{"gname":"COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv","grp_id":"181.","rels":[{"rel_title":"Ecological Cascades and Future Hantavirus Spillover Risk in a Changing Climate","rel_doi":"10.64898\/2026.07.13.738318","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.13.738318","rel_abs":"Anthropogenic climate change is reshuffling global biodiversity and accelerating zoonotic spillover at the human-wildlife interface. The 2026 multi-country cruise ship outbreak of Andes virus highlights the unpredictable and globalized threat posed by rodent-borne orthohantaviruses, which cause severe, highly fatal human diseases worldwide. Despite this significant public health risk, macroecological synthesis linking environmental drivers to systemic shifts in hantavirus hazards has been lacking. Here, we implement an integrated ecological and machine learning framework combining 89 unique virus-host associations across 61 reservoir species with mechanistic Force-of-Infection (FOI) modeling to project global spillover hazards under current and future climate scenarios (SSP2-4.5 and SSP5-8.5) for 2041-2060. Our models demonstrate a spatially uneven but geographically extensive expansion of spillover hazards, with approximately 74.9% of modeled land area experiencing an increase in FOI. We identify three distinct high-hazard belts heavily concentrated in already-temperate reservoir ranges: western and central North America, central and northeastern Europe extending into western Russia, and discrete patches within central South America. Crucially, our findings reveal that hantavirus hazards are fundamentally shaped along virus-specific ecological axes. While thermal and precipitation anomalies predominate the transmission dynamics of Old and New World lineages like Sin-Nombre virus and Thailand virus, distinct urban-centric Profiles emerge for Seoul virus and Mamore virus, driven explicitly by fine-scale anthropogenic landscape modifications. These results reveal that climate change will not simply intensify viral spillover uniformly but will fundamentally restructure it across varied climatic and human-dominated environments. Our maps provide a critical baseline for targeted global surveillance and highlight the urgent need to integrate spatial conservation planning with public health preparedness.","rel_num_authors":4,"rel_authors":[{"author_name":"Pranav Pandit","author_inst":"UC Davis Weill School of Veterinary Medicine"},{"author_name":"Andie H. Jian","author_inst":"UC Davis Weill School of Veterinary Medicine"},{"author_name":"Ayushi Gupta","author_inst":"UC Davis Weill School of Veterinary Medicine"},{"author_name":"Pranav Kulkarni","author_inst":"University of California Davis School of Veterinary Medicine"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Three phylogenetic metrics are compatible with natural evolution of the earliest SARS-CoV-2 sequence","rel_doi":"10.64898\/2026.07.08.737272","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.08.737272","rel_abs":"Comparative analyses of coronavirus sequences can unravel important aspects of their complex evolution. Here we develop a method to infer past recombination breakpoints based on minimizing homoplasies count. We test it on three outbreak viruses (SARS-CoV-1, MERS-CoV, and SARS-CoV-2) and various chimeric coronaviruses as positive controls. We identify genomic regions evolving under distinct selective pressures. We also trace possible signs of human-made manipulations using metrics such as synonymous and non-synonymous mutation rates, codon usage and insertion patterns. Our pipeline appears to efficiently detect synthetic sequence optimization or genome re-encoding, but does not identify chimeras of natural viruses. Unlike in positive controls, with our method no signal of human-made manipulation is detected in SARS-CoV-1, MERS-CoV, nor SARS-CoV-2.","rel_num_authors":6,"rel_authors":[{"author_name":"Jean-Noel Lorenzi","author_inst":"I2BC"},{"author_name":"Francois Graner","author_inst":"Univ. Paris 7 - Denis Diderot"},{"author_name":"Thomas Bigot","author_inst":"Institut Pasteur"},{"author_name":"Etienne Decroly","author_inst":"Aix-Marseille Universite - Polytech."},{"author_name":"Virginie Courtier-Orgogozo","author_inst":"Institut Jacques Monod"},{"author_name":"Guillaume Achaz","author_inst":"College de France"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"SARS-CoV-2 ORF9b exploits mitochondrial recruitment to TOMM70 for proteasomal protection and tunes inflammatory remodeling during lung infection","rel_doi":"10.64898\/2026.07.13.738231","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.13.738231","rel_abs":"Mitochondrial outer membrane proteins are exploited by diverse intracellular pathogens, to modulate cell metabolism and innate sensing pathways. Here, we demonstrate that TOMM70-dependent mitochondrial recruitment is required to protect SARS-CoV-2 ORF9b from proteasomal degradation, a dependency conserved across ORF9b homologs from related coronaviruses. ORF9b mitochondrial recruitment requires the E477 residue of TOMM70, a surface distinct from that used by the parasite Toxoplasma gondii to engage host mitochondria. We further show that TOMM70 is not a passive scaffold: its depletion activates interferon-stimulated gene expression independently of infection and remodels host immunity distinctly from ORF9b, establishing the receptor and viral protein as mechanistically separable. Using ORF9b-deficient SARS-CoV-2, we demonstrate that ORF9b is dispensable for viral replication and pathological responses in human respiratory epithelial cells and lungs of infected golden Syrian hamsters. Omics profiling of SARS-CoV-2 infected lungs revealed an induction of pathways related to COVID-19 in the absence of ORF9b. Notably, ORF9b-deficient virus-infected lungs show elevated expression of C15ORF48, a nuclear-encoded mitochondrial protein that substitutes for Complex IV subunit NDUFA4 to attenuate inflammation. Collectively, we propose that ORF9b is a receptor-gated viral protein whose principal measurable consequence during authentic infection is a restraint on inflammatory respiratory-chain remodeling.","rel_num_authors":17,"rel_authors":[{"author_name":"Yining Zhao","author_inst":"Institut Pasteur"},{"author_name":"Lauriane Kergoat","author_inst":"Institut Pasteur"},{"author_name":"Guilherme Dias de Melo","author_inst":"Institut Pasteur"},{"author_name":"Florence Larrous","author_inst":"Institut Pasteur"},{"author_name":"Guillaume Drumont","author_inst":"Universite Grenoble Alpes"},{"author_name":"Juan Diego Hernandez Camacho","author_inst":"Institut Pasteur"},{"author_name":"Elodie Vimont","author_inst":"Institut Pasteur"},{"author_name":"Elodie Le Seac'h","author_inst":"Institut Pasteur"},{"author_name":"Nell Saunders","author_inst":"Institut Pasteur"},{"author_name":"Martin Kaechele","author_inst":"Institut Pasteur"},{"author_name":"Etienne Kornobis","author_inst":"Institut Pasteur"},{"author_name":"Quentin Giai Gianetto","author_inst":"Institut Pasteur"},{"author_name":"Mariette Matondo","author_inst":"Institut Pasteur"},{"author_name":"Isabelle Tardieux","author_inst":"Universite Grenoble Alpes"},{"author_name":"Olivier Schwartz","author_inst":"Institut Pasteur"},{"author_name":"Herve Bourhy","author_inst":"Institut Pasteur"},{"author_name":"Timothy Wai","author_inst":"Institut Pasteur"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"AI-Driven Discovery and BSL-4 Validation of Cross-Filovirus Ebola-Marburg Inhibitors and their Synergistic Combinations","rel_doi":"10.64898\/2026.07.09.737586","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.09.737586","rel_abs":"Filovirus outbreaks caused by Ebola virus (EBOV) and Marburg virus (MARV), pose severe global health threats characterized by high rates of fatal hemorrhagic fever. While species-specific vaccines and therapeutic monoclonal antibodies are approved for Zaire ebolavirus, broadly-active therapeutics remain unavailable, leaving populations vulnerable to MARV and other pathogenic Ebola species, such as Bundibugyo (BDBV) and Sudan (SUDV) ebolaviruses. Here we report a computationally guided, infectious virus validated screening platform for the rapid discovery of broad-spectrum filovirus antivirals. By leveraging quantitative structure-activity relationship (QSAR) models, we screened 142,382 compounds in silico to prioritize 125 high-potential candidates. Subsequent dose-response and viability profiling identified 23 compounds exhibiting potent, low-micromolar pan-filovirus activity and favorable cytotoxicity profiles. Molecular docking indicates these compounds target conserved structural and functional domains--primarily the VP35 and L proteins--which may disrupt essential viral replication and immune antagonism. Furthermore, systematic combinatorial screening revealed three highly synergistic compound pairs, notably NCGC00113249-01 and NCGC00118008-01, demonstrating robust cross-species efficacy. By targeting conserved vulnerabilities across the filovirus family, this integrated in silico and in vitro pipeline provides a scalable framework to rapidly nominate and optimize synergistic therapeutic regimens against both endemic and emerging viral threats including BDBV.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC=\"FIGDIR\/small\/737586v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (34K):\norg.highwire.dtl.DTLVardef@1247879org.highwire.dtl.DTLVardef@1617a93org.highwire.dtl.DTLVardef@b68a3aorg.highwire.dtl.DTLVardef@2d1356_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":14,"rel_authors":[{"author_name":"Holli-Joi Martin","author_inst":"UNC Chapel Hill"},{"author_name":"Marcus Tullius Scotti","author_inst":"Universidade Federal da Paraiba"},{"author_name":"Sankalp Jain","author_inst":"NCATS"},{"author_name":"Laura McMullan","author_inst":"CDC"},{"author_name":"Payel Chatterjee","author_inst":"CDC"},{"author_name":"Cleber Melo-Filho","author_inst":"UNC-Chapel Hill"},{"author_name":"Maximilian Caza","author_inst":"UNC-Chapel Hill"},{"author_name":"Alexander Tropsha","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Hsiuling Lin","author_inst":"NCATS"},{"author_name":"Mike Flint","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Emily M. Lee","author_inst":"National Institutes of Health"},{"author_name":"Michael K Lo","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Alexey V. Zakharov","author_inst":"National Center for Advancing Translational Sciences"},{"author_name":"Eugene Muratov","author_inst":"UNC Chapel Hill"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"A Variant-Resistant Linear Epitope in the SARS-CoV-2 Nucleocapsid Protein for Antigen Detection","rel_doi":"10.64898\/2026.07.10.737673","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.10.737673","rel_abs":"We previously generated a mouse monoclonal antibody, N179, against the SARS-CoV-2 nucleocapsid (N) protein and developed a colloidal gold-based immunochromatographic test strip. This assay achieved a detection limit of 2 ng\/mL and displayed 98% concordance with RT-qPCR results. However, the precise epitope recognized by mAb N179 had not been defined. Using a panel of GST-fused N protein truncation fragments, we mapped the linear B-cell epitope recognized by mAb N179 to the flexible C-terminal tail of the N protein by Western blotting and ELISA. The minimal binding motif required for mAb N179 recognition was identified as 390QTVTLL395. Multiple sequence alignment of 11 representative SARS-CoV-2 lineages, including Alpha, Beta, Gamma, Delta, and Omicron subvariants BA.1, BA.2, and BA.3.2, revealed that this epitope was completely conserved across all variants analyzed. Stringent local pairwise alignment analysis using EMBOSS WATER further showed that the 390QTVTLL395 motif achieved a perfect 6\/6 match exclusively in SARS-CoV-2; no identical sequence was detected in the seven common human coronaviruses, four influenza viruses, or five bat coronaviruses examined. Structural prediction analyses indicated that this region is surface-exposed and possesses a strong linear B-cell epitope propensity. Together, these findings identify 390QTVTLL395 as a specific molecular signature of SARS-CoV-2 among the viruses analyzed. Our results provide an epitope-level explanation for the sustained diagnostic reliability of the mAb N179-based assay against emerging variants, clarify the molecular basis for its lack of cross-reactivity, and may inform the rational design of SARS-CoV-2 diagnostics targeting conserved, mutation-resistant epitopes.\n\nImportanceWe identified the exact nucleocapsid protein epitope recognized by monoclonal antibody N179, a diagnostic antibody used in a colloidal gold rapid assay. The identified 390QTVTLL395 motif at residues 390 to 395 was conserved among the SARS-CoV-2 variants analyzed and was not present as an identical continuous sequence in the related respiratory viruses examined. This work supports precise epitope mapping as a useful strategy for evaluating and revalidating diagnostic antibodies as respiratory viruses evolve.","rel_num_authors":8,"rel_authors":[{"author_name":"Zhoujun Su","author_inst":"Zunyi Medical University - Zhuhai Campus"},{"author_name":"Junhao Guo","author_inst":"Zunyi Medical University - Zhuhai Campus"},{"author_name":"Hefeng Zhou","author_inst":"Zunyi Medical University - Zhuhai Campus"},{"author_name":"Jun Ni","author_inst":"Macau University of Science and Technology"},{"author_name":"Yongjun Cao","author_inst":"Zunyi Medical University - Zhuhai Campus"},{"author_name":"Liping Peng","author_inst":"Zunyi Medical University - Zhuhai Campus"},{"author_name":"Min Shao","author_inst":"Zunyi Medical University - Zhuhai Campus"},{"author_name":"Haitao Li","author_inst":"Zunyi Medical University - Zhuhai Campus"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Molecular-level analysis of serum IgG repertoires in COVID-19-vaccinated people with cystic fibrosis identifies abundant convergent antibodies","rel_doi":"10.64898\/2026.07.08.737356","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.08.737356","rel_abs":"BackgroundPeople with cystic fibrosis (pwCF) are at increased risk of severe disease following respiratory viral infections including influenza and respiratory syncytial virus, and were therefore given priority for COVID-19 vaccination. Retrospective epidemiological data have revealed a lower incidence of SARS-CoV-2 infection and a reduced fatality rate among pwCF than in the general population, possibly from the stringent infection control measures and early adoption of protective behaviors. Despite several reports of adequate binding and neutralizing titers after vaccination, the molecular features of vaccine-elicited serum antibody repertoires in pwCF remain unknown.\n\nMethodsWe performed high-resolution proteomic analysis of serum IgG, combined with next-generation sequencing of B cells, to quantitatively profile Spike (S)-reactive serological repertoires from nine infection-naive pwCF after two doses of COVID-19 mRNA vaccine. We recombinantly expressed 20 IgG clonotypes from 6 pwCF as monoclonal antibodies (mAbs) and measured their binding and neutralization against vaccine-strain and variant viruses.\n\nResultsAll donors mounted strong binding and neutralizing titers to vaccine-strain virus. Ig-Seq revealed diverse serum repertoires in all vaccinees, with antibodies targeting the receptor-binding domain (RBD) comprising 64% of each circulating repertoire by abundance. Several serum IgG clonotypes identified across our cohort shared identical or similar IGHV and CDRH3 amino acid sequences with serum IgG from other pwCF or S-reactive mAbs isolated from non-CF individuals. These  convergent antibodies made up 14.6% of the anti-S repertoires in our cohort, reaching 24.8% in one pwCF. Convergent antibodies tended to be RBD-reactive and enriched in specific IGHV; surprisingly, a higher abundance of convergent antibodies in serum correlated with a lower breadth of serum neutralization. All 20 mAbs bound Wuhan S with high affinity (EC50 < 10 nM), and only RBD-reactive mAbs conferred neutralization to vaccine or variant pseudovirus. While most mAbs bound both the B.1.617.2 (Delta, 17\/20) and B.1.1.529 (Omicron, 12\/20) strains, convergent mAbs were less likely to bind either variant.\n\nConclusionsPost-vaccine serum IgG repertoires in pwCF are dominated by RBD-focused, high-affinity antibodies and include a substantial convergent component shared with non-CF vaccinees. These findings demonstrate that pwCF mount antibody responses comparable to the general population, and a large group of convergent antibodies may contribute to strain-specific rather than cross-variant immunity.","rel_num_authors":10,"rel_authors":[{"author_name":"Jiwon Lee","author_inst":"Korea University College of Medicine"},{"author_name":"Steven Ionov","author_inst":"Dartmouth College"},{"author_name":"Ruth I. Connor","author_inst":"Dartmouth Health"},{"author_name":"Nicholas C Curtis","author_inst":"Dartmouth College"},{"author_name":"Seung Min Shin","author_inst":"Dartmouth College"},{"author_name":"Brian H Kim","author_inst":"Dartmouth College"},{"author_name":"Niklas Koehne","author_inst":"Dartmouth College"},{"author_name":"Ji-Ye Park","author_inst":"Korea University School of Medicine"},{"author_name":"Alix Ashare","author_inst":"Dartmouth Health"},{"author_name":"Peter F Wright","author_inst":"Dartmouth College"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Mutational bias shapes protein evolution across RNA viruses","rel_doi":"10.64898\/2026.07.07.737047","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.07.737047","rel_abs":"Mutational biases can influence genome composition, but their contribution to protein evolution remains difficult to quantify. Here we utilize a nearly neutral framework that translates nucleotide mutational spectra into expected amino acid substitution patterns and equilibrium amino acid compositions. Using SARS-CoV-2 as a model system, we show that the viral mutational spectrum explains more than 50% of the variation in observed single-nucleotide amino acid substitutions and predicts the overall direction of proteome-wide amino acid composition change during the COVID-19 pandemic. The predictive power of the model varies with selection regime: effectively neutral and weakly deleterious substitutions conform most closely to the mutational expectation, whereas strongly constrained sites and mutational hotspots show larger deviations. This indicates that departures from the nearly neutral baseline provide a quantitative proxy for purifying and positive selection. Extending the analysis across 34 RNA virus species, we find that positive-sense, negative-sense and double-stranded RNA viruses differ systematically in their mutational spectra, and that these differences are associated with predictable shifts in proteome composition. The same relationship is detectable in RNA-dependent RNA polymerase sequences from more than 77,000 viral species. These results indicate that taxon-specific mutational bias contributes persistently to protein evolution across evolutionary scales.","rel_num_authors":10,"rel_authors":[{"author_name":"Bogdan Efimenko","author_inst":"Center for Mitochondrial Functional Genomics, Immanuel Kant Baltic Federal University, Kaliningrad, Russian Federation"},{"author_name":"Alexandr Voronka","author_inst":"Center for Mitochondrial Functional Genomics, Immanuel Kant Baltic Federal University, Kaliningrad, Russian Federation"},{"author_name":"Victoriya Skripskaya","author_inst":"Center for Mitochondrial Functional Genomics, Immanuel Kant Baltic Federal University, Kaliningrad, Russian Federation"},{"author_name":"Valeria Timonina","author_inst":"School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland"},{"author_name":"Alexey Agranovsky","author_inst":"Faculty of Biology, Lomonosov Moscow State University, Moscow, Russian Federation"},{"author_name":"Valerian Yurov","author_inst":"Center for Mitochondrial Functional Genomics, Immanuel Kant Baltic Federal University, Kaliningrad, Russian Federation"},{"author_name":"Konstantin Khrapko","author_inst":"Northeastern University, Massachusetts, USA"},{"author_name":"Jacques Fellay","author_inst":"School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland"},{"author_name":"Konstantin Gunbin","author_inst":"Center for Mitochondrial Functional Genomics, Immanuel Kant Baltic Federal University, Kaliningrad, Russian Federation"},{"author_name":"Konstantin Popadin","author_inst":"CellKinetica, Switzerland"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Ebola virus exploits host lncRNA LINC01740 to enhance ATF3 and suppress antiviral immune responses","rel_doi":"10.64898\/2026.07.06.731958","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.06.731958","rel_abs":"Ebola virus (EBOV) infection causes severe hemorrhagic fever marked by dysregulated cytokine production, impaired antiviral defenses, and multi-organ failure. Macrophages are primary targets of EBOV, and viral replication profoundly alters macrophage transcriptional programs, driving hyperinflammation. Although long non-coding RNAs (lncRNAs) are increasingly recognized as regulators of immunity and viral pathogenesis, their roles in EBOV infection remain poorly understood. We performed comprehensive transcriptomic profiling of primary human monocyte-derived macrophages infected with the highly pathogenic EBOV Mayinga variant. Infection triggered extensive remodeling of both coding and non-coding transcriptomes, including hundreds of differentially expressed lncRNAs. Functional analysis of neighboring protein-coding genes of EBOV-induced lncRNAs (EVILs) revealed enrichment of pathways linked to cytokine signaling, transcriptional regulation, and cell signaling, all of which are central to Ebola virus disease (EVD) pathogenesis. Among the most strongly induced EVILs, LINC01740 and its neighboring protein-coding gene, Activating Transcription Factor 3 (ATF3), were significantly upregulated. Antisense oligonucleotide-mediated inhibition of LINC01740 reduced ATF3 mRNA and protein levels. CRISPR\/Cas13d-mediated knockdown of ATF3 restored type I interferon (IFN-I) signaling and antiviral gene expression in EBOV-infected macrophages. Mechanistically, ATF3 functions as a negative regulator of IFN-I and type I interferon-stimulated gene expression, thereby suppressing antiviral immune responses in EBOV-infected macrophages. Together, these findings identify a previously unrecognized LINC01740-ATF3-IFN-I regulatory axis that EBOV exploits to promote immune suppression and viral replication.","rel_num_authors":9,"rel_authors":[{"author_name":"Olena Shtanko","author_inst":"Texas Biomedical Research Institute"},{"author_name":"Tanuj Gunturu","author_inst":"Texas Biomedical Research Institute"},{"author_name":"Anu Gopal","author_inst":"Texas Biomedical Research Institute"},{"author_name":"Marija Djurkovic-Lopez","author_inst":"UT Health San Antonio"},{"author_name":"Hoang Nguyen","author_inst":"Texas Biomedical Research Institute"},{"author_name":"Sahana Jayakumar","author_inst":"UT Health San Antonio"},{"author_name":"Ajai Lawrence DSilva","author_inst":"The Pirbright Institute, Woking, GU24 ONF, UK"},{"author_name":"Asha Thomas","author_inst":"Texas Biomedical Research Institute"},{"author_name":"Smita Kulkarni","author_inst":"Texas Biomedical Research Institute"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Bulk and single-cell transcriptomics reveal elevated endogenous retrovirus expression linked to immunopathology in severe COVID-19.","rel_doi":"10.64898\/2026.07.08.737320","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.08.737320","rel_abs":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers expression of endogenous retroviruses (ERVs), but whether this persists during coronavirus disease 2019 (COVID-19) and contributes to disease severity has not been well characterized. In this study, we used bulk and single-cell RNA-sequencing data from the blood of severe COVID-19 patients to investigate the role of ERVs in the immunopathology of COVID-19. Upon quantification of proviral ERV expression, we identified 33 independently transcribed ERV loci that were differentially expressed in severe COVID-19 compared with healthy individuals (\"severe COVID-19 signature ERVs\"). ERV activation was associated with changes in the epigenetic regulators of ERVs and strongly correlated with key inflammatory pathways of COVID-19, including neutrophil degranulation, interleukin signaling, and inflammasome activation. Six of the upregulated ERV loci were specific to intensive care unit (ICU) admission and significantly correlated with disease severity, as measured by hospital-free days at day 45 (HFD-45). Finally, at the single-cell level, we detected significant upregulation of severe COVID-19 signature ERVs in erythroid-like and erythroid precursor cells and macrophages of patients with severe disease. Within these cell populations, we found evidence of ERV-associated differences in inflammatory gene expression, whereby cells expressing signature ERVs showed heightened expression of innate immune genes compared with cells not expressing these ERVs. Together, our study unmasked specific ERV loci activated in severe COVID-19 that are linked to the immunopathology that drives progression of severe COVID-19.","rel_num_authors":4,"rel_authors":[{"author_name":"Bessie Wang","author_inst":"The University of British Columbia"},{"author_name":"Thomas Deckers","author_inst":"The University of British Columbia"},{"author_name":"Eric Liu","author_inst":"The University of British Columbia"},{"author_name":"Maria Tokuyama","author_inst":"The University of British Columbia"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Coordinated expansion of CD163\u207a monocytes and immature CD177\u207a neutrophils marks severe neurotoxicity after CD19 CAR T cell therapy","rel_doi":"10.64898\/2026.07.07.737099","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.07.737099","rel_abs":"Immune effector cell-associated neurotoxicity syndrome (ICANS) is a major complication after CAR T cell therapy, but its underlying mechanisms remain poorly understood. We performed longitudinal immune profiling of paired whole blood and serum samples from patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) treated with CD19 CAR T cells. At peak neurotoxicity, high-dimensional mass cytometry and serum proteomics identified the expansion of CD163 monocytes and immature CD10lowCD101low neutrophils correlated with elevated serum ST2 and IL-2RA concentrations. Integrative immune module analysis identified these features among the strongest predictors of ICANS severity. Independent single-cell transcriptomic profiling validated the emergence of immunoregulatory CD163 monocytes and identified CD177 as a biomarker of ICANS-associated immature neutrophils. Together, these findings reveal a coordinated myeloid inflammatory network associated with ICANS and nominate candidate biomarkers and therapeutic targets for improving the safety of CAR T cell therapy.\n\nSignificanceWe demonstrate that immunoregulatory CD163+ monocytes and immature, activated CD177hiCD10lowCD101low neutrophils emerge in patients with moderate to severe ICANS at peak toxicity following CD19 CAR T cell therapy. These findings identify an uncharacterized myeloid network potentially contributing towards ICANS pathogenesis.","rel_num_authors":19,"rel_authors":[{"author_name":"Tony Chour","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Nikhita Poole","author_inst":"Seattle Children's Research Institute"},{"author_name":"Hugh MacMillian","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Katelyn Burleigh","author_inst":"Seattle Children's Research Institute"},{"author_name":"David R Glass","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Emily C Liang","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Ryan Basom","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Bobbie-Jo Webb-Robertson","author_inst":"Pacific Northwest National Laboratory"},{"author_name":"Kelly Stratton","author_inst":"Pacific Northwest National Laboratory"},{"author_name":"Derrick Gratz","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Annalyssa N Long","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Anna E Elz","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Jennifer J Huang","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Alexandre Hirayama","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Stanley R Riddell","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Jordan Gauthier","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Heather H Gustafson","author_inst":"Seattle Children's Research Institute"},{"author_name":"Evan W Newell","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Sylvain Simon","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"The nucleoside analog CMX521 inhibits coronavirus RNA-dependent RNA polymerase via a two-pronged mechanism","rel_doi":"10.64898\/2026.07.07.737000","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.07.737000","rel_abs":"The SARS-CoV-2 pandemic has underscored the urgent need for broad-spectrum antivirals in pandemic preparedness efforts. Nucleoside analogs targeting viral polymerases are often considered in this context. Here, we employ ensemble biochemical assays and single-molecule magnetic tweezers to characterize the detailed mechanism of action of the adenosine analog CMX521 (developed through Phase 1 clinical studies), a broad-spectrum antiviral against caliciviruses and coronaviruses, against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). The triphosphate form of CMX521 is efficiently incorporated by RdRp, even against saturating ATP concentrations. Analog incorporation induces only a brief pause in nascent RNA synthesis. When embedded in the template strand, CMX521 causes the polymerase to stall [~]9 s on average due to impaired uridine opposite incorporation. Multiple CMX521 residues in the template strand completely inhibit polymerase elongation. When the coronavirus polymerase is associated with the viral helicase, CMX521 strongly promotes copy-back RNA synthesis suggesting a second inhibitory mechanism for CMX521. Collectively, our findings establish a two-pronged mode of coronavirus polymerase inhibition by CMX521.","rel_num_authors":14,"rel_authors":[{"author_name":"Asif Rakib","author_inst":"VU Amsterdam"},{"author_name":"Calvin Gordon","author_inst":"University of Alberta"},{"author_name":"Thomas K. Anderson","author_inst":"University of Wisconsin-Madison"},{"author_name":"John C. Marecki","author_inst":"University of Arkansas for Medical Sciences"},{"author_name":"Quinte Smitskamp","author_inst":"VU Amsterdam"},{"author_name":"Nathaniel Moorman","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Mark T. Heise","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Heidi Colton","author_inst":"Chimerix"},{"author_name":"Dean Selleseth","author_inst":"Chimerix"},{"author_name":"Randall Lanier","author_inst":"Chimerix"},{"author_name":"Kevin D Raney","author_inst":"University of Arkansas for Medical Sciences"},{"author_name":"Robert D Kirchdoerfer","author_inst":"University of Wisconsin-Madison"},{"author_name":"Matthias Gotte","author_inst":"University of Alberta"},{"author_name":"David Dulin","author_inst":"VU Amsterdam"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Human cardiomyocytes with trisomy 21 exhibit heightened susceptibility and immunological response to SARS-CoV-2 infection","rel_doi":"10.64898\/2026.06.22.733265","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.22.733265","rel_abs":"Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is associated with significant cardiovascular complications, including myocardial injury and long-term cardiac dysfunction. Individuals with Down syndrome (trisomy 21) exhibit increased susceptibility to severe COVID-19 outcomes, yet the cardiomyocyte-intrinsic mechanisms underlying this vulnerability remain poorly understood. To investigate genotype-specific responses to SARS-CoV-2 infection, we generated induced pluripotent stem cell-derived cardiomyocytes from individuals with trisomy 21 and their euploid, sex-matched biological relatives. Cardiomyocytes were inoculated with SARS-CoV-2, and viral susceptibility was assessed by immunofluorescence. Bulk RNA sequencing was performed under baseline and infected conditions to define transcriptional programs associated with viral response. Trisomy 21 iPSC-CMs exhibited increased susceptibility to SARS-CoV-2 infection, with greater viral protein expression and a higher proportion of infected cardiomyocytes compared to controls. Baseline transcriptomic analysis revealed no significant differences in canonical viral entry factors including ACE2 and TMPRSS2, suggesting that differential susceptibility is not driven by entry receptor availability. Following infection, both trisomy 21 and euploid control groups activated conserved antiviral pathways; however, trisomy 21 cardiomyocytes displayed a markedly amplified transcriptional response, with substantially greater numbers of differentially expressed genes. Upregulated pathways included interferon signaling, NF-{kappa}B activation, cytokine and chemokine signaling, and innate immune responses, while downregulated pathways were enriched for cardiomyocyte structural integrity, calcium handling, and metabolic processes. Notably, inflammatory and cytokine-related transcripts were significantly more elevated in trisomy 21 cells, consistent with an exaggerated immune response. These findings provide mechanistic insight into the increased cardiovascular risk observed in individuals with Down syndrome and highlight dysregulated immune signaling as a potential therapeutic target in this high-risk population.","rel_num_authors":9,"rel_authors":[{"author_name":"Matthew Alonzo","author_inst":"Nationwide Children's Hospital"},{"author_name":"KC Mahesh","author_inst":"Nationwide Children's Hospital"},{"author_name":"Cankun Wang","author_inst":"The Ohio State University"},{"author_name":"Jerry Wang","author_inst":"The Ohio State University"},{"author_name":"Jakob Bering","author_inst":"The Ohio State University"},{"author_name":"Qin Ma","author_inst":"The Ohio State University"},{"author_name":"Vidu Garg","author_inst":"Nationwide Children's Hospital"},{"author_name":"Mark E Peeples","author_inst":"The Research Institute at Nationwide Children's Hospital"},{"author_name":"Mingtao Zhao","author_inst":"Nationwide Children's Hospital"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"SARS-CoV-2 S1 spike protein induces a temporal systemic immune response and promotes long-term anxiety-like behaviors","rel_doi":"10.64898\/2026.06.17.733010","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.17.733010","rel_abs":"The SARS-CoV-2 S1 protein is associated with immune cell activation and persistent neurological symptoms, yet the underlying mechanisms remain unclear, posing a major challenge in elucidating Long COVID pathophysiology. To investigate how circulating S1 contributes to long-term neurological alterations, we intravenously injected hACE2 mice with varying doses of S1 (5, 10, and 20 {micro}g) and observed temporally dysregulated systemic inflammatory responses accompanied by sub-acute CD4+ T cell infiltration into central limbic regions. This immune response induced mild sustained increases in cFos+ cells in the amygdala and mild neuroinflammation in the hippocampal CA1 region, resulting in both acute and long-term anxiety-like behaviors, while working memory remained unaffected. Together, these findings suggest that systemic S1 protein induces a sustained proinflammatory response that promotes lasting neurological alterations through immune-to-brain signaling pathways.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC=\"FIGDIR\/small\/733010v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (36K):\norg.highwire.dtl.DTLVardef@10982caorg.highwire.dtl.DTLVardef@169a275org.highwire.dtl.DTLVardef@28e66aorg.highwire.dtl.DTLVardef@12f6c85_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":10,"rel_authors":[{"author_name":"Leyre Merino-Galan","author_inst":"Seattle Children's Research Institute"},{"author_name":"John Hemenway","author_inst":"Seattle Children's Research Institute"},{"author_name":"Hawa L Jagana","author_inst":"Seattle Children's Research Institute"},{"author_name":"Taylor S Jackson","author_inst":"Seattle Children's Research Institute"},{"author_name":"Ashmitha Rajendran","author_inst":"University of Washington School of Medicine"},{"author_name":"Asheema Khanna","author_inst":"Seattle Children's Research Institute"},{"author_name":"Sergio Ortiz-Espinosa","author_inst":"Fred Hutchinson Cancer Research Cente"},{"author_name":"Surojit Sarkar","author_inst":"Seattle Children's Research Institute"},{"author_name":"Vandana Kalia","author_inst":"Seattle Children's Research Institute"},{"author_name":"Siobhan S Pattwell","author_inst":"Seattle Children's; University of Washington School of Medicine; Fred Hutchinson Cancer Center"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"Linking Host Covariates to COVID-19 Vaccine-Induced Antibody Dynamics in a Large Healthcare Worker Cohort","rel_doi":"10.64898\/2026.06.11.731600","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.11.731600","rel_abs":"Antibody responses to COVID-19 vaccination vary widely across individuals, but the factors shaping these differences and their relation to underlying host-response processes are still not fully understood. Here, we combined longitudinal serological data from 4,553 healthcare workers with a nonlinear mixed-effects model to quantify determinants of vaccine-induced antibody dynamics. This framework captured both population-level trends and inter-individual variability in anti-spike antibody trajectories after vaccination. We found that age, sex, and pre-vaccine infection significantly influenced response dynamics. Male sex and increasing age were associated with weaker initial antibody production but slower waning, while individuals with a pre-vaccine infection had pre-existing anti-spike antibodies and slower initial antibody production and faster waning. These effects translated into substantial long-term differences in predicted antibody levels, reaching up to a 27% decrease in antibody levels one year after the third vaccination. Our results provide a dynamic view of the determinants of vaccine-induced humoral immunity and establish a framework for analyzing heterogeneous immune responses in large longitudinal cohorts.","rel_num_authors":9,"rel_authors":[{"author_name":"Clemens Peiter","author_inst":"Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. Bonn Center for Mathematical Life Sciences, University of Bonn, Bonn, Germany."},{"author_name":"Emma Sala","author_inst":"Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy."},{"author_name":"Giuseppe De Palma","author_inst":"Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy."},{"author_name":"Carlotta Zunarelli","author_inst":"Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy."},{"author_name":"Michelle B. Hanson","author_inst":"Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy."},{"author_name":"Mahsa Abedini","author_inst":"Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. Department of Business and Management, Luiss Guido Carli University, Italy."},{"author_name":"Evelina Tacconelli","author_inst":"Division of Infectious Diseases, Department of Diagnostics and Public Health, University of Verona, Verona, Italy."},{"author_name":"Paolo Boffetta","author_inst":"Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA."},{"author_name":"Jan Hasenauer","author_inst":"Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. Bonn Center for Mathematical Life Sciences, University of Bonn, Bonn, Germany."}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"SARS-CoV-2 membrane protein conformations induce distinct membrane curvatures","rel_doi":"10.64898\/2026.07.06.736641","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.06.736641","rel_abs":"The assembly and budding of enveloped viruses requires thousands of membrane proteins to collectively remodel host-cell membranes into highly curved virions. In SARS-CoV-2, this process is driven by interactions between viral structural proteins and the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) membrane. The membrane (M) protein, an embedded homodimer and the most abundant viral component, exists in two conformations: a compact \"short\" form and an elongated \"long\" form. Although M is essential for virion assembly, how its conformations contribute to the generation and organization of the membrane curvature required for budding has remained unknown. Here, we used all-atom and Martini coarse-grained molecular dynamics simulations to show that individual M proteins can induce distinct membrane curvatures, depending on their conformation. The long form bends the membrane around its C-terminal, forming a valley-like depression, while the short form predominantly bends the membrane away from the C-terminal producing an anisotropic ridge. The induced curvatures correspond to the bulb and neck regions of a budding virion, respectively. Coarse-grained simulations of M protein pairs further reveal that curvature modulates long-range, membrane-mediated M-M interactions, leading to repulsion between dissimilar conformations. Together, these results suggest that the long and short forms of M naturally segregate to shape the virions bulb and neck, potentially facilitating genome encapsulation and membrane scission. This mechanism provides a physical basis for coronavirus budding and suggests that conformationally encoded curvature fields may represent a general principle underlying the formation of enveloped viruses.\n\nSignificance StatementEnveloped viruses must bend host cell membranes to form new viral particles, but the driving force for membrane bending has been unclear. Using molecular dynamics simulations, we show that the SARS-CoV-2 membrane protein, the most abundant structural protein of the virus, drives membrane bending, and that its two natural conformations generate opposite signs of curvature which match the geometry of distinct regions of a budding virus. Moreover, these induced curvatures cause proteins in different conformations to repel one another providing a physical basis for their spatial segregation. Our results suggest that the membrane proteins conformations can contribute significantly to the membrane remodeling needed for virus assembly and release, revealing a simple mechanism that may apply to other enveloped viruses.","rel_num_authors":4,"rel_authors":[{"author_name":"Joseph McTiernan","author_inst":"University of California, Merced"},{"author_name":"Roya Zandi","author_inst":"University of California, Riverside"},{"author_name":"Michael E. Colvin","author_inst":"University of California, Merced"},{"author_name":"Ajay Gopinathan","author_inst":"University of California, Merced"}],"rel_date":"2026-07-08","rel_site":"biorxiv"},{"rel_title":"A Procoagulant Peptide Analog of the SARS-CoV-2 Nucleocapsid C-terminal Domain","rel_doi":"10.64898\/2026.07.04.736500","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.04.736500","rel_abs":"BackgroundUncontrolled bleeding complicates trauma, surgery and many medical conditions. While currently available procoagulant therapies (e.g., plasma-derived factors, recombinant proteins, antifibrinolytics) have crucial limitations.\n\nMethodsN389 (CQQTVTLLPAADLDDFSC) was synthesized by Fmoc solid-phase chemistry, characterized by HPLC and LC-MS, then tested in normal human pooled plasma in microplate mechanical clot-formation assays using incubated and immediate addition formats. Kinetic parameters (plasma recalcification, PRT; maximum absorbance, Amax) were obtained from absorbance curves fit to four-parameter logistic models. Mixing studies with modified (i.e., aged, adsorbed) plasma probed factor dependence.\n\nResultsIn plasma coagulation assays activated with 25 mM CaCl{square}, baseline clotting showed a PRT of 23.74 {+\/-} 0.27 min and Amax of 0.1813 {+\/-} 0.0043 (n = 3), whereas N389 significantly reduced PRT to 8.442 {+\/-} 6.0395 min without incubation (p = 0.0012), further decreased PRT after incubation (p < 0.0001), increased Amax to 0.2523, and retained comparable activity across normal, adsorbed, and aged plasma, in contrast to S1255 which showed a faster but incubation-labile effect with PRT 2.353 {+\/-} 1.3685 min (p = 0.0007) and marked attenuation in factor-depleted and aged plasma. Mixing studies showed N389 activity persisted across normal, aged and adsorbed plasma, consistent with a mechanism that does not require intact plasma coagulation factor profiles (specifically factors II, V, VIII, VII, IX, X).\n\nDiscussionCollectively with prior evidence on anionic surfaces, Ca2{square}-binding Gla domains, and peptide-modulated fibrin polymerization, these results support a model in which N389 functions as a stable, charge-based scaffold that coordinates divalent cations and\/or directly nucleates fibrin(ogen), while highlighting limitations of bulk clotting assays and the need for targeted thrombin generation, binding, aggregation, and contact-activation studies.\n\nConclusionsThe aspartate-rich peptide N389 is a sustained, factor-independent procoagulant at least in vitro. N389 thus merits further mechanistic and translational evaluation as a synthetic hemostatic agent.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC=\"FIGDIR\/small\/736500v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (29K):\norg.highwire.dtl.DTLVardef@1e3e895org.highwire.dtl.DTLVardef@1baba40org.highwire.dtl.DTLVardef@19f3edorg.highwire.dtl.DTLVardef@1dd708f_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":3,"rel_authors":[{"author_name":"Brian Andrich La Valle Pollo","author_inst":"Biomedical Innovations Research for Translational Health Science (BIRTHS) Laboratory, Department of Biochemistry and Molecular Biology, University of the Philip"},{"author_name":"Fresthel Monica Climacosa","author_inst":"Department of Medical Microbiology, College of Public Health, University of the Philippines Manila, Manila, Philippines"},{"author_name":"Salvador Eugenio Caoili","author_inst":"Biomedical Innovations Research for Translational Health Science (BIRTHS) Laboratory, Department of Biochemistry and Molecular Biology, University of the Philip"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"SARS-CoV-2 Spike H655Y drives protease preference but does not dictate cellular tropism","rel_doi":"10.64898\/2026.07.05.736580","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.05.736580","rel_abs":"Throughout the COVID-19 pandemic, SARS-CoV-2 has undergone rapid adaptation, with the Omicron variant exhibiting an unexpected shift towards upper airway infection and preference for membrane fusion activated by endosomal cathepsins, a reversion to ancestral sarbecovirus entry mechanisms. This phenotype coincides with convergent acquisition of the spike mutation H655Y, which reduces TMPRSS2-mediated activation. Here, using a comprehensive panel of 13 spikes of SARS-CoV-2 variants, we interrogated whether H655Y-mediated protease switching explains Omicrons upper airway phenotype, challenging several existing hypotheses, from spike stability, shedding and acquired intra-molecular interactions by H655Y. Our findings reveal that protease preference and tissue tropism are mechanistically uncoupled. While spike pre-processing by furin determines protease preference in pre-Omicron variants, this relationship breaks down in H655Y-bearing viruses. Notably, mutations in the NTD and RBD of BA.2.86 can override the H655Y phenotype entirely, indicating that RBD-mediated interactions, rather than protease usage, represent the critical determinants of Omicrons upper airway adaptation. This work reframes our understanding of coronavirus spike evolution, revealing that tissue tropism operates through mechanisms fundamentally distinct from those dictating protease preference.","rel_num_authors":10,"rel_authors":[{"author_name":"Diego Cantoni","author_inst":"MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom"},{"author_name":"Wilhelm Furnon","author_inst":"Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands"},{"author_name":"Sarah Little","author_inst":"MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom"},{"author_name":"Vanessa Cowton","author_inst":"MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom"},{"author_name":"Bridget Larman","author_inst":"MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom"},{"author_name":"Reehana Damasceno","author_inst":"MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom"},{"author_name":"Brian Willet","author_inst":"MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom"},{"author_name":"Arvind H Patel","author_inst":"MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom"},{"author_name":"Massimo Palmarini","author_inst":"Erasmus Medical Center"},{"author_name":"Joe Grove","author_inst":"MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Fitness flux in SARS-CoV-2 and influenza H3N2","rel_doi":"10.64898\/2026.07.05.736619","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.05.736619","rel_abs":"The tempo of viral adaptation is usually read indirectly from the composition of mutations, through measures such as dN\/dS. Here we measure it directly from the dynamics of variant frequencies, where we use multinomial logistic regression to estimate a fitness for each co-circulating variant. We aggregate these estimates to derive the rate of change of mean population fitness, referred to as fitness flux. Tracing SARS-CoV-2 from its emergence, we find that it initially adapted rapidly, doubling in fitness every 6 months from Jan 2021 to Jun 2022, but slowing to every 2.4 years from Jul 2022 to Dec 2025. Seasonal influenza H3N2 sustained a slower, steadier pace doubling in fitness every 10.0 years. In both, the rate of fitness gain closely tracks the variance in fitness, matching the 1:1 expectation of Fishers fundamental theorem. Phylogenetic contrasts between parent and child lineages localize most fitness gain to spike, and within spike to the receptor-binding domain, where a simple count of spike S1 substitutions predicts lineage fitness about as well as deep-learning escape and protein-language-model scores. Measuring fitness directly thus offers a transparent, frequency-based alternative to mutational proxies for tracking and anticipating viral adaptation.\n\nThe website blab.github.io\/fitness-flux\/ is the intended reading experience of this paper, providing responsive layout and interactive figures.","rel_num_authors":1,"rel_authors":[{"author_name":"Trevor Bedford","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Clade 2.3.4.4b H5N1 influenza virus and SARS-CoV-2 seroprevalence among owned and feral cats in Philadelphia and surrounding communities","rel_doi":"10.64898\/2026.07.03.736283","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.03.736283","rel_abs":"Clade 2.3.4.4b H5NX influenza viruses have spread widely in birds since 2020. In addition to causing disease in birds, these viruses have infected a variety of mammals, including humans. Clade 2.3.4.4b H5N1 viruses are currently causing an outbreak among dairy cattle in the United States, and it is important to determine if other mammals have been exposed to H5NX viruses. Cats, specifically outdoor and feral cats, frequently predate wild birds. Recent studies have shown that cats living on dairy cattle farms can be infected with H5N1. Here, we completed serological studies to determine if owned and feral cats living in an urban environment in the United States have evidence of past H5N1 exposures. We used multianalyte bead-based assays to measure clade 2.3.4.4b hemagglutinin (HA) antibody levels in serum samples collected in July 2023 to June 2025 from 417 feral and 228 owned cats from the greater Philadelphia area. We also measured antibody levels against a panel of HAs from other human and non-human influenza viruses, and the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We completed additional H5N1 and SARS-CoV-2 neutralization assays using samples that had detectable antibodies in the multianalyte bead-based assays. One cat (0.16%) was positive for H5 antibodies and twenty cats (3.1%) were positive for SARS-CoV-2 antibodies in both binding and neutralization assays. These data suggest that cats in the Philadelphia area have not been routinely exposed to clade 2.3.4.4b H5N1 viruses but have been more commonly exposed to SARS-CoV-2.\n\nImportanceHighly pathogenic H5NX avian influenza viruses have caused widespread disease and mortality in both wild and domestic birds, and have infected marine mammals, cattle, and humans. Recent studies have demonstrated that cats can also be infected with H5NX viruses, but it is unknown if these infections are common. In this report, we completed a seroprevalence study and found that H5NX exposure in feral and owned cats in the Philadelphia area appears to be rare. We also completed SARS-CoV-2 serological experiments and found that 3.1% of cats possessed antibodies reactive to this virus.","rel_num_authors":12,"rel_authors":[{"author_name":"Gabrielle Scher","author_inst":"University of Pennsylvania"},{"author_name":"Kathrine Maguire","author_inst":"University of Pennsylvania"},{"author_name":"Caitlin Duffy","author_inst":"University of Pennsylvania"},{"author_name":"Katie Mina","author_inst":"University of Pennsylvania"},{"author_name":"Clara Malekshahi","author_inst":"University of Pennsylvania"},{"author_name":"Stephen D Cole","author_inst":"University of Pennsylvania School of Veterinary Medicine"},{"author_name":"Laura Ahlers","author_inst":"Meso Scale Diagnostics LLC"},{"author_name":"Jacob Wohlstadter","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"George B. Sigal","author_inst":"Meso Scale Diagnostics, LLC"},{"author_name":"Roderick B. Gagne","author_inst":"University of Pennsylvania"},{"author_name":"Louise Moncla","author_inst":"University of Pennsylvania School of Veterinary Medicine"},{"author_name":"Scott E. Hensley","author_inst":"University of Pennsylvania"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Drug Functional Site-Unknown Molecular Targets Exemplified by SARS-CoV-2 pseudoknot and ribosomal frameshifting-modulators","rel_doi":"10.64898\/2026.07.02.735960","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.02.735960","rel_abs":"The -1 Programmed Ribosomal Frameshifting (-1 PRF) signal of SARS-CoV-2, driven by a conserved three-stemmed RNA pseudoknot (PK), is indispensable for viral replication and represents a structurally stable yet underexplored therapeutic target. Unlike rapidly mutating viral proteins, this RNA element offers an opportunity for durable intervention but has historically been considered \"undruggable\". We developed an integrative drug discovery and characterization pipeline that combines molecular docking, molecular dynamics simulations, and dual-luciferase assays to systematically identify and validate frameshifting-efficiency (Feff) modulators from FDA-approved compounds. To move beyond traditional similarity-based screening, we introduced a contact-distribution-matching method, which ranks candidate compounds by comparing their predicted RNA interaction fingerprints with those of reference modulators. This computational approach, paired with experimental validation, enabled us to expand the repertoire of Feff modulators and establish correlations between binding patterns and functional outcomes. To uncover the underlying mechanisms, we applied steered molecular dynamics simulations and single-molecule optical tweezers measurements, revealing that Feff-enhancing modulators preferentially stabilize the remote stem (stem 3) of the PK, promoting variety of intermediate force species with the beginning base pairs of stem 1 being refolded, even after those base pairs have been unwound by ribosome. The refold of the tips of the stem 1 in turn \"push back\" the ribosome on the slippery sequence to result in enhanced frameshifting. On the other hand, Feff-suppressing modulators rigidify early stem regions, increasing resistance to ribosomal progression and increase the drop-off rate, eventually leading to a reduced -1 frame to 0 frame ratio in translation. Together, these findings provide the first integrated demonstration of how small molecules can modulate -1 PRF by altering RNA PK folding dynamics. More broadly, our framework establishes a generalizable strategy for rationally targeting structured RNAs with repurposed drugs and offers new opportunities to expand the druggable genome to include noncoding RNA elements and other biomolecular targets lacking known functional sites.","rel_num_authors":6,"rel_authors":[{"author_name":"Ahmed Mohamed Ragab","author_inst":"Institute of Bioinformatics and Structural Biology, National Tsing Hua University"},{"author_name":"Christopher Llynard D Ortiz","author_inst":"Institute of Bioinformatics and Structural Biology, National Tsing Hua University"},{"author_name":"Yu-Tong Huang","author_inst":"Institute of Molecular and Cellular Biology, National Taiwan University"},{"author_name":"Jian-Zhou Wang","author_inst":"Institute of Molecular and Cellular Biology, National Taiwan University"},{"author_name":"Jin-Der Wen","author_inst":"Institute of Molecular and Cellular Biology, National Taiwan University"},{"author_name":"Lee-Wei Yang","author_inst":"National Tsing Hua University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Material-specific quarantine durations for SARS-CoV-2 inactivation on musical instruments and music-related materials","rel_doi":"10.64898\/2026.07.01.735763","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.01.735763","rel_abs":"The COVID-19 pandemic has imposed a reevaluation of safety protocols across various sectors, including the arts. This study addresses a critical gap in understanding SARS-CoV-2 persistence on materials commonly associated with musical instruments and scores, such as alloys, varnishes, reeds, and paper. While previous research has explored viral survival on various surfaces, limited data exists for materials specific to musical contexts. In this work, we investigate the efficacy of quarantine as a non-destructive method for inactivating SARS-CoV-2 on 16 materials, including brass, silver plating, ABS plastic, ebonite, and various varnishes and paper types.\n\nResults revealed significant variability in viral persistence across materials. Non-porous surfaces like metals and ABS plastic cleared infectivity within 3 days, while porous materials such as reeds and music scores required up to 7 days. Gold-plated brass and certain varnishes showed intermediate persistence, with infectivity clearing after 4 days. These findings are in agreement with prior studies indicating that SARS-CoV-2 survival is highly dependent on surface composition, with porous and organic-coated materials retaining viable virus longer due to reduced environmental stress.\n\nOur results highlight the feasibility of stratified quarantine protocols based on material type, offering practical guidelines for musicians and institutions and provides critical insights for mitigating SARS-CoV-2 transmission risks in musical settings.","rel_num_authors":9,"rel_authors":[{"author_name":"Boris Pastorino","author_inst":"Aix Marseille university"},{"author_name":"Franck Touret","author_inst":"Unite des Virus Emergents (UVE : Aix-Marseille Univ, Universita di Corsica, IRD 190, Inserm 1207, IRBA), France"},{"author_name":"Milena Creton","author_inst":"Buffet Crampon, 203 bis blvd Saint-Germain, 75007 Paris, France"},{"author_name":"Romain Viala","author_inst":"ITEMM-Institut Technologique Europeen des Metiers de la musique, 71 avenue Olivier MESSIAEN, 72000 Le Mans, France"},{"author_name":"Jean Charles Morand","author_inst":"Vandoren, 56 rue Lepic, 75018 Paris, France"},{"author_name":"Fanny Reyre","author_inst":"CSFI-Chambre Syndicale de la Facture Instrumentale, 9 rue Saint-Martin, 75004 Paris, France"},{"author_name":"Michael Jousserand","author_inst":"Buffet Crampon, 203 bis bld Saint-Germain, 75007 Paris, France"},{"author_name":"Francois Billecard","author_inst":"Buffet Crampon, 203 bis bld Saint-Germain, 75007 Paris, France"},{"author_name":"Remi N. Charrel Charrel","author_inst":"Unite des Virus Emergents (UVE : Aix-Marseille Univ, Universita di Corsica, IRD 190, Inserm 1207, IRBA), France"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Wobble Vaccines: Cross-Strain Protection Through Epitope Hierarchy Manipulation","rel_doi":"10.64898\/2026.07.01.735277","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.07.01.735277","rel_abs":"Vaccination remains the most successful preventative measure against viral infection, but methods to stably deter rapidly-evolving pathogens have remained elusive. Vaccines capable of incorporating and anticipating viral evolution could address current challenges in seasonal vaccination efforts against SARS-CoV-2 and influenza where economic and disease burdens remain high despite decades of combined study. Rare epitope suppression (RES) is an underutilized concept within vaccine design, where humoral epitope targeting can be molded using complex antigen pools. Based in mRNA vaccine technology,  wobble vaccines represent the novel application of RES to human pathogens designed to anticipate and resist viral evolution. To establish this platform, public SARS-CoV-2 sequencing data was compiled from the first two years of the COVID-19 pandemic to identify high-diversity sites across the receptor binding domain (RBD) of the spike protein. Wobble RBD (WobbRBD) libraries reflecting that entropy were synthesized and incorporated into established self-amplifying (SA) vaccine constructs. Animals immunized with these complex antigen pools showed no obvious adverse effects. By three days-post vaccination, WobbRBD stimulated robust primary immune activation with distinctive characteristics compared to traditional single-strain vaccine modalities. By day 14, germinal centers, class switching, and antibody-secreting cells were induced, creating potent SARS-CoV-2 spike-binding IgG antibodies. Despite similar overall activation profiles, WobbRBD generated significantly increased breadth against SARS-CoV-2 variant spikes in comparison to single-strain controls - even against future-emerging strains. Taken together, wobble vaccines represent a novel method for anticipating and preventing viral escape with promising applications in SARS-CoV-2, influenza, HIV, and beyond.","rel_num_authors":12,"rel_authors":[{"author_name":"Peter R McIlroy","author_inst":"Emory University"},{"author_name":"Wendy M Zinzow-Kramer","author_inst":"Emory University"},{"author_name":"Madison L Ellis","author_inst":"Emory University"},{"author_name":"Eduard Melief","author_inst":"AstraZeneca"},{"author_name":"Mohammad Ali","author_inst":"Emory University"},{"author_name":"Hannah E Peck","author_inst":"Emory University"},{"author_name":"Loren E Sasser","author_inst":"Emory University"},{"author_name":"Daryll Vanover","author_inst":"Emory University"},{"author_name":"Philip J Santangelo","author_inst":"Emory University"},{"author_name":"Mehul S Suthar","author_inst":"Emory University"},{"author_name":"Emily A Voigt","author_inst":"Oregon Health & Science University"},{"author_name":"Matthew C Woodruff","author_inst":"Emory University"}],"rel_date":"2026-07-01","rel_site":"biorxiv"},{"rel_title":"Epistasis between SARS-CoV-2 M and N Proteins Balances Particle Assembly and Immune Evasion","rel_doi":"10.64898\/2026.06.29.735107","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.29.735107","rel_abs":"Since its emergence in the human population, SARS-CoV-2 has continuously evolved to evade immune responses and robustly establish global circulation. In this process, the structural viral membrane (M) protein has accumulated amino acid changes whose impact on viral particle assembly and innate immune evasion remains incompletely understood. Here, we designed a SARS-CoV-2 replicon system lacking M that assesses the influence of transiently transfected M protein variants on viral particle production independently of viral RNA replication. We found that M protein variants have reduced particle assembly while innate immune antagonism functions are strengthened. Notably, the assembly defect is rescued by co-evolving N protein variants, highlighting how SARS-CoV-2 evolution coordinates between two of its structural proteins to optimize viral infection. Our work underscores the complex evolutionary trajectories of SARS-CoV-2 variants across different viral proteins and informs future therapeutic strategies targeting viral assembly and limiting infection.\n\nAuthor summarySince the onset of the COVID-19, SARS-CoV-2 has been changing continuously in ways that help it spread efficiently and evade human defenses. The viral membrane (M) protein is a key structural component required to form new viral particles. Nevertheless, it has accumulated changes over time with overlooked functions. In this study, we developed an experimental system to examine the impact of these changes on virus assembly and host immune system. We found that recent M variants are better than older variants at suppressing immune responses but less efficient at forming viral particles. This defect seems to be compensated for by coordinated changes in another structural protein, nucleocapsid (N). These findings reveal that SARS-CoV-2 evolution involves trade-offs between different viral characteristics, with changes in one protein balancing changes in another. Understanding these trade-offs provides new insight into how the virus adapts to humans and may help guide therapeutic strategies to limit infection.","rel_num_authors":8,"rel_authors":[{"author_name":"Aldo Barrera-Vasquez","author_inst":"Departamento de Enfermedades Infecciosas e Inmunologia Pediatricas. Escuela de Medicina. Pontificia Universidad Catolica de Chile, Santiago, Chile."},{"author_name":"Mir M Khalid","author_inst":"Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Hade Ramos","author_inst":"Departamento de Enfermedades Infecciosas e Inmunologia Pediatricas. Escuela de Medicina. Pontificia Universidad Catolica de Chile, Santiago, Chile."},{"author_name":"Julia Rosecrans","author_inst":"Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Marcela Ferres","author_inst":"Departamento de Enfermedades Infecciosas e Inmunologia Pediatricas. Escuela de Medicina. Pontificia Universidad Catolica de Chile, Santiago, Chile."},{"author_name":"jenniffer Angulo","author_inst":"Departamento de Enfermedades Infecciosas e Inmunologia Pediatricas. Escuela de Medicina. Pontificia Universidad Catolica de Chile, Santiago, Chile."},{"author_name":"Melanie Ott","author_inst":"Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Taha Y. Taha","author_inst":"Gladstone Institutes, San Francisco, CA, USA"}],"rel_date":"2026-06-30","rel_site":"biorxiv"},{"rel_title":"Age-dependent disease tolerance to SARS-CoV-2 infection","rel_doi":"10.64898\/2026.06.27.734955","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.27.734955","rel_abs":"Disease tolerance limits infectious disease severity through tissue damage control mechanisms that do not target pathogens directly. Here we demonstrate that age-dependent decline in adipose tissue lipolysis compromises disease tolerance to SARS-CoV-2 infection. Young adult mice exhibited robust adipocyte lipolysis and 80% survival, whereas old mice showed impaired adipocyte lipolysis and only 20% survival. Genetic repression of adipocyte lipolysis eliminated this age-dependent survival advantage without affecting viral titers, revealing that adipocyte lipolysis is essential for disease tolerance to SARS-CoV-2 in young adults. Impaired adipocyte lipolysis in aged mice was associated with a plasma lipidomic signature that predicts COVID-19 severity and mortality in three independent human cohorts. Mechanistically, adipocyte lipolysis provides free fatty acids (FFA) to support bone marrow emergency myelopoiesis, through CD36- and CPT1-dependent FFA cellular uptake and mitochondrial import, respectively. Bone marrow derived monocytes migrate to the lung via CCL2\/CCR2-dependent mechanism where they enforce an immune-metabolic communication network with parenchymal cells to sustain lung structure and function. This circuit is not required to confer protection against influenza infection, revealing pathogen-specific disease tolerance mechanisms. These findings reveal adipose tissue catabolism as a central age-dependent factor responsible for exacerbated COVID-19 mortality in aged populations.\n\nOne-Sentence SummarySARS-CoV-2 infection induces adipose tissue lipolysis to release fatty acids that drive myelopoiesis and monocyte production for lung protection and COVID-19 disease tolerance, but this protective circuit declines with age, increasing disease severity in the elderly.","rel_num_authors":18,"rel_authors":[{"author_name":"Sonia Trikha Rastogi","author_inst":"Gulbenkian Institute for Molecular Medicine (GIMM), Oeiras, Portugal"},{"author_name":"Miguel Mesquita","author_inst":"Gulbenkian Institute for Molecular Medicine (GIMM), Oeiras, Portugal"},{"author_name":"Diogo Martins Fonseca","author_inst":"Gulbenkian Institute for Molecular Medicine (GIMM), Oeiras, Portugal; Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal"},{"author_name":"Sara Salazar","author_inst":"Gulbenkian Institute for Molecular Medicine (GIMM), Oeiras, Portugal"},{"author_name":"Silvia Cardoso","author_inst":"Gulbenkian Institute for Molecular Medicine (GIMM), Oeiras, Portugal"},{"author_name":"Pedro Faisca","author_inst":"Gulbenkian Institute for Molecular Medicine (GIMM), Oeiras, Portugal"},{"author_name":"Bernhard Drotleff","author_inst":"Metabolomics Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany"},{"author_name":"Marta Alenquer","author_inst":"Catolica Medical School, Universidade Catolica Portuguesa, Lisboa, Portugal"},{"author_name":"Jean-Christophe Lone","author_inst":"Gulbenkian Institute for Molecular Medicine (GIMM), Oeiras, Portugal; Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal"},{"author_name":"Veronica Miguel","author_inst":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain"},{"author_name":"David Sancho","author_inst":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain"},{"author_name":"Laura Herrero","author_inst":"Institute of Biomedicina of the University of Barcelona (IBUB), Centro de Investigacion Biomedica en Red de Fisiopatologia de la Obesidad y Nutricion (CIBEROBN)"},{"author_name":"Tiago Paixao","author_inst":"Gulbenkian Institute for Molecular Medicine (GIMM), Oeiras, Portugal"},{"author_name":"Maria Joao Amorim","author_inst":"Catolica Biomedical Research Centre (CBR), Catolica Medical School, Universidade Catolica Portuguesa, Lisboa, Portugal"},{"author_name":"Elisa Jentho","author_inst":"Gulbenkian Institute for Molecular Medicine (GIMM), Oeiras, Portugal"},{"author_name":"Luis Graca","author_inst":"Gulbenkian Institute for Molecular Medicine (GIMM), Oeiras, Portugal; Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal"},{"author_name":"Jamil Zola Kitoko","author_inst":"Gulbenkian Institute for Molecular Medicine (GIMM), Oeiras, Portugal"},{"author_name":"Miguel P. Soares","author_inst":"Gulbenkian Institute for Molecular Medicine (GIMM), Oeiras, Portugal"}],"rel_date":"2026-06-30","rel_site":"biorxiv"},{"rel_title":"CyStainer: A transformer-based variational autoencoder for robust marker imputation in high-parameter cytometry","rel_doi":"10.64898\/2026.06.30.735235","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.30.735235","rel_abs":"High parameter cytometry is essential for clinical diagnostics through precise immune cell profiling, improved patient stratification, and monitoring, while also enhancing the understanding of cellular responses in disease and therapeutic contexts. The amount of cytometry data is growing fast, and with that, the need to merge different datasets for unified analysis. Here, we present CyStainer, a transformer-based variational autoencoder that demonstrates competitive or superior performance to existing methods on several key tasks related to marker prediction. As a key novelty, we demonstrate that CyStainer can impute markers without having a set of shared backbone markers. We performed several benchmarks using real-world FACS, CyTOF, InfinityFlow and CITE-seq datasets to show that CyStainer is a robust and flexible tool for panel merging, marker imputation, dataset integration and virtual staining of unseen samples.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=43 SRC=\"FIGDIR\/small\/735235v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (15K):\norg.highwire.dtl.DTLVardef@1e76266org.highwire.dtl.DTLVardef@1ed5303org.highwire.dtl.DTLVardef@1e4ff76org.highwire.dtl.DTLVardef@13faa48_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":9,"rel_authors":[{"author_name":"Konstantin Ivanov","author_inst":"School of Medicine, University of Eastern Finland, Kuopio, Finland"},{"author_name":"Mouhamad Al Moussawy","author_inst":"School of Medicine, University of Eastern Finland, Kuopio, Finland"},{"author_name":"Frederik Kirk","author_inst":"Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark"},{"author_name":"Rounioja Samuli","author_inst":"Department of Hematology, Fimlab Laboratories, Tampere, Finland"},{"author_name":"Olli Lohi","author_inst":"Faculty of Medicine and Health Technology, Tampere University Hospital, Tampere, Finland"},{"author_name":"Lars Olsen","author_inst":"Department of Clinical Medicine, Copenhagen University, Copenhagen, Denmark"},{"author_name":"Signe Modvig","author_inst":"Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark"},{"author_name":"Ville Hautam\u00e4ki","author_inst":"School of Computing, University of Eastern Finland, Joensuu, Finland"},{"author_name":"Merja Hein\u00e4niemi","author_inst":"School of Medicine, University of Eastern Finland, Kuopio, Finland"}],"rel_date":"2026-06-30","rel_site":"biorxiv"},{"rel_title":"Diversifications of both the three domains of life and SARS-CoV-2 possibly driven by biases between amino acid biosynthetic families","rel_doi":"10.64898\/2026.06.22.733698","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.22.733698","rel_abs":"All cellular life forms fall under the three-domain classification of life, raising a fundamental evolutionary question: why does this classification feature three rather than two or four? To answer this question, a more general method, rather than the traditional one based on comparing small-subunit ribosomal RNAs, is required. The three-base periodicity in genomes is a common feature of both cellular life forms and viruses, which is species-specifically biased between amino acid biosynthetic families. Based on comparing such a common feature of all life forms, a global triangular diversification picture has been obtained, whose three angular regions correspond to the three domains, respectively. This mechanism of diversification of life attributes the evolutionary driving forces in diversification of the three domains of life to the biases between amino acid biosynthetic families. Notably, the same mechanism also applies to the contemporary diversification of SARS-CoV-2, whose reasonable results in turn corroborate the above explanation of primordial diversification of life and in addition shed light on the mechanism of speciation.","rel_num_authors":1,"rel_authors":[{"author_name":"Dirson Jian Li","author_inst":"Xi'an Jiaotong University"}],"rel_date":"2026-06-30","rel_site":"biorxiv"},{"rel_title":"Conversion of a Viral Glycan Shield into a Binding Anchor via Causal-Driven Antibody Optimization","rel_doi":"10.64898\/2026.06.25.734658","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.25.734658","rel_abs":"Therapeutic antibodies are challenged by rapidly evolving pathogens that exploit glycosylation to shield epitopes. SARS-CoV-2 JN.1 exemplifies this, escaping antibodies through the N354-linked glycan. However, targeting glycosylated epitopes remains vacant, as scarce and heterogeneous glycan structures render existing approaches ineffective. Here, we introduce the Antibody Evolution Nexus with Causal-Driven Simulation (AENCS), integrating molecular simulation with causal inference. Applying AENCS to restore S309 efficacy against JN.1, we identified ACC01, exhibiting [~]24-fold improved neutralization. With limited prior knowledge of the N354 glycosylation site, ACC01 stabilized this glycan conformation, facilitating the determination of its cryo-EM structure. Causal dissection revealed how this glycan shield is functionally inverted into a binding anchor through multi-layered interactions. This mechanistic conversion, combined with the conservation of N354 glycosylation, enabled ACC01 to maintain potent activity against the latest variant NB.1.8.1. Collectively, AENCS demonstrates causal-driven antibody engineering can illuminate cryptic glycosylated epitopes, providing viable paradigms for exploring this vacant frontier.","rel_num_authors":23,"rel_authors":[{"author_name":"Xin Wang","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Guanying Zhang","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Mingda Hu","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Jin Han","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Chao Shang","author_inst":"Key Laboratory of Jilin Province for Zoonoses Prevention and Control, State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences"},{"author_name":"Lejin Zhang","author_inst":"Division of Life Sciences and Medicine, University of Science and Technology of China"},{"author_name":"Zhengshan Chen","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Ping Huang","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Wentao Wang","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Xinru Zhao","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Yunzhu Dong","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Yunxiang Zhao","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Peng Lv","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Xiaodong Zai","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Ruochun Jin","author_inst":"College of Computer Science, National University of Defense Technology"},{"author_name":"Haotian Wang","author_inst":"College of Computer Science, National University of Defense Technology"},{"author_name":"Congwen Wei","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Xiao Li","author_inst":"Key Laboratory of Jilin Province for Zoonoses Prevention and Control, State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences"},{"author_name":"Liming Yan","author_inst":"School of Basic Medical Sciences, Tsinghua University"},{"author_name":"Zhiyong Lou","author_inst":"School of Basic Medical Sciences, Tsinghua University"},{"author_name":"Hongguang Ren","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Junjie Xu","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"},{"author_name":"Xiangyang Chi","author_inst":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences"}],"rel_date":"2026-06-26","rel_site":"biorxiv"},{"rel_title":"Dose optimisation of favipiravir against RNA viruses using physiologically-based pharmacokinetic modelling.","rel_doi":"10.64898\/2026.06.24.733995","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.24.733995","rel_abs":"Favipiravir (FPV) is an RdRp inhibitor developed and licensed in Japan for influenza but which has shown promising in-vitro activity against a range of RNA viruses. A physiologically-based pharmacokinetic model was developed for oral FPV and its metabolite M1 in order to optimise the dose regimen against plasma concentration targets for a number of viral pathogens. The model was validated using clinical data and was able to capture the variability in plasma concentrations for a population of individuals. FPV doses predicted to cause in-vivo exposures exceeding in-vitro IC90 targets against influenza, Ebola, Lassa fever, CCHF, SFTS, Andes virus and SARS-CoV-2, lie within the window of observed safe dosing, with SARS-CoV-2 requiring predicted doses of 2400 mg twice daily due to lower in-vitro potency. Simulations showed that a loading dose on day one of treatment should allow plasma targets to be exceeded on day one. Simulations of chronic kidney disease (CKD) showed no change to FPV plasma concentration in individuals with CKD3 and CKD5 compared to healthy individuals.\n\nClinical data suggested active renal efflux of M1 which led to a predicted 2.2 and 11.5 fold increase in the maximum plasma concentrations of M1 in individuals with CKD3 and CKD5 respectively in comparison with healthy individuals.","rel_num_authors":5,"rel_authors":[{"author_name":"William HJ Wood","author_inst":"University of Liverpool"},{"author_name":"Henry Pertinez","author_inst":"University of Liverpool"},{"author_name":"Tim Rowland","author_inst":"Liverpool School of Tropical Medicine"},{"author_name":"Andrew Owen","author_inst":"University of Liverpool"},{"author_name":"Tom Fletcher","author_inst":"Liverpool School of Tropical Medicine"}],"rel_date":"2026-06-26","rel_site":"biorxiv"},{"rel_title":"Coevolving Mutations in Chronic SARS-CoV-2 Infections","rel_doi":"10.64898\/2026.06.11.731720","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.11.731720","rel_abs":"The SARS-CoV-2 pandemic has been marked by two outstanding features that have had major impacts on global public health: the repeated emergence and growth of highly divergent saltation variants with no known close relatives and the development of adverse health effects extending beyond the period of acute infection, called long Covid, in a proportion of the population. Chronic infections in immunocompromised hosts are the most likely explanation for the emergence of saltation variants, and some evidence indicates that viral persistence contributes to long Covid. Knowledge of intrahost evolution during prolonged SARS-CoV-2 infection is therefore vital for understanding the global evolution of SARS-CoV-2 and for deciphering the nature of long Covid and promising avenues for treatment. We assembled a collection of over 3000 independent, full-length SARS-CoV-2 sequences deriving from posited or confirmed chronic infections. We describe 14 distinct mutation patterns (MPs) that repeatedly appear in these sequences--each involving mutations in multiple genomic regions--including four CD8 T cell-escape MPs and two MPs that represent adaptation to tissue compartments outside the upper-respiratory tract. The existence of these MPs promises new insights into the life cycle and evolution of SARS-CoV-2 and the nature of persistent SARS-CoV-2 infection.","rel_num_authors":3,"rel_authors":[{"author_name":"Ryan Hisner","author_inst":"Uiversity of Cape Town"},{"author_name":"Ravindra K Gupta","author_inst":"University of Cambridge"},{"author_name":"Darren Martin","author_inst":"Division of Computational Biology"}],"rel_date":"2026-06-25","rel_site":"biorxiv"},{"rel_title":"Development of GS-441524 Derivatives as Potent SARS-CoV-2 Mac1 Inhibitors via a Direct-to-Biology Approach","rel_doi":"10.64898\/2026.06.24.734322","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.24.734322","rel_abs":"Targeting viral macrodomains (Mac) has emerged as a promising strategy for antiviral drug development, especially after the outbreak of COVID-19 that claimed millions of lives worldwide. Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mac1 inhibitors have been reported in the past few years. In the present work, we converted GS-441524 (IC50 of [~]10 M for SARS-CoV-2 Mac1) to KP-S54 (18c), a potent inhibitor of both SARS-CoV-2 Mac1 (IC50: 44 nM) and Middle East respiratory syndrome coronavirus (MERS-CoV) Mac1 (IC50: 91 nM) through an iterative direct-to-biology approach. This approach leverages efficient amide-coupling reaction and the mix-and-read fluorescence polarization (FP) assays where reaction mixtures could be screened directly without purification. Cocrystal structure of a selected derivative (12p) binding to SARS-CoV-2 Mac1 revealed the binding mode, which will guide future drug development against viral macrodomains.","rel_num_authors":10,"rel_authors":[{"author_name":"Kewen Peng","author_inst":"The University of Chicago"},{"author_name":"Suryadeep Chakraborty","author_inst":"The University of Chicago"},{"author_name":"Shamar D. Wallace","author_inst":"Cornell University"},{"author_name":"Jessica Caroline Gomes Noll","author_inst":"Cornell University"},{"author_name":"Jialin Shang","author_inst":"Cornell University"},{"author_name":"Xuan Lu","author_inst":"The University of Chicago"},{"author_name":"Annette Choi","author_inst":"Cornell University"},{"author_name":"Gary Whittaker","author_inst":"Cornell University"},{"author_name":"J. Christopher Fromme","author_inst":"Cornell University"},{"author_name":"Hening Lin","author_inst":"Howard Hughes Medical Institute, The University of Chicago"}],"rel_date":"2026-06-25","rel_site":"biorxiv"},{"rel_title":"DextraDemixer enables accurate identification of antigen-specific T cells from pMHC multimer experiments","rel_doi":"10.64898\/2026.06.23.733339","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.23.733339","rel_abs":"Antigen specificity of T cells defines the adaptive immune response, yet the vast majority of known T cell receptors (TCRs) lack annotated antigen targets. Single-cell peptide-MHC (pMHC) multimer assays offer a scalable approach to map TCR-antigen interactions. Still, their utility is limited by pervasive non-specific binding and severe overlap between signal and noise, which confound the accurate identification of antigen-specific cells. To address these limitations, we present DextraDemixer, a Bayesian hierarchical mixture model that disentangles antigen-specific T cells from background noise in pMHC multimer data. The model integrates information from negative controls and clonotype structure while providing calibrated uncertainty estimates for classification. We further introduce a dynamic thresholding scheme that enables credible interval-bounded control of the false discovery rate. Extensive benchmarking on simulated datasets and antigen-specific spike-in experiments demonstrated the models robustness and improved accuracy over established methods. In a longitudinal SARS-CoV-2 vaccine study, DextraDemixer identified antigen-specific TCRs characterized by high sequence similarity, elevated antigen-specificity prediction scores, and strong clonal purity. Annotations showed high concordance with external validation data and supported the identification of antigen-specific motifs. Overall, DextraDemixer provides a principled probabilistic framework for reliable identification of antigen-specific TCRs from single-cell pMHC-multimer assays.","rel_num_authors":6,"rel_authors":[{"author_name":"Yang An","author_inst":"Helmholtz Munich"},{"author_name":"Felix Drost","author_inst":"Helmholtz Munich"},{"author_name":"Irene Bonafonte-Pard\u00e0s","author_inst":"Helmholtz Munich"},{"author_name":"Myriam Grotz","author_inst":"University Hospital Erlangen"},{"author_name":"Kilian Schober","author_inst":"University Hospital Erlangen"},{"author_name":"Benjamin Schubert","author_inst":"Helmholtz Munich"}],"rel_date":"2026-06-25","rel_site":"biorxiv"},{"rel_title":"Quantitative modeling of SARS-CoV-2 replication reveals phase-specific bottlenecks and antiviral targets","rel_doi":"10.64898\/2026.06.23.733955","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.23.733955","rel_abs":"SARS-CoV-2 replication depends on a tightly coordinated series of intracellular processes that remain incompletely quantified. Here, we integrated high-resolution time-resolved measurements of viral RNA, protein expression, and infectious virion production with mechanistic mathematical modeling to obtain a quantitative description of the viral replication cycle in human lung cells. Using transcriptomic, proteomic, and infectivity data collected over the first 24 hours of infection, we calibrated an ordinary differential equation model that captures genomic and subgenomic RNA synthesis, viral protein production, virion assembly, and virus release. The model accurately reproduced the observed replication dynamics and enabled estimation of kinetic parameters that are difficult to measure experimentally. Sensitivity analysis identified viral RNA replication and non-structural protein maturation as dominant determinants of viral replication efficiency. To assess predictive power, the model was challenged with independent antiviral perturbation experiments using remdesivir, nirmatrelvir, and montelukast. Model predictions closely matched experimentally observed treatment responses and correctly reproduced drug interaction effects during combination therapy. Furthermore, comparison of alternative mechanistic hypotheses supported NSP5 rather than NSP1 as the primary antiviral target of montelukast. Together, these results establish a predictive framework for dissecting intracellular coronavirus replication and evaluating antiviral intervention strategies.","rel_num_authors":10,"rel_authors":[{"author_name":"Simon T. Herrmann","author_inst":"Department of Emerging Viruses, Leibniz Institute of Virology (LIV), Hamburg, Germany."},{"author_name":"Timon Kapischke","author_inst":"Institute of Bioinformatics, University Medicine Greifswald, Greifswald, Germany."},{"author_name":"Saskia Westhoven","author_inst":"Department of Emerging Viruses, Leibniz Institute of Virology (LIV), Hamburg, Germany."},{"author_name":"Natalie Heinen","author_inst":"Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany."},{"author_name":"Luca D. Bertzbach","author_inst":"Department of Emerging Viruses, Leibniz Institute of Virology (LIV), Hamburg, Germany."},{"author_name":"Toni L. Meister","author_inst":"Institute for Infection Research and Vaccine Development, University Medical Center Hamburg-Eppendorf, Hamburg, Germany."},{"author_name":"Barbara Sitek","author_inst":"Ruhr-University Bochum, Knappschaft Kliniken University Hospital Bochum, Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Bochum, Germany"},{"author_name":"Thilo Bracht","author_inst":"Ruhr-University Bochum, Knappschaft Kliniken University Hospital Bochum, Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Bochum, Germany"},{"author_name":"Stephanie Pfaender","author_inst":"Department of Emerging Viruses, Leibniz Institute of Virology (LIV), Hamburg, Germany."},{"author_name":"Lars Kaderali","author_inst":"Institute of Bioinformatics, University Medicine Greifswald, Greifswald, Germany."}],"rel_date":"2026-06-24","rel_site":"biorxiv"},{"rel_title":"Expanded protocadherin-1 usage reveals a broader hantavirus entry landscape","rel_doi":"10.64898\/2026.06.23.734139","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.23.734139","rel_abs":"Mammalian hantaviruses are RNA viruses that cause hantavirus cardiopulmonary syndrome in the Americas and hemorrhagic fever with renal syndrome in Eurasia. The cellular entry mechanisms of most hantaviruses remain poorly defined. To examine entry by phylogenetically distinct hantaviruses, we generated replication-competent recombinant vesicular stomatitis viruses (rVSVs) bearing Gn\/Gc proteins from Necocli, Sangassou, Thottapalayam, Kenkeme, Nova, Oxbow, and Tula viruses. All these Gn\/Gc proteins except Kenkeme supported infection of primary human endothelial cells, indicating that endothelial cell entry is permissive for a broader range of hantaviruses than previously appreciated. Except for rVSV-Kenkeme, these rVSVs did not acquire additional mutations beyond pre-engineered rescue-enhancing changes during rescue and passaging. Genetic studies in human cells lacking protocadherin-1 (PCDH1) showed that Necocli, Tula, and Nova viruses use PCDH1 for efficient infection, although the Nova phenotype was weaker. These three Gn\/Gc proteins bound soluble PCDH1 with different apparent avidities, and infection by the corresponding rVSVs was inhibited by soluble PCDH1; Necocli and Tula, but not Nova, were also blocked by a PCDH1-targeting monoclonal antibody. Authentic Tula virus infection was similarly reduced in PCDH1 knockout endothelial cells. Finally, the broadly reactive anti-Gn\/Gc human monoclonal antibody ADI-42898 efficiently neutralized Necocli, Nova, Sangassou, and Kenkeme rVSVs but showed weak or undetectable activity against Oxbow, Tula, and Thottapalayam rVSVs. Together, these findings expand the range of hantavirus glycoproteins capable of mediating infection of human endothelial cells, broaden the phylogenetic scope of PCDH1-dependent entry, and identify receptor-targeted and viral glycoprotein-targeted strategies with differential activity.\n\nImportanceMany newly discovered hantaviruses are known only from sequence data, leaving their ability to enter human cells and their receptor usage unresolved. Using a BSL2-compatible rVSV system, we show that glycoproteins from several divergent hantaviruses can mediate infection of primary human endothelial cells, indicating that endothelial cell entry is permissive for a broader range of hantaviruses than previously appreciated. We also show that protocadherin-1 (PCDH1), previously linked mainly to New World hantaviruses, is used by Necocli, Tula, and Nova viruses but not universally across the panel, revealing broader but heterogeneous receptor usage. An authentic Tula virus experiment supports this conclusion beyond the surrogate system. Finally, a broadly reactive anti-Gn\/Gc antibody neutralizes several, but not all, of these viruses, highlighting both the promise and the limits of broadly protective countermeasures and the utility of these rVSVs for evaluating entry inhibitors.","rel_num_authors":9,"rel_authors":[{"author_name":"Cierra Word","author_inst":"LSU Health Shreveport"},{"author_name":"Nahomi Guerra-Pilaquinga","author_inst":"LSU Health Shreveport"},{"author_name":"Ezgi Kasikci","author_inst":"Albert Einstein College of Medicine Department of Microbiology & Immunology"},{"author_name":"Lohit Khera","author_inst":"LSU Health Shreveport"},{"author_name":"Ramandeep Kaur","author_inst":"LSU Health Shreveport"},{"author_name":"Upendra P Lambe","author_inst":"LSU Health Shreveport"},{"author_name":"M Eugenia Dieterle","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Kartik Chandran","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Rohit K Jangra","author_inst":"Louisiana State University Health Sciences Center Shreveport School of Medicine"}],"rel_date":"2026-06-24","rel_site":"biorxiv"},{"rel_title":"Adjuvant selection for optimally balanced humoral and cellular immunity induced by SARS-CoV-2 Spike virosome vaccines","rel_doi":"10.64898\/2026.06.23.733553","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.23.733553","rel_abs":"Current SARS-CoV-2 vaccines provide limited breadth of protection, underscoring the need for vaccine strategies that optimize immune responses. Virosomesoffer a modular vaccine platform that enables multivalent antigen display and incorporation of adjuvants which can steer immune responses. We evaluated the immune response in BALB\/c mice with virosomes displaying SARS-CoV-2 Wuhan or Delta spike antigens and coupled with various distinct adjuvants. Adjuvant selection differentially influenced both humoral and cellular immune outcomes. The TLR7\/8 agonist 3M -052 induced a strong Th1-biased response, characterized by elevated IgG2a\/IgG1 ratios and robust type 1 cytokine induction with suppression of Th2-associated cytokines. In contrast, the saponin QS-21 enhanced antibody functional quality, illustrated by improved virus neutralization potency and breadth. Furthermore, the combined incorporation of both 3M-052 and QS-21 induced an elevated Th1-biased response without improving neutralization capacity. In conclusion, different adjuvants added onto our virosome-basedvaccine led to distinct antibody responses and splenic T-cell profiles, reflective of differences in immune programming. This information guides the selection of adjuvants for respiratory virus vaccines.","rel_num_authors":19,"rel_authors":[{"author_name":"Marloes Grobben","author_inst":"RIVM"},{"author_name":"Gius Kerster","author_inst":"Amsterdam UMC"},{"author_name":"Ester Siteur-van Rijnstra","author_inst":"Amsterdam UMC"},{"author_name":"Mitch Brinkkemper","author_inst":"Amsterdam UMC"},{"author_name":"Meliawati Poniman","author_inst":"Amsterdam UMC"},{"author_name":"Judith A Burger","author_inst":"Amsterdam UMC"},{"author_name":"Khadija Tejjani","author_inst":"Amsterdam UMC"},{"author_name":"Jacqueline van Rijswijk","author_inst":"Amsterdam UMC"},{"author_name":"Widad Ait Addouch","author_inst":"Amsterdam UMC"},{"author_name":"Melissa Oomen","author_inst":"Amsterdam UMC"},{"author_name":"Joey H Bouhuijs","author_inst":"Amsterdam UMC"},{"author_name":"Tom Bijl","author_inst":"Amsterdam UMC"},{"author_name":"Ronald Kempers","author_inst":"Mymetics BV"},{"author_name":"Kwinten Sliepen","author_inst":"Amsterdam UMC"},{"author_name":"Toon Stegmann","author_inst":"Mymetics BV"},{"author_name":"Marit J van Gils","author_inst":"Amsterdam UMC"},{"author_name":"Mathieu Claireaux","author_inst":"Erasmus MC"},{"author_name":"Yme U van der Velden","author_inst":"Amsterdam UMC"},{"author_name":"Rogier W Sanders","author_inst":"Amsterdam UMC"}],"rel_date":"2026-06-24","rel_site":"biorxiv"},{"rel_title":"Scalable Production of a De Novo SARS-CoV-2 Antiviral miniprotein in Escherichia coli","rel_doi":"10.64898\/2026.06.23.734092","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.23.734092","rel_abs":"The rapid emergence of SARS-CoV-2 variants that evade neutralizing antibodies underscores the need for next-generation antiviral biologics that combine molecular precision with scalable, cost-effective manufacturing. Computationally designed miniproteins targeting the receptor-binding domain (RBD) of the spike protein offer a compelling alternative to monoclonal antibodies due to their small size, high thermal stability, and compatibility with microbial expression systems. Here we report the end-to-end development and cGMP production of IPD-52520, a de novo antiviral miniprotein, using an optimized E. coli platform. Two miniprotein candidates, a homotrimeric construct (Trimer is referred to as IPD-52520, 17 kDa) and a tandem fusion (Daisy is referred to as IPD-52521, 25 kDa), were evaluated in parallel through systematic optimization of strain selection, media composition, fed-batch fermentation, inclusion-body solubilization, refolding, and chromatographic purification. The Trimer was downselected as the lead molecule based on superior preclinical efficacy, favorable pharmacokinetic properties, and higher volumetric manufacturing yields. The optimized process delivers approximately 2 g\/L of purified protein at greater than 90% purity. Scale-up from 5 L to 50 L under cGMP conditions demonstrated excellent batch-to-batch reproducibility across six independent batches, supporting nonclinical and Phase 1 clinical supply. Comprehensive biophysical characterization confirmed a well-folded, predominantly alpha-helical trimer (Tm = 73.4 {degrees}C; polydispersity = 1.005) with an intact primary structure and strong target-binding affinity (KD < 1 pM). Real-time stability studies indicate that the drug substance is stable at 2-8 {degrees}C for at least 12 months, with ongoing stability studies. These results demonstrate the feasibility of translating computationally designed antiviral miniproteins into manufacturable biologics and provide a platform applicable to rapid-response therapeutics against current and future pandemic threats.","rel_num_authors":15,"rel_authors":[{"author_name":"Jinhwan Shin","author_inst":"SK Bioscience"},{"author_name":"Eu-min KIm","author_inst":"SK Bioscience"},{"author_name":"Jun-hong Jang","author_inst":"SK Bioscience"},{"author_name":"Seok-won Jee","author_inst":"SK Bioscience"},{"author_name":"Sang-hoon Kim","author_inst":"SK Bioscience"},{"author_name":"Seonggwan Yu","author_inst":"SK Bioscience Ltd"},{"author_name":"Minguen Yoon","author_inst":"SK Bioscience Ltd"},{"author_name":"Daniel Craig","author_inst":"IAVI"},{"author_name":"Ryan Swoyer","author_inst":"IAVI"},{"author_name":"Praveen Alamuri","author_inst":"IAVI"},{"author_name":"Albert Price","author_inst":"IAVI"},{"author_name":"Sandip Patel","author_inst":"IAVI"},{"author_name":"Rashmi Ravichandran","author_inst":"Institute for Protein Design - University of Washington"},{"author_name":"Lauren Carter","author_inst":"Gates Medical Research Institute"},{"author_name":"Sammaiah Pallerla","author_inst":"IAVI"}],"rel_date":"2026-06-24","rel_site":"biorxiv"},{"rel_title":"DNA-barcode labelled MHCII multimers for detection of antigen-specific CD4 T cells across large libraries of epitopes","rel_doi":"10.64898\/2026.06.23.733927","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.23.733927","rel_abs":"The role of antigen-specific T cells responding to antigen is a topic of intense studies, and critical for mechanistic insight of diseases and development of therapeutic strategies. Methods for broad-scale detection of antigen-specific CD4 T cells are lacking, while such methods have demonstrated great value in exploring CD8 T cell response in health and disease. Furthermore, major histocompatibility complex II (MHCII) assays are technically challenging due to high HLA diversity, lower binding affinities, low frequencies of ex vivo antigen-specific CD4 T cells and several bottlenecks in production and peptide exchange of MHCII monomers.\n\nHere we use peptide-loaded MHCII (pMHCII) proteins multimerized on a barcode- and fluorophore-labelled dextran backbone to provide a method for the detection of peptide-specific CD4 T cells by using a large display of MHCII-associated peptides. We have established a protocol for MHCII production and peptide-exchange suitable for the generation of large libraries of peptide-MHCII complexes. We validate the use of such pMHCII complexes in the form of barcode-labelled MHCII multimers to detect antigen-specific CD4 T cells. We demonstrate that we can identify antigen specific CD4 T cells, using these DNA barcoded peptide-MHCII multimer. The multimer bound CD4 T cells were selected based on the fluorochrome signal, and the co-attached DNA barcodes were hereafter amplified and used to identify the peptide-MHCII response\/binding. In cases where the peptide-specific CD4 T cells frequencies are very low, we expanded the cell population with peptide-pools and in the presence of IL2. The given CD4 T cell populations hereby reach a cell number allowing for the DNA-barcoded pMHCII multimers to detect responses otherwise missed out.\n\nApplying this technology, we utilized a panel of 150 peptides derived from human cytomegalo virus (CMV), Epstein barr virus (EBV), Influenza (Flu), SARS CoV 2 and SARS CoV1, Hepatitis B virus (HBV), and Hepatitis C virus (HCV) loaded onto HLA-DRB1*01:01 and DRB1*04:01 to screen peripheral blood mononuclear cells (PBMC). We assessed ex vivo responses in 16 participants with HCV infection, and successfully detected naturally occurring viral-specific CD4 T cells at frequencies as low as 0.004% of total CD4 T cells. The low-frequency responses, identified via the barcode screen, were rigorously validated using individual fluorophore-labelled tetramer staining after a peptide-driven expansion in 15 participants. Furthermore, we assessed the recognition of novel HCV epitopes in 11 additional participants. Through this, we identified a total of 12 distinct HCV epitopes, including 9 that have not been previously utilized in assays to detect CD4 T cells.\n\nOverall, this barcoded-multimer platform provides a powerful tool for the large-scale discovery of class II epitopes and the broad profiling of CD4 T cell specificities. This method will allow for in-depth analyses of immune interactions, provide a better understanding of the antigen-driven associations between CD4 and CD8 T cell responses, and help dissect the complexities of CD4 T cell protection in HCV infection.","rel_num_authors":9,"rel_authors":[{"author_name":"Yogesh Basavaraju","author_inst":"Section of Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark"},{"author_name":"Suzan Dijkstra","author_inst":"Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA and The Broad Institute of Harvard University and Massa"},{"author_name":"Tripti Tamhane","author_inst":"Section of Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark"},{"author_name":"Signe Koggersbol Skadborg","author_inst":"Section of Experimental and Translational Immunology, Department of Health Technology, Technical 6 University of Denmark, Lyngby, Denmark"},{"author_name":"Liying Lu","author_inst":"Department of Pathology, UMass Chan Medical School, Worcester MA, USA"},{"author_name":"William W Kwok","author_inst":"Beneroya Research Institute, Kwok lab, Seattle WA, USA"},{"author_name":"Lawrence J Stern","author_inst":"Department of Pathology, UMass Chan Medical School, Worcester MA, USA"},{"author_name":"Georg M Lauer","author_inst":"Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA and The Broad Institute of Harvard University and Massa"},{"author_name":"Sine Reker Hadrup","author_inst":"Section of Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Post-infection immune response in adults with COVID-19 with and without nirmatrelvir-ritonavir treatment and virologic rebound","rel_doi":"10.64898\/2026.06.22.733737","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.22.733737","rel_abs":"BackgroundNirmatrelvir-ritonavir (N-R) reduces morbidity and mortality from COVID-19 in high-risk individuals; however, N-R use has been associated with risk of SARS-CoV-2 virologic rebound. The mechanisms contributing to virologic rebound after N-R treatment are currently unknown. One plausible mechanism is that antiviral treatment may alter the development of immune responses to SARS-CoV-2 infection, thereby contributing to rebound after cessation of therapy.\n\nMethodsWe profiled immune responses in a case-ascertained, longitudinal, prospective cohort of ambulatory individuals with COVID-19. Participants were grouped according to whether virological rebound occurred and whether they had received N-R treatment. We assessed antibody, T-cell, and innate responses.\n\nResultsWe observed no differences in the binding or neutralizing antibody, T-cell, and innate immune responses between participants with virologic rebound compared to participants without virologic rebound. N-R use was associated with slightly weaker antibody responses overall, even after adjustment for immunosuppression.\n\nConclusionVirologic rebound after N-R treatment is likely driven by non-immune mechanisms.\n\nFundingThe project was supported by the National Institutes of Health (R01 AI 138801) and the Massachusetts Consortium on Pathogen Readiness. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.","rel_num_authors":25,"rel_authors":[{"author_name":"Dibya Ghimire","author_inst":"Massachusetts General Hospital, Boston, Massachusetts"},{"author_name":"Chloe M. Hasund","author_inst":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA, Infectious Disease and Microbiome Program, Broad I"},{"author_name":"John Bianchi Colangeli","author_inst":"Massachusetts General Hospital, Boston, Massachusetts, Broad Institute, Cambridge, Massachusetts"},{"author_name":"May Y. Liew","author_inst":"Massachusetts General Hospital, Boston, Massachusetts"},{"author_name":"Emory Abar","author_inst":"Massachusetts General Hospital, Boston, Massachusetts"},{"author_name":"Mamadou Barry","author_inst":"Massachusetts General Hospital, Boston, Massachusetts"},{"author_name":"Andrew Alexandrescu","author_inst":"Massachusetts General Hospital, Boston, Massachusetts"},{"author_name":"Benjamin L. Kotzen","author_inst":"Massachusetts General Hospital, Boston, Massachusetts"},{"author_name":"Zahra Reynolds","author_inst":"Massachusetts General Hospital, Boston, Massachusetts"},{"author_name":"Eliza Passell","author_inst":"Massachusetts General Hospital, Boston, Massachusetts"},{"author_name":"Chase Mandell","author_inst":"Massachusetts General Hospital, Boston, Massachusetts"},{"author_name":"Zoie Smith-Sparks","author_inst":"Massachusetts General Hospital, Boston, Massachusetts"},{"author_name":"Karry Su","author_inst":"Massachusetts General Hospital, Boston, Massachusetts"},{"author_name":"Julie Boucau","author_inst":"Ragon Institute of Mass General Brigham, MIT, and Harvard, Cambridge, Massachusetts"},{"author_name":"Owen T. Glover","author_inst":"Ragon Institute of Mass General Brigham, MIT, and Harvard, Cambridge, Massachusetts"},{"author_name":"Brooke Leeman","author_inst":"Brigham and Women's Hospital, Boston, Massachusetts"},{"author_name":"Gregory E. Edelstein","author_inst":"Brigham and Women's Hospital, Boston, Massachusetts"},{"author_name":"Manish C. Choudhary","author_inst":"Brigham and Women's Hospital, Boston, Massachusetts"},{"author_name":"Yijia Li","author_inst":"Brigham and Women's Hospital, Boston, Massachusetts, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania"},{"author_name":"Naomi Patel","author_inst":"Massachusetts General Hospital, Boston, Massachusetts"},{"author_name":"Jeffrey A. Sparks","author_inst":"Brigham and Women?s Hospital, Boston, Massachusetts"},{"author_name":"Amy K. Barczak","author_inst":"Massachusetts General Hospital, Boston, Massachusetts, Ragon Institute of Mass General Brigham, MIT, and Harvard, Cambridge, Massachusetts, Harvard Medical Scho"},{"author_name":"Jonathan Z. Li","author_inst":"Brigham and Women?s Hospital, Boston, Massachusetts"},{"author_name":"Mark J. Siedner","author_inst":"Massachusetts General Hospital, Boston, Massachusetts, Harvard Medical School, Boston, Massachusetts"},{"author_name":"Jacob E. Lemieux","author_inst":"Massachusetts General Hospital, Boston, Massachusetts, Broad Institute, Cambridge, Massachusetts, Harvard Medical School, Boston, Massachusetts"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Multi-Scale Machine Learning for Antibody-Antigen Binding Affinity Prediction Using Deep Mutational Scanning and Structural Features","rel_doi":"10.64898\/2026.06.09.730151","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.09.730151","rel_abs":"Predicting how mutations alter antibody-antigen binding affinity is essential for antibody engineering and vaccine design, yet current methods generalize poorly to unseen complexes. We present a multi-scale machine learning framework integrating 93 descriptors across four modalities: physicochemical, structural, ESM-2 protein language model, and solvent-accessible surface area (SASA)\/{Delta}{Delta}Gfold features. Under leave-one-complex-out deep mutational scanning (LOCO-DMS) cross-validation on AbAgym (36,541 mutations, 68 experiments, 13 pathogens), gradient boosting achieved MCC = 0.206; a confidence-stratified ensemble reached MCC = 0.374 (83.5% accuracy, 25.5% coverage). No single modality exceeds the majority baseline alone; only multi-scale fusion succeeds. Boltzmann ceiling analysis shows 45.9% of mutations are near-neutral (|{Delta}{Delta}G| < kBT), bounding theoretical maximum MCC at 0.473; our method achieves 79.1% of this limit. Five deep learning architectures benchmarked under LOCO-DMS showed self-attention matching gradient boosting (MCC = 0.200). Cross-pathogen transfer failed systematically (mean 46.7%), confirming universal binding predictors remain an open challenge.","rel_num_authors":1,"rel_authors":[{"author_name":"SANTHOSH Sivasubramani","author_inst":"IIT DELHI"}],"rel_date":"2026-06-23","rel_site":"biorxiv"},{"rel_title":"Identification of Altered Potassium Channels for Drug Repurposing in Long COVID Patients","rel_doi":"10.64898\/2026.06.18.733062","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.18.733062","rel_abs":"Long COVID (LC) is a complex condition characterized by persistent, chronic multisystem manifestations, with a significant proportion of patients exhibiting neurological symptoms. Human ion channels (HICs), particularly potassium channels, are abundantly expressed in the nervous system and linked to key metabolic processes, making them potential candidates for understanding LC pathophysiology and drug repurposing. Meta-analysis of RNA-Seq datasets from COVID-19 recovered and LC patients was performed to identify altered HICs in LC. Differential gene expression analysis, functional enrichment analysis, and weighted gene co-expression network analysis (WGCNA) were performed to uncover key genes, pathways, and co-expression modules consisting of HICs, lipid metabolism-, and immune signaling-related genes. Drug-gene interaction analysis was performed to identify approved drugs targeting potential HICs. A total of 715 dysregulated genes, including eighteen HICs were identified, among which seven were potassium channels. Three significant modules containing HICs, lipid metabolism-, and immune signaling-related genes were identified and found to be associated with antigen processing and presentation, complement and coagulation cascades, and cytokine-related pathways. Approved drugs targeting KCNA6, KCNJ10, KCNN3, and KCNH4 were identified. With further experimental validation, these dysregulated potassium channels, supported by their co-expression networks and pathway associations, may act as potential candidates for drug repurposing in LC patients.","rel_num_authors":3,"rel_authors":[{"author_name":"John P. George","author_inst":"Institute of Bioinformatics, Bangalore"},{"author_name":"Kiran Bharat Gaikwad","author_inst":"Institute of Bioinformatics, Bangalore"},{"author_name":"Jyoti Sharma","author_inst":"Institute of Bioinformatics, Bangalore"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"SARS-CoV-2 saltational events are recurrent and trace to persistent human infections","rel_doi":"10.64898\/2026.06.18.733214","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.18.733214","rel_abs":"SARS-CoV-2 evolution is characterized by gradual mutation accumulation but has been punctuated by rare yet impactful highly mutated variants. Whether such saltational jumps are a broad feature of SARS-CoV-2 evolution or rare anomalies remains unclear. We systematically investigate SARS-CoV-2 saltational evolution by developing a scalable framework to detect saltational events from 4.4 million high-quality viral genomes. Saltational events occurred at low but detectable rates during the pandemic and post-pandemic periods and across geographies. Their mutational signature closely matches that seen in persistent human infections but is inconsistent with the signatures of mink or deer infections. This points to persistent infection, rather than reverse zoonosis, as their primary source. While most saltational events lack evidence of onward transmission, those that do tend to carry mutations found in successful clades. Our work demonstrates that the emergence of highly mutated SARS-CoV-2 variants reflects a recurrent evolutionary process, with implications for preparedness.","rel_num_authors":4,"rel_authors":[{"author_name":"Cecile Tran-Kiem","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Kathryn Kistler","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Ryan Hisner","author_inst":"Uiversity of Cape Town"},{"author_name":"Trevor Bedford","author_inst":"Fred Hutchinson Cancer Research Center"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Pandemic Coronavirus Genome Packaging Relies on Multiple Dispersed Packaging Signals","rel_doi":"10.64898\/2026.06.18.733228","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.18.733228","rel_abs":"Packaging of viral genomes into progeny virions is a critical step in the viral life cycle. Coronaviruses such as SARS-CoV-2 possess unusually large RNA genomes ([~]30 kb), yet the mechanism by which these genomes are selectively condensed and incorporated into virions remains poorly understood. Here, we demonstrate that the SARS-CoV-2 genome contains multiple dispersed RNA structures, termed packaging signals (PSs), which cooperate with a dominant central PS to direct genomic RNA incorporation into infectious particles. We identify the dominant PS within the coding region of the nsp15 gene, downstream of a packaging signal previously described in Embecoviruses. Using virus-like particles (VLPs), we investigate its role in virion assembly and selective genomic RNA packaging, and show that it promotes the formation of ribonucleoprotein (RNP) complexes with the viral nucleocapsid protein (N), as revealed by mass photometry. Notably, we uncover a unique N-induced conformational rearrangement of the PS RNA, from an extended structure to a double stem-loop architecture. This dominant PS acts together with a nearby stem-loop element to assemble a higher-order RNP complex containing 12 N-protein dimers. Using a SARS-CoV-2 replicon system, we further demonstrate functional cooperativity between the dominant PS, its proximal partner stem-loop, and additional packaging elements located approximately 10 kb upstream. Collectively, our findings support a highly dynamic and cooperative mechanism of SARS-CoV-2 genome packaging that relies on multiple dispersed packaging signals organized around a dominant central PS. These insights provide a mechanistic framework for understanding coronavirus genome packaging and reveal new opportunities for antiviral intervention through disruption of this process. They also have important implications for vaccine development and may enable the design of membrane-based vector systems capable of efficiently delivering large nucleic acid cargoes, expanding the potential of bionanotechnology and genetic medicine.","rel_num_authors":13,"rel_authors":[{"author_name":"Taha Y. Taha","author_inst":"Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Nikesh Patel","author_inst":"Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK"},{"author_name":"Sam Clark","author_inst":"Departments of Mathematics and Biology, University of York, YO10 5GE, UK"},{"author_name":"Julia Rosecrans","author_inst":"Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Abdullah M. Syed","author_inst":"Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Rebecca Chandler-Bostock","author_inst":"Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK"},{"author_name":"Erik R. Farquhar","author_inst":"CWRU Center for Synchrotron Biosciences, NSLS-II, Brookhaven National Laboratory, Upton, NY 11973, USA"},{"author_name":"Lekshmi B.G. Nair","author_inst":"Departments of Mathematics and Biology, University of York, YO10 5GE, UK"},{"author_name":"Abid Javed","author_inst":"Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK"},{"author_name":"Jennifer A. Doudna","author_inst":"Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Peter G. Stockley","author_inst":"Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK"},{"author_name":"Melanie Ott","author_inst":"Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Reidun Twarock","author_inst":"Departments of Mathematics and Biology, University of York, YO10 5GE, UK"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"A novel model demonstrating that human immune cells promote multiorgan SARS-CoV-2 dissemination and human T cells limit anti-viral innate immunity","rel_doi":"10.64898\/2026.06.18.733232","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.18.733232","rel_abs":"Despite extensive studies, many questions remain regarding the pathology and mechanisms behind Coronavirus disease 2019 (COVID-19), and particularly on post-acute sequelae of COVID-19 (PASC). Because existing mouse models cannot recapitulate human immune responses, we developed a human immune system (HIS) mouse model with physiologic expression of hACE2. After intranasal infection, persistent viral RNA was observed in multiple organs for 8 weeks, despite the generation of human SARS-CoV-2-specific T cell responses. Human immune cells increased viral infection in the lung and non-pulmonary tissues. COVID-19-related pathology was recapitulated in the lungs, with fibrosis peaking at 14 days post-infection. Immune activation was detected in the lungs, hearts, intestines and brains of acutely infected mice and persisted at 8 weeks in the heart and lungs. The presence of human T cells correlated with attenuated innate antiviral transcriptional signatures in the lung, where a persisting cytotoxic mature CD4+ T cell population with JAK-STAT activation was enriched in infected mice. Thus, human T cells mount an antigen-specific but ultimately dysfunctional response, while paradoxically suppressing the innate interferon response, permitting chronic interferon activation and long-term viral persistence, recapitulating several immunologic and histopathologic features associated with PASC. This model will uniquely facilitate understanding of virus-human immune dynamics and therapeutic approaches to PASC.","rel_num_authors":15,"rel_authors":[{"author_name":"Amber Wolabaugh","author_inst":"Columbia University"},{"author_name":"Vrushali V Agashe","author_inst":"Columbia University"},{"author_name":"Zicheng Wang","author_inst":"Columbia University"},{"author_name":"Nichole M. Danzl","author_inst":"Columbia University"},{"author_name":"Christopher A. Parks","author_inst":"Columbia University"},{"author_name":"Mohsen Khosravi-Maharlooei","author_inst":"Columbia University"},{"author_name":"Xiaolan Ding","author_inst":"Columbia University"},{"author_name":"Hao Wei Li","author_inst":"Columbia University"},{"author_name":"Candace Castagna","author_inst":"Columbia University"},{"author_name":"Giorgia Zanetti","author_inst":"Columbia University"},{"author_name":"Katherine D. Long","author_inst":"Columbia University"},{"author_name":"Yasmeen S. Saad","author_inst":"Columbia University"},{"author_name":"Anjali Saqi","author_inst":"Columbia University"},{"author_name":"Moriya Tsuji","author_inst":"Columbia University"},{"author_name":"Megan Sykes","author_inst":"Columbia University"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Geometric Deep Learning Reveals Ligandable and Cryptic RNA Binding Small Molecule Pockets (SMARTPocket)","rel_doi":"10.64898\/2026.06.18.732920","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.18.732920","rel_abs":"RNAs are important therapeutic targets, however identifying ligandable small-molecule binding pockets remains a major barrier to RNA-targeted drug discovery. Here, SMARTPocket, an atomic-level geometric deep learning framework for predicting RNA-small molecule binding pockets directly from three-dimensional structure is introduced. SMARTPocket represents RNA as full-atom point clouds and uses transfer learning from more than 110,000 protein binding interface structures to overcome the limited number of experimentally elucidated RNA-ligand complexes. Across four established single-chain benchmarks and three broader curated benchmarks, SMARTPocket consistently outperforms existing RNA pocket predictors and general biomolecular modeling approaches. The model generalizes to apo RNA structures when conformational changes are modest, identifies cryptic ligandable pockets, and recapitulates experimentally validated binding sites in the SARS-CoV-2 frameshifting element and an RNA aptamer evolved to bind small molecules. SMARTPocket-guided docking further improves near-native RNA-ligand pose recovery and computational efficiency compared with blind docking. These results establish SMARTPocket as a generalizable framework for structure-based identification of ligandable RNA pockets and for accelerating discovery of RNA-targeted small molecules.","rel_num_authors":7,"rel_authors":[{"author_name":"Riddhish H. Thakare","author_inst":"University of Florida, Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development, Gainesville, FL 32610, USA."},{"author_name":"Amirhossein Taghavi","author_inst":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Department of Chemistry, 130 Scripps Way, Jupiter, FL 33458, USA."},{"author_name":"Jielei Wang","author_inst":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Department of Chemistry, 130 Scripps Way, Jupiter, FL 33458, USA. The Scripp"},{"author_name":"Jessica L. Childs-Disney","author_inst":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Department of Chemistry, 130 Scripps Way, Jupiter, FL 33458, USA."},{"author_name":"Chenglong Li","author_inst":"University of Florida, Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development, Gainesville, FL 32610, USA."},{"author_name":"Matthew D. Disney","author_inst":"The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Department of Chemistry, 130 Scripps Way, Jupiter, FL 33458, USA. The Scripp"},{"author_name":"Yanjun Li","author_inst":"University of Florida, Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development, Gainesville, FL 32610. University of Flor"}],"rel_date":"2026-06-19","rel_site":"biorxiv"},{"rel_title":"Antagonism of stress granules key for SARS-CoV-2 infection and pathogenesis.","rel_doi":"10.64898\/2026.06.16.732644","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.16.732644","rel_abs":"Viruses must subvert host responses to facilitate successful infection. While most antiviral responses are associated with interferons, stress granules (SG) are another barrier to viral infection by inducing translation arrest. To combat SG activity, viruses have evolved mechanisms to disrupt formation and disassemble these complexes. Our prior studies identified residues in SARS-CoV-2 NSP3 (Y138\/F145) and nucleocapsid (F17) that independently antagonize SG activity. Disrupting these key residues in NSP3 or nucleocapsid attenuated viral replication, but only modestly impacted in vivo pathogenesis suggesting overlap in SG antagonism partially compensate for the individual losses. In this study, we evaluated a SARS-CoV-2 mutant (YF\/F17A) that combines the NSP3 and N mutations. We find that loss of both SG antagonizing functions attenuates SARS-CoV-2 replication in vitro. While no changes are seen in type I IFN sensitivity, attenuation corresponds to increased induction of SGs. Importantly, the SARS-CoV-2 YF\/F17A mutant has significant attenuation in vivo with reduced viral replication, less weight loss, and limited immune pathology. Notably, infection with the YF\/F17A mutant stimulated less interferon and inflammation. Despite these muted host responses, the YF\/F17A mutant stimulated robust protection against subsequent challenge with WT SARS-CoV-2. Overall, the study highlights the importance of SG control for SARS-CoV-2 infection and offers a novel, interferon independent target for vaccination and therapeutic treatment going forward.\n\nImportanceThis study demonstrates that SARS-CoV-2 uses multiple mechanisms to block host stress granules during infection. Knocking out both N and NSP3 mediated antagonism of stress granules attenuates viral replication and disease caused by SARS-CoV-2. Importantly, while most therapeutics target key viral processes or induce interferon pathways, this study shows stress granule activation as a novel approach to attenuate and treat coronavirus infection.","rel_num_authors":18,"rel_authors":[{"author_name":"R. Elias Alvarado","author_inst":"University of Texas Medical Branch"},{"author_name":"Jennifer Chen","author_inst":"UTMB"},{"author_name":"Yiyang Zhou","author_inst":"Emory University"},{"author_name":"Kumari G Lokugamage","author_inst":"Emory University"},{"author_name":"Leah K Estes","author_inst":"UTMB"},{"author_name":"Angelica L Morgan","author_inst":"Emory University"},{"author_name":"Yani P Ahearn","author_inst":"UTMB"},{"author_name":"Xiangxue Deng","author_inst":"UTMB"},{"author_name":"Lilin Lai","author_inst":"Emory University Emory National Primate Research Center"},{"author_name":"Arian Moayyed","author_inst":"UTMB"},{"author_name":"William Meyers","author_inst":"UTMB"},{"author_name":"Jessica A Plante","author_inst":"University of Texas Medical Branch"},{"author_name":"Kenneth S Plante","author_inst":"The University of Texas Medical Branch at Galveston"},{"author_name":"David  H. S Walker","author_inst":"The University of Texas Medical Branch at Galveston"},{"author_name":"Xuping Xie","author_inst":"University of Texas Medical Branch"},{"author_name":"Mehul Suthar","author_inst":"Emory University"},{"author_name":"Bryan A Johnson","author_inst":"University of Texas Medial Branch"},{"author_name":"Vineet D Menachery","author_inst":"Emory University"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Laudanosine restricts Ebola virus entry by targeting TPC2-dependent endolysosomal trafficking","rel_doi":"10.64898\/2026.06.17.732874","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.17.732874","rel_abs":"Late endosome-dependent viruses, including filo- and arenaviruses, rely on host endolysosomal trafficking for productive infection. Here, we used a dual-colour Vesicular stomatitis virus (VSV) based pseudoparticle screen of CytoSorb-derived fractions to identify inhibitors of the Zaire Ebolavirus glycoprotein (GP)-mediated entry. Iterative chromatographic purification and mass spectrometry identified Laudanosine, a degradation product of the clinically used neuromuscular blocker Atracurium, as the antiviral compound. Laudanosine specifically inhibited entry mediated by Ebola, Marburg, Lymphocytic choriomeningitis and Lassa virus glycoproteins without affecting VSV-G-dependent entry. Importantly, Laudanosine inhibited authentic Ebola virus infection without detectable cytotoxicity in cell culture and embryonic zebrafish. Molecular dynamics simulations suggest stable association of Laudanosine with the allosteric inhibitory pocket of the lysosomal two-pore channel (TPC2). Consistently, Laudanosine impairs autophagic flux and disrupts endolysosomal trafficking. Together, our findings identify Laudanosine as a previously unrecognised inhibitor of TPC2-dependent entry of highly lethal viral pathogens.","rel_num_authors":18,"rel_authors":[{"author_name":"Tom Seitz","author_inst":"Ulm University Medical Center, Institute of Molecular Virology"},{"author_name":"Julian Koengeter","author_inst":"Ulm University, Institute of Electrochemistry"},{"author_name":"Susanne Klute","author_inst":"Ulm University Medical Center, Institute of Molecular Virology"},{"author_name":"Franziska Kraft","author_inst":"Philipps-University Marburg, Institute for Virology"},{"author_name":"Denise Christine Clesle","author_inst":"Ulm University Medical Center, Institute of Molecular Virology"},{"author_name":"Lily Tschampel","author_inst":"Ulm University Medical Center, Institute of Molecular Virology"},{"author_name":"Nico Preising","author_inst":"Ulm University Medical Center, Core Facility Functional Peptidomics"},{"author_name":"Armando Alexei Rodr\u00edguez Alfonso","author_inst":"Ulm University Medical Center, Core Facility Functional Peptidomics \/ Core Facility of Mass Spectrometry and Proteomics"},{"author_name":"Sebastian Wiese","author_inst":"Ulm University Medical Center, Core Facility of Mass Spectrometry and Proteomics"},{"author_name":"Ludger St\u00e4ndker","author_inst":"Ulm University Medical Center, Core Facility Functional Peptidomics"},{"author_name":"Christoph Jung","author_inst":"Ulm University, Institute of Electrochemistry"},{"author_name":"Timo Jacob","author_inst":"Ulm University, Institute of Electrochemistry"},{"author_name":"Janet K\u00f6hler","author_inst":"Ulm University, Institute of Biochemistry and Molecular Biology"},{"author_name":"Gilbert Weidinger","author_inst":"Ulm University, Institute of Biochemistry and Molecular Biology"},{"author_name":"Nadine Biedenkopf","author_inst":"Philipps-University Marburg, Institute for Virology"},{"author_name":"Konstantin Maria Johannes Sparrer","author_inst":"German Center for Neurodegenerative Diseases (DZNE)"},{"author_name":"Frank Kirchhoff","author_inst":"Ulm University Medical Center, Institute of Molecular Virology"},{"author_name":"Fabian Zech","author_inst":"Ulm University Medical Center, Institute of Molecular Virology"}],"rel_date":"2026-06-18","rel_site":"biorxiv"},{"rel_title":"Circular RNA vaccine performance is determined by RNA quality and epitranscriptomic tuning rather than innate activation","rel_doi":"10.64898\/2026.06.11.731499","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.11.731499","rel_abs":"Circular RNA (circRNA) is an emerging vaccine modality that is proposed to improve stability, reduce reactogenicity and extend antigen expression compared with linear mRNA. However, the relative contributions to vaccine performance of its covalently closed structure, its purity, and of nucleotide modifications remain poorly described. Here, we systematically dissected these parameters in vivo across two antigen systems. We identified RNA quality as a major determinant of circRNA reactogenicity, with differences in innate immune activation tracking with the presence of residual RNA species in less refined preparations. In contrast, highly purified circRNA exhibited markedly reduced reactogenicity compared with linear mRNA, independent of nucleotide modification. Despite these differences, circRNA and mRNA vaccines elicited comparable antibody titres and T cell responses, indicating that reduced innate activation does not enhance adaptive immune magnitude. Notably, incorporating N6-methyladenosine (m6A) did not affect reactogenicity or antigen expression but selectively enhanced antibody quality, increasing binding affinity and neutralisation capacity. CircRNA vaccination also altered the anatomical distribution of germinal centre responses, reducing splenic antigen-specific germinal centre B cells while preserving lymph node responses. Together, these findings show that circRNA vaccine performance is governed by RNA preparation quality and epitranscriptomic tuning rather than innate activation alone.","rel_num_authors":15,"rel_authors":[{"author_name":"Abby L Martin","author_inst":"Malaghan Institute of Medical Research"},{"author_name":"Jessica F Cotterell","author_inst":"Malaghan Institute of Medical Research"},{"author_name":"Kaitlin H Buick","author_inst":"Malaghan Institute of Medical Research"},{"author_name":"Thomas W Bird","author_inst":"Malaghan Institute of Medical Research"},{"author_name":"Joanna Kuang","author_inst":"Malaghan Institute of Medical Research"},{"author_name":"Olga R Palmer","author_inst":"Malaghan Institute of Medical Research"},{"author_name":"Ngarangi C Mason","author_inst":"Malaghan Institute of Medical Research"},{"author_name":"Lydia White","author_inst":"Malaghan Institute of Medical Research"},{"author_name":"Sarah L Draper","author_inst":"Ferrier Research Institute, Victoria University of Wellington"},{"author_name":"Amy J Foster","author_inst":"Ferrier Research Institute, Victoria University of Wellington"},{"author_name":"Gavin F Painter","author_inst":"Ferrier Research Institute, Victoria University of Wellington"},{"author_name":"Isabelle Montgomerie","author_inst":"Malaghan Institute of Medical Research"},{"author_name":"Tifany Oulavallickal","author_inst":"Victoria University of Wellington"},{"author_name":"Wayne M Patrick","author_inst":"Victoria University of Wellington"},{"author_name":"Lisa M Connor","author_inst":"Malaghan Institute of Medical Research"}],"rel_date":"2026-06-15","rel_site":"biorxiv"},{"rel_title":"Emulating the gingival-tooth interface during bacterial, fungal, and viral infection in a microphysiological model of the human oral cavity","rel_doi":"10.64898\/2026.06.11.731421","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.11.731421","rel_abs":"The anatomical complexity and distinctive tissue environment of the human oral cavity pose major challenges to modeling oral infection and host-microbe interactions in preclinical laboratory settings. Here we present a bioengineered oral microphysiological system comprising vascularized human gingival tissue integrated with tooth analogs that together recreate a functional unit of the human oral cavity. We incorporated Streptococcus mutans and Candida albicans into this system to model cross-kingdom biofilm formation, microbial dissemination, and host-microbial interactions at the gingival-tooth interface. Single-cell RNA sequencing and global metabolomics analysis revealed that fungal colonization induces epithelial-to-mesenchymal transition associated with distinct transcriptional and metabolic signatures. Our platform also allowed us to simulate SARS-CoV-2 infection and examine gingival responses to live-virus challenge. Finally, we integrated the engineered gingival tissue with controlled human saliva flow to show that hyposalivation potentiates the pathogenic capacity of fungal infection. This work demonstrates the potential of oral microphysiological systems as an experimental platform for in vitro modeling and mechanistic investigation of host-microbe interactions under controlled, human-relevant conditions.","rel_num_authors":7,"rel_authors":[{"author_name":"Mousa Younesi","author_inst":"University of Pennsylvania"},{"author_name":"Pouria Fattahi","author_inst":"University of Pennsylvania"},{"author_name":"Zhi Ren","author_inst":"University of Pennsylvania"},{"author_name":"Won Dong Lee","author_inst":"Princeton University"},{"author_name":"Sara Cherry","author_inst":"University of Pennsylvania"},{"author_name":"Hyun Koo","author_inst":"University of Pennsylvania"},{"author_name":"Dan Dongeun Huh","author_inst":"University of Pennsylvania"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Molecular and ecological determinants of effective reassortment in orthohantaviruses","rel_doi":"10.64898\/2026.06.10.731004","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.10.731004","rel_abs":"A central unsolved problem in RNA virus evolution is understanding why some viral reassortants establish and persist while others do not. To answer this question, we reconstructed reassortant histories across 553 viral genomes from seven orthohantavirus species between 1983 and 2024 using phylogenetic reconciliation and molecular dating. We found that the frequency of retained reassortants varied among orthohantaviruses. For example, reassortment ranged from absent in Andes virus to frequent in Dobrava-Belgrade, Sin Nombre, Seoul, Puumala, and Tula viruses, showing that effective reassortment is not a genus-wide constant. Our Bayesian hierarchical models identified local host overlap as the strongest ecological factor associated with viral reassortment, while cross-segment linkage and terminal RNA structure serve as a molecular filter. We found that the probability of reassortment establishment is highest when ecological opportunity is paired with molecular permissiveness, with their interaction term inferred as the strongest signal in our establishment models (posterior probability = 0.97). These results suggest that reassortment in orthohantaviruses is a sequentially filtered evolutionary process in which divergent lineages must first meet in a host through ecological overlap, exchange segments that are molecularly compatible, and do so within a lineage background permissive to establishment in the host population.","rel_num_authors":10,"rel_authors":[{"author_name":"Ricardo Rivero","author_inst":"Washington State University"},{"author_name":"David Simons","author_inst":"Pennsylvania State University"},{"author_name":"Lambodhar Damodaran","author_inst":"Emory University"},{"author_name":"Irene Karegi","author_inst":"Washington State University"},{"author_name":"Sarah Gurev","author_inst":"Harvard Medical School"},{"author_name":"Daniel J Becker","author_inst":"University of Oklahoma"},{"author_name":"Dan L Warren","author_inst":"Charles Sturt University"},{"author_name":"Nicola F Mueller","author_inst":"University of California San Francisco"},{"author_name":"David A Rasmussen","author_inst":"North Carolina State University"},{"author_name":"Stephanie N Seifert","author_inst":"Washington State University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Hantavirus Disease in Uruguay: Trends and Mortality Before and During the COVID-19 Pandemic.","rel_doi":"10.64898\/2026.06.10.26355375","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.06.10.26355375","rel_abs":"IntroductionHantavirus disease is an emerging and potentially severe zoonosis of global distribution. In Uruguay, it is transmitted by rodents inhabiting peridomestic, suburban, and rural areas. Global incidence is estimated at 150,000 to 200,000 cases per year, with up to 300 annual cases in the Americas. Since 1997, Uruguays Ministry of Public Health (MPH) has monitored Hantavirus cardiopulmonary syndrome (HCPS), the most common clinical presentation in the region. By 2019, a total of 271 cases had been identified in the country, with an estimated mortality rate of nearly 50%.\n\nObjectivesTo describe the clinical, epidemiological, and occupational characteristics of patients with Hantavirus disease in Uruguay during the pre-pandemic (2018-2019) and pandemic (2020-2021) periods.\n\nMethodsA descriptive, cross-sectional, observational study was conducted, including all serologically confirmed cases of Hantavirus infection reported to the MPH between 2018 and 2021. Clinical and demographic data were extracted from the mandatory reporting form for zoonotic diseases. Incidence and case fatality rates were calculated, and factors associated with fatal outcomes were analyzed.\n\nResultsA total of 58 confirmed cases were identified between 2018 and 2021. Most patients were male (62%), with a mean age of 36.5 years (SD 16). A decline in incidence was observed during 2020-2021, with no significant change in case fatality. Direct rodent exposure was the most frequently associated risk factor. Montevideo and Canelones were the most affected departments. Renal and pulmonary involvement were significantly associated with mortality.\n\nConclusionHantavirus remains a relevant public health concern in Uruguay. Although a decrease in incidence was observed during the COVID-19 pandemic years, case fatality rates remained high. The findings underscore the need for sustained surveillance and early recognition, particularly in urbanizing regions.","rel_num_authors":9,"rel_authors":[{"author_name":"zelika criscuolo","author_inst":"Internal Medicina Department, Academic Unit 1. Hospital Maciel."},{"author_name":"Leandro Blanco","author_inst":"Internal Medicina Department, Academic Unit 1. Hospital Maciel."},{"author_name":"Federico Ferrara","author_inst":"Faculty of Medicine, University of the Republic, Montevideo, Uruguay."},{"author_name":"Karen Ciaccio","author_inst":"Faculty of Medicine, University of the Republic, Montevideo, Uruguay."},{"author_name":"Leandro Gomez Carassale","author_inst":"Faculty of Medicine, University of the Republic, Montevideo, Uruguay"},{"author_name":"Maria Gonzalez Reyes","author_inst":"Faculty of Medicine, University of the Republic, Montevideo, Uruguay"},{"author_name":"Bruno Machado Rivero","author_inst":"Faculty of Medicine, University of the Republic, Montevideo, Uruguay."},{"author_name":"Federico Sosa Dias","author_inst":"Faculty of Medicine, University of the Republic, Montevideo, Uruguay."},{"author_name":"Jorge Antonio Facal Castro","author_inst":"Internal Medicina Department. Academic Unit 1. Hospital Maciel."}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Secreted ORF8 reprograms macrophages to enhance SARS-CoV-2 infection of lung epithelial cells","rel_doi":"10.64898\/2026.06.10.731427","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.10.731427","rel_abs":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily targets the respiratory epithelium, yet severe disease features diffuse lung injury and hyperinflammatory syndromes driven by dysregulated immune activation. Emerging evidence indicates that resident and infiltrating immune cells in the lung can encounter the virus early in infection and, under specific conditions, become infected (1, 2). This process amplifies local inflammation and facilitates viral propagation in the lower airways and distal lung regions (3, 4), where angiotensin converting enzyme 2 (ACE2) expression is limited (5, 6). However, how epithelial and immune cell compartments interact to produce the hallmark pulmonary pathology of SARS-CoV-2 infection remains unresolved. Here we show that secreted ORF8, a SARS-CoV-2 accessory protein, drives inflammatory lung pathology by increasing macrophage permissiveness to infection, triggering pyroptosis, and amplifying viral replication in alveolar epithelial cells. Co-culture of macrophages with human alveolar type II (AT2) cells overrides ORF8s previously reported inhibition of AT2 infection (7, 8), restoring productive viral replication. In vivo, IL-17RA blockade counteracts ORF8 activity, lowering viral burden and attenuating pulmonary inflammation and fibrosis. These findings reveal a paracrine role for ORF8 in reprogramming macrophages, thereby establishing a feedforward proviral circuit that accelerates lung pathology in COVID-19 and are clinically relevant given the recurrent emergence of SARS-CoV-2 variants with either intact or deleted ORF8 since the beginning of the pandemic.","rel_num_authors":15,"rel_authors":[{"author_name":"Yusuke Matsui","author_inst":"Gladstone Institutes"},{"author_name":"Rahul K Suryawanshi","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Mauricio Montano","author_inst":"Gladstone Institutes"},{"author_name":"Taha Y Taha","author_inst":"Gladstone Institutes"},{"author_name":"Mir Khalid","author_inst":"Gladstone Institutes"},{"author_name":"Limeng Sun","author_inst":"Gladstone Insituites"},{"author_name":"Kanika Khanna","author_inst":"Gladstone Institutes"},{"author_name":"Jin Tang","author_inst":"Gladstone Institutes"},{"author_name":"Yuan Zhou","author_inst":"Gladstone Institutes"},{"author_name":"Robyn M Kaake","author_inst":"Gladstone Institutes"},{"author_name":"Xiaohui Fang","author_inst":"University of California San Francisco"},{"author_name":"Mazharul Maishan","author_inst":"University of California San Francisco"},{"author_name":"Michael A Matthay","author_inst":"University of California San Francisco"},{"author_name":"Nevan J Krogan","author_inst":"University of California San Francisco"},{"author_name":"Melanie Ott","author_inst":"Gladstone Institutes"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Cross-protection against Bundibugyo by Ebola and Sudan vaccines","rel_doi":"10.64898\/2026.06.10.731377","rel_link":"http:\/\/biorxiv.org\/cgi\/content\/short\/2026.06.10.731377","rel_abs":"Ebola outbreaks continue to expand across Central Africa, yet available countermeasures remain limited and virus-specific. Whether available vaccines developed against the related Ebola virus (EBOV) and Sudan virus (SUDV) can confer cross-protection against Bundibugyo virus (BDBV) is incompletely understood. Here, we developed a BDBV surrogate challenge model and evaluated cross-protective immunity conferred by a set of monovalent vaccine candidates representing all three Orthoebolavirus species affecting humans. A yellow fever 17D-vectored BDBV vaccine (YF-BDB) expressing the BDBV glycoprotein (GP) as antigen conferred homologous protection in Ifnar-\/- mice, preventing systemic viral dissemination and providing survival following surrogate BDBV challenge. Intriguingly, also vaccination with YF-EBO or YF-SUD protected mice from such BDBV surrogate challenge. Conversely, while YF-BDB and YF-EBO fully protected against respective heterologous EBOV or BDBV infection, they conferred only partial protection against lethal challenge in a comparable SUDV model. Serological analyses revealed comparable titers of cross-reactive antibodies across all vaccine groups. However, neutralization, especially cross-neutralization, was limited suggesting a major role for non-neutralizing mechanisms in protection. These findings demonstrate asymmetry in cross-protective immunity among Orthoebolavirus vaccines and indicate that SUDV GP-based antigens may provide broader protection than EBOV- or BDBV-targeted candidates. However, our data add to the preliminary yet limited evidence that EBOV GP-based vaccines might offer at least some degree of protection against BDBV, the virus driving current Public Health Emergency of International Concern (PHIEC) in the Central-East Africa region.","rel_num_authors":5,"rel_authors":[{"author_name":"Lara Kelchtermans","author_inst":"KU Leuven Rega Institute"},{"author_name":"Viktor Lemmens","author_inst":"KU Leuven Rega Institute"},{"author_name":"Johan Neyts","author_inst":"KU Leuven Rega Institute"},{"author_name":"Yeranddy A Alpizar","author_inst":"KU Leuven Rega Institute"},{"author_name":"Kai Dallmeier","author_inst":"KU Leuven Rega Institute"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"A Clinical Predictor of Lung Molecular Endotype Identifies Heterogeneity in Corticosteroid Response in Severe COVID-19: an Emulated Target Trial","rel_doi":"10.64898\/2026.06.08.26355201","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.06.08.26355201","rel_abs":"BackgroundCorticosteroids reduce mortality in severe COVID-19 requiring oxygen or invasive mechanical ventilation, yet emerging data suggest that SARS-CoV-2-associated acute lung injury is biologically heterogeneous and that treatment response may vary across molecularly defined disease states. Lung-derived molecular endotypes of severe COVID-19-associated acute lung injury have been described, but direct molecular profiling is not routinely available at the bedside. We evaluated whether a clinical predictor of previously defined lung molecular endotype identifies heterogeneity in corticosteroid treatment effect among mechanically ventilated patients with COVID-19.\n\nMethodsWe utilized a single-center cohort of 5,000 patients with COVID-19 treated at the University of North Carolina Hospital between January 1, 2020, and December 31, 2022, to emulate a target trial assessing the effect of corticosteroid receipt on mortality, length of stay, and incident organ support. Confounding was addressed through inverse probability of treatment weighting (IPTW). Outcomes for severely ill patients requiring mechanical ventilation were compared to the RECOVERY trial results, with subsequent moderation analysis and stratified analysis by clinically predicted lung molecular endotype and vaccination status. The primary outcome was 28-day mortality. Secondary Outcomes were time to discharge alive and progression to additional organ support.\n\nResultsThis emulated target trial showed a directionally favorable but non-statistically significant association between corticosteroid treatment and reduced 28-day mortality in patients requiring mechanical ventilation for SARS-CoV-2 infection. A clinical predictor of lung molecular endotype moderated the effect of corticosteroids on 28-day mortality (p-value for interaction 0.038) and identified distinct predicted endotype-specific treatment effect. Corticosteroid treatment was associated with lower 28-day mortality in the predicted Hyper-Inflammatory endotype (OR 0.62, 95% CI 0.39, 0.99) but not in the predicted Metabolic Dysregulation endotype (OR 1.15, 95% CI 0.82, 1.61). We did not detect significant effect modification by vaccination status (p-value for interaction 0.65), although inference was limited by the small, vaccinated subgroup (28-mortality OR 0.78, 95% CI 0.37, 1.65 in vaccinated vs 0.94, 95% CI 0.70, 1.26 in unvaccinated).\n\nConclusionsIn this target trial emulation of mechanically ventilated patients with severe COVID-19, corticosteroid treatment showed a directionally favorable but non-statistically significant association with reduced 28-day mortality in the overall cohort. However, a clinical predictor of lung molecular endotype identified significant heterogeneity in treatment effect, with benefit concentrated in the predicted Hyper-Inflammatory endotype and no apparent benefit in the predicted Metabolic Dysregulation endotype. These findings support prospective validation of clinically deployable endotype-guided corticosteroid treatment strategies in acute lung injury and ARDS.","rel_num_authors":12,"rel_authors":[{"author_name":"Benjamin Sines","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Robert Hagan","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Xi Jiang","author_inst":"SAS Institute, Inc"},{"author_name":"Ella Pavlechko","author_inst":"SAS Institute, Inc"},{"author_name":"Scott McClain","author_inst":"SAS Institute, Inc"},{"author_name":"Xin Hunt","author_inst":"SAS Institute, Inc"},{"author_name":"Julia Florou-Moreno","author_inst":"SAS Institute, Inc"},{"author_name":"Jake Acquadro","author_inst":"SAS Institute, Inc"},{"author_name":"Gabriel Risa","author_inst":"SAS Institute, Inc"},{"author_name":"Varunraj Valsaraj","author_inst":"SAS Institute, Inc"},{"author_name":"Jonathan Schisler","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Matthew C Wolfgang","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"A risk-of-contagion index using a Bayesian based model for the COVID-19 epidemic in Mexico","rel_doi":"10.64898\/2026.06.09.26355274","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.06.09.26355274","rel_abs":"During the COVID-19 pandemic, limited testing capacity and reporting delays complicated epidemic surveillance and decision-making in Mexico. We calibrated covidestim, a Bayesian nowcasting model, to estimate the total SARS-CoV-2 infections from reported cases and deaths using Mexican surveillance data. Disease-progression distribution priors were calibrated using Mexico City records and validated through comparisons with national seroprevalence surveys, hospitalization data, and annual reported severe-case rates across all states.\n\nUsing the reconstructed estimates of active infections, we implemented an event-based risk framework that quantifies the probability of encountering at least one infectious individual in gatherings of different sizes. This probability was subsequently translated into a four-level epidemiological traffic-light indicator and computed at both state and municipality levels. The resulting estimates revealed substantial spatial heterogeneity that is obscured by state-level aggregation, particularly in states with marked differences between urban and rural municipalities.\n\nTo evaluate consistency with public-health indicators, we compared the proposed risk classification with the official Mexican epidemiological traffic-light system, considering interpretable gathering sizes relevant to public-health decision making.\n\nWeekly reports derived from this framework were delivered to policymakers in the State of Queretaro in Mexico, as an anticipation tool for school reopening and public-space management. This demonstrates that this Bayesian reconstruction of infections combined with event-based risk metrics can provide an interpretable and generalizable municipality-level complement to routine surveillance systems, particularly in regions with limited testing capacity and heterogeneous local transmission dynamics.","rel_num_authors":4,"rel_authors":[{"author_name":"Ruth Corona-Moreno","author_inst":"Universidad Nacional Autonoma de Mexico"},{"author_name":"Manuel Adrian Acuna-Zegarra","author_inst":"Universidad de Sonora"},{"author_name":"Mario Santana-Cibrian","author_inst":"Universidad Nacional Autonoma de Mexico"},{"author_name":"Jorge X. Velasco-Hernandez","author_inst":"Universidad Nacional Autonoma de Mexico"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Estimating COVID-19 Cumulative Incidence from Seroprevalence Surveys accounting for Time-Varying Seroreversion: A Fully Bayesian Methodology","rel_doi":"10.64898\/2026.06.09.26355264","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.06.09.26355264","rel_abs":"Seroprevalence surveys reveal the extent of humoral immunity against pathogens such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and under some circumstances represent cumulative incidence of prior infection. However, antibody waning-or seroreversion-biases these estimates by reducing assay sensitivity in a time-varying manner. Because assay sensitivity decays over time, naively using serosurveys can substantially bias estimates of SARS-CoV-2 cumulative incidence and fatality rates. The Bayesian assay-specific, time-varying sensitivity adjustment developed in this paper can reliably correct for this bias and account for the delay between infection and serosurvey. In seroprevalence studies conducted in the United States in 2020, adjusting for time-varying sensitivity increased cumulative incidence by up to 1.4-fold, with an adjustment of 1.08 for a national study. Our estimates contrast with a previously published 2-fold adjustment that did not account for assay design. This suggests that previous analyses overestimated cumulative incidence by applying seroreversion corrections that did not account for assay-specific effects, or underestimated cumulative incidence by not applying seroreversion corrections. These biases imply fatality rate underestimation and overestimation, respectively. Our model provides a framework for design-specific time-varying sensitivity corrections in seroprevalence surveys for other pathogens.","rel_num_authors":8,"rel_authors":[{"author_name":"Nana Owusu-Boaitey","author_inst":"Fischell Department of Bioengineering, University of Maryland, College Park, Maryland, USA"},{"author_name":"Mark J. Meyer","author_inst":"Department of Mathematics and Statistics, Georgetown University, Washington, DC, USA"},{"author_name":"Daniel Herrera-Esposito","author_inst":"Computational Neuroscience Initiative, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"author_name":"Lucas Bottcher","author_inst":"Department of Computational Science and Philosophy, Frankfurt School of Finance and Management, Frankfurt, Germany"},{"author_name":"Maria Lukz","author_inst":"School of Public Health, University of Maryland, College Park, Maryland, USA"},{"author_name":"Sydney Cook","author_inst":"Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA"},{"author_name":"Michael A. Stoto","author_inst":"Department of Health Management and Policy, Georgetown University, Washington, DC, USA"},{"author_name":"John D. Kraemer","author_inst":"Department of Health Management and Policy, Georgetown University, Washington, DC, USA"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Polypore Mushroom Mycelia for Treatment of Active COVID-19 Infection: A Randomized Clinical Trial","rel_doi":"10.64898\/2026.06.01.26354267","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.06.01.26354267","rel_abs":"Use of fungal mycelia, which has antiviral properties, constitutes a novel strategy for addressing existing and newly emerging viral diseases. We evaluated safety and feasibility of fungal mycelia (Fomitopsis officinalis and Trametes versicolor, FoTv) for treatment of COVID-19 and assessed its antiviral effects and potential to reduce symptoms. In a randomized, double-blind, placebo-controlled, dual site (UCSD\/UCLA medical centers) clinical trial we examined non-hospitalized patients who contracted mild-to-moderate COVID-19 [&le;] 96 hours, and experienced symptom onset [&le;] nine days, before enrollment. FoTv was safe, well-tolerated, and feasible for COVID-19 treatment. Minor differences in biochemical markers were observed between groups (26 FoTv, 24 Placebo). FoTv significantly reduced the number and severity of symptoms, particularly sore throat\/cough, and in vitro SARS-CoV-2 (pseudovirus) cellular infection. In conclusion, FoTv was safe and reduced COVID-19 symptoms and cellular viral infection. Future studies should investigate therapeutic benefits of fungal mycelia for SARS-CoV-2 and other viruses. Clinicaltrials.gov registration:NCT04667247.","rel_num_authors":16,"rel_authors":[{"author_name":"Gordon Saxe MD\/PHD","author_inst":"University of California San Diego"},{"author_name":"Andrew Shubov MD","author_inst":"University of California Los Angeles"},{"author_name":"Christine N Smith PHD","author_inst":"University of California San Diego"},{"author_name":"Shahrokh Golshan PHD","author_inst":"University of California San Diego"},{"author_name":"Tatyana Shekhtman MS","author_inst":"University of California San Diego"},{"author_name":"Stephen Wilson PHD","author_inst":"Botnar Institute of Immune Engineering"},{"author_name":"Daniel Slater MD\/FAAFP","author_inst":"University of California San Diego"},{"author_name":"Zolton J Bair PHD","author_inst":"Fungi Perfecti, LLC"},{"author_name":"Chase Beathard PHD","author_inst":"Fungi Perfecti, LLC"},{"author_name":"Renee A Davis MA","author_inst":"University of Washington"},{"author_name":"Lauray MacElhern MBA","author_inst":"University of California San Diego"},{"author_name":"Lan K Kao DACM","author_inst":"University of California Los Angeles"},{"author_name":"Phoebe Senowitz MEd","author_inst":"University of California San Diego"},{"author_name":"Natalie Gosnell BS","author_inst":"Cornell University"},{"author_name":"David Buchholz PHD","author_inst":"University of California Los Angeles"},{"author_name":"Hector Aguilar-Carreno PHD","author_inst":"University of California Los Angeles"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"Computational and Experimental Antibody Affinity and Diagnostic Accuracy Quantification of SARS-CoV-2 SD2 Major Disulfide Loop Analog","rel_doi":"10.64898\/2026.06.05.26353587","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.06.05.26353587","rel_abs":"IntroductionSynthetic oligopeptides provide a rapid and cost-efficient approach to developing antibodies and diagnostics for emerging viral variants.\n\nMethodsThis study computationally and experimentally characterized a synthetic peptide analog of the SARS-CoV-2 spike subdomain 2 major disulfide loop (SD2MDL), designated S621 (CPVAIHADQLTPTWRVYSTC). Binding affinity was computationally estimated using the Heuristic Affinity Prediction Tool for Immune Complexes (HAPTIC), while experimental validation was performed using enzyme-linked immunosorbent assay (ELISA) with rabbit-derived antipeptide antibodies. Clinical diagnostic accuracy testing was done using plasma samples from RT-PCR- confirmed COVID-19 patients and pre-COVID-19 controls.\n\nResultsS621 demonstrated nanomolar binding affinity [Formula] and high avidity (3.67 nM), closely matching HAPTIC predictions (3.54 nM). Diagnostic evaluation yielded a sensitivity of 89.92% and specificity of 27.79%, corresponding to an overall accuracy of 71.79%.\n\nDiscussionThese findings demonstrate that a single synthetic peptide derived from a conserved spike subdomain can function as a high-affinity surrogate for full-length antigens, supporting its potential application in rapid peptide-based immunodiagnostics.","rel_num_authors":9,"rel_authors":[{"author_name":"Brian Andrich La Valle Pollo","author_inst":"Biomedical Innovations Research for Translational Health Science (BIRTHS) Laboratory, College of Medicine, Manila, Philippines"},{"author_name":"Glenmarie Angelica Perias","author_inst":"Biomedical Innovations Research for Translational Health Science (BIRTHS) Laboratory, College of Medicine, Manila, Philippines"},{"author_name":"Riziel Hannah Aguimatang","author_inst":"Biomedical Innovations Research for Translational Health Science (BIRTHS) Laboratory, College of Medicine, Manila, Philippines"},{"author_name":"Ayra Patrice Espiritu","author_inst":"Biomedical Innovations Research for Translational Health Science (BIRTHS) Laboratory, College of Medicine, Manila, Philippines"},{"author_name":"Danica Ching","author_inst":"Institute of Clinical Epidemiology, National Institutes of Health, Manila, Philippines"},{"author_name":"Maria Isabel Idolor","author_inst":"Biomedical Innovations Research for Translational Health Science (BIRTHS) Laboratory, College of Medicine, Manila, Philippines"},{"author_name":"Ruby Anne King","author_inst":"Department of Science and Technology - Philippine Council for Health Research and Development (DOST-PCHRD), Taguig, Philippines"},{"author_name":"Fresthel Monica Climacosa","author_inst":"Department of Medical Microbiology, College of Public Health, University of the Philippines Manila, Manila, Philippines"},{"author_name":"Salvador Eugenio Caoili","author_inst":"Biomedical Innovations Research for Translational Health Science (BIRTHS) Laboratory, College of Medicine, Manila, Philippines"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Investigation of the continuous spread of SARS-CoV-2 in the post pandemic time - Insights into the reason for the sustained spread despite the establishment of population immunity","rel_doi":"10.64898\/2026.06.05.26355009","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.06.05.26355009","rel_abs":"In spite of well-established global immune landscape, SARS-CoV-2 is still able to further spread and continue causing infection waves. The current understanding about the reason behind is limited, and it is still difficult to predict the evolution or spreading tread of SARS-CoV-2. Therefore, it is necessary to investigate whether the establishment of population immunity has changed the virus evolution or spreading pattern.\n\nIn this investigation, one overall analysis of the SARS-CoV-2 spreading in the past several years have been carried out through one thorough genomic epidemiology study, with Germany being chosen as one representative location in view of the systemic efforts for genomic surveillance. The growth advantage of a few predominant variants in its early spreading period has been evaluated through a logistic regression model. The results have revealed that the major circulating SARS-CoV-2 variants since 2023 are mainly derived from the Omicron BA.2 family. Since middle of 2024, most predominant variants were produced primarily through recombination, indicating that the evolution derived from recombination might be the major driving force for the continuous spread of SARS-CoV-2 despite the existence of population immunity. Furthermore, the lower growth advantage of recently emerged variants might possibly lead to a tread of reduction in the frequency of infection wave.\n\nThe information revealed from this investigation suggests that although short-term spreading tread can be affected by specific virus feature as well as local immunity landscape, the long-term spreading tread is mainly decided by the genomic diversity of the viruses, and can be predicted through phylogenetic and genomic epidemiology investigation. The results have emphasized the importance of maintaining the efforts for genomic surveillance of SARS-CoV-2, which is essential from both medical and research perspectives.","rel_num_authors":1,"rel_authors":[{"author_name":"Buqing Yi","author_inst":"Institute of Medical Microbiology and Virology, University Hospital Carl Gustav Carus, TUD, Dresden, Germany; Medizinische Klinik und Poliklinik I, University H"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Disentangling infectiousness and susceptibility by age group using transmission pair data: a study of SARS-CoV-2 household transmission","rel_doi":"10.64898\/2026.06.04.26354892","rel_link":"http:\/\/medrxiv.org\/cgi\/content\/short\/2026.06.04.26354892","rel_abs":"BackgroundDifferential contributions to transmission across age groups have been reported for many respiratory infections, including SARS-CoV-2. They are crucial for estimating the impact of age-specific interventions. Disentangling these age-dependent contributions remains challenging, as they may reflect differences in contact rates, biological susceptibility, or infectiousness.\n\nAimWe aim to jointly estimate age-specific per-contact infectiousness and susceptibility and their effect on the impact of age-specific interventions.\n\nMethodsThe age-specific infectiousness and susceptibility were jointly estimated in a Bayesian framework by combining contact data with transmission pair data (who-infected-whom). We applied this approach to 197,840 self-reported household transmission pairs collected in the Netherlands during the COVID-19 pandemic. Using these estimates, we projected the expected impact of school closure and work-from-home measures during the early stages of an epidemic in the absence of other interventions.\n\nResultsBoth infectiousness and susceptibility to SARS-CoV-2 infection were lowest in children aged 0-9 years and highest in adults over 30 years old, with 2-to 4.5-fold differences between these groups. Projected impacts of age-specific interventions indicated that school closures would reduce the reproduction number by 8% or 29% when age-specific susceptibility and infectiousness were or were not considered, respectively. Conversely, working-from-home policies would lead to reductions of 41% with and 20% without age-specific infectiousness and susceptibility.\n\nConclusionOur method enables robust estimation of age-specific infectiousness and susceptibility. Accounting for these age heterogeneities is essential for projecting the impact of age-targeted interventions. Our approach is adaptable to other respiratory infections and can guide more tailored public health responses.","rel_num_authors":3,"rel_authors":[{"author_name":"Ka Yin Leung","author_inst":"National Institute for Public Health and the Environment"},{"author_name":"Fuminari Miura","author_inst":"National Institute for Public Health and the Environment"},{"author_name":"Jantien A. Backer","author_inst":"National Institute for Public Health and the Environment"}],"rel_date":"2026-06-05","rel_site":"medrxiv"},{"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":"ObjectiveThe 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.\n\nResultsDuring 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":10,"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":"Adidja Amani","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":"Collins Asaah Tatang","author_inst":"Sub-Directorate of Vaccination, Department of Family Health, Ministry of Public Health, Yaounde, Cameroon"},{"author_name":"Aime Gilbert Mbonda Noula","author_inst":"Department of Public Health, Faculty of Medicine and Biomedical Sciences, The University of Yaounde 1, Yaounde, Cameroon"},{"author_name":"Christian Noel Bayiha","author_inst":"Health Projects Implementation Unit-BID, Yaounde, Cameroun"},{"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":"BackgroundThe 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.\n\nMethodsIn 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.\n\nResultsGAD 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.\n\nConclusionsThese 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.\n\nWe 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.\n\nDuring the study period, pooled testing was offered to 21187 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.\n\nUnder 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. Spearmans correlations ({rho}) between wastewater virus RNA concentrations and infection counts were calculated.\n\nFrom 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.\n\nHighlightsO_LIHealthcare facility-level wastewater surveillance may be useful as a complementary surveillance method for infectious disease targets, including SARS-CoV-2.\nC_LIO_LITwo virus concentration methods were compared, electronegative membrane filtration (enMF) and Nanotrap(R) Magnetic Virus Particles (NP).\nC_LIO_LISpearmans correlations ({rho}) between wastewater virus RNA concentrations and infection counts were calculated among several subpopulations at three skilled nursing facilities.\nC_LI\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC=\"FIGDIR\/small\/26354622v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (29K):\norg.highwire.dtl.DTLVardef@1727d04org.highwire.dtl.DTLVardef@16db53aorg.highwire.dtl.DTLVardef@19523c8org.highwire.dtl.DTLVardef@602d9d_HPS_FORMAT_FIGEXP  M_FIG C_FIG","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":"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 Japans 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":"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":7,"rel_authors":[{"author_name":"Rachel A Silverman","author_inst":"Virginia Tech"},{"author_name":"Monica L Ahrens","author_inst":"University of Kansas Medical Center"},{"author_name":"Meagan Helmick","author_inst":"Virginia Department of Health"},{"author_name":"Carla V Finkielstein","author_inst":"Virginia Tech"},{"author_name":"Alasdair Cohen","author_inst":"Virginia Tech"},{"author_name":"Erica Short","author_inst":"Virginia Department of Health"},{"author_name":"Paige Bordwine","author_inst":"Virginia Department of Health"}],"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":1,"rel_authors":[{"author_name":"Laurence A Jacobs","author_inst":"University of Zurich"}],"rel_date":"2026-05-29","rel_site":"medrxiv"},{"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":"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":"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":"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":"Pachiyappan Kamarajan","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":"BackgroundPersistent 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.\n\nMethods76 COVID-19 recovered participants (CRPs) and 51 healthy controls (HCs) underwent multimodal MRI comprising T1-weighted structural, diffusion, and resting-state functional acquisitions. Grey-matter morphology was assessed using voxel-based morphometry (VBM), 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)).\n\nResultsNo 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).\n\nConclusionsOur 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":"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":"ObjectivesTo quantify the frequency of baseline control-group use in published long COVID prevalence studies and assess their key methodological features.\n\nMethodsWe 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).\n\nResultsAmong 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).\n\nConclusions\n\nMost 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.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat is the frequency of baseline control group inclusion and the reliance on subjective outcomes in published long COVID prevalence studies?\n\nFindingsThis meta-epidemiological analysis demonstrates that over 80% of published long COVID prevalence studies lacked a baseline non-COVID control group. Most of these investigations also relied exclusively on subjective patient-reported outcomes without explicitly acknowledging the absence of a comparator as a limitation.\n\nMeaningThese findings suggest that the majority of the long COVID prevalence literature is poorly suited to accurately estimate the symptom burden specifically attributable 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":"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":"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":"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":"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":"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@151c2b4org.highwire.dtl.DTLVardef@c5b819org.highwire.dtl.DTLVardef@b98117org.highwire.dtl.DTLVardef@ca3147_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":0,"rel_authors":[],"rel_date":"2026-05-12","rel_site":"medrxiv"},{"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":"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"}]}