Nour Hassan","author_inst":"University of Calgary"},{"author_name":"Olivia Magwood","author_inst":"Bruyere Health Research Institute"},{"author_name":"Samuel T. Edwards","author_inst":"Oregon Health & Science University"},{"author_name":"Denise Spitzer","author_inst":"University of Alberta"},{"author_name":"Annalee Coakley","author_inst":"University of Calgary"},{"author_name":"Kevin Pottie","author_inst":"Western University"},{"author_name":"Gabriel E. Fabreau","author_inst":"University of Calgary"}],"rel_date":"2026-05-20","rel_site":"medrxiv"},{"rel_title":"Exploring the genetic architecture of multimorbidity and its impact on long COVID risk","rel_doi":"10.64898\/2026.05.18.26353402","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.18.26353402","rel_abs":"Multimorbidity, the co-occurrence of multiple long-term conditions, represents a major challenge for ageing populations, yet its genetic architecture and relationship to long COVID remain unclear, despite shared epidemiological risk factors. We analysed multimorbidity patterns in 86,756 White British UK Biobank participants aged [&ge;]65 years, identifying six clusters spanning neurodegenerative, cardiac, gastrointestinal, musculoskeletal, vascular, and cancer & eye disease domains. Genome-wide association studies and post-GWAS analyses revealed significant loci in five clusters, including APOE, LPA, and CDKN2B-AS1, with patterns of genetic correlation consistent with known disease relationships. Notably, a shared variant within the APOE-APOC1 locus showed opposite effect directions for the musculoskeletal and vascular clusters, consistent with their negative genetic correlation. Investigating the multimorbidity-long COVID relationship via genetic correlation and Mendelian randomisation revealed no evidence of significant shared genetic architecture or causal effects. These findings indicate that multimorbidity clusters represent biologically structured, partly heritable phenotypes, whereas genetic overlap with long COVID appears limited.","rel_num_authors":8,"rel_authors":[{"author_name":"Sasha J. M. Bauer","author_inst":"King's College London"},{"author_name":"Ruth C. E. Bowyer","author_inst":"King's College London"},{"author_name":"Laura Bravo Merodio","author_inst":"University of Birmingham"},{"author_name":"Georgios Gkoutos","author_inst":"University of Birmingham"},{"author_name":"Davide Vetrano","author_inst":"Karolinska Institutet"},{"author_name":"Thomas Jackson","author_inst":"University of Birmingham"},{"author_name":"Claire J. Steves","author_inst":"King's College London"},{"author_name":"Maxim B. Freidin","author_inst":"King's College London"}],"rel_date":"2026-05-20","rel_site":"medrxiv"},{"rel_title":"The Potential Clinical and Economic Impact of a Combination COVID-19 and Influenza Vaccine (mRNA-1083) in Canada","rel_doi":"10.64898\/2026.05.18.26353482","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.18.26353482","rel_abs":"AimsCOVID-19 and influenza continue to impose a substantial burden on the Canadian healthcare system, particularly among adults aged [&ge;]65 years. This study compared the clinical and economic outcomes of a \"Stand-alone\" vaccination strategy with separate influenza and COVID-19 vaccines versus a \"Combination\" strategy incorporating mRNA-1083, an investigational vaccine targeting both infections.\n\nMethodsThe study adopted the public healthcare payer perspective and adapted a previously published static model to predict COVID-19 and influenza infections across a one-year time horizon. Relative vaccine effectiveness (rVE) for mRNA-1083 against COVID-19 compared with the stand-alone vaccine (SPIKEVAX (R)) was based on the pivotal clinical trial of mRNA-1083s COVID-19 component (mRNA-1283). For influenza, no incremental VE was assumed versus the adjuvanted stand-alone vaccine (FLUAD(R)). Infections were modeled independently. Clinical outcomes included symptomatic infections, hospitalizations, and deaths. The economically justifiable price (EJP) was calculated at the willingness-to-pay (WTP) threshold of $50,000 per quality-adjusted life-year (QALY) gained. mRNA-1083 uptake was assumed to yield absolute increases in COVID-19 and influenza coverage by 10% and 3%, respectively.\n\nResultsCompared with the Stand-alone strategy, the Combination strategy was projected to reduce the number of COVID-19-related symptomatic infections, hospitalizations, and deaths (n=71,074; 5,008; 935, respectively), and corresponding influenza outcomes (n=3,985; 362; 69, respectively). The use of mRNA-1083 within the Combination strategy generated a cost-savings of $90,440,471 in vaccine administration fees and an EJP of $304 per dose. Results were sensitive to rVE, coverage, administration fees, mortality and incidence.\n\nLimitationsmRNA-1083s rVE is being evaluated in clinical trials and the impact of mRNA-1083 on vaccine coverage and administration fees is uncertain.\n\nConclusionsmRNA-1083 may reduce the burden of COVID-19 and influenza in adults aged [&ge;]65 years in Canada, while offering good economic value because it has the potential to increase coverage and VE while reducing administration fees.","rel_num_authors":6,"rel_authors":[{"author_name":"Kelly Fust","author_inst":"Quadrant Health Economics, Inc."},{"author_name":"Michele Kohli","author_inst":"Quadrant Health Economics, Inc."},{"author_name":"Shannon Cartier","author_inst":"Quadrant Health Economics, Inc."},{"author_name":"Nicolas Van de Velde","author_inst":"Moderna Tx, Inc."},{"author_name":"Darshan Mehta","author_inst":"Moderna Tx, Inc."},{"author_name":"Michelle Blake","author_inst":"Moderna Biopharma Corporation"}],"rel_date":"2026-05-20","rel_site":"medrxiv"},{"rel_title":"Mechanochemical Decoupling of ATP Hydrolysis and RNA Translocation in SARS-CoV-2 nsp13 by the L405D Mutation","rel_doi":"10.64898\/2026.05.18.726016","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.18.726016","rel_abs":"SARS-CoV-2 nonstructural protein 13 (nsp13) is a highly conserved helicase that couples ATP hydrolysis to RNA translocation through long-range allosteric communication between its ATPase and RNA-binding domains. In prior work, we identified L405 as a key regulator of interdomain motions and proposed that the L405D mutation would disrupt this coupling by perturbing conformational translocations required for translocation [J. Phys. Chem. B 2024 v128 492-503]. Subsequent experiments confirmed that L405D attenuates helicase activity while largely preserving ATPase activity, implicating a breakdown in ATP-to-RNA coupling [J. Biol. Chem. 2026 v302 111198]. Here, we provide a data-driven explanation for this decoupling by combining Gaussian accelerated molecular dynamics (GaMD) simulations with Shape-GMM clustering and linear discriminant analysis. Whereas wild-type nsp13 exhibits both conformational selection and induction, L405D collapses the conformational landscape to operate predominantly through selection, eliminating ATP-induced structural transitions required for efficient catalytic cycling. This loss of induction traps the ATP-binding pocket in a mid-open conformation, impairing product release and reducing ATP turnover, while simultaneously disrupting coordinated motif-RNA interactions required for inchworm translocation. These findings establish that mutation-induced reshaping of conformational ensembles can modulate access to reaction-competent states, providing a general framework for understanding how targeted mutations disrupt catalytic function through allosteric ensemble remodeling in motor proteins.","rel_num_authors":0,"rel_authors":[],"rel_date":"2026-05-20","rel_site":"biorxiv"},{"rel_title":"Direct serological antibody discovery by integrative proteomics yields potent neutralizers overlooked by single-cell BCR sequencing","rel_doi":"10.64898\/2026.05.20.725438","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.20.725438","rel_abs":"Human antibody discovery relies on accessing in vivo-matured repertoires, yet conventional single-cell B cell receptor sequencing (scBCR-seq) often overlooks the most relevant, functional antibodies secreted by plasma cells. Here, we introduce AbDirect, a protein-centric discovery platform that obtains antibody sequences directly from small-volume biofluids. In this proof-of-concept, we apply AbDirect to potent COVID-19 plasma from which an early-pandemic scBCR-seq study did not identify neutralizers. Upfront reactivity screening of anti-SARS-CoV-2 spike protein repertoires revealed diverse clonal profiles with distinct cross-reactivity and subunit specificity. Targeted de novo sequencing via standalone integrative proteomics yielded 14 IgG1 and 4 IgA1 clones that diverged markedly from peripheral B cell counterparts in germline usage and phylogeny, indicating distinct immunological compartments. Validation via recombinant mAbs demonstrated superior binding and highly potent neutralization for multiple sequenced clones (three with IC50 [&le;]1.4 nM). AbDirect thus yielded potent antibodies overlooked by scBCR-seq, demonstrating serological discovery as a powerful complementary approach for uncovering functional repertoires that may be inaccessible to cell-based methods.","rel_num_authors":10,"rel_authors":[{"author_name":"Sem Tamara","author_inst":"Abvion Biologics B.V."},{"author_name":"Danique M.H. van Rijswijck","author_inst":"Utrecht University"},{"author_name":"Jacqueline van Rijswijk","author_inst":"Amsterdam UMC"},{"author_name":"Judith A. Burger","author_inst":"Amsterdam UMC"},{"author_name":"Douwe Schulte","author_inst":"Utrecht University"},{"author_name":"Marta Moreschini","author_inst":"Abvion Biologics B.V."},{"author_name":"Godelieve J. de Bree","author_inst":"Amsterdam UMC"},{"author_name":"Marit J. van Gils","author_inst":"Amsterdam UMC"},{"author_name":"Albert J.R. Heck","author_inst":"Utrecht University"},{"author_name":"Maurits A. den Boer","author_inst":"Abvion Biologics B.V."}],"rel_date":"2026-05-20","rel_site":"biorxiv"},{"rel_title":"Wastewater Surveillance as an Event Detection System: Outbreak and Peak Detection of SARS-CoV-2 Across 281 U.S. Counties","rel_doi":"10.64898\/2026.05.14.26353186","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.14.26353186","rel_abs":"Wastewater-based surveillance (WBS) is increasingly used to monitor infectious disease dynamics, yet most evaluations focus on correlation or forecasting--neither of which directly assesses whether wastewater signals can identify the epidemiological events most relevant to public health decision-making. We argue that outbreak onset and epidemic peak detection are the operationally critical use cases of WBS, requiring a fundamentally different evaluation framework. We introduce a classification-based framework that treats WBS as an event-detection problem, defining outbreaks and peaks as discrete events, establishing detection intervals to account for timing uncertainty, and incorporating censoring and data completeness criteria for valid comparisons against imperfect clinical reference outcomes. Within this framework, we apply a Bayesian exponential growth model for outbreak detection - benchmarked against a standard reproductive number (Rt)-based method - and a rule-based algorithm for peak detection, evaluating performance via sensitivity and positive predictive value (PPV). Applied to county-level SARS-CoV-2 wastewater data from 281 U.S. counties (Biobot, 2021-2024), the exponential growth approach substantially outperforms the Rt-based baseline: sensitivity 0.82 and PPV 0.64 versus sensitivity 0.58 and PPV 0.19 for the best-performing Rt variant. Peak detection achieves sensitivity 0.84 and PPV 0.70 at the county level. Both peak and outbreak detection achieve strong and consistent performance against hospitalizations and deaths at the state level. Spatial aggregation yields a statistically significant improvement in peak detection PPV against a curated reference standard (p < 0.001), while outbreak detection improvements under aggregation are directionally consistent but not statistically significant. Wastewater leads case-defined outbreaks by 4-6 days but minimally leads epidemic peaks, consistent with wastewater approximating prevalence rather than incidence. These findings demonstrate that wastewater signals can reliably detect outbreak onset and epidemic peaks across spatial scales and clinical outcomes, and that the choice of detection method matters substantially in practice. The classification framework developed here provides a reusable and principled tool for evaluating any surveillance signal as an event-detection system, with direct relevance to how WBS is actually used in public health decision-making.\n\nHighlightsO_LIWe evaluate wastewater surveillance as an event-detection system for outbreak onset and epidemic peak timing.\nC_LIO_LIWe introduce a classification-based framework that accounts for timing uncertainty, censoring, and data completeness.\nC_LIO_LIWastewater signals detect case-defined outbreaks and peaks with strong sensitivity and positive predictive value across spatial scales.\nC_LIO_LIPeak and outbreak detection show modest gains under aggregation, particularly for noisier outcomes such as deaths.\nC_LIO_LIThe proposed framework provides a reusable approach for evaluating surveillance signals against epidemiologically meaningful events.\nC_LI","rel_num_authors":4,"rel_authors":[{"author_name":"Nicholas B Link","author_inst":"Network Science Institute, Northeastern University"},{"author_name":"Raul Garrido","author_inst":"Network Science Institute, Northeastern University; Physics Department, Northeastern University"},{"author_name":"Anjalika Nande","author_inst":"Nuffield Department of Primary Care Health Sciences, University of Oxford; Institute for Computational Medicine, Johns Hopkins University"},{"author_name":"Mauricio Santillana","author_inst":"Network Science Institute, Northeastern University"}],"rel_date":"2026-05-19","rel_site":"medrxiv"},{"rel_title":"How the COVID-19 pandemic and cost-of-living crisis shaped reach and engagement in the ECAIL trial targeting socially disadvantaged families: an interdisciplinary implementation study","rel_doi":"10.64898\/2026.05.14.26353230","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.14.26353230","rel_abs":"BackgroundThe ECAIL trial, launched in 2017, targets hard-to-reach families and evaluates a multicomponent childhood obesity prevention intervention. At a maternity hospital in Lille, France, healthcare providers screened pregnant women experiencing social vulnerability, and dietitians delivered a home-based intervention until age 2. The COVID-19 pandemic led to a six-month suspension in 2020. This study compared eligibility and participation before the pandemic and after resumption, and examined how the pandemic and subsequent cost-of-living crisis shaped implementation and reach.\n\nMethodsWe analyzed 5,744 eligibility questionnaires distributed at the maternity ward. Inclusion criteria included [&ge;]1 indicator of social vulnerability (e.g., socioeconomic disadvantage, precarious housing, or social isolation). To capture implementation experiences, a psychosocial researcher conducted a focus group with six dietitians delivering the intervention; it was recorded, transcribed, and analyzed thematically focusing on reach, acceptability, and adaptation.\n\nResultsEligibility increased from 29.7% (n=955) prepandemic to 33.6% (n=849) after resumption, while the distribution of vulnerability criteria remained similar across periods: 78.3% received social\/medical benefits; employment was not the main source of household income for 58.7%; 24.4% experienced financial hardship; 14.7% reported social isolation; 6.0% lived in precarious housing; and 19.0% had three or more vulnerabilities. Participation among eligible women remained stable (24.6%; n=443). Qualitative findings indicated dietitians satisfaction and participants enthusiasm for the resumption of home visits, particularly in addressing social isolation. After resumption, the introduction of a pre-visit COVID-19 questionnaire reduced missed appointments. Converging qualitative and quantitative findings indicated sustained, and in some cases strengthened, provider engagement despite pandemic-related strain on hospital services.\n\nConclusionsThis study shows that a complex intervention can maintain reach and acceptability through adaptive implementation under major contextual disruptions. The rapid resumption of home-based services emerged as a robust strategy for engaging and retaining socially disadvantaged families, highlighting the importance of flexible, context-sensitive approaches during social and economic crises.\n\nTrial registrationClinicaltrials.gov NCT03003117; registration date: 21\/12\/2016; https:\/\/clinicaltrials.gov\/study\/NCT03003117","rel_num_authors":17,"rel_authors":[{"author_name":"Delphine Poquet","author_inst":"INSERM"},{"author_name":"Camille Le Gal","author_inst":"INSERM"},{"author_name":"Pascale Hincker","author_inst":"CHU Lille: Centre Hospitalier Universitaire de Lille"},{"author_name":"Laurent B\u00e9ghin","author_inst":"CHU Lille: Centre Hospitalier Universitaire de Lille"},{"author_name":"Dominique Deplanque","author_inst":"CHU Lille: Centre Hospitalier Universitaire de Lille"},{"author_name":"Damien Subtil","author_inst":"CHU Lille: Centre Hospitalier Universitaire de Lille"},{"author_name":"Oriane Sion","author_inst":"Programme Malin"},{"author_name":"Benjamin Cavalli","author_inst":"Programme Malin"},{"author_name":"Lucie VANHOUTTE","author_inst":"INSERM"},{"author_name":"Victoria Jacobsen","author_inst":"INSERM"},{"author_name":"Ketevan Marr","author_inst":"INSERM"},{"author_name":"Ioannis Sakellaris","author_inst":"INSERM"},{"author_name":"Blandine de Lauzon Guillain","author_inst":"INSERM"},{"author_name":"Marie-Aline Charles","author_inst":"INSERM"},{"author_name":"Delphine Ley","author_inst":"CHU Lille: Centre Hospitalier Universitaire de Lille"},{"author_name":"Priscille Sauvegrain","author_inst":"INSERM"},{"author_name":"Sandrine Lioret","author_inst":"INSERM"}],"rel_date":"2026-05-19","rel_site":"medrxiv"},{"rel_title":"The SARS-CoV-2 Integrated Genomic Epidemiology Database (IGED): Linking viral genomes with patient-level metadata to advance statewide genomic surveillance in California","rel_doi":"10.64898\/2026.05.14.26353263","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.14.26353263","rel_abs":"In July 2021, the California Code of Regulations Title 17 required all laboratories performing SARS-CoV-2 whole genome sequencing (WGS) to report their sequencing results to the California Department of Public Health (CDPH). These viral genomic data and patient metadata were compiled into the Integrated Genomic Epidemiology Database (IGED). Linking anonymized viral sequences with patient-level information enabled monitoring of infectiousness, pathogenicity, transmission dynamics, evolution, and vaccine evasion among emerging SARS-CoV-2 lineages. Laboratories performing SARS-CoV-2 WGS transmitted sequencing results to CDPH through Electronic Laboratory Reporting (ELR) and non-ELR pathways. CDPH applied uniform reporting requirements but allowed flexibility in specific data formats to accommodate diverse data systems. To preserve data quality and interoperability across heterogeneous sources, CDPH implemented standardization, validation, and deduplication protocols. Snowflake, a cloud-based data storage and analytics platform, and Posit Connect, a cloud deployment and automation platform, supported the management, processing, and integration of data within the IGED. The IGED established links between SARS-CoV-2 WGS data and epidemiologic metadata for 801,418 sequences, representing 81.7% of all sequences reported in California. Lineages reported to the IGED showed strong concordance with lineage proportions in GISAID. Sequences reported to the IGED had average turnaround times longer than one month, and the majority of sequencing was performed in Southern California and Los Angeles. The IGED enhanced genomic surveillance through predictive modeling and monitoring concerning evolutionary trends such as recombination and saltations in persistent infections. Development of the IGED highlighted the need for standardized data requirements, sustained funding for sequencing, incentives for data submission, and interdisciplinary collaboration to build an effective genomic surveillance system. This framework for linking genomic and epidemiologic data has not only generated critical insights for SARS-CoV-2 but also provided the foundation for CDPH and other public health organizations to develop similar IGED-like systems for other priority pathogens as genomic surveillance expands.\n\nAuthor SummaryIn California, the COVID-19 pandemic generated an unprecedented volume of anonymized viral genomic data, creating a critical need to link sequencing results with patient information for genomic epidemiology. To meet this need, we developed the Integrated Genomic Epidemiology Database (IGED), a comprehensive resource that connects SARS-CoV-2 whole-genome sequencing (WGS) data with corresponding patient records. Using cloud-based computational infrastructure, we standardized and integrated submissions from numerous laboratories and jurisdictions, each with distinct technical requirements for providing data to CDPH. Of nearly one million records received, we successfully linked 801,418 WGS records to patient data. The IGED supported public reporting of circulating SARS-CoV-2 lineages, improved understanding of viral evolutionary dynamics, and served as the foundation for a genomic epidemiology tool used in outbreak investigations. By establishing a robust framework for linking WGS and patient-level data, we provide a model that can be adapted by other public health agencies for emerging pathogens of concern.","rel_num_authors":28,"rel_authors":[{"author_name":"Rahil Ryder","author_inst":"California Department of Public Health"},{"author_name":"Jesse Elder","author_inst":"California Department of Public Health"},{"author_name":"Mayuri Panditrao","author_inst":"California Department of Public Health"},{"author_name":"Kaitlin Grosgebauer","author_inst":"California Department of Public Health"},{"author_name":"Rebecca Katz","author_inst":"California Department of Public Health"},{"author_name":"Lawrence Tello","author_inst":"California Department of Public Health"},{"author_name":"Ellaison Carroll","author_inst":"California Department of Public Health"},{"author_name":"Deva Borthwick","author_inst":"California Department of Public Health"},{"author_name":"Chaman Kaur","author_inst":"California Department of Public Health"},{"author_name":"Romario Smith","author_inst":"California Department of Public Health"},{"author_name":"Victor Shiau","author_inst":"California Department of Public Health"},{"author_name":"Will Wheeler","author_inst":"California Department of Public Health"},{"author_name":"Emilia Reilly","author_inst":"California Department of Public Health"},{"author_name":"Jennifer Myers","author_inst":"California Department of Public Health"},{"author_name":"Lauren Nelson","author_inst":"California Department of Public Health"},{"author_name":"Esther Lim","author_inst":"California Department of Public Health"},{"author_name":"Phacharee Arunleung","author_inst":"California Department of Public Health"},{"author_name":"Elizabeth Baylis","author_inst":"California Department of Public Health"},{"author_name":"Sabrina Gilliam","author_inst":"California Department of Public Health"},{"author_name":"Tamara Hennesy-Burt","author_inst":"California Department of Public Health"},{"author_name":"Brooke Bregman","author_inst":"California Department of Public Health"},{"author_name":"Elana Silver","author_inst":"California Department of Public Health"},{"author_name":"Curtis Kapsak","author_inst":"Theiagen Genomics"},{"author_name":"Sage Wright","author_inst":"Theiagen Genomics"},{"author_name":"Tomas Leon","author_inst":"California Department of Public Health"},{"author_name":"John Bell","author_inst":"California Department of Public Health"},{"author_name":"Christina Morales","author_inst":"California Department of Public Health"},{"author_name":"Debra  A. Wadford","author_inst":"California Department of Public Health"}],"rel_date":"2026-05-19","rel_site":"medrxiv"},{"rel_title":"SARS-CoV-2 Vaccination Status and MIS-C Incidence: A Systematic Review","rel_doi":"10.64898\/2026.05.15.26353349","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.15.26353349","rel_abs":"Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious condition associated with pediatric SARS-CoV-2 infection. While COVID-19 vaccines prevent infection and reduce severity, less conclusive evidence exists regarding their role in preventing MIS-C during breakthrough infections. This systematic review assessed the impact of SARS-CoV-2 vaccination on MIS-C risk during breakthrough infection. Cross-sectional studies, surveillance studies, and cohort studies were included. Of the 944 studies identified, 6 were included. A significant protective effect was seen in patients who received two doses of SARS-CoV-2 vaccination after exclusion of a biased sample (d= 0.71 [95% CI 0.07 to 1.35; p=0.03]). A trend towards a protective effect was seen after one dose of vaccination, but this effect was not statistically significant. Current literature supports a protective effect of two doses of SARS-CoV-2 vaccination against development of MIS-C in breakthrough COVID-19. The evidence supports clinician advocacy for continued vaccination of children against SARS-CoV-2.\n\nArticle Summary LineThis systematic review investigates the protective effect of SARSCoV-2 vaccination against development of MIS-C in breakthrough COVID-19 infections.","rel_num_authors":5,"rel_authors":[{"author_name":"Katherine Katherine Carroll","author_inst":"Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Hanwen Yang","author_inst":"Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Ariana Mastrogiannis","author_inst":"Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Kianna Rojas","author_inst":"Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Joseph  Steven Cervia","author_inst":"Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"}],"rel_date":"2026-05-19","rel_site":"medrxiv"},{"rel_title":"Variant emergence, not vaccine deployment, drives episodic positive selection on the SARS-CoV-2 spike at provincial scale in Canada","rel_doi":"10.64898\/2026.05.16.725625","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.16.725625","rel_abs":"Mass immunization against SARS-CoV-2 created a heterogeneous landscape of antibody-mediated immune pressure, yet whether this pressure measurably altered episodic positive selection on spike remains unresolved. Using Canadian genomic surveillance data spanning the five major variants of concern (Alpha, Beta, Gamma, Delta, and Omicron), we inferred time-resolved phylogenies from spike-coding sequences and applied site- and branch-level episodic selection models to identify when and where adaptive change occurred. To evaluate whether vaccination intensity was associated with selection, we integrated these phylogenetic analyses with provincial vaccination time series using cross-correlation and lagged panel regression models that accounted for province and time effects, lineage prevalence, and sampling heterogeneity. Episodic positive selection was concentrated at a limited number of spike codons, especially within the N-terminal domain, receptor-binding domain, and furin cleavage region. However, these signals were dominated by substitutions associated with variant emergence, particularly during the Alpha-to-Delta transition, rather than by vaccination rollout. Whole-gene tests provided no evidence that vaccine intensity was associated with elevated episodic selection, and residualized vaccination trajectories did not predict selection at biologically plausible lags. Across provinces, the timing and distribution of selection events were inconsistent with a vaccine-driven escape model. Together, these results indicate that, at provincial resolution in Canada, episodic positive selection on SARS-CoV-2 spike was driven primarily by variant turnover rather than vaccine deployment. More broadly, this study provides a quantitative, VOC-resolved assessment of spike evolution in a structured epidemic and suggests that population-level vaccination intensity was not a detectable determinant of spike adaptation in the period examined.","rel_num_authors":4,"rel_authors":[{"author_name":"Marissa Tomas","author_inst":"University of Ottawa"},{"author_name":"Cheikh Pape Khary Ndongo","author_inst":"University of Ottawa"},{"author_name":"Matthieu Vilain","author_inst":"University of Ottawa"},{"author_name":"Stephane Aris-Brosou","author_inst":"University of Ottawa"}],"rel_date":"2026-05-19","rel_site":"biorxiv"},{"rel_title":"Orally Bioavailable SARS-CoV-2 Protease Inhibitors Bearing a Hydroxymethyl Ketone Warhead","rel_doi":"10.64898\/2026.05.15.725542","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.15.725542","rel_abs":"The use of covalent warheads targeting the catalytic cysteine has been a cornerstone in coronavirus main protease (Mpro) inhibitor development, where various electrophilic motifs have been used including aldehydes, nitriles, ketoamides, and hydroxymethyl ketones (HMKs). Recent efforts have been mostly centered around nitrile warheads, given the success of compounds like Nirmatrelvir and Ensitrelvir in the clinic. However, finding and advancing alternative chemotypes with differentiating chemical and pharmacological profiles is essential for future pandemic preparedness. Among such alternatives, HMKs hold special interest because they balance reduced intrinsic electrophilicity with an excellent selectivity profile. Nevertheless, early HMK-based compounds, such as the clinical-stage Mpro inhibitor PF-00835231, suffered from poor oral bioavailability and therefore required intravenous administration, with or without prodrug derivatization of the hydroxyl group. Here, we describe our efforts in advancing the HMK field via the discovery of mCMX110, a lead that has superior potency, increased unbound exposure in vivo, and favorable oral bioavailability in preclinical studies.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC=\"FIGDIR\/small\/725542v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (22K):\norg.highwire.dtl.DTLVardef@d222b1org.highwire.dtl.DTLVardef@1e3a34corg.highwire.dtl.DTLVardef@1f5f566org.highwire.dtl.DTLVardef@c206cd_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":30,"rel_authors":[{"author_name":"N. G. R. Dayan Elshan","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Karen C. Wolff","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Frank Weiss","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Sourav Ghorai","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Gennadii Grabovyi","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Katy Wilson","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Laura Riva","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Ashley K. Woods","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"James Pedroarena","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Armen Nazarian","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Yuyin Liu","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Wrickban Mazumdar","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Lirui Song","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Neechi Okwor","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Jacqueline Malvin","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Malina A. Bakowski","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Melanie G. Kirkpatrick","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Amal Gebara-Lamb","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Edward Huang","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Van T. B. Nguyen-Tran","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Victor Chi","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Shuangwei Li","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Kyoung-Jin Lee","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Case W. McNamara","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Anil Kumar Gupta","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Alireza Rahimi","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Jian Jeffrey Chen","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Sean B. Joseph","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"author_name":"Peter G. Schultz","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Chemistr"},{"author_name":"Arnab K. Chatterjee","author_inst":"Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"rel_date":"2026-05-18","rel_site":"biorxiv"},{"rel_title":"Environmental stochasticity can account for patterns of within-host respiratory virus evolution","rel_doi":"10.64898\/2026.05.15.725410","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.15.725410","rel_abs":"The ecological and evolutionary dynamics of populations, including viral populations, are known to be jointly shaped by deterministic and stochastic processes. While the impact of stochastic processes has been rigorously explored for viral dynamics at the level of the host population, most dynamic models for acutely-infecting respiratory viral pathogens at the within-host scale remain deterministic in their formulation. While this may be reasonable for identifying key processes shaping their within-host viral population dynamics, recent studies indicate that stochastic processes need to be invoked for understanding patterns of within-host viral evolution. Specifically, several studies have shown that viral allele frequencies can change dramatically over the time course of days in acute infections. Here, we use stochastic dynamic models to explore the role of environmental noise in shaping observed patterns of virus evolution in acute respiratory virus infections. We summarize ways in which environmental stochasticity can be biologically realized in these acute viral infections and describe within-host models that can be implemented to jointly yield viral population dynamics and evolutionary dynamics. We further develop a statistical approach to estimate the extent of environmental noise from observed within-host allele frequency changes. We test this approach on simulated data and apply it to existing influenza A virus and SARS-CoV-2 within-host data. With these applications, we show that environmental stochasticity can parsimoniously reproduce key features of empirically observed allele frequency changes without needing to invoke demographic stochasticity or to adopt Wright-Fisher model formulations with a constant effective population size. Finally, we show that purifying selection and positive selection can both still contribute to within-host viral evolution in the context of a noisy environment, providing theoretical support for studies that have found purifying and positive selection in acutely-infecting respiratory virus populations.","rel_num_authors":4,"rel_authors":[{"author_name":"Wenfei Fiona Xiao","author_inst":"Emory University"},{"author_name":"Mireille Noor Farjo","author_inst":"Emory University"},{"author_name":"Anice C Lowen","author_inst":"Emory University School of Medicine"},{"author_name":"Katia Koelle","author_inst":"Emory University"}],"rel_date":"2026-05-18","rel_site":"biorxiv"},{"rel_title":"Who infected the reported cases? Evidence from 678,482 COVID-19 cases with identified infector collected in routine surveillance in the Netherlands, 2020-2022.","rel_doi":"10.64898\/2026.05.15.26347859","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.15.26347859","rel_abs":"BackgroundDuring infectious disease outbreaks, characteristics of reported cases are routinely collected. These give information on becoming infected but not on infecting others. We assess whether linking infectees to infectors, together with their characteristics, can help understand transmission.\n\nMethodsFrom the start of the COVID-19 pandemic in the Netherlands, reported cases were asked to identify their most probable infector in routine surveillance, enabling the linking of cases. We assess for the period 27 February 2020 - 11 April 2022 whether the infectees of these transmission pairs are representative of all reported cases, whether the transmission pairs yield verifiable estimates of epidemiological characteristics (here the serial interval), and whether they provide information on transmission that cannot be obtained otherwise.\n\nResultsOf 8,003,008 reported cases, 678,482 (8.5%) could be linked to their most probable infector. These infectees were largely representative of the reported cases regarding age group, sex, and geographical location. The mean serial interval of 3.6 days (sd 3.4 days) from transmission pairs aligns with literature. Transmissions between age groups largely follow known contact patterns. Most transmissions in September 2021 occurred between persons who were not (fully) vaccinated, indicating the effectiveness of the vaccine, and relatively few between persons with different vaccination status, indicating assortative mixing in vaccination status.\n\nConclusionTransmission pairs can be efficiently collected in routine surveillance, providing insight into disease transmission. The current post-pandemic period provides an excellent opportunity to adjust reporting systems for linking infectees to their most probable infector as preparation for future outbreaks.","rel_num_authors":7,"rel_authors":[{"author_name":"Jantien A. Backer","author_inst":"National Institute for Public Health and the Environment (RIVM)"},{"author_name":"Ka Yin Leung","author_inst":"National Institute for Public Health and the Environment (RIVM)"},{"author_name":"Stijn P. Andeweg","author_inst":"National Institute for Public Health and the Environment (RIVM)"},{"author_name":"Jan Van de Kassteele","author_inst":"National Institute for Public Health and the Environment (RIVM)"},{"author_name":"Irene Veldhuijzen","author_inst":"National Institute for Public Health and the Environment (RIVM)"},{"author_name":"Susan Hahne","author_inst":"National Institute for Public Health and the Environment (RIVM)"},{"author_name":"Jacco Wallinga","author_inst":"National Institute for Public Health and the Environment (RIVM)"}],"rel_date":"2026-05-17","rel_site":"medrxiv"},{"rel_title":"Expansion Revealing of Pathology Resolves Nanostructures Associated with Inflammatory Phenotypes in COVID-19 Decedent Human Brain Tissue","rel_doi":"10.64898\/2026.05.14.725177","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.14.725177","rel_abs":"Expansion revealing (ExR) elucidates cellular organization by separating proteins within dense nanostructures by 20x linear expansion, but requires fixation procedures incompatible with human pathology specimens. Here, we report ExR of pathology (ExRPath), which attains [~]20 nm resolution and decrowding of such tissues, through iterative 20x expansion, adapted to human brain pathology specimens. We also report a single-shot 15x expansion protocol for such tissues (15ExMPath), achieved through one-shot 15x expansion. Applying ExRPath and 15ExMPath to COVID-19-decedent brain tissue reveals periodic amyloid nanoclusters that co-localize with SARS-CoV-2 in a rare minority of patient specimens, pointing to a potential neuroinflammatory phenotype associated with COVID-19, and highlighting the power of high-throughput nanoimaging, empowered by expansion microscopy, for discovering potential novel disease mechanisms.","rel_num_authors":21,"rel_authors":[{"author_name":"Alice E Stanton","author_inst":"Harvard Medical School, and the Center for Genomic Medicine, Massachusetts General Hospital"},{"author_name":"Jinyoung Kang","author_inst":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology"},{"author_name":"Joel W Blanchard","author_inst":"Icahn School of Medicine at Mt. Sinai"},{"author_name":"Carles A Boix","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Margaret E Schroeder","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Youngmi Lee","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Hanquan Su","author_inst":"Harvard University"},{"author_name":"Shiwei Wang","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Eunah Yu","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Amauche Emenari","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Zhuyu Peng","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Emre Agbas","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Oyku Cerit","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Demian Park","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Ruihan Zhang","author_inst":"Massachusetts Institute of Technology"},{"author_name":"David A Bennett","author_inst":"Rush University Medical Center"},{"author_name":"Peng Yin","author_inst":"Harvard University"},{"author_name":"Manolis Kellis","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Robert Langer","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Edward Boyden","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Li-Huei Tsai","author_inst":"Massachusetts Institute of Technology"}],"rel_date":"2026-05-15","rel_site":"biorxiv"},{"rel_title":"A Structural Domain in the genomic RNA of SARS-CoV-2 Folds into a Compact Granular Structure without the N protein: A Single-Molecule Fluorescence Spectroscopic Investigation","rel_doi":"10.64898\/2026.05.15.725307","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.15.725307","rel_abs":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) packages its single-stranded genomic RNA (gRNA) having about 30,000 nucleotides into virions by forming 35-40 granular ribonucleoprotein (RNP) units. Each RNP unit has a diameter of [~]15 nm. While it is generally assumed that the assembly of these RNPs is driven by the binding of the nucleocapsid (N) protein to the gRNA in the cytoplasm, the precise molecular mechanism remains to be fully elucidated. In this study, we develop an experimental strategy based on single-molecule fluorescence and fluorescence correlation spectroscopies to examine the formation of long-range base pairing within a candidate structural domain corresponding to nt 12230-12686 of the gRNA (gRNA12k). Our results demonstrate that the 5 and 3 regions of gRNA12k autonomously form long-range base pairing in near-physiological buffers containing mono- and divalent cations, independently of the N protein. This domain possesses an extensive secondary structure, is compact, and can unfold and refold reversibly upon heat treatment and cooling. Notably, the addition of the N protein melts the long-range base pairs, and causes the aggregation of multiple molecules of gRNA12k. Based on these observations, we propose a refined mechanism for the genome assembly in SARS-CoV-2: gRNA initially forms autonomous granular structures, which are subsequently reorganized and condensed by the N protein to chaperone the assembly of the entire gRNA.\n\nSignificanceSARS-CoV-2 organizes its exceptionally long genomic RNA (gRNA) having about 30,000 nt into 35-40 granular ribonucleoprotein (RNP) units for viral packaging. It has been assumed that the nucleocapsid (N) protein drives the formation of the RNP granules. In this study, we challenge this prevailing view by demonstrating that a specific region of the gRNA sequence inherently encodes the information to fold into a compact, granular architecture independently of any proteins. Unexpectedly, we found that the N protein partially melts the autonomous structures, suggesting that it acts as an RNA chaperone to facilitate flexible genome assembly. Our findings redefine the interplay between viral proteins and gRNA, offering a new perspective on the mechanism of coronavirus replication.","rel_num_authors":11,"rel_authors":[{"author_name":"Takahiro Kimura","author_inst":"Institute of Multidisciplinary Research for Advanced Materials, Tohoku University"},{"author_name":"Takuya Katayama","author_inst":"Institute of Multidisciplinary Research for Advanced Materials, Tohoku University"},{"author_name":"Shion Ishikawa","author_inst":"Institute of Multidisciplinary Research for Advanced Materials, Tohoku University"},{"author_name":"Shrutarshi Mitra","author_inst":"Institute of Multidisciplinary Research for Advanced Materials, Tohoku University"},{"author_name":"Yuuhei Yamano","author_inst":"Institute of Multidisciplinary Research for Advanced Materials, Tohoku University"},{"author_name":"Kazumitsu Onizuka","author_inst":"Institute of Multidisciplinary Research for Advanced Materials, Tohoku University"},{"author_name":"Fumi Nagatsugi","author_inst":"Institute of Multidisciplinary Research for Advanced Materials, Tohoku University"},{"author_name":"Shilpi Laha","author_inst":"Department of Biotechnology, Bhupat & Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras"},{"author_name":"Athi N Naganathan","author_inst":"Department of Biotechnology, Bhupat & Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras"},{"author_name":"Yuji Itoh","author_inst":"Institute of Multidisciplinary Research for Advanced Materials, Tohoku University"},{"author_name":"Satoshi Takahashi","author_inst":"Institute of Multidisciplinary Research for Advanced Materials, Tohoku University"}],"rel_date":"2026-05-15","rel_site":"biorxiv"},{"rel_title":"Immunological imprinting shapes the cross-reactive antibody responses to the KP.2 and LP.8.1 vaccine doses","rel_doi":"10.64898\/2026.05.13.725047","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.13.725047","rel_abs":"The emergence of the SARS-CoV-2 Omicron BA.2.86 subvariant, a lineage derived from the BA.2 strain, led to the 2024-2025 COVID-19 vaccine update to include KP.2 or related JN.1-lineage spike antigens. We evaluated the magnitude, breadth, and durability of humoral immune responses following a single KP.2 vaccine dose in a longitudinal cohort of 21 individuals up to six months. KP.2 vaccination increased spike-specific binding and neutralizing antibodies against the ancestral WA1 strain, alongside the BA.5, XBB.1.5, and KP.2 variants. Power law modeling estimated half-lives for WA1- and KP.2-specific IgG responses at 770 and 248 days, respectively. Additionally, the KP.2 dose increased IgG1 and IgG4 subclasses more than IgG2 and IgG3 responses to both spike proteins. Serum depletion experiments using WA1 or KP.2 proteins demonstrated most vaccine-elicited antibodies were cross-reactive. Consequently, KP.2 vaccine-induced antibodies retained broad neutralizing activity against recently circulating Omicron subvariants (BA.2.86, KP.3.1.1, XEC, LP.8.1, LF.7, XFG.3.12, PQ.1, BA.3.2.1, and RE.2). Using a live virus neutralization assay, XFG.3.12 showed the greatest reduction in neutralizing titers relative to KP.2 (4.2-fold). In a small subset, an LP.8.1 vaccine dose increased neutralizing activity against the matched variant while maintaining WA1 and KP.2 cross-reactivity, but only modestly increased antibodies to divergent variants BA.3.2.1 and RE.2. Ultimately, these data indicate the KP.2 mRNA vaccine generates durable, cross-reactive responses against current Omicron subvariants. However, ongoing spike evolution impacts neutralization of emerging lineages, highlighting the need for continued viral monitoring and timely vaccine updates.\n\nIMPORTANCESARS-CoV-2 continues to evolve, raising ongoing concerns about how well updated vaccines protect against emerging variants. This study evaluates antibody responses after KP.2 spike mRNA vaccine dose and shows that a single dose induces durable and broadly cross-reactive immunity against both earlier strains and recently circulating Omicron subvariants. Despite this breadth, reduced neutralizing activity against certain emerging variants indicates that ongoing antigenic changes can impact vaccine induced antibody effectiveness. These findings provide insight into how current vaccines perform over time and highlight the need to track viral evolution and update vaccine antigens to maintain broad protection against severe disease, hospitalization, and death.","rel_num_authors":19,"rel_authors":[{"author_name":"Sanjeev Kumar","author_inst":"Emory University School of Medicine"},{"author_name":"Lilin Lai","author_inst":"Emory University Emory National Primate Research Center"},{"author_name":"Madison Ellis","author_inst":"Emory University"},{"author_name":"Anamika B Patel","author_inst":"Emory University School of Medicine"},{"author_name":"Devyani Jaideep Joshi","author_inst":"Emory University"},{"author_name":"Jacob Vander Velden","author_inst":"Emory University Emory National Primate Research Center"},{"author_name":"Jana Ziad Abu Faraj","author_inst":"Emory University School of Medicine"},{"author_name":"Sonia T. Wimalasena","author_inst":"Emory University School of Medicine"},{"author_name":"Ramitha R. Pallavi","author_inst":"Emory University School of Medicine"},{"author_name":"Jad Iriss","author_inst":"Emory University School of Medicine"},{"author_name":"Kareem Bechnak","author_inst":"Emory University School of Medicine"},{"author_name":"Srilatha Edupuganti","author_inst":"Emory University School of Medicine"},{"author_name":"Nadine Rouphael","author_inst":"Emory University School of Medicine"},{"author_name":"Eric Ortlund","author_inst":"Emory University"},{"author_name":"Alberto Moreno","author_inst":"Emory University Emory National Primate Research Center"},{"author_name":"Vineet D. Menachery","author_inst":"Emory University"},{"author_name":"Veronika I Zarnitsyna","author_inst":"Emory University School of Medicine"},{"author_name":"Jens Wrammert","author_inst":"Emory University"},{"author_name":"Mehul S Suthar","author_inst":"Emory University Department of Pediatrics"}],"rel_date":"2026-05-15","rel_site":"biorxiv"},{"rel_title":"Transcranial direct current stimulation-augmented cognitive training for post-COVID-19 cognition: A phase IIb randomized controlled trial","rel_doi":"10.64898\/2026.05.11.26352906","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.11.26352906","rel_abs":"BackgroundCognitive dysfunction is a prevalent and debilitating symptom of post-COVID-19 condition with limited evidence-based interventions. Here, we assessed the efficacy of cognitive training (CT) alone and combined with transcranial direct current stimulation (tDCS) for cognitive enhancement in post-COVID-19 patients.\n\nMethodsNeuromod-COV was a phase IIb, prospective, randomized, open-label, blinded-endpoint trial conducted at University Medicine Greifswald, Germany. The tDCS intervention was evaluated through a double-blind, sham-controlled design. Adults aged 18-60 with confirmed SARS-CoV-2 infection [&ge;] 6 weeks prior and post-infection cognitive complaints were eligible. Participants were randomly assigned (1:1:1) to CT with active tDCS (CT+AtDCS), CT with sham tDCS (CT+StDCS), or progressive muscle relaxation (PMR, non-cognitive control intervention) with sham tDCS. Intervention consisted of nine 20-minute sessions over three weeks of CT (letter updating task) or PMR with 2 mA tDCS (active\/sham) applied over the left dorsolateral prefrontal cortex. The primary outcome was untrained working memory (WM; measured by N-back task accuracy) comparing CT with PMR at post-intervention. Secondary outcomes included trained and untrained WM, visuospatial memory, and self-report measures at post-intervention and 1-month follow-up comparing CT vs. PMR and CT+AtDCS vs. CT+StDCS. The trial was registered at ClinicalTrials.gov (NCT04944147).\n\nResultsBetween October 1, 2021, and August 7, 2024, 60 participants were randomized (76.7% female) to CT+AtDCS (n = 20), CT+StDCS (n = 20), or PMR (n = 20). CT did not improve untrained WM at post-intervention compared with PMR (primary outcome: {beta} = 1.59, 95% CI - 1.30 to 4.48, p = 0.278; 1-back: {beta} = 2.52, 95% CI -1.27 to 6.31, p = 0.191; 2-back: {beta} = 0.66, 95% CI -3.12 to 4.44, p = 0.732). However, CT+AtDCS enhanced untrained WM at post-intervention and follow-up, and visuospatial memory at post-intervention compared with CT+StDCS (secondary outcomes). No intervention improved self-report outcomes. No serious adverse events occurred and incidence rate ratios were similar between groups.\n\nConclusionCT alone did not improve untrained WM performance. However, CT with tDCS enhanced untrained WM and visuospatial memory, suggesting potential benefits of combined neuromodulation approaches for cognitive enhancement in post-COVID-19 patients.","rel_num_authors":9,"rel_authors":[{"author_name":"Catalina Trujillo Llano","author_inst":"University Medicine Greifswald"},{"author_name":"Anna Elisabeth Fromm","author_inst":"University Medicine Greifswald"},{"author_name":"Lydia Lingemann","author_inst":"University Medicine Greifswald"},{"author_name":"Ulrike Grittner","author_inst":"Charite University Medicine"},{"author_name":"Marcus F Meinzer","author_inst":"University Medicine Greifswald"},{"author_name":"Robert Fleischmann","author_inst":"University Medicine Greifswald"},{"author_name":"Eva-Lotta Brakemeier","author_inst":"University of Greifswald"},{"author_name":"Daria F Antonenko","author_inst":"University Medicine Greifswald"},{"author_name":"Agnes Floeel","author_inst":"University Medicine Greifswald"}],"rel_date":"2026-05-14","rel_site":"medrxiv"},{"rel_title":"Pathogen-specific host responses define distinct pneumonia endotypes in the human lung","rel_doi":"10.64898\/2026.05.12.724509","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.12.724509","rel_abs":"Pneumonia is the leading cause of death from infectious disease worldwide. The diagnosis and treatment of patients with pneumonia lag behind other major conditions, relying on syndromic definitions that lack molecular resolution and ignore underlying endotypes. We sought to test the hypothesis that dynamic pathogen-specific host responses in the alveolar space represent distinct pneumonia endotypes linked to different clinical features and outcomes. We prospectively enrolled a cohort of 690 patients (including immunocompromised patients) with known or suspected pneumonia receiving mechanical ventilation in whom the etiology of pneumonia was determined by gold-standard analysis of distal lung fluid obtained by bronchoalveolar lavage (BAL) combined with clinical adjudication. From these patients, we analyzed 792 BAL fluid samples, including 310 serial samples, using flow cytometry (482 patients) and single-cell RNA-sequencing (170 patients; 263 samples, complemented by 9 healthy controls and 25 post-COVID-19 patients, yielding [~]2.4 million single cells across 28 cell types), and extracted daily clinical data from the electronic health record (>15,000 patient-days). We used machine learning models to identify pathogen-specific host responses in the transcriptome of alveolar immune cells that were associated with changes in alveolar cell abundance and clinical features. Our results suggest that therapeutic strategies for pneumonia should be individualized to specific host-pathogen interactions.","rel_num_authors":35,"rel_authors":[{"author_name":"Nikolay S Markov","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Marcin Mo\u017cejko","author_inst":"Faculty of Mathematics, Informatics and Mechanics, University of Warsaw, Warsaw, Poland"},{"author_name":"Vijeeth Guggilla","author_inst":"Division of Biostatistics and Informatics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Ma\u0142gorzata \u0141az\u0119cka","author_inst":"Faculty of Mathematics, Informatics and Mechanics, University of Warsaw, Warsaw, Poland"},{"author_name":"Helen K Donnelly","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Alvaro Donayre","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Samuel Fenske","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Alec Peltekian","author_inst":"Department of Computer Science, Northwestern University McCormick School of Engineering and Applied Science, Chicago, IL, USA"},{"author_name":"Bruno Puczko-Szyma\u0144ski","author_inst":"Faculty of Mathematics, Informatics and Mechanics, University of Warsaw, Warsaw, Poland"},{"author_name":"Paulina Szymczak","author_inst":"Institute of AI for Health, Helmholtz Zentrum Munchen, Munich, Germany"},{"author_name":"Adam Izdebski","author_inst":"Institute of AI for Health, Helmholtz Zentrum Munchen, Munich, Germany"},{"author_name":"Lucy Luo","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Karolina J Senkow","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Luisa Cusick","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Zhan Yu","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Suchitra Swaminathan","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Ziyan Lu","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Hiam Abdala-Valencia","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Duc Phan","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Rebecca K Clepp","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Luke V Rasmussen","author_inst":"Division of Biostatistics and Informatics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Anna Pawlowski","author_inst":"Northwestern Medicine Enterprise Data Warehouse, Chicago, IL, USA"},{"author_name":"Chiagozie O Pickens","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Nandita R Nadig","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Theresa Walunas","author_inst":"Division of General Internal Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Robert Tighe","author_inst":"Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University School of Medicine, Duke University, Durham, NC, USA"},{"author_name":"- The Neu-Lung Investigators","author_inst":""},{"author_name":"Richard G Wunderink","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"GR Scott Budinger","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Luisa Morales-Nebreda","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Catherine A Gao","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Benjamin D Singer","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Alexander V Misharin","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"author_name":"Ewa Szczurek","author_inst":"Institute of AI for Health, Helmholtz Zentrum Munchen, Munich, Germany; Faculty of Mathematics, Informatics and Mechanics, University of Warsaw, Warsaw, Poland"},{"author_name":"- The NU SCRIPT Study Investigators","author_inst":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"rel_date":"2026-05-14","rel_site":"biorxiv"},{"rel_title":"Independent Validation of Test-Adjusted COVID-19 Incidence Estimates Using Wastewater Surveillance Data in Ontario, Canada","rel_doi":"10.64898\/2026.05.08.26352754","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.08.26352754","rel_abs":"BackgroundCase-based infectious disease surveillance is subject to ascertainment bias when testing intensity varies across time and population subgroups. We previously developed a regression-based test adjustment methodology using Standardized Testing Ratios (STRs) to correct for differential testing patterns in COVID-19 surveillance data. Wastewater-based surveillance (WWS) measures viral burden in the community independently of diagnostic testing behavior, making it a valuable external validation tool for test-adjusted case estimates.\n\nMethodsWe analyzed 111 weeks of paired wastewater and case surveillance data from Ontario, Canada (July 19, 2020 to August 28, 2022). Wastewater SARS-CoV-2 signals from 107 sewersheds across 34 public health units were normalized within sewersheds and aggregated using population-weighted averages. We compared wastewater correlations with crude reported and test-adjusted case counts using Spearman rank correlations, linear regression, and negative binomial distributed lag nonlinear models (DLNM), stratified by epidemic period.\n\nResultsTest-adjusted cases correlated substantially more strongly with wastewater signals than crude reported cases overall (Spearman {rho} = 0.849 vs. 0.679; linear R{superscript 2} = 0.609 vs. 0.191). The advantage of test adjustment was greatest during the Omicron wave, when population-level diagnostic testing contracted sharply following PCR eligibility restrictions ({rho} = 0.924 vs. 0.604; R{superscript 2} = 0.815 vs. 0.470). DLNM incorporating the wastewater signal explained substantially more variance in test-adjusted than crude reported cases (McFadden pseudo-R{superscript 2} 0.898 vs. 0.776), despite similar lag-response structure for both outcomes.\n\nConclusionsWastewater surveillance provides compelling independent validation of a previously described test adjustment methodology for COVID-19 case surveillance. The agreement between wastewater signals and test-adjusted cases was strongest precisely when testing scarcity was most severe, supporting the use of test adjustment to recover accurate infection dynamics from case surveillance data during periods of changing testing access and policy.","rel_num_authors":4,"rel_authors":[{"author_name":"David Fisman","author_inst":"University of Toronto"},{"author_name":"Natalie Wilson","author_inst":"University of Toronto"},{"author_name":"Clara Eunyoung Lee","author_inst":"University of Toronto"},{"author_name":"Ashleigh Tuite","author_inst":"Public Health Agency of Canada"}],"rel_date":"2026-05-12","rel_site":"medrxiv"},{"rel_title":"Monocyte Oxidative Stress Underlies Persistent Immune Activation in Long-COVID Postural Orthostatic Tachycardia Syndrome","rel_doi":"10.64898\/2026.05.08.26352776","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.08.26352776","rel_abs":"Long COVID Postural Orthostatic Tachycardia Syndrome (LCPOTS) is characterized by persistent orthostatic tachycardia and systemic symptoms following SARS-CoV-2 infection. Many features of LCPOTS suggest ongoing immune activation, but the mechanisms driving this response remain unclear. In this study, we show that patients with LCPOTS, compared with individuals who recovered from SARS-CoV-2 without POTS, exhibit increased monocyte mitochondrial content and superoxide production, along with downregulation of NRF2-dependent antioxidant enzymes. This is accompanied by a marked increase in the formation of isolevuglandins (IsoLGs) in monocytes, which modify self-proteins and act as neoantigens capable of activating T cells. Consistent with this, LCPOTS patients exhibit a 3-fold increase in circulating T cell-monocyte doublets with immunological synapse formation. T cells in these complexes display a proinflammatory effector-memory and TEMRA phenotype, producing IFN-{gamma} and IL-17A, which correlated with symptom severity. Circulating cytokines, including IL-17A, IFN-{gamma}, and TNF-, are elevated in patients with LCPOTS by 1.5 to 3-fold. This immune response likely drives systemic inflammation and impaired cardiovagal regulation, hallmarks of LCPOTS. Our findings suggest that monocyte oxidative stress and IsoLG neoantigen formation sustain T cell activation, linking immune dysregulation to cardiovagal dysfunction. Targeting these pathways may offer novel therapeutic opportunities.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC=\"FIGDIR\/small\/26352776v2_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (69K):\norg.highwire.dtl.DTLVardef@1d24038org.highwire.dtl.DTLVardef@762cdaorg.highwire.dtl.DTLVardef@7aaee9org.highwire.dtl.DTLVardef@716932_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":0,"rel_authors":[],"rel_date":"2026-05-12","rel_site":"medrxiv"},{"rel_title":"Recovery of proofreading-impaired SARS-CoV-2 reveals a mutator phenotype and an ExoN activity threshold for viability","rel_doi":"10.64898\/2026.05.12.724615","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.12.724615","rel_abs":"Coronaviruses (CoVs) replicate unusually large RNA genomes that necessitate proofreading by the 3'-to-5' exoribonuclease (ExoN) formed by nonstructural proteins 14 (nsp14) and 10 (nsp10). Previous studies suggested that inactivation of the ExoN catalytic site in severe acute respiratory syndrome CoV 2 (SARS-CoV-2) is lethal, leaving unresolved whether the virus can tolerate impaired proofreading activity. Here, we investigated the functional requirement for ExoN in SARS-CoV-2 replication by combining a continuous fluorescence-based biochemical assay with an optimized single-bacmid reverse genetics system. Mutational analysis of residues involved in RNA binding or catalysis revealed graded effects on ExoN activity in vitro. Alanine substitution of Lys9, a residue positioned near the RNA-binding interface, did not reduce ExoN activity, whereas charge reversal at this position (K9E) impaired activity more strongly than alanine substitutions of the catalytic motif I residues D90 and E92 (D90A\/E92A). Correspondingly, recombinant SARS-CoV-2 carrying K9A was readily recovered, whereas the D90A\/E92A mutant was recovered only after an extended delay and K9E could not be rescued despite repeated attempts. The D90A\/E92A mutant exhibited reduced replication while maintaining the engineered ExoN substitutions during serial passage. Deep sequencing of viral populations revealed a marked increase in genome-wide sequence variation in the D90A\/E92A mutant, demonstrating a stable mutator phenotype. Together, these findings indicate that SARS-CoV-2 can tolerate substantial impairment of ExoN activity but depends on a minimal activity threshold for viability. This system provides a platform for defining how SARS-CoV-2 proofreading controls genome stability, viral fitness, and sensitivity to antiviral strategies that exploit reduced replication fidelity.\n\nImportanceCoronaviruses have unusually large RNA genomes because they encode a proofreading enzyme that removes copying errors during replication. It has been unclear whether SARS-CoV-2 can survive when this proofreading function is strongly weakened, because earlier studies suggested that loss of the enzymes catalytic activity is lethal. We show that SARS-CoV-2 can tolerate substantial impairment of proofreading, but only when residual exonuclease activity remains above a minimal threshold. A virus with impaired proofreading replicates less efficiently and accumulates mutations across its genome, whereas a more severe defect prevents virus recovery. These findings clarify how coronavirus proofreading balances genome stability with viral fitness and provide a useful system for studying how reduced replication fidelity affects viral evolution, antiviral sensitivity, and attenuation. Defining this activity threshold may also help guide antiviral strategies that target coronavirus proofreading.","rel_num_authors":10,"rel_authors":[{"author_name":"Li He","author_inst":"The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine"},{"author_name":"Yuan-Wei Norman Su","author_inst":"The University of North Carolina at Chapel Hill School of Medicine"},{"author_name":"Fushun Zhang","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Ibrahim Moustafa Abdelrady","author_inst":"Pennsylvania State University"},{"author_name":"David W Gohara","author_inst":"Research Computing Consultants, LLC"},{"author_name":"Chengjin Ye","author_inst":"Texas Biomedical Research Institute"},{"author_name":"Luis Martinez-Sobrido","author_inst":"Texas Biomedical Research Institute"},{"author_name":"Jamie J Arnold","author_inst":"The University of North Carolina at Chapel Hill School of Medicine"},{"author_name":"Craig E. Cameron","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Yan Xiang","author_inst":"The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine"}],"rel_date":"2026-05-12","rel_site":"biorxiv"},{"rel_title":"AI-discovered protein fragments as generalizable regulators of biomolecular condensates","rel_doi":"10.64898\/2026.05.08.723928","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.08.723928","rel_abs":"Biomolecular condensates are a major driver of cellular organization; however, we lack a predictable and systematic approach to modulate the multivalent interactions underlying their formation. Here, we demonstrate that the AI-driven FragFold method enables robust and generalizable design of protein fragments to control biomolecular condensate formation. We apply this approach across diverse proteins: G3BP1, SARS-CoV-2 nucleocapsid, TDP-43, and focal adhesion kinase (FAK). Computationally screening 2,235 fragments, we selected 18 candidates for further investigation. Overall, we attain a 50% success rate (9\/18 designs) in discovering condensate-controlling protein fragments, experimentally testing just 3-5 candidates per protein. For each condensate-forming protein, the success rate is at least 40%. Furthermore, FragFold-predicted fragment binding modes align with their condensate-inhibitory or -enhancing activities, revealing both known and newly identified interactions underlying condensate formation. In FAK, a condensate-inhibitory fragment uncovered a domain interaction required for phase separation, and mutational analysis validated its importance. Notably, this inhibitory fragment also suppresses FAK condensate formation in living mammalian cells. Together, these results establish AI-guided protein fragment discovery as a generalizable strategy to dissect and control the molecular interactions that govern biomolecular condensates.","rel_num_authors":6,"rel_authors":[{"author_name":"Andrew Savinov","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Jibin Sadasivan","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Kyle J. White","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Jack D. Rubien","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Gene-Wei Li","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Lindsay B. Case","author_inst":"Massachusetts Institute of Technology"}],"rel_date":"2026-05-12","rel_site":"biorxiv"},{"rel_title":"Crude Fucus vesiculosus fucoidan demonstrates superior SARS-CoV-2 antiviral activity compared to its pure form: binding kinetics and functional studies","rel_doi":"10.64898\/2026.05.07.723385","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.07.723385","rel_abs":"Fucoidans have been widely reported to show SARS-CoV-2 antiviral activity. In this study, we observed a striking difference in the inhibitory potency between two commercially available fucoidans: Fucus vesiculosus crude (Fvc) and pure (Fvp). SEC-MALS analysis revealed two molecular weight populations for Fvc (1098 kDa, 58.58 kDa) and one for Fvp (40.48 kDa). At micromolar concentrations of fucoidans, the binding affinities (KDs) of Fvc_1098 (223 nM) and Fvc_58 (4.27 {micro}M) for the amine-biotinylated SARS-CoV-2 receptor binding domain (RBD) were higher than that of Fvp (76.5 {micro}M). At nanomolar concentrations, binding was observed only to the Avi-tag-, but not amine-biotinylated RBDs, suggesting better accessibility of their binding sites. The association rates (kon) were faster for Fvc than for Fvp. Similarly, affinities of Fvc_1098 (23.4 nM) and Fvc_58 (4.48 M) for ACE2 were greater than that of Fvp (66.8 M), indicating that Fvc can bind directly to both RBD and ACE2. Fvc demonstrated enhanced inhibitory potency (IC50 = 58 g\/mL) compared to Fvp (IC50 > 239 g\/mL) in the pseudovirus entry assay and did not induce cytotoxicity in HEK293T cells. In conclusion, crude fucoidan with high fucose content and high molecular weight shows promising antiviral activity.","rel_num_authors":4,"rel_authors":[{"author_name":"Anna Dudek","author_inst":"Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan"},{"author_name":"Rajendra Prasad Janapatla","author_inst":"Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan"},{"author_name":"Chyi Liang Chen","author_inst":"Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan"},{"author_name":"Cheng Hsun Chiu","author_inst":"Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan"}],"rel_date":"2026-05-12","rel_site":"biorxiv"},{"rel_title":"Temperature-Dependent Replication and Sensitivity to Innate Immunity of Human Coronavirus HKU1","rel_doi":"10.64898\/2026.05.07.723210","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.07.723210","rel_abs":"The human coronavirus HKU1, causing common colds and occasionally severe illness, remains largely uncharacterized because it has not been successfully grown on immortalized cells. Here, we identified Caco2 cells overexpressing TMPRSS2, the HKU1 receptor, as being highly permissive to infection. HKU1 replicated efficiently, formed syncytia and released infectious progeny in these cells at 33{degrees}C, the temperature of the nasal cavity, but was attenuated at 37{degrees}C. Viral entry occurred similarly at both temperatures, but subsequent viral RNA synthesis was enhanced at 33{degrees}C. Released virions displayed higher stability at 33{degrees}C. In Caco2 and primary epithelial nasal cells, HKU1 was sensitive to interferons (IFN), but induction of IFN stimulated genes, such as IFN-Induced Transmembrane Proteins (IFITMs), was delayed at 33{degrees}C. Once expressed, IFITMs comparably inhibited HKU1 fusion at both temperatures. In contrast, SARS-CoV-2 robustly replicated at 37{degrees}C. Thus, cellular permissiveness, innate immunity and viral properties collectively explain why HKU1 replicates more efficiently at nasal temperature. Our results highlight temperature-sensitivity disparities between coronaviruses, likely associated to different pathogenic outcomes.","rel_num_authors":29,"rel_authors":[{"author_name":"Julian Buchrieser","author_inst":"Virus and Immunity Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Eva Thuillier","author_inst":"Virus and Immunity Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Jeanne Postal","author_inst":"Virus and Immunity Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Amelie Wileveau","author_inst":"Virus and Immunity Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Florence Guivel-Benhassine","author_inst":"Virus and Immunity Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Isabelle Staropoli","author_inst":"Virus and Immunity Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Nell Saunders","author_inst":"Virus and Immunity Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Delphine Planas","author_inst":"Virus and Immunity Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Jamie Sugrue","author_inst":"Translational Immunology Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Vincent Bondet","author_inst":"Translational Immunology Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Ignacio Fernandez","author_inst":"Structural Virology Unit, Institut Pasteur, Universite de Paris Cite, CNRS UMR 3569, Paris, France."},{"author_name":"Francois Bontems","author_inst":"Structural Virology Unit, Institut Pasteur, Universite de Paris Cite, CNRS UMR 3569, Paris, France."},{"author_name":"Francoise Porrot","author_inst":"Virus and Immunity Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Chloe Petiot","author_inst":"Virus and Immunity Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Matthieu Prot","author_inst":"Evolutionary Genomics of RNA Viruses Unit, Institut Pasteur, Universite Paris Cite, CNRS UMR2000, Paris, France."},{"author_name":"Martin Jungbauer-Groznica","author_inst":"Virus and Immunity Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Laurence Arowas","author_inst":"Investigation and Volontaires (INVOLvE)"},{"author_name":"Vincent Michel","author_inst":"Pathogenesis of Vascular Infections Unit, Institut Pasteur, INSERM, Paris, France"},{"author_name":"Catherine Blanc","author_inst":"Virology Department, Institut Pasteur, paris, France"},{"author_name":"Sophie Trouillet-Assant","author_inst":"Joint Research Unit Hospices Civils de Lyon-bioMerieux, Hospices Civils de Lyon, Lyon Sud Hospital, Oullins-Pierre-Benite, France."},{"author_name":"Timothee Bruel","author_inst":"Virus and Immunity Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Felix A. Rey","author_inst":"Structural Virology Unit, Institut Pasteur, Universite de Paris Cite, CNRS UMR 3569, Paris, France."},{"author_name":"Marie-Anne Rameix-Welti","author_inst":"11\tMolecular Mechanisms of Multiplication of Pneumoviruses Unit (M3P), Institut Pasteur, Universite Paris-Saclay, Universite de Versailles St. Quentin"},{"author_name":"Nicoletta Casartelli","author_inst":"Virus and Immunity Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Arnaud Fontanet","author_inst":"Emerging Diseases Epidemiology Unit, Institut Pasteur, paris, France"},{"author_name":"Michael White","author_inst":"Emerging Diseases Epidemiology Unit, Institut Pasteur"},{"author_name":"Darragh Duffy","author_inst":"Translational Immunology Unit, Institut Pasteur, Universite Paris Cite, Paris, France."},{"author_name":"Etienne Simon-Loriere","author_inst":"Evolutionary Genomics of RNA Viruses Unit, Institut Pasteur, Universite Paris Cite, CNRS UMR2000, Paris, France."},{"author_name":"Olivier Schwartz","author_inst":"Virus and Immunity Unit, Institut Pasteur, Universite Paris Cite, Paris, France."}],"rel_date":"2026-05-12","rel_site":"biorxiv"},{"rel_title":"SARS CoV 2 Associated Shifts in the Upper Respiratory Tract Mycobiome in Non Hospitalized Cases","rel_doi":"10.64898\/2026.05.07.26352639","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.07.26352639","rel_abs":"SARS{square}CoV{square}2 infection is associated with marked changes of the upper respiratory tract mycobiome. URT mycobiome Changes in non-hospitalized patients however, remains poorly defined. We performed shotgun metagenomic sequencing of 95 upper respiratory tract swab samples from 48 symptomatic SARS{square}CoV{square}2-positive individuals and 47 healthy controls from central India. Fungal diversity and community structure were compared using alpha- and beta-diversity analyses, while differential taxa were identified using prevalence-based testing and LEfSe. SARS{square}CoV{square}2-positive samples showed significantly higher fungal alpha diversity than controls, with increased Shannon diversity (p = 0.000319) and Simpson diversity (p = 0.017). Beta-diversity analysis showed significant separation between groups for both Bray-Curtis and Jaccard distances (PERMANOVA p = 0.001), with significant dispersion effects as well (PERMDISP p = 0.001). Differential analysis identified more SARS{square}CoV{square}2-enriched than control-enriched taxa, including Candida orthopsilosis, Malassezia furfur, M. sympodialis, M. globosa, Aspergillus niger, A. terreus, and A. nidulans. Aspergillus sydowii was the main control-enriched taxon. LEfSe and concordant multi-test analysis supported these findings, and sensitivity analysis confirmed robustness across thresholds. Certain SARS{square}CoV{square}2-enriched taxa were linked to confirmed or probable COVID{square}19-associated fungal infections, whereas no such pathogens were detected in controls. These findings indicate that SARS{square}CoV{square}2 infection is associated with URT mycobiome dysbiosis and enrichment of clinically relevant opportunistic fungi in community cases.","rel_num_authors":2,"rel_authors":[{"author_name":"Siddharth Singh Tomar","author_inst":"CSIR-NEERI"},{"author_name":"Krishna Khairnar","author_inst":"CSIR-NEERI"}],"rel_date":"2026-05-10","rel_site":"medrxiv"},{"rel_title":"Delayed humoral kinetics but stabilization of IgG responses in common variable immunodeficiency after SARS-CoV-2 mRNA booster vaccination","rel_doi":"10.64898\/2026.05.07.26352649","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.07.26352649","rel_abs":"PurposePatients with common variable immunodeficiency (CVID) frequently exhibit impaired antibody responses to vaccination, yet the dynamics of humoral and cellular immunity following mRNA immunisation remain incompletely defined. This study aimed to characterise the temporal evolution of anti-SARS-CoV-2 antibody and T cell responses across successive vaccine doses in a well-characterised CVID cohort, and to identify key determinants of vaccine responsiveness in this population.\n\nMethodsWe performed a longitudinal and cross-sectional analysis of serum and peripheral blood mononuclear cell (PBMC) samples collected from 88 CVID patients after two, three, or four doses of mRNA vaccine (Moderna\/mRNA-1273 or Pfizer-BioNTech\/BNT162b2). Anti-receptor-binding domain (RBD) IgG titers were quantified in relation to vaccine dose, time since last vaccination, and clinical characteristics. Vaccine-specific CD4+ and CD8+ T cell responses were assessed ex vivo using an activation-induced marker (AIM) assay by flow cytometry.\n\nResultsThe proportion of patients with detectable anti-RBD IgG increased from 35% after two doses to more than 80% after four doses. Boosting-dependent increases in IgG titers were observed exclusively in samples collected more than three months after the last dose, and antibody levels correlated positively with time since vaccination, consistent with delayed but progressive humoral kinetics that stabilised after the third dose. In contrast, spike-specific CD4+ and CD8+ T cell responses were rapidly induced and remained stable across all timepoints.\n\nConclusionVaccine-induced immunity in CVID is characterised by delayed humoral responses alongside preserved cellular immunity. Early post-vaccination serology may systematically underestimate vaccine responsiveness, and booster vaccination supports stabilisation of antibody responses in this population.","rel_num_authors":18,"rel_authors":[{"author_name":"Lorenzo Federico","author_inst":"University of Oslo"},{"author_name":"Ragnhild Oeye Loeken","author_inst":"Oslo University Hospital"},{"author_name":"Khang Le Quy","author_inst":"University of Oslo"},{"author_name":"Julie Roekke Osen","author_inst":"University of Oslo"},{"author_name":"Viktoriia Chaban","author_inst":"University of Oslo"},{"author_name":"Ingvild Nordoey","author_inst":"Oslo University Hospital"},{"author_name":"Tonje Skarpengland","author_inst":"Oslo University Hospital"},{"author_name":"Knut Erik Lundin","author_inst":"Oslo University Hospital"},{"author_name":"Silje Fjellgaard Joergensen","author_inst":"Oslo University Hospital"},{"author_name":"Mai Sasaki Aanensen Fraz","author_inst":"Oslo University Hospital"},{"author_name":"Paal Aukrust","author_inst":"Oslo University Hospital"},{"author_name":"Katrine Persgaard Lund","author_inst":"Oslo University Hospital"},{"author_name":"Trung The Tran","author_inst":"University of Oslo"},{"author_name":"Liv Toril Nygaard Osnes","author_inst":"University of Oslo"},{"author_name":"Fridtjof Lund-Johansen","author_inst":"University of Oslo"},{"author_name":"Hassen Kared","author_inst":"University of Oslo"},{"author_name":"Boerre Fevang","author_inst":"Oslo University Hospital"},{"author_name":"Ludvig Andre Munthe","author_inst":"University of Oslo"}],"rel_date":"2026-05-08","rel_site":"medrxiv"},{"rel_title":"Positive Registration Rate as a Key Determinant of COCOA Effectiveness: Empirical Evidence from Individual-Level Key-Match Data during the Sixth and Seventh COVID-19 Waves in Japan","rel_doi":"10.64898\/2026.05.06.26352506","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.06.26352506","rel_abs":"BackgroundCOCOA, Japans Bluetooth-based COVID-19 contact tracing app, was widely regarded as ineffective due to persistently low key-match counts. However, this assessment may have conflated two distinct phenomena: (1) a structurally suppressed positive registration rate caused by administrative friction in the HER-SYS linkage, and (2) genuine epidemiological inefficacy.\n\nObjectiveTo empirically examine whether the correlation between individual COCOA key-match counts and regional COVID-19 case numbers depended on positive registration rate, using a unique longitudinal dataset from a single observer with a rigorously controlled behavioral pattern.\n\nMethodsThe corresponding author (S.N.) recorded daily key-match counts from his personal iPhone from January 10 to October 8, 2022, encompassing the Sixth Wave (January 10-April 20, 2022) and Seventh Wave (July 9-September 2, 2022). Daily reported COVID-19 cases in Tokyo were obtained from publicly available NHK data. Pearson correlation coefficients were calculated for each wave period separately.\n\nResultsDuring the Sixth Wave, no meaningful correlation was observed between key-match counts and daily case numbers (r2 = 0.018, p = 0.059, n = 194). In contrast, during the Seventh Wave, a strong positive correlation emerged (r2 = 0.530, p < 0.001, n = 56). This correlation disappeared abruptly after September 12, 2022, coinciding with Japans revision of the mandatory full case reporting (Zenshu Todokedashi) policy, which substantially reduced positive registrations in COCOA.\n\nConclusionsCOCOAs utility as an individual infection risk indicator was critically dependent on positive registration rate rather than app installation rate. These findings provide the first real-world empirical evidence supporting the threshold effect predicted by prior simulation studies, and offer important lessons for the design of digital tools in future pandemic preparedness.","rel_num_authors":3,"rel_authors":[{"author_name":"Shinichi Nakagawa","author_inst":"Research Institute of Info-Commiunication Medicine"},{"author_name":"Seiji Kumagai","author_inst":"Research Institute of Info-Communication Medicine"},{"author_name":"Akira Yamamoto","author_inst":"Faculty of Human Data Science, Juntendo University"}],"rel_date":"2026-05-08","rel_site":"medrxiv"},{"rel_title":"Safety first: should the high tolerability of intramuscular anti-spike COVID-19 monoclonal antibody change our expectations of vaccine safety?","rel_doi":"10.64898\/2026.05.08.26352596","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.08.26352596","rel_abs":"IntroductionPublic and regulatory scrutiny of immunization safety has intensified in recent years. The COVID-19 pandemic has been instrumental in this. The accelerated timeline of COVID-19 vaccine development combined with the amplification of resultant side effects have proven corrosive to confidence. Unsurprisingly, COVID-19 vaccine uptake has declined year-on-year. This conflicts with the threat that infection still presents: predictors and prognoses of post-acute complications remain uncertain. Restoring public trust in these technologies will require meaningful progress in the availability and accessibility of clinical safety and pharmacovigilance data.\n\nMethodsExpanding upon recent comparisons of COVID-19 vaccine reactogenicity, we present a post-hoc safety analysis of adintrevimab, an intramuscular (IM) anti-SARS-CoV-2 spike recombinant investigational monoclonal antibody (mAb) for the pre-exposure and post-exposure prophylaxis of COVID-19, as assessed by the multi-center, double-blind, Phase 2\/3 randomized placebo-controlled EVADE study (NCT04859517). Exploratory endpoints included the incidence of [&ge;]1 systemic symptoms within 7 days of study drug administration as well as symptom number, duration and severity. Safety reporting encompassed solicited and unsolicited treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), vital signs, and clinical laboratory assessments.\n\nResultsEVADE study participants (n=2582) were randomized between April 2021 - January 2022. Baseline characteristics were balanced across treatment groups. Within the 7 day post-dose period, 25\/1241 (2.0%) of adintrevimab recipients and 12\/1242 (1.0%) of placebo recipients reported at least one systematic TEAE. Multiple systemic TEAEs were less prevalent, with 0.3% and 0.1% reporting two systemic TEAEs, and 0.1% and 0.1% reporting three TEAEs in adintrevimab and placebo groups, respectively. The majority of TEAEs reported were mild to moderate in severity, primarily involving headache (0.4% adintrevimab, 0.8% placebo), fatigue (adintrevimab 0.4%, placebo 0.2%), and nausea\/vomiting (adintrevimab 0.4%, placebo 0.1%). For those participants who experienced any TEAEs in the 7 day post-dose period, mean (+\/-standard deviation) number of systemic symptoms was 1.2 (0.5) for adintrevimab and 1.3 (0.6) for placebo with symptoms consistently resolving within 3 days.\n\nConclusionsIncreased expectations for pharmaceutical safety data generation are to be welcomed, offering patients the information they need to appropriately weigh the benefits and risks of any novel therapeutic. These analysis results support the high tolerability of IM-administered adintrevimab, with reactogenicity data broadly comparable to placebo. While the co-administration of vaccines and monoclonal antibodies limit direct comparisons between historical safety reports, findings such as these demonstrate the potential clinical value of controlled head-to-head studies such as the anticipated LIBERTY trial.","rel_num_authors":7,"rel_authors":[{"author_name":"David Putrino","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Allison Curtis","author_inst":"Invivyd, Inc."},{"author_name":"Meredith Leston","author_inst":"Invivyd, Inc."},{"author_name":"Ilker Yalcin","author_inst":"Invivyd, Inc."},{"author_name":"Rachael Gerlach","author_inst":"Invivyd, Inc."},{"author_name":"Marc Elia","author_inst":"Invivyd, Inc."},{"author_name":"Michael Mina","author_inst":"Invivyd, Inc."}],"rel_date":"2026-05-08","rel_site":"medrxiv"},{"rel_title":"The Effect of Vaccination on the Evolution of the SARS-CoV-2 B.1.351 Variant","rel_doi":"10.64898\/2026.05.06.723356","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.06.723356","rel_abs":"Since the initial distribution of the SARS-CoV-19 vaccine, its widespread use has been hypothesized to act as a selective pressure that drives the COVID-19 virus to mutate. This study aims to investigate the correlation between global vaccination rates and the mutation rate of the SARS-CoV-2 Beta variant (B.1.351). From January to July 2021, nucleotide diversity increased in tandem with vaccination rates, demonstrating that the virus evolved more rapidly in response to selective pressure from mass vaccination. Statistical analysis revealed statistically significant positive correlations between both vaccination rates and vaccine doses administered with nucleotide diversity. Thus, our findings indicate a positive correlation between rising vaccination rates and nucleotide diversity, suggesting that increased vaccination coverage acted as a selective pressure that accelerated viral evolution of SARS CoV2.","rel_num_authors":7,"rel_authors":[{"author_name":"Ziyi Wang","author_inst":"Stony Brook University"},{"author_name":"Madeline Raeihle","author_inst":"Binghamton University"},{"author_name":"Shannon Braun-Gorman","author_inst":"Binghamton University"},{"author_name":"Isaac Leung","author_inst":"Binghamton University"},{"author_name":"Claire Richards","author_inst":"Binghamton University"},{"author_name":"Lea Gabbay","author_inst":"Binghamton University"},{"author_name":"Michel Shamoon-Pour","author_inst":"Binghamton University"}],"rel_date":"2026-05-08","rel_site":"biorxiv"},{"rel_title":"Site-Specific Entry Factors Define Cellular Susceptibility to SARS-CoV-2 in Human Tissues","rel_doi":"10.64898\/2026.05.07.723425","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.07.723425","rel_abs":"SARS-CoV-2 primarily infects the respiratory epithelium through entry factors ACE2 and TMPRSS2. However, alternative viral entry receptors and\/or modulators of viral entry factors expression may contribute to infection in respiratory as well as non-respiratory tissues, including the kidneys and colon. Using single-cell analyses, we identified novel candidates for spike-mediated viral entry in epithelial cells from diverse fresh human tissues exposed to a labeled spike-pseudotyped virus. Systematic viral tracking revealed tissue-specific membrane receptors that contribute to viral entry, functionally validated in human tissues and partially predicted by molecular modeling. We found ADAM17 and IL1R1, together with canonical molecules, to significantly facilitate viral entry in the lung parenchyma, while entry into the renal cortex was less dependable on canonical factors, but strongly modulated by JAK1\/2 engagement. These findings uncover distinct viral entry mechanisms across tissues and suggest novel organ-specific therapeutic targets for patients at risk.","rel_num_authors":23,"rel_authors":[{"author_name":"Mireia Vivas-Roca","author_inst":"Department of Infectious Diseases, Institut de Recerca Vall Hebron (VHIR), Instituto de Investigacion Sanitaria Hospital Universitario Vall Hebron (IISIR-HUVH),"},{"author_name":"Cristina Mancebo-Perez","author_inst":"Department of Infectious Diseases, Institut de Recerca Vall Hebron (VHIR), Instituto de Investigacion Sanitaria Hospital Universitario Vall Hebron (IISIR-HUVH),"},{"author_name":"Mohmed Abdalfttah","author_inst":"Centre Nacional Analisi Genomica (CNAG), Barcelona, Spain"},{"author_name":"Ismael Balafkir","author_inst":"Barcelona Supercomputing Center, Barcelona, Spain."},{"author_name":"Aleix Benitez-Martinez","author_inst":"Department of Infectious Diseases, Institut de Recerca Vall Hebron (VHIR), Instituto de Investigacion Sanitaria Hospital Universitario Vall Hebron (IISIR-HUVH),"},{"author_name":"Victor Montal","author_inst":"Barcelona Supercomputing Center, Barcelona, Spain."},{"author_name":"Alba Gonzalez","author_inst":"Department of Infectious Diseases, Institut de Recerca Vall Hebron (VHIR), Instituto de Investigacion Sanitaria Hospital Universitario Vall Hebron (IISIR-HUVH),"},{"author_name":"Irene Mota-Gomez","author_inst":"Department of Infectious Diseases, Institut de Recerca Vall Hebron (VHIR), Instituto de Investigacion Sanitaria Hospital Universitario Vall Hebron (IISIR-HUVH),"},{"author_name":"Judith Grau-Exposito","author_inst":"Department of Infectious Diseases, Institut de Recerca Vall Hebron (VHIR), Instituto de Investigacion Sanitaria Hospital Universitario Vall Hebron (IISIR-HUVH),"},{"author_name":"Daan KJ Pieren","author_inst":"Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands."},{"author_name":"Bibiana Planas","author_inst":"Department of Infectious Diseases, Institut de Recerca Vall Hebron (VHIR), Instituto de Investigacion Sanitaria Hospital Universitario Vall Hebron (IISIR-HUVH),"},{"author_name":"Joel Rosado","author_inst":"Thoracic Surgery and Lung Transplantation Department, Hospital Universitari Vall Hebron, Vall Hebron Research Institute (VHIR), Universitat Autonoma de Barcelon"},{"author_name":"Maria Eugenia Semidey","author_inst":"Anatomical Pathology Department, Hospital Universitari Vall Hebron, Vall Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain."},{"author_name":"Stefania Landolfi","author_inst":"Anatomical Pathology Department, Hospital Universitari Vall Hebron, Vall Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain."},{"author_name":"Eloy Espin-Bassany","author_inst":"Colorectal Unit, General and Digestive Surgery Department, Hospital Universitari Vall Hebron, Vall Hebron Research Institute (VHIR), Universitat Autonoma de Bar"},{"author_name":"Enric Trilla","author_inst":"Department of Urology, Hospital Universitari Vall Hebron, Vall Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain."},{"author_name":"Vicenc Falco","author_inst":"Department of Infectious Diseases, Institut de Recerca Vall Hebron (VHIR), Instituto de Investigacion Sanitaria Hospital Universitario Vall Hebron (IISIR-HUVH),"},{"author_name":"Adria Curran","author_inst":"Department of Infectious Diseases, Institut de Recerca Vall Hebron (VHIR), Instituto de Investigacion Sanitaria Hospital Universitario Vall Hebron (IISIR-HUVH),"},{"author_name":"Joaquin Burgos","author_inst":"Department of Infectious Diseases, Institut de Recerca Vall Hebron (VHIR), Instituto de Investigacion Sanitaria Hospital Universitario Vall Hebron (IISIR-HUVH),"},{"author_name":"Maria J Buzon","author_inst":"Department of Infectious Diseases, Institut de Recerca Vall Hebron (VHIR), Instituto de Investigacion Sanitaria Hospital Universitario Vall Hebron (IISIR-HUVH),"},{"author_name":"Victor Guallar","author_inst":"Barcelona Supercomputing Center, Barcelona, Spain."},{"author_name":"Holger Heyn","author_inst":"Centre Nacional Analisi Genomica (CNAG), Barcelona, Spain."},{"author_name":"Meritxell Genesca","author_inst":"Department of Infectious Diseases, Institut de Recerca Vall Hebron (VHIR), Instituto de Investigacion Sanitaria Hospital Universitario Vall Hebron (IISIR-HUVH),"}],"rel_date":"2026-05-08","rel_site":"biorxiv"},{"rel_title":"Helminth-remodeled microbial indole-3-lactic acid drives AhR-dependent disease tolerance","rel_doi":"10.64898\/2026.05.06.723221","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.06.723221","rel_abs":"Helminths systemically suppress host immunity, yet whether they impose immune tolerance by rewiring host-associated microbial metabolism remains unclear. Here we show that Trichinella spiralis infection remodels intestinal tryptophan metabolism to generate an AhR-dependent regulatory immune state. T. spiralis infection enriched the commensal bacterium Ligilactobacillus murinus, which converted tryptophan into indole-3-lactic acid (ILA), a microbial metabolite that directly engaged the aryl hydrocarbon receptor. Antibiotic-mediated microbiota depletion abolished infection-induced ILA accumulation, AhR activation and Treg\/Th17 rebalancing, whereas fecal microbiota transplantation from infected donors or supplementation with L. murinus or ILA restored these effects. Pharmacological blockade or genetic deletion of AhR eliminated the ability of T. spiralis, L. murinus and ILA to restrain LPS-induced cytokine-storm-like lung inflammation, establishing AhR as an essential host node in this circuit. Extending these findings to viral inflammatory disease, oral ILA improved survival and reduced pulmonary immunopathology in SARS-CoV-2-infected K18-hACE2 mice. Re-analysis of human COVID-19 metabolomic data further revealed reduced circulating ILA in severe disease. These findings define a helminth-remodeled microbial tryptophan metabolic pathway that promotes disease tolerance and identify the ILA-AhR axis as a candidate postbiotic strategy for limiting hyperinflammatory tissue injury.","rel_num_authors":13,"rel_authors":[{"author_name":"Ruohang Sun","author_inst":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Inst"},{"author_name":"Yi Liu","author_inst":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Inst"},{"author_name":"Yang Wang","author_inst":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Inst"},{"author_name":"Nuo Xu","author_inst":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Inst"},{"author_name":"Xiaoxiao Ma","author_inst":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Inst"},{"author_name":"Qingbo Lv","author_inst":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Inst"},{"author_name":"Xiufeng Zhao","author_inst":"Wurzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians University of Wurzburg Wurzburg, Germany"},{"author_name":"Isabelle Vallee","author_inst":"ANSES, Laboratory for Animal Health, Maisons-Alfort, France"},{"author_name":"Pascal Boireau","author_inst":"ANSES, Laboratory for Animal Health, Maisons-Alfort, France"},{"author_name":"Zeming Wu","author_inst":"School of Life Sciences, Jilin University, Changchun 130012, China"},{"author_name":"Mingyuan Liu","author_inst":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Inst"},{"author_name":"Xiaolei Liu","author_inst":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Inst"},{"author_name":"Xuemin Jin","author_inst":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Inst"}],"rel_date":"2026-05-08","rel_site":"biorxiv"},{"rel_title":"vartracker: an end-to-end tool for pathogen longitudinal variant analysis and visualisation","rel_doi":"10.64898\/2026.05.06.723370","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.06.723370","rel_abs":"Longitudinal sequencing can reveal fine-grained pathogen evolution during acute and chronic infections and inform public health responses. However, integrating ordered pathogen genomic data into a coherent evolutionary and clinical framework can be tedious and error-prone. We present vartracker, an open-source tool for longitudinal pathogen variant analysis and visualisation. Given an ordered sample manifest, vartracker supports three entry points: raw sequence reads, reference-aligned BAM files, or user-supplied VCF and coverage inputs. Raw-read and BAM inputs are processed through an integrated Snakemake workflow, whereas VCF mode starts from precomputed files. Variants are normalised and annotated relative to a reference genome, tracked across timepoints, and classified as original or newly emerging and as transient or persistent. Inferred amino acid changes are reported, and for SARS-CoV-2 analyses, relevant published literature for key mutations can be automatically linked through a functional database. vartracker outputs a schema-documented results table, provenance metadata for reproducibility, publication-quality static figures, and an interactive heatmap for data exploration. Although packaged with SARS-CoV-2 reference assets and initially developed for SARS-CoV-2 datasets, vartracker is pathogen-agnostic when appropriate reference data are supplied. We demonstrate its utility using SARS-CoV-2 and respiratory syncytial virus A (RSV-A) datasets. vartracker is freely available through GitHub, PyPI and Bioconda.","rel_num_authors":2,"rel_authors":[{"author_name":"Charles S.P. Foster","author_inst":"University of New South Wales"},{"author_name":"William D Rawlinson","author_inst":"Prince of Wales Hospital"}],"rel_date":"2026-05-08","rel_site":"biorxiv"},{"rel_title":"Determinants and long-term outcomes of COVID-19 undervaccination: a cohort study of 6.8 million individuals in Lombardy, Italy","rel_doi":"10.64898\/2026.05.06.26352509","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.06.26352509","rel_abs":"BackgroundReceiving fewer COVID-19 vaccine doses than recommended (\"undervaccination\") may increase risks of death, severe COVID-19, and post-COVID condition. However, population-scale evidence from Italy remains limited. We aimed to characterise determinants of undervaccination in Lombardy and to quantify its association with mortality, severe COVID-19, and long COVID outcomes.\n\nMethodsWe conducted a population-based study including all residents of Lombardy aged [&ge;]30 years who were alive on June 1, 2022 (n=6,836,566), and followed them until Dec 31, 2024. Vaccine deficit was defined as the difference between age-specific recommended doses (three for <60 years; four for [&ge;]60 years) and doses received, and was modelled as a time-varying exposure. Outcomes were all-cause mortality, severe COVID-19 (hospitalisation or COVID-19-related death), and long COVID defined using symptom-based ICD codes recorded [&ge;]1 month after infection. Determinants of undervaccination were assessed using multivariable logistic regression. Age-stratified Cox models estimated adjusted hazard ratios (HRs). Counterfactual vaccination scenarios were simulated using fitted survival models.\n\nResultsOn June 1, 2022, 1,668,014 individuals (24{middle dot}4%) were not up to date with recommended vaccination. Undervaccination was more frequent in younger adults, women, individuals born outside Europe, rural residents, and those with high comorbidity burden. During follow-up, 265,383 deaths, 52,121 severe COVID-19 events, and 23,780 long COVID events occurred. In adults aged [&ge;]60 years, increasing vaccine deficit was associated with progressively higher risks of mortality (HR up to 1{middle dot}63) and severe COVID-19 (HR up to 2{middle dot}16). Associations were weaker in younger adults. For long COVID, effect estimates were modest and sensitive to outcome definition. Simulated universal booster coverage in adults [&ge;]60 years was associated with substantial reductions in expected deaths and severe COVID-19 events.\n\nConclusionAbout one in four adults in Lombardy was undervaccinated by mid-2022. An increasing vaccine deficit was associated with a higher risk of severe COVID-19 and mortality, particularly in older adults. Sustaining booster uptake in high-risk groups remains central to mitigating the COVID-19 burden.","rel_num_authors":4,"rel_authors":[{"author_name":"Andrea Corbetta","author_inst":"Human Technopole"},{"author_name":"Katherine Marie Logan","author_inst":"Human Technopole"},{"author_name":"Francesca Ieva","author_inst":"Politecnico di Milano"},{"author_name":"Emanuele Di Angelantonio","author_inst":"Human Technopole"}],"rel_date":"2026-05-07","rel_site":"medrxiv"},{"rel_title":"SARS-CoV-2 Nsp2 reprograms host immunity to drive pathogenic inflammation","rel_doi":"10.64898\/2026.05.06.723222","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.06.723222","rel_abs":"Despite the end of the COVID-19 pandemic, SARS-CoV-2 continues to circulate endemically, highlighting the need to better understand the viral determinants of pathogenesis. Non-structural protein 2 (Nsp2) has been implicated in host-virus interactions, yet its function remains poorly defined in the context of infection.\n\nHere, we generated a recombinant SARS-CoV-2 lacking Nsp2 ({Delta}Nsp2) to investigate its role in viral replication and disease. While {Delta}Nsp2 replicated comparably to wild-type virus in vitro and in vivo, its deletion resulted in markedly attenuated disease in K18-hACE2 mice.\n\nWild-type infection induced a strong pro-inflammatory response associated with increased recruitment of monocytes and macrophages, whereas {Delta}Nsp2 infection promoted a more balanced antiviral response characterized by enhanced lymphocyte and NK cell recruitment. This was accompanied by reduced pulmonary and systemic inflammation and distinct transcriptional programs, including downregulation of pathways related to RNA processing and translation.\n\nMechanistically, CLIP-seq and proximity labeling suggest that Nsp2 interacts with host RNA and components of the translational machinery.\n\nTogether, our findings identify Nsp2 as a key virulence factor that drives immunopathology by skewing host immune responses, highlighting its role as a regulator of host-pathogen interactions.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC=\"FIGDIR\/small\/723222v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (36K):\norg.highwire.dtl.DTLVardef@540e40org.highwire.dtl.DTLVardef@73c663org.highwire.dtl.DTLVardef@e5c535org.highwire.dtl.DTLVardef@f62d7f_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":11,"rel_authors":[{"author_name":"Emile Lacasse","author_inst":"Centre de recherche du CHU de Quebec-Universite Laval"},{"author_name":"Isabelle Dubuc","author_inst":"Centre de recherche du CHU de Quebec-Universite Laval"},{"author_name":"Joannie Leclerc","author_inst":"Centre de recherche du CHU de Quebec-Universite Laval"},{"author_name":"Annie Gravel","author_inst":"Centre de recherche du CHU de Quebec-Universite Laval"},{"author_name":"Leslie Gudimard","author_inst":"Centre de recherche du CHU de Quebec-Universite Laval"},{"author_name":"Charles Joly-Beauparlant","author_inst":"Centre de recherche du CHU de Quebec-Universite Laval"},{"author_name":"Marion Faure","author_inst":"Centre de recherche du CHU de Quebec-Universite Laval"},{"author_name":"Patrick Fortin","author_inst":"Centre de recherche du CHU de Quebec-Universite Laval"},{"author_name":"Marie-Renee Blanchet","author_inst":"Universite Laval"},{"author_name":"Arnaud Droit","author_inst":"Universite Laval"},{"author_name":"Louis Flamand","author_inst":"Universite Laval"}],"rel_date":"2026-05-07","rel_site":"biorxiv"},{"rel_title":"Functional Landscape of Motifs within the Sarbecovirus Spike Cytoplasmic Tail","rel_doi":"10.64898\/2026.05.06.723231","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.06.723231","rel_abs":"Sarbecoviruses exhibit extensive diversity in host range and zoonotic potential. Although the ectodomain of the viral spike protein has been well characterized, the functional landscape of the cytoplasmic tail (CT) remains poorly defined. To address this gap, we systematically generated CT truncation variants of representative spike proteins from all major ACE2-utilizing clades to define the roles of conserved host factor-interacting motifs associated with COPI, COPII, FERM, and SNX27. Using vesicular stomatitis virus (VSV)- and lentivirus-based pseudotyping systems, we evaluated viral entry in cells expressing varying levels of ACE2 and TMPRSS2. Our results demonstrate that CT-associated motifs differentially regulate viral infectivity. Specifically, truncation of the COPI- or SNX27-binding motifs markedly reduces entry efficiency, whereas disruption of the COPII-binding motif produces the opposite outcome. By contrast, removal of the FERM-binding motif consistently enhances infectivity across lineages. Mechanistically, truncation of this motif increases spike expression, cell surface localization, incorporation into virions, and particle stability. Importantly, despite these pronounced effects on viral infectivity, deletion of the FERM-binding motif does not affect antigenicity, receptor dependence, or sensitivity to protease inhibitors, as demonstrated by neutralization and inhibition assays. In addition, this approach substantially increases spike protein density on virus-like particles (VLPs). Collectively, by extending the analysis beyond SARS-CoV-1 and SARS-CoV-2, our study reveals a generalizable mechanism in which cytoskeletal anchoring mediated by the FERM-binding motif acts as a limiting determinant of viral assembly. These findings provide a practical framework for optimizing pseudovirus platforms and guiding vaccine development against emerging viral threats.","rel_num_authors":9,"rel_authors":[{"author_name":"Shixiong Zhou","author_inst":"Wuhan University"},{"author_name":"Chong Chen","author_inst":"Wuhan University"},{"author_name":"Chunhai Liu","author_inst":"Wuhan University"},{"author_name":"Xinhao Zheng","author_inst":"Wuhan University"},{"author_name":"Lanfang Shi","author_inst":"Wuhan University"},{"author_name":"Lina Ma","author_inst":"Wuhan University Hospital"},{"author_name":"Pengfei Cheng","author_inst":"Wuhan University Hospital"},{"author_name":"Qian Wang","author_inst":"Wuhan University"},{"author_name":"Lihong Liu","author_inst":"Wuhan University"}],"rel_date":"2026-05-07","rel_site":"biorxiv"},{"rel_title":"The conserved QTQTX motif in the SARS-CoV-2 spike protein is dispensable for cleavage and lung cell entry of the emerging variant BA.3.2","rel_doi":"10.64898\/2026.05.04.722688","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.05.04.722688","rel_abs":"The furin motif in the SARS-CoV-2 spike (S) protein is important for lung cell entry. It is embedded in an extended loop structure and preceded by a highly conserved QTQTX motif that is required for efficient furin cleavage of the SARS-CoV-2 WA-1 S protein. BA.3.2 is an emerging SARS-CoV-2 saltation variant that is spreading globally in April 2026 and encodes for a highly mutated S protein. Here, we analyzed whether the QTQTX motif is also required for spike protein cleavage and lung cell entry of BA.3.2. We report that two patient-derived spike sequences of the BA.3.2 subvariant BA.3.2.2 lack the first QT repeat of the QTQTX motif and show that this motif is largely dispensable for both cleavage and lung cell entry of BA.3.2.2, which we found to depend on TMPRSS2. Our results suggest that the reconfiguration of the BA.3.2 S protein during persistent infection may have significantly altered the determinants of furin cleavage.\n\nIMPORTANCEThe furin motif in the SARS-CoV-2 spike (S) protein is unique among sarbecoviruses and constitutes a virulence determinant. A QTQTX motif located immediately upstream of the furin motif is required for furin cleavage of the S protein of the virus that circulated early in the pandemic. Here, we show that the QTQTX motif is largely dispensable for S protein processing and S protein-driven lung cell entry of the emerging saltation variant BA.3.2, which is currently spreading globally. Thus, BA.3.2 evolution within immunocompromised individuals may have relaxed the requirements for furin processing of the spike protein.","rel_num_authors":9,"rel_authors":[{"author_name":"Lu Zhang","author_inst":"German Primate Center"},{"author_name":"Nianzhen Chen","author_inst":"German Primate Center - Leibniz Institute for Primate Research"},{"author_name":"Amy Eichmann","author_inst":"Deutsches Primatenzentrum GmbH - Leibniz-Institut fur Primatenforschung"},{"author_name":"Inga Nehlmeier","author_inst":"German Primate Center"},{"author_name":"Ryan Hisner","author_inst":"University of Cape Town"},{"author_name":"Christine Happle","author_inst":"Medizinische Hochschule Hannover"},{"author_name":"Georg M.N. Behrens","author_inst":"Hannover Medical School"},{"author_name":"Markus Hoffmann","author_inst":"Deutsches Primatenzentrum GmbH - Leibniz-Institut fur Primatenforschung"},{"author_name":"Stefan H. P\u00f6hlmann","author_inst":"Deutsches Primatenzentrum GmbH - Leibniz-Institut fur Primatenforschung"}],"rel_date":"2026-05-07","rel_site":"biorxiv"},{"rel_title":"Inequalities in early childhood developmental concerns before, during and after the COVID-19 pandemic in Scotland: a retrospective cohort study","rel_doi":"10.64898\/2026.04.30.26352025","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.04.30.26352025","rel_abs":"BackgroundThe COVID-19 pandemic was associated with increased child developmental concerns in Scotland. However, it is not known whether this increase was uniform across social groups, and there is particular concern that children from low-income households, urban areas and ethnic minority groups may have been disproportionately affected. This retrospective, population-based, cohort study aimed to examine whether the pandemic was associated with changes in developmental inequalities in Scotland.\n\nStudy designWe linked national birth records, the COVID-19 in Pregnancy in Scotland (COPS) dataset, and 13-15 month and 27-30 month child health review records, covering all children born in Scotland who undertook reviews between January 2019 and August 2023 and had full developmental data. Logistic regression models estimated inequalities in odds of developmental concerns, before, during and after the pandemic and across Scottish Index of Multiple Deprivation (SIMD) quintiles, parental National Statistics Socioeconomic Classification (NS-SEC), urban-rural classification, child ethnicity and child sex. Interaction analysis formally tested for any significant changes in inequalities.\n\nFindingsThe analyses included 254,367 children, covering 13-15 month child health review records for 183,439 children and 27-30 month child health review records for 184,689 children. Children in more deprived SIMD quintiles and lower parental NS-SEC categories had significantly higher odds of developmental concerns, as did African and Asian children (at 27-30 months only). Children who were female and in rural areas (27-30 months only) had significantly lower odds of developmental concerns. Developmental inequalities were broadly consistent at each time point and interaction analysis suggested that there was no widening of inequalities during or after the pandemic.\n\nConclusionsDevelopmental inequalities in Scotland did not widen during or after the COVID-19 pandemic. However, substantial pre-existing inequalities persist, underscoring the need for interventions to reduce disparities and support national policy goals on child development.","rel_num_authors":10,"rel_authors":[{"author_name":"Iain Hardie","author_inst":"University of Edinburgh"},{"author_name":"Louise Marryat","author_inst":"University of Glasgow"},{"author_name":"Aja Murray","author_inst":"University of Edinburgh"},{"author_name":"Josiah King","author_inst":"University of Edinburgh"},{"author_name":"Kenneth Okelo","author_inst":"University of Edinburgh"},{"author_name":"Lynda Fenton","author_inst":"Public Health Scotland"},{"author_name":"James P Boardman","author_inst":"University of Edinburgh"},{"author_name":"Philip Wilson","author_inst":"University of Copenhagen"},{"author_name":"Rachael P Wood","author_inst":"Public Health Scotland"},{"author_name":"Bonnie Auyeung","author_inst":"University of Edinburgh"}],"rel_date":"2026-05-06","rel_site":"medrxiv"},{"rel_title":"Identifying the determinants of health protective behaviors during the COVID-19 pandemic using machine learning: an analysis of six countries","rel_doi":"10.64898\/2026.05.05.26352439","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.05.26352439","rel_abs":"Individuals adapt their behavior in response to infectious disease epidemics. Understanding the determinants of behavior, particularly the impact of infections themselves, can help model the feedback loop between disease and behavior in epidemic models. We combined the Imperial College London YouGov COVID-19 behavior survey with hospitalization data and the Oxford COVID-19 government response tracker stringency index to identify the key predictors of three health behaviors--social distancing, masking, and personal protective measures (e.g. handwashing)-- during an early phase of the COVID-19 pandemic in six different countries. We compared two machine learning algorithms--logistic regression with stepwise Akaike Information Criterion and extreme gradient boosting (XGBoost). Top predictors of health behavior were perceived disease severity, hospitalizations, willingness to isolate, and intervention effectiveness, across the six countries. Logistic regression and XGBoost had comparable performance. Machine learning algorithms trained on real-world data could be used to predict individual behavior uptake in agent-based network models.","rel_num_authors":14,"rel_authors":[{"author_name":"Joshua M Chevalier","author_inst":"University Medical Center Utrecht"},{"author_name":"Leonard M Stellbrink","author_inst":"University of Luebeck"},{"author_name":"Lisanne Steijvers","author_inst":"Maastricht University"},{"author_name":"Senne Wijnen","author_inst":"Maastricht University"},{"author_name":"Florian van Daalen","author_inst":"Maastricht University"},{"author_name":"Lilian Kojan","author_inst":"University of Luebeck"},{"author_name":"Nannan Li","author_inst":"Maastricht University"},{"author_name":"Beate Jahn","author_inst":"UMIT TIROL-University for Health Sciences and Health Technology"},{"author_name":"Uwe Siebert","author_inst":"UMIT TIROL-University for Health Sciences and Health Technology"},{"author_name":"Andre Calero Valdez","author_inst":"University of Luebeck"},{"author_name":"Mickael Hiligsmann","author_inst":"Maastricht University"},{"author_name":"Rik Crutzen","author_inst":"UM FHML: Universiteit Maastricht Faculty of Health Medicine and Life Sciences"},{"author_name":"Nicole HTM Dukers-Muijrers","author_inst":"Maastricht University\/Public Health Service"},{"author_name":"Mirjam E Kretzschmar","author_inst":"University Medical Center Utrecht"}],"rel_date":"2026-05-06","rel_site":"medrxiv"},{"rel_title":"Ethnic Inequalities in COVID-19 Vaccination Uptake Among Older Adults in Australia: A Nationwide Linked Data Study","rel_doi":"10.64898\/2026.05.03.26351251","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.05.03.26351251","rel_abs":"BackgroundInternational evidence has documented ethnic inequalities in COVID-19 vaccine uptake, but national evidence for Australia remains limited. We aimed to quantify ethnic inequalities in COVID-19 vaccine uptake in the first 6 months of 2024 and examine retrospective trends in Dose 1-4 (2021-22) across detailed ethnic groups among older adults.\n\nMethodsWe conducted a nationwide cohort study of Australian residents aged [&ge;]75 years who were not Aboriginal or Torres Strait Islander (N=2,038,522) by linking the 2021 Census, Australian Immunisation Register, death, and migration data. Age-standardized uptake of any COVID-19 vaccine dose by ethnic group was calculated (Jan 1-June 30, 2024). Stratified descriptive analyses were conducted to explore intersections between ethnicity and other key sociodemographic characteristics. Uptake of Dose 1-4 during 2021-22 was also assessed across ethnic groups.\n\nResultsIn the first 6 months of 2024, 31.1% of the cohort received a COVID-19 vaccine. Uptake was substantially lower in several ethnic groups, including Central Asian (<10.0%, 95% CI <10.0-10.7), North African and Middle Eastern (<10.0%, 95% CI <10.0-<10.0), Pasifika (13.0%, 95% CI 11.7-14.4), and South Eastern European (10.5%, 95% CI 10.3-10.7) groups. These differences persisted even among individuals born in Australia, with higher English proficiency, higher educational attainment, and living in less disadvantaged areas. Similar inequalities were observed across earlier vaccine doses.\n\nConclusionsSubstantial ethnic inequalities in COVID-19 vaccination uptake persist among older Australians. Reliance on country of birth, language, or socioeconomic factors alone does not fully identify groups with the lowest uptake. Incorporating more detailed ethnicity information may improve identification of under-served groups and inform more targeted and culturally appropriate vaccination strategies.","rel_num_authors":13,"rel_authors":[{"author_name":"Peiyao Xu","author_inst":"The University of Sydney"},{"author_name":"Saman Khalatbari-Soltani","author_inst":"The University of Sydney"},{"author_name":"Meru Sheel","author_inst":"The University of Sydney"},{"author_name":"Maarit A. Laaksonen","author_inst":"The University of Sydney"},{"author_name":"Lin Zhu","author_inst":"The University of Sydney"},{"author_name":"Yiyi Lin","author_inst":"The University of Sydney"},{"author_name":"Christina Abdel Shaheed","author_inst":"The University of Sydney"},{"author_name":"Mouna Sawan","author_inst":"The University of Sydney"},{"author_name":"Assel Mussagulova","author_inst":"The University of Sydney"},{"author_name":"Danijela Gnjidic","author_inst":"The University of Sydney"},{"author_name":"Pani Patu","author_inst":"The University of Sydney"},{"author_name":"Bette Liu","author_inst":"National Centre for Immunisation Research and Surveillance"},{"author_name":"Fiona F Stanaway","author_inst":"The University of Sydney"}],"rel_date":"2026-05-05","rel_site":"medrxiv"},{"rel_title":"Early functional maturation of anti-Spike antibodies predicts SARS-CoV-2 RNA clearance in mild infection","rel_doi":"10.64898\/2026.04.30.26352163","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.04.30.26352163","rel_abs":"SARS-CoV-2 infection exhibits heterogeneous viral clearance kinetics even in individuals with mild disease. The immunological determinants underlying rapid versus prolonged viral RNA detection remain incompletely defined. Here, we performed a three-year longitudinal analysis of 77 healthcare professionals infected with the ancestral Wuhan strain. Participants were stratified according to viral RNA clearance kinetics into non-persistent ([&le;]21 days) and persistent (>21 days) groups. Non-persistent individuals exhibited accelerated seroconversion to Spike and receptor-binding domain (RBD) antigens during the first 11 days after symptom onset. Early antibody responses were characterized by higher functional activity, including significantly greater neutralizing activity against the ancestral strain. In contrast, persistent individuals displayed delayed seroconversion, prolonged IgM responses, and weaker coordination among IgG subclasses, with less synchronized subclass responses, during early infection. Importantly, total immunoglobulin levels did not distinguish the groups. Cross-variant antibody recognition during acute infection was limited and largely strain-focused in both groups. During convalescence, durable anti-Spike IgG responses were maintained independently of persistence status, without significant differences in cross-variant breadth. Vaccination robustly amplified antibody titers, enhanced variant recognition, and sustained high-affinity responses in both groups. Together, our findings demonstrate that the timing and functional quality of early humoral maturation, reflected by neutralizing antibody activity, rather than antibody magnitude or breadth, are key determinants of SARS-CoV-2 RNA clearance in mild infection. These results highlight the importance of early neutralizing antibody generation in shaping acute viral control and the long-term immune architecture.","rel_num_authors":22,"rel_authors":[{"author_name":"Danielle Rodrigues","author_inst":"UFRJ"},{"author_name":"Barbara Araujo","author_inst":"UFRJ"},{"author_name":"Julia Pestana","author_inst":"UFRJ"},{"author_name":"Lendel da Costa","author_inst":"UFRJ"},{"author_name":"Matheus Andrade","author_inst":"UFRJ"},{"author_name":"Layla de Freitas","author_inst":"UFRJ"},{"author_name":"Brenda Nery","author_inst":"UFRJ"},{"author_name":"Vicente Bozza","author_inst":"UFRJ"},{"author_name":"Luciana Conde","author_inst":"UFRJ"},{"author_name":"Leticia Raposo","author_inst":"UNIRIO"},{"author_name":"Andreza Gama","author_inst":"UFRJ"},{"author_name":"Vinicius Mendes","author_inst":"UFRJ"},{"author_name":"Elena Cobos","author_inst":"UFRJ"},{"author_name":"Luiza Higa","author_inst":"UFRJ"},{"author_name":"Rafael Galliez","author_inst":"UFRJ"},{"author_name":"Amilcar Tanuri","author_inst":"UFRJ"},{"author_name":"Orlando Ferreira Jr.","author_inst":"UFRJ"},{"author_name":"Leda Castilho","author_inst":"UFRJ"},{"author_name":"Terezinha Castineiras","author_inst":"UFRJ"},{"author_name":"Julia Echevarria","author_inst":"UFRJ"},{"author_name":"Marcelo Bozza","author_inst":"UFRJ"},{"author_name":"Andre Macedo Vale","author_inst":"UFRJ"}],"rel_date":"2026-05-03","rel_site":"medrxiv"},{"rel_title":"Global burden of foreign bodies and impact of COVID-19 pandemic","rel_doi":"10.64898\/2026.04.29.26352072","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.04.29.26352072","rel_abs":"BackgroundForeign bodies (FBs) can cause obstruction, infection, or injury, yet comprehensive global assessments remain limited. This study evaluated the burden of FBs from 1990-2021, projected trends to 2050, and identified high-risk populations.\n\nMethodsUsing Global Burden of Disease 2021 data, we estimated age-standardized incidence ratio (ASIR), death ratio (ASDR), and disability-adjusted life years (DALYs) by age, sex, and region. Temporal trends were assessed with estimated annual percentage change (EAPC) and Joinpoint regression; projections applied Bayesian age-period-cohort models; decomposition quantified the effects of aging, population, and epidemiological change.\n\nResultsFrom 1990-2021, global ASIR declined from 660.75 to 561.16 per 100,000 (EAPC: -0.84), ASDR from 2.11 to 1.41 (-1.47), and DALYs from 145.14 to 77.87 (- 2.13). Males had consistently higher burden (2021: 725.96 versus 394.11 per 100,000 in females). Children under 5 and adults over 80 bore the highest risks, with intraocular FBs dominating incidence and pulmonary aspiration\/airway FBs driving mortality. Western Europe had the highest ASIR, Andean Latin America the highest ASDR. Since 2019, the onset of the COVID-19 pandemic, intraocular FBs incidence has surged in East Asia, mainly China. Projections suggest ASIR will continue to rise through 2050, while ASDR and DALYs continue to decline, driven by global population growth (187.27%) and aging (46.82%) but offset by epidemiological improvements (-134.09%).\n\nConclusionsDespite long-term declines, FB incidence is rebounding, with marked disparities across sex, age, and region. Targeted interventions, including workplace safety, pediatric and geriatric care, and region-specific policies, are needed to mitigate risks and reduce inequalities.","rel_num_authors":1,"rel_authors":[{"author_name":"Feiruzi Simayi","author_inst":"The First Hospital of Jilin University"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"Changing COVID-19 vaccine eligibility could reshape disease burden for all","rel_doi":"10.64898\/2026.04.27.26351870","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.04.27.26351870","rel_abs":"COVID-19 vaccine recommendations are evolving in the United States. While older adults are most at risk of severe COVID-19 outcomes and therefore experience the greatest direct benefits of vaccination, limiting vaccination to only this age group could worsen outcomes in this higher-risk population. Here, we leveraged data from a statewide survey in Illinois to inform transmission models accounting for contact and vaccination rates across age. Simulating a single season of COVID-19 transmission, we compared deaths under existing vaccination coverage against counterfactual scenarios where individuals under 5 or under 65 were never vaccinated. We find substantial indirect vaccine impacts for older adults. Our results suggest that existing vaccination coverage among younger people is mitigating COVID-19 mortality for older populations. These findings can provide insights into the long-term consequences of deprioritizing young adults and children from vaccination campaigns, and suggest that a lack of vaccine-induced immunity may impact outcomes in other age groups. This underscores the importance of considering indirect vaccine impacts when developing policy.","rel_num_authors":3,"rel_authors":[{"author_name":"Soren L Larsen","author_inst":"University of California, Berkeley"},{"author_name":"Pamela P. Martinez","author_inst":"University of Illinois at Urbana Champaign"},{"author_name":"Ayesha Mahmud","author_inst":"University of California, Berkeley"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"Detection and characterization of single SARS-CoV-2 viral particles by flow virometry","rel_doi":"10.64898\/2026.04.28.26351941","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.04.28.26351941","rel_abs":"Virus infected cells release viral particles, which have variable protein content and are functionally diverse. Deciphering this heterogeneity remains a challenge. Here, we adapt flow virometry to detect and phenotype severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) particles. In supernatants of infected cells, we observe particles measuring 70-100 nm. The appearance of these particles is associated to the increase in viral RNA and infectivity. Sample inactivation using temperature or detergent leads to the disappearance of these particles. Using antibodies and dyes for lipid membranes and nucleic acids, we detect the spike protein, the lipid envelope and the RNA genome. We further confirm the presence of viral particles by electron microscopy. Analyzing different viral preparations demonstrate that spike detection in particles outcompetes particle concentration to predict infectivity. Antibodies against different spike epitopes enable probing of spike conformation changes in the presence of soluble ACE2. Lastly, we detect SARS-CoV-2 particles in PCR-confirmed patient nasal swabs without prior purification steps. In summary, we developed an efficient framework to detect and characterize single SARS-CoV-2 particles.","rel_num_authors":15,"rel_authors":[{"author_name":"Martin Jungbauer-Groznica","author_inst":"Insitut Pasteur"},{"author_name":"Pierre-Henri Commere","author_inst":"Institut Pasteur"},{"author_name":"Andrea Cottignies-Calamarte","author_inst":"Institut Pasteur"},{"author_name":"Alejandro De Cruz","author_inst":"Insitut Pasteur"},{"author_name":"Aura Fantin","author_inst":"Institut Pasteur"},{"author_name":"Cyril Planchais","author_inst":"Institut Pasteur"},{"author_name":"Florence Guivel-Benhassine","author_inst":"Institut Pasteur"},{"author_name":"Isabelle Staropoli","author_inst":"Institut Pasteur"},{"author_name":"Sandrine Schmutz","author_inst":"Institut Pasteur"},{"author_name":"Sophie Novault","author_inst":"Institut Pasteur"},{"author_name":"David Veyer","author_inst":"APHP"},{"author_name":"Helene Pere","author_inst":"APHP"},{"author_name":"Hugo Mouquet","author_inst":"Institut Pasteur"},{"author_name":"Olivier Schwartz","author_inst":"Institut Pasteur"},{"author_name":"Timoth\u00e9e Bruel","author_inst":"Institut Pasteur"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"COVID-19 onset, stay-at-home orders, and racialized inequities in homicide mortality across the US","rel_doi":"10.64898\/2026.04.28.26351994","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.04.28.26351994","rel_abs":"We examined the impact of COVID-19 pandemic onset (2020 April) on homicide mortality in the United States.\n\nWe conducted a single interrupted time series analysis using homicide events from the National Vital Statistics System that occurred over six years (2017-2022), with COVID-19 onset as an interruption. Monthly homicide deaths rates were calculated per 100,000 person-years to create a monthly time series. We used autoregressive integrated moving average regression, adjusted for seasonality, to model the immediate and sustained trend changes in the homicide mortality rate ratios due to the pandemic. We stratified models by length of stay-at-home order, race and ethnicity, sex, age, and weapon used to examine effect measure modification.\n\nIn Jan 2017, the US homicide mortality rate was 5.9\/100,000 PY. While there were annual seasonal changes, the overall time trend before April 2020 was stable. However, with COVID-19 onset, the overall homicide mortality rate ratio increased by 32% (95% CI: 0.23, 0.41), which persisted through 2022 without additional trend changes, but with seasonal variations. Immediate increases with stable sustained trends in homicide rates were also observed in most stratified analyses.\n\nCOVID-19 pandemic onset is associated with US homicide mortality rates immediately increasing and remaining stable and higher afterwards.","rel_num_authors":8,"rel_authors":[{"author_name":"Maryam Tanveer","author_inst":"University of Washington"},{"author_name":"N. Jeanie Santaularia Gomez","author_inst":"University of Washington"},{"author_name":"Kate Vinita Fitch","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"George Mark Holmes","author_inst":"University of North Carolina, Chapel Hill"},{"author_name":"Kathryn E. Moracco","author_inst":"University of North Carolina, Chapel Hill"},{"author_name":"Mike Dolan Fliss","author_inst":"University of North Carolina, Chapel Hill"},{"author_name":"Naoko Fulcher","author_inst":"UNC Injury Prevention Research Center"},{"author_name":"Shabbar I Ranapurwala","author_inst":"University of North Carolina, Chapel Hill"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"A Deterministic-Stochastic Model for COVID-19 and Malaria Co-Infection with Malaria-Acquired Partial Immunity","rel_doi":"10.64898\/2026.04.27.26351858","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.04.27.26351858","rel_abs":"Coinfection of COVID-19 and malaria in endemic regions may generate complex epidemiological interactions that influence susceptibility patterns, disease burden, and outbreak risk. Although malaria-acquired immunity has been hypothesized to modulate host responses to other infections, its population-level implications for COVID-19 transmission under uncertainty remain insufficiently understood. In this study, we develop a deterministic-stochastic compartmental model for the coupled dynamics of COVID-19, malaria, and their co-infection. Malaria-acquired partial immunity is incorporated through a relative susceptibility parameter that reduces the risk of COVID-19 infection among malaria-recovered individuals.\n\nFor the deterministic system, we establish positivity, boundedness, an invariant feasible region, and basic reproduction numbers for the COVID-19-only and malaria-only subsystems. We then use numerical simulations to examine how immunity-mediated reductions in susceptibility may influence COVID-19 incidence, peak burden, hospitalization, and cumulative mortality. To account for environmental and transmission variability, we extend the deterministic model to an Ito stochastic differential equation framework and use repeated realizations to characterize uncertainty in epidemic trajectories, peak distributions, and outbreak risk. In addition, global sensitivity analysis based on partial rank correlation coefficients (PRCCs) is performed to identify the parameters with the greatest influence on COVID-19 outcomes.\n\nOur results suggest that, under the assumed modeling framework, malaria-acquired partial immunity may reduce the peak infectious burden and cumulative mortality associated with COVID-19. The stochastic simulations further show substantial variability around deterministic trajectories and indicate a non-negligible probability of large outbreak events that are not fully captured by mean-field predictions alone. Overall, the proposed framework provides an uncertainty-aware, mechanistic basis for studying COVID-19-malaria co-dynamics and for assessing how interacting disease processes may shape epidemic outcomes in endemic settings.","rel_num_authors":2,"rel_authors":[{"author_name":"Kabir Oluwatobi Idowu","author_inst":"Purdue University"},{"author_name":"Guang Lin","author_inst":"Purdue University"}],"rel_date":"2026-04-28","rel_site":"medrxiv"},{"rel_title":"Disentangling Fatigue from Depression among Survivors of Severe COVID-19","rel_doi":"10.64898\/2026.04.24.26351694","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.04.24.26351694","rel_abs":"PurposeSurvivors of severe COVID-19 commonly experience post-intensive care syndrome (PICS), which includes depression and fatigue. Fatigue is far more common and may inflate depression severity given overlapping symptoms. We sought to disentangle fatigue from depression in PICS.\n\nMethodsWe conducted a cross-sectional analysis of the RAFT COVID study, a national multicenter longitudinal cohort of severe prolonged COVID-19 survivors. We included participants who completed validated surveys at 1-year from hospitalization for depression (PHQ-9) and fatigue (FACIT-Fatigue). We described correlation of FACIT-fatigue with the PHQ9, and separately with PHQ-2 and PHQ-7, which both omit the two items we hypothesized are influenced by fatigue--tiredness and sleeping. Using a MIMIC model, we performed differential item functioning to evaluate the impact of fatigue on depression directly through these two questions and indirectly with the latent depression construct. We then compared PHQ-7 to PHQ-9 scores by fatigue status.\n\nResultsAmong 82 participants, 61.0% reported fatigue (reverse-scored FACIT-Fatigue [&ge;]9), and 15.9% moderately severe depression (PHQ-9 [&ge;]10). FACIT-fatigue was strongly correlated with PHQ-9 (r=.87, p<.001), but less so for PHQ-2 (r=.76, p<.001) and PHQ-7 (r=.82, p<.001). The MIMIC model identified significant direct effects on tiredness ({lambda}=.89, p<.001) and sleep ({lambda}=.52, p<.001). Among fatigued participants, the rescaled PHQ-7 was lower than the PHQ-9 (median of 4.5, IQR 1.50-9.75, vs 7, IQR 4-9.75).\n\nConclusionsFatigue significantly inflated depression symptoms in severe COVID-19 survivors through tiredness and sleeping PHQ-9 items. PHQ-2 may better screen for true depressive symptoms in PICS, minimizing the risk of misdiagnosis and overtreatment.\n\nPLAIN ENGLISH SUMMARYSurvivors of severe COVID-19 illness commonly experience post-intensive care syndrome (PICS), which includes depression and fatigue. Fatigue is far more common and may inflate depression severity given overlapping symptoms. We sought to disentangle fatigue from depression in PICS. We found that the presence of fatigue inflated depression severity through symptoms of tiredness and difficulty sleeping, which are two of the nine items of a commonly used depression screening tool, known as the Patient Health Questionnaire-9 (PHQ-9). Depression screening tools that omit these two items, such as the PHQ-2, may better screen for depressive symptoms in PICS, minimizing the risk of overestimating depression symptoms and potentially misdiagnosis.","rel_num_authors":4,"rel_authors":[{"author_name":"Juan R Cabrera","author_inst":"University of California, Berkeley"},{"author_name":"Peter Pham","author_inst":"University of California,Berkeley"},{"author_name":"W John Boscardin","author_inst":"University of California, San Francisco"},{"author_name":"Anil N Makam","author_inst":"University of California, San Francisco"}],"rel_date":"2026-04-27","rel_site":"medrxiv"}]}