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Orthohantaviruses are emerging zoonotic viruses that can infect humans via the respiratory tract. There is an unmet need for an in vivo model to study infection of different orthohantaviruses in physiologically relevant tissue and to assess the efficacy of novel pan-orthohantavirus countermeasures. Here, we describe the use of a human lung xenograft mouse model to study the permissiveness for different orthohantavirus species and to assess its utility for preclinical testing of therapeutics. Following infection of xenografted human lung tissues, distinct orthohantavirus species differentially replicated in the human lung and subsequently spread systemically. The different orthohantaviruses primarily targeted the endothelium, respiratory epithelium and macrophages in the human lung. A proof-of-concept preclinical study showed treatment of these mice with a virus neutralizing antibody could block Andes orthohantavirus infection and dissemination. This pan-orthohantavirus model will facilitate progress in the fundamental understanding of pathogenesis and virus-host interactions for orthohantaviruses. Furthermore, it is an invaluable tool for preclinical evaluation of novel candidate pan-orthohantavirus intervention strategies., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays, NDV-based SARS-CoV-2 vaccines, influenza virus vaccines and influenza virus therapeutics which list FK as co-inventor and of which several have been licensed. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, Castlevax, to develop SARS-CoV-2 vaccines. FK is co-founder and scientific advisory board member of Castlevax. FK has consulted for Merck, Curevac, Seqirus and Pfizer and is currently consulting for 3rd Rock Ventures, GSK, Gritstone and Avimex. The Krammer laboratory is also collaborating with Dynavax on influenza vaccine development. All other authors have no conflicts of interest to report., (Copyright: © 2025 Rissmann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Coronavirus disease 2019 (COVID-19) poses significant risks for solid organ transplant recipients, who have atypical but poorly characterized immune responses to infection. We aim to understand the host immunologic and microbial features of COVID-19 in transplant recipients by leveraging a prospective multicenter cohort of 86 transplant recipients age- and sex-matched with 172 non-transplant controls. We find that transplant recipients have higher nasal SARS-CoV-2 viral abundance and impaired viral clearance, and lower anti-spike IgG levels. In addition, transplant recipients exhibit decreased plasmablasts and transitional B cells, and increased senescent T cells. Blood and nasal transcriptional profiling demonstrate unexpected upregulation of innate immune signaling pathways and increased levels of several proinflammatory serum chemokines. Severe disease in transplant recipients, however, is characterized by a less robust induction of pro-inflammatory genes and chemokines. Together, our study reveals distinct immune features and altered viral dynamics in solid organ transplant recipients., Competing Interests: Competing interests: F.K. has the following financial interests: The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays, NDV-based SARS-CoV-2 vaccines, influenza virus vaccines, and influenza virus therapeutics which list Florian Krammer as co-inventor (Patent title and number: Influenza Virus Vaccines and Uses Thereof (Chimeric HA 2) 9,371,366; Influenza Virus Vaccines and Uses Thereof (Chimeric HA 1) 10,131,695; Influenza Virus Vaccines and Uses Thereof (Chimeric HA 2) 2934581; Influenza Virus Vaccines and Uses Thereof (Chimeric HA 2) 9,968,670; Influenza Virus Vaccines and Uses Thereof (Chimeric HA 2) 10,137,189, Influenza Virus Vaccines and Uses Thereof (Chimeric HA 2) 10,583,188; Influenza Virus Vaccines and Uses Thereof (Chimeric HA 1) EP2758075; Influenza Virus Vaccination Regimens (Neuraminidase) 10,736,956; Anti-Influenza B Virus Neuraminidase Antibodies and Uses Thereof 11254733; Influenza Virus Hemagluttinin Proteins and Uses Thereof (Mosaic) 7237344). Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, Castlevax, to develop SARS-CoV-2 vaccines. F.K. is a co-founder and scientific advisory board member of Castlevax. F.K. has consulted for Merck, Curevac, Seqirus, and Pfizer and is currently consulting for 3rd Rock Ventures, GSK, Gritstone, and Avimex. The Krammer laboratory is also collaborating with Dynavax on influenza vaccine development. R.R.M. has a Leadership Councilor role 2018-2021 for the Society of Leukocyte Biology. O.L. has received support as a speaker for presentation regarding the Coronavirus pandemic from Midsized Bank Coalition of Americ (MBCA) and Moody’s Analytics. N.G.R. has research grants from Pfizer, Merck, Sanofi, Quidel, Immorna, Vaccine Company, and Lilly, serves on safety committees for ICON and EMMES and the advisory boards of Moderna, Seqirus, Pfizer, and Sanofi, and is a paid safety consultant for ICON, CyanVac and EMMES. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Frequent recent spillovers of subtype H5N1 clade 2.3.4.4b highly pathogenic avian influenza (HPAI) virus into poultry and mammals, especially dairy cattle, including several human cases, increased concerns over a possible future pandemic. Here, we performed an analysis of epitope data curated in the Immune Epitope Database (IEDB). We found that the patterns of immunodominance of seasonal influenza viruses circulating in humans and H5N1 are similar. We further conclude that a significant fraction of the T-cell epitopes is conserved at a level associated with cross-reactivity between avian and seasonal sequences, and we further experimentally demonstrate extensive cross-reactivity in the most dominant T-cell epitopes curated in the IEDB. Based on these observations, and the overall similarity of the neuraminidase (NA) N1 subtype encoded in both HPAI and seasonal H1N1 influenza virus as well as cross-reactive group 1 HA stalk-reactive antibodies, we expect that a degree of pre-existing immunity is present in the general human population that could blunt the severity of human H5N1 infections.IMPORTANCEInfluenza A viruses (IAVs) cause pandemics that can result in millions of deaths. The highly pathogenic avian influenza (HPAI) virus of the H5N1 subtype is presently among the top viruses of pandemic concern, according to the WHO and the National Institute of Allergy and Infectious Diseases (NIAID). Previous exposure by infection and/or vaccination to a given IAV subtype or clade influences immune responses to a different subtype or clade. Analysis of human CD4 and CD8 T-cell epitope conservation between HPAI H5N1 and seasonal IAV sequences revealed levels of identity and conservation conducive to T cell cross-reactivity, suggesting that pre-existing T cell immune memory should, to a large extent, cross-recognize avian influenza viruses. This observation was experimentally verified by testing responses from human T cells to non-avian IAV and their HPAI H5N1 counterparts. Accordingly, should a more widespread HPAI H5N1 outbreak occur, we hypothesize that cross-reactive T-cell responses might be able to limit disease severity.

Neutralizing antibodies correlate with protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent studies, however, show that binding antibody titers, in the absence of robust neutralizing activity, also correlate with protection against disease progression. Non-neutralizing antibodies cannot directly protect against infection but may recruit effector cells and thus contribute to the clearance of infected cells. Additionally, they often bind conserved epitopes across multiple variants. Here, we characterize 42 human monoclonal antibodies (mAbs) from coronavirus disease 2019 (COVID-19)-vaccinated individuals. Most of these antibodies exhibit no neutralizing activity in vitro, but several non-neutralizing antibodies provide protection against lethal challenge with SARS-CoV-2 in different animal models. A subset of those mAbs shows a clear dependence on Fc-mediated effector functions. We have determined the structures of three non-neutralizing antibodies, with two targeting the receptor-binding domain and one that binds the subdomain 1 region. Our data confirm the real-world observation in humans that non-neutralizing antibodies to SARS-CoV-2 can be protective., Competing Interests: Declaration of interests The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays, NDV-based SARS-CoV-2 vaccines, influenza virus vaccines, and influenza virus therapeutics, which list F.K. as co-inventor. V.S. is also listed as inventor on the SARS-CoV-2 serological assays patent, and W.S. is listed as inventor on the NDV-based SARS-CoV-2 vaccine IP. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, Castlevax, to develop SARS-CoV-2 vaccines. F.K. and W.S. are co-founders and scientific advisory board members of Castlevax. F.K. has consulted for Merck, Curevac, Seqirus, GSK, and Pfizer and is currently consulting for Third Rock Ventures, Sanofi, Gritstone, and Avimex. F.K. is a recipient of royalties from a licensing agreement with Leyden Laboratories B.V. The Krammer laboratory is also collaborating with Dynavax on influenza vaccine development and VIR on influenza therapeutics development. The Ellebedy laboratory has received funding under sponsored research agreements from Moderna, Emergent BioSolutions, and AbbVie. A.H.E. has received consulting and speaking fees from InBios International, Inc., Fimbrion Therapeutics, RGAX, Mubadala Investment Company, AstraZeneca, Moderna, Pfizer, GSK, Danaher, Third Rock Ventures, Goldman Sachs, and Morgan Stanley, is the founder of ImmuneBio Consulting, and is a recipient of royalties from licensing agreements with Abbvie and Leyden Laboratories B.V., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Hospitalized COVID-19 patients exhibit diverse immune responses during acute infection, which are associated with a wide range of clinical outcomes. However, understanding these immune heterogeneities and their links to various clinical complications, especially long COVID, remains a challenge. In this study, we performed unsupervised subtyping of longitudinal multi-omics immunophenotyping in over 1,000 hospitalized patients, identifying two critical subtypes linked to mortality or mechanical ventilation with prolonged hospital stay and three severe subtypes associated with timely acute recovery. We confirmed that unresolved systemic inflammation and T-cell dysfunctions were hallmarks of increased severity and further distinguished patients with similar acute respiratory severity by their distinct immune profiles, which correlated with differences in demographic and clinical complications. Notably, one critical subtype (SubF) was uniquely characterized by early excessive inflammation, insufficient anticoagulation, and fatty acid dysregulation, alongside higher incidences of hematologic, cardiac, and renal complications, and an elevated risk of long COVID. Among the severe subtypes, significant differences in viral clearance and early antiviral responses were observed, with one subtype (SubC) showing strong early T-cell cytotoxicity but a poor humoral response, slower viral clearance, and greater risks of chronic organ dysfunction and long COVID. These findings provide crucial insights into the complex and context-dependent nature of COVID-19 immune responses, highlighting the importance of personalized therapeutic strategies to improve both acute and long-term outcomes.

We have developed a new universal influenza B vaccination strategy based on inactivated influenza B viruses displaying mosaic hemagglutinins (mHAs). Recombinant mHA viruses were constructed by replacing the four major antigenic sites of influenza B virus HAs, with those from exotic avian influenza A virus HAs. Sequential vaccination of naïve mice with mHA-based vaccines elicited higher immune responses towards the immuno-subdominant conserved epitopes of the HA than vaccination with wildtype viruses. Among the different preparations tested, mHA split vaccines were less immunogenic than their whole inactivated virus counterparts. This lower immunogenicity was overcome by the combination with adjuvants. mHA split vaccines adjuvanted with a Toll-like receptor-9 agonist (CpG 1018) increased Th1 immunity and in vivo cross-protection, whereas adjuvanting with an MF59-like oil-in-water nano-emulsion (AddaVax) enhanced and broadened humoral immune responses and antibody-mediated cross-protection. The mHA vaccines with or without adjuvant were subsequently evaluated in mice that were previously immunized to closely mimic human pre-existing immunity to influenza B viruses and the contribution of innate and cellular immunity was evaluated in this model. We believe these preclinical studies using the mHA strategy represent a major step toward the evaluation of a universal influenza B virus vaccine in clinical trials., Competing Interests: Competing interests The Icahn School of Medicine at Mount Sinai and Dynavax have filed a patent application in which P.P., W.S., I.G.D. and F.K. are listed as co-inventors. The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays, NDV-based SARS-CoV-2 vaccines, influenza virus vaccines and influenza virus therapeutics which list F.K. as co-inventor. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, Castlevax, to develop SARS-CoV-2 vaccines. F.K., P.P. and W.S. are co-founder of Castlevax. F.K. has consulted for Merck, Curevac, Seqirus and Pfizer and is currently consulting for 3rd Rock Ventures, GSK, Gritstone and Avimex. The Krammer laboratory is also collaborating with Dynavax on influenza A virus vaccine development. All other authors declare no competing interests., (© 2024. The Author(s).)

Chronic viral infections are ubiquitous in humans, with individuals harboring multiple latent viruses that can reactivate during acute illnesses. Recent studies have suggested that SARS-CoV-2 infection can lead to reactivation of latent viruses such as Epstein-Barr Virus (EBV) and cytomegalovirus (CMV), yet, the extent and impact of viral reactivation in COVID-19 and its effect on the host immune system remain incompletely understood. Here we present a comprehensive multi-omic analysis of viral reactivation of all known chronically infecting viruses in 1,154 hospitalized COVID-19 patients, from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, who were followed prospectively for twelve months. We reveal significant reactivation of Herpesviridae , Enteroviridae , and Anelloviridae families during acute stage of COVID-19 (0-40 days post-hospitalization), each exhibiting distinct temporal dynamics. We also show that viral reactivation correlated with COVID-19 severity, demographic characteristics, and clinical outcomes, including mortality. Integration of cytokine profiling, cellular immunophenotyping, metabolomics, transcriptomics, and proteomics demonstrated virus-specific host responses, including elevated pro-inflammatory cytokines (e.g. IL-6, CXCL10, and TNF), increased activated CD4+ and CD8+ T-cells, and upregulation of cellular replication genes, independent of COVID-19 severity and SARS-CoV-2 viral load. Notably, persistent Anelloviridae reactivation during convalescence (≥3 months post-hospitalization) was associated with Post-Acute Sequelae of COVID-19 (PASC) symptoms, particularly physical function and fatigue. Our findings highlight a remarkable prevalence and potential impact of chronic viral reactivation on host responses and clinical outcomes during acute COVID-19 and long term PASC sequelae. Our data provide novel immune, transcriptomic, and metabolomic biomarkers of viral reactivation that may inform novel approaches to prognosticate, prevent, or treat acute COVID-19 and PASC., Competing Interests: IMPACC Network Competing Interests The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays and NDV-based SARS-CoV-2 vaccines which list Florian Krammer as co-inventor. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2. Florian Krammer has consulted for Merck and Pfizer (before 2020), and is currently consulting for Pfizer, Seqirus, 3rd Rock Ventures, Merck and Avimex. The Krammer laboratory is also collaborating with Pfizer on animal models of SARS-CoV-2. Viviana Simon is a co-inventor on a patent filed relating to SARS-CoV-2 serological assays (the “Serology Assays”). Ofer Levy is a named inventor on patents held by Boston Children’s Hospital relating to vaccine adjuvants and human in vitro platforms that model vaccine action. His laboratory has received research support from GlaxoSmithKline (GSK) and is a co-founder of and advisor to Ovax, Inc. Charles Cairns serves as a consultant to bioMerieux and is funded for a grant from Bill & Melinda Gates Foundation. James A Overton is a consultant at Knocean Inc. Jessica Lasky-Su serves as a scientific advisor of Precion Inc. Scott R. Hutton, Greg Michelloti and Kari Wong are employees of Metabolon Inc. Vicki Seyfert-Margolis is a current employee of MyOwnMed. Nadine Rouphael reports grants or contracts with Merck, Sanofi, Pfizer, Vaccine Company, Quidel, Lilly and Immorna, and has participated on data safety monitoring boards for Moderna, Sanofi, Seqirus, Pfizer, EMMES, ICON, BARDA, Imunon, CyanVac and Micron. Nadine Rouphael has also received support for meetings/travel from Sanofi and Moderna and honoraria from Virology Education. Adeeb Rahman is a current employee of Immunai Inc. Steven Kleinstein is a consultant related to ImmPort data repository for Peraton. Nathan Grabaugh is a consultant for Tempus Labs and the National Basketball Association. Akiko Iwasaki is a consultant for 4BIO, Blue Willow Biologics, Revelar Biotherapeutics, RIGImmune, Xanadu Bio, Paratus Sciences. Monika Kraft receives research funds paid to her institution from NIH, ALA; Sanofi, Astra-Zeneca for work in asthma, serves as a consultant for Astra-Zeneca, Sanofi, Chiesi, GSK for severe asthma; is a co-founder and CMO for RaeSedo, Inc, a company created to develop peptidomimetics for treatment of inflammatory lung disease. Esther Melamed received research funding from Babson Diagnostics and honorarium from Multiple Sclerosis Association of America and has served on the advisory boards of Genentech, Horizon, Teva, and Viela Bio. Carolyn Calfee receives research funding from NIH, FDA, DOD, Roche-Genentech and Quantum Leap Healthcare Collaborative as well as consulting services for Janssen, Vasomune, Gen1e Life Sciences, NGMBio, and Cellenkos. Wade Schulz was an investigator for a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion; collaborates with the National Center for Cardiovascular Diseases in Beijing; is a technical consultant to Hugo Health, a personal health information platform; cofounder of Refactor Health, an AI-augmented data management platform for health care; and has received grants from Merck and Regeneron Pharmaceutical for research related to COVID-19. Grace A McComsey received research grants from Redhill, Cognivue, Pfizer, and Genentech, and served as a research consultant for Gilead, Merck, Viiv/GSK, and Jenssen. Linda N. Geng received research funding paid to her institution from Pfizer, Inc.

The emergence of highly pathogenic H5N1 avian influenza in dairy cattle herds across the United States has caused multiple mild human infections. There is an urgent need to understand the risk of spillover into humans. Here, we show that pre-existing immunity from the 2009 H1N1 pandemic influenza virus provided protection from mortality and severe clinical disease to ferrets intranasally infected with bovine H5N1. H1N1 immune ferrets exhibited a differential tissue tropism with little bovine H5N1 viral dissemination to organs outside the respiratory tract and significantly less H5N1 virus found in nasal secretions and the respiratory tract. Additionally, ferrets with H1N1 prior immunity produced antibodies that cross-reacted with H5N1 neuraminidase protein. Taken together, these results suggest that mild disease in humans may be linked to prior immunity to human seasonal influenza viruses., Competing Interests: Competing interest statement The Icahn School of Medicine at Mount Sinai has filed patent applications relating to influenza virus vaccines and therapeutic vaccines which list Florian Krammer as co-inventor. Several of these patents have been licensed and Florian Krammer has received royalty payments from commercial entities. Florian Krammer has consulted for Merck, Pfizer, Seqirus, GSK and Curevac and is currently consulting for Gritstone, 3rd Rock Ventures and Avimex and he is a co-founder and scientific advisory board member of CastleVax. The Krammer laboratory is also collaborating with Dynavax on influenza virus vaccine development and with VIR on influenza therapeutics. All other authors declare no competing financial and/or non-financial interests in relation to the work described.

In 2021, an ultra-rapid rollout vaccination campaign in the Schwaz district, Tyrol, Austria, delivered the COVID-19 vaccine BNT162b2 to 66.9% of eligible residents (dose 1: March 11-16, dose 2: April 8-13). Alongside the campaign, we recruited 11,955 residents into the prospective study REDUCE, of whom 3,859 participated in a booster vaccination initiative (November 20-28, 2021). Over a 24-month follow-up, 1,672 participants had incident RT-PCR-confirmed SARS-CoV-2. Compared to other Tyrolean districts, effectiveness in reducing SARS-CoV-2 infection at months 1-9 versus months 10-24 was 81.6% (95% CI 80.0-83.2%; hazard ratio 0.18 [0.17-0.20]) versus 38.2% (35.8-40.6%; 0.62 [0.59-0.64]) among REDUCE participants, and 22.5% (20.5-24.4%; 0.78 [0.76-0.80]) versus 17.0% (16.2-17.8%; 0.83 [0.82-0.84]) in the entire Schwaz district, with substantial variability during follow-up. By March 2023, 61% of Schwaz residents had received booster vaccination versus 55% in other Tyrolean districts. Consequently, vaccinating individuals at high pace effectively reduced SARS-CoV-2 infections and achieved higher vaccination coverage., Competing Interests: P.W. reports consulting fees from Novartis Pharmaceuticals; outside the submitted work. The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays, NDV-based SARS-CoV-2 vaccines influenza virus vaccines and influenza virus therapeutics which list F.K. as co-inventor. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, CastleVax, to develop SARS-CoV-2 vaccines. F.K.is co-founder and scientific advisory board member of CastleVax. F.K. has consulted for Merck, Curevac, Seqirus, and Pfizer and is currently consulting for 3rd Rock Ventures, GSK, Gritstone, and Avimex. The Krammer laboratory is collaborating with Dynavax on influenza vaccine development., (© 2024 The Author(s).)

Background: This report summarizes the discussions and conclusions from the "Correlates of Protection for Next Generation Influenza Vaccines: Lessons Learned from the COVID-19 Pandemic" meeting, which took place in Seattle, USA, from March 1, 2023, to March 3, 2023., Conclusions: Discussions around influenza virus correlates of protection and their use continued from where the discussion had been left off in 2019. While there was not much progress in the influenza field itself, many lessons learned during the coronavirus disease 2019 (COVID-19) pandemic, especially the importance of mucosal immunity, were discussed and can directly be applied to influenza correlates of protection., (© 2024 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Influenza viruses continually evolve new antigenic variants, through mutations in epitopes of their major surface proteins, hemagglutinin (HA) and neuraminidase (NA). Antigenic drift potentiates the reinfection of previously infected individuals, but the contribution of this process to variability in annual epidemics is not well understood. Here, we link influenza A(H3N2) virus evolution to regional epidemic dynamics in the United States during 1997-2019. We integrate phenotypic measures of HA antigenic drift and sequence-based measures of HA and NA fitness to infer antigenic and genetic distances between viruses circulating in successive seasons. We estimate the magnitude, severity, timing, transmission rate, age-specific patterns, and subtype dominance of each regional outbreak and find that genetic distance based on broad sets of epitope sites is the strongest evolutionary predictor of A(H3N2) virus epidemiology. Increased HA and NA epitope distance between seasons correlates with larger, more intense epidemics, higher transmission, greater A(H3N2) subtype dominance, and a greater proportion of cases in adults relative to children, consistent with increased population susceptibility. Based on random forest models, A(H1N1) incidence impacts A(H3N2) epidemics to a greater extent than viral evolution, suggesting that subtype interference is a major driver of influenza A virus infection ynamics, presumably via heterosubtypic cross-immunity., Competing Interests: AP, JH, JB, TR, XX, RK, DW, NL, LW, BE, RH, MG, RD, SF, KN, NK, SW, HH, TB No competing interests declared, CH Received personal fees from Sanofi outside the submitted work, JM Received consulting fees, honoraria, and travel support from Sanofi Pasteur and Sequris, SS The WHO Collaborating Centre for Reference and Research on Influenza in Melbourne has a collaborative research and development agreement (CRADA) with CSL Seqirus for isolation of candidate vaccine viruses in cells and an agreement with IFPMA for isolation of candidate vaccine viruses in eggs. SGS reports honoraria from CSL Seqirus, Moderna, Pfizer, and Evo Health, IB, KS The WHO Collaborating Centre for Reference and Research on Influenza in Melbourne has a collaborative research and development agreement (CRADA) with CSL Seqirus for isolation of candidate vaccine viruses in cells and an agreement with IFPMA for isolation of candidate vaccine viruses in eggs, FK The Icahn School of Medicine at Mount Sinai has filed patent applications relating to influenza virus vaccines (U.S. patent numbers: 12030928, 11865173, 11266734, 11254733, 10736956, 10583188, 10137189, 10131695, 9968670, 9371366; publication numbers: 20230181715, 20220403358, 20220249652, 20220242935, 20220153873, 20210260179, 20190125859, 20190106461, 20180333479), SARS-CoV-2 serological assays (publication number: 20240210415), and SARS-CoV-2 vaccines (publication numbers: 20230310583, 20230226171), which list FK as co-inventor. FK has consulted for Merck and Pfizer (before 2020), and is currently consulting for Pfizer, Seqirus, 3rd Rock Ventures, GSK and Avimex. The Krammer laboratory is also collaborating with Pfizer on animal models of SARS‐CoV‐2 and with Dynavax on universal influenza virus vaccines, CV Received honoraria for serving as an Editor in Chief of the journal Epidemics (Elsevier)

Invariant natural killer T (iNKT) cells are glycolipid-reactive T cells with potent immunoregulatory properties. iNKT cells activated with the marine-sponge-derived glycolipid, α-galactosylceramide (αGC), provide a universal source of T-cell help that has shown considerable promise for a wide array of therapeutic applications. This includes harnessing iNKT-cell-mediated immune responses to adjuvant whole inactivated influenza virus (WIV) vaccines. An important concern with WIV vaccines is that under certain circumstances, they are capable of triggering vaccine-associated enhanced respiratory disease (VAERD). This immunopathological phenomenon can arise after immunization with an oil-in-water (OIW) adjuvanted WIV vaccine, followed by infection with a hemagglutinin and neuraminidase mismatched challenge virus. This elicits antibodies (Abs) that bind immunodominant epitopes in the HA2 region of the heterologous virus, which purportedly causes enhanced virus fusion activity to the host cell and increased infection. Here, we show that αGC can induce severe VAERD in pigs. However, instead of stimulating high concentrations of HA2 Abs, αGC elicits high concentrations of interferon (IFN)-γ-secreting cells both in the lungs and systemically. Additionally, we found that VAERD mediated by iNKT cells results in distinct cytokine profiles and altered adaptation of the challenge virus following infection compared to an OIW adjuvant. Overall, these results provide a cautionary note about considering the formulation of WIV vaccines with iNKT-cell agonists as a potential strategy to modulate antigen-specific immunity.

Influenza viruses pose a threat to public health as evidenced by severe morbidity and mortality in humans on a yearly basis. Given the constant changes in the viral glycoproteins owing to antigenic drift, seasonal influenza vaccines need to be updated periodically and effectiveness often drops due to mismatches between vaccine and circulating strains. In addition, seasonal influenza vaccines are not protective against antigenically shifted influenza viruses with pandemic potential. Here, we have developed a highly immunogenic vaccination regimen based on live-attenuated influenza vaccines (LAIVs) comprised of an attenuated virus backbone lacking non-structural protein 1 (ΔNS1), the primary host interferon antagonist of influenza viruses, with chimeric hemagglutinins (cHA) composed of exotic avian head domains with a highly conserved stalk domain, to redirect the humoral response towards the HA stalk. In this study, we showed that cHA-LAIV vaccines induce robust serum and mucosal responses against group 1 stalk and confer antibody-dependent cell cytotoxicity activity. Mice that intranasally received cH8/1-ΔNS1 followed by a cH11/1-ΔNS1 heterologous booster had robust humoral responses for influenza A virus group 1 HAs and were protected from seasonal H1N1 influenza virus and heterologous highly pathogenic avian H5N1 lethal challenges. When compared with mice immunized with the standard of care or cold-adapted cHA-LAIV, cHA-ΔNS1 immunized mice had robust antigen-specific CD8 + T-cell responses which also correlated with markedly reduced lung pathology post-challenge. These observations support the development of a trivalent universal influenza vaccine for the protection against group 1 and group 2 influenza A viruses and influenza B viruses., (© 2024. The Author(s).)

Live attenuated influenza vaccines (LAIV) typically induce a poor hemagglutination inhibition (HI) response, which is the standard correlate of protection for inactivated influenza vaccines. The significance of the HI response is complicated because the LAIV vaccine primarily induces the local mucosal immune system, while the HI assay measures the circulating serum antibody response. However, age and pre-existing immunity have been identified as important factors affecting LAIV immunogenicity. This study aimed to extend our understanding of LAIV-induced immunity, particularly, the impact age and pre-existing immunity have on eliciting functional and neutralising antibody responses in paediatric and adult populations vaccinated with LAIV. Thirty-one children and 26 adults were immunized with the trivalent LAIV during the 2013-2014 influenza season in Norway. Children under 9 years received a second dose of LAIV 28 days after the first dose. Blood samples were collected pre- and post-vaccination. HI, microneutralization (MN) and enzyme-linked lectin assay for neuraminidase (NA) antibodies were measured against the vaccine strains. IgG antibody avidity against hemagglutinin (HA) and NA proteins from the vaccine strains was also assessed. Significant correlations were observed between HI and MN responses to A/California/7/2009 (A/H1N1)pdm09-like strain and B/Massachusetts/2/2012-like strain, suggesting that MN is a potential immunological correlate for LAIV. However, the relationship between recipient age (or priming status) and serological response varied between vaccine strains. There was a notable increase in HI and MN responses in all cohorts except naive children against the H1N1 strain, where most recipients had responses below the protective antibody threshold. NAI responses were generally weak in naive children against all vaccine strains compared with adults or antigen-primed children. Post-vaccination antibody avidity increased only in primed children below nine years of age against the A/H1N1 strain. Overall, our findings indicate that LAIV elicits functional and neutralizing antibody responses in both naive and antigen experienced cohorts, however, the magnitude and kinetics of the response varies between vaccine strains.

Monoclonal antibodies (mAbs) are an attractive therapeutic platform for the prevention and treatment of influenza virus infection. There are two major glycoproteins on the influenza virion surface: hemagglutinin (HA), which is responsible for viral attachment and entry, and neuraminidase (NA), which mediates viral egress by enzymatically cleaving sialic acid to release budding particles from the host cell surface. Broadly neutralizing antibodies (bNAbs) that target the conserved HA central stalk region, such as CR9114, can inhibit both viral entry and egress. More recently, broadly binding mAbs that engage and inhibit the NA active site, such as 1G01, have been described to prevent viral egress. Here, we engineered bispecific antibodies (bsAbs) that combine the variable domains of CR9114 and 1G01 into a single molecule and evaluated if simultaneous targeting of two different glycoproteins improved antiviral properties in vitro and in vivo . Several CR9114/1G01 bsAbs were generated with various configurations of the two sets of the variable domains ("bsAb formats"). We found that combinations employing the addition of a single-chain variable fragment in the hinge region of an IgG scaffold had the best properties in terms of expression, stability, and binding. Further characterization of selected bsAbs showed potent neutralizing and egress-inhibiting activity. One such bsAb ("hSC_CR9114_1G01") provided higher levels of prophylactic protection from mortality and morbidity upon challenge with H1N1 than either of the parental mAbs at low dosing (1 mg/kg). These results highlight the potential use of bsAbs that simultaneously target HA and NA as new influenza immunotherapeutics., Importance: Infection by the influenza virus remains a global health burden. The approaches utilized here to augment the activity of broadly protective influenza virus antibodies may lead to a new class of immunotherapies with enhanced activity., Competing Interests: The Icahn School of Medicine at Mount Sinai has filed patent applications regarding influenza virus vaccines and therapeutics which list F.K. as an inventor. The Krammer laboratory has received support for influenza virus research in the past from GSK and is currently receiving support from Dynavax. F.K. is currently consulting for GSK, Third Rock Ventures, Gritstone, and Avimex.

The emergence of highly contagious and immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has required reformulation of coronavirus disease 2019 (COVID-19) vaccines to target those new variants specifically. While previous infections and booster vaccinations can enhance variant neutralization, it is unclear whether the monovalent version, administered using either mRNA or protein-based vaccine platforms, can elicit de novo B-cell responses specific for Omicron XBB.1.5 variants. Here, we dissected the genetic antibody repertoire of 603 individual plasmablasts derived from five individuals who received a monovalent XBB.1.5 vaccination either with mRNA (Moderna or Pfizer/BioNtech) or adjuvanted protein (Novavax). From these sequences, we expressed 100 human monoclonal antibodies and determined binding, affinity and protective potential against several SARS-CoV-2 variants, including JN.1. We then select two vaccine-induced XBB.1.5 mAbs, M2 and M39. M2 mAb was a de novo , antibody, i.e., specific for XBB.1.5 but not ancestral SARS-CoV-2. M39 bound and neutralized both XBB.1.5 and JN.1 strains. Our high-resolution cryo-electron microscopy (EM) structures of M2 and M39 in complex with the XBB.1.5 spike glycoprotein defined the epitopes engaged and revealed the molecular determinants for the mAbs' specificity. These data show, at the molecular level, that monovalent, variant-specific vaccines can elicit functional antibodies, and shed light on potential functional and genetic differences of mAbs induced by vaccinations with different vaccine platforms.\., Competing Interests: Competing interests The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARSCoV-2 serological assays, NDV-based SARS-CoV-2 vaccines influenza virus vaccines and influenza virus therapeutics which list Florian Krammer as co-inventor. Viviana Simon is listed on the SARS-CoV-2 serological assay patent application as co-inventor. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, CastleVax, to develop SARS-CoV-2 vaccines. Florian Krammer is co-founder and scientific advisory board member of CastleVax. Florian Krammer has consulted for Merck, Curevac, GSK, Seqirus and Pfizer and is currently consulting for 3rd Rock Ventures, Gritstone and Avimex. The Krammer laboratory is collaborating with Dynavax on influenza vaccine development and with VIR on influenza virus therapeutics.

Sero-monitoring provides context to the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and changes in population immunity following vaccine introduction. Here, we describe results of a cross-sectional hospital-based study of anti-spike seroprevalence in New York City (NYC) from February 2020 to July 2022, and a follow-up period from August 2023 to October 2023. Samples from 55,092 individuals, spanning five epidemiological waves were analyzed. Prevalence ratios (PR) were obtained using Poisson regression. Anti-spike antibody levels increased gradually over the first two waves, with a sharp increase during the 3rd wave coinciding with SARS-CoV-2 vaccination in NYC resulting in seroprevalence levels >90% by July 2022. Our data provide insights into the dynamic changes in immunity occurring in a large and diverse metropolitan community faced with a new viral pathogen and reflects the patterns of antibody responses as the pandemic transitions into an endemic stage., (© 2024. The Author(s).)

Avian influenza A virus (IAV) surveillance in Northern California, USA, revealed unique IAV hemagglutinin (HA) genome sequences in cloacal swabs from lesser scaups. We found two closely related HA sequences in the same duck species in 2010 and 2013. Phylogenetic analyses suggest that both sequences belong to the recently discovered H19 subtype, which thus far has remained uncharacterized. We demonstrate that H19 does not bind the canonical IAV receptor sialic acid (Sia). Instead, H19 binds to the major histocompatibility complex class II (MHC class II), which facilitates viral entry. Unlike the broad MHC class II specificity of H17 and H18 from bat IAV, H19 exhibits a species-specific MHC class II usage that suggests a limited host range and zoonotic potential. Using cell lines overexpressing MHC class II, we rescued recombinant H19 IAV. We solved the H19 crystal structure and identified residues within the putative Sia receptor binding site (RBS) that impede Sia-dependent entry., Competing Interests: Declaration of interests The A.G.-S. laboratory has received research support from GSK, Pfizer, Senhwa Biosciences, Kenall Manufacturing, Blade Therapeutics, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories, and Merck outside of the reported work. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Castlevax, Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, CureLab Oncology, CureLab Veterinary, Synairgen, Paratus, Pfizer, and Prosetta, outside of the reported work. A.G.-S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott, and Astrazeneca. A.G.-S. is an inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work. The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays, NDV-based SARS-CoV-2 vaccines, influenza virus vaccines, and influenza virus therapeutics, which list F.K. as co-inventor. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, Castlevax, to develop SARS-CoV-2 vaccines. F.K. is a co-founder and scientific advisory board member of Castlevax. F.K. has consulted for Merck, Curevac, Seqirus, and Pfizer and is currently consulting for 3rd Rock Ventures, GSK, Gritstone, and Avimex. The Krammer laboratory is also collaborating with Dynavax on influenza vaccine development., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: In order to prevent the emergence and spread of future variants of concern of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), developing vaccines capable of stopping transmission is crucial. The SARS-CoV-2 vaccine NDV-HXP-S can be administered live intranasally (IN) and thus induce protective immunity in the upper respiratory tract. The vaccine is based on Newcastle disease virus (NDV) expressing a stabilised SARS-CoV-2 spike protein. NDV-HXP-S can be produced as influenza virus vaccine at low cost in embryonated chicken eggs., Methods: The NDV-HXP-S vaccine was genetically engineered to match the Omicron variants of concern (VOC) BA.1 and BA.5 and tested as an IN two or three dose vaccination regimen in female mice. Furthermore, female mice intramuscularly (IM) vaccinated with mRNA-lipid nanoparticles (LNPs) were IN boosted with NDV-HXP-S. Systemic humoral immunity, memory T cell responses in the lungs and spleens as well as immunoglobulin A (IgA) responses in distinct mucosal tissues were characterised., Findings: NDV-HXP-S Omicron variant vaccines elicited high mucosal IgA and serum IgG titers against respective SARS-CoV-2 VOC in female mice following IN administration and protected against challenge from matched variants. Additionally, antigen-specific memory B cells and local T cell responses in the lungs were induced. Host immunity against the NDV vector did not interfere with boosting. Intramuscular vaccination with mRNA-LNPs was enhanced by IN NDV-HXP-S boosting resulting in improvement of serum neutralization titers and induction of mucosal immunity., Interpretation: We demonstrate that NDV-HXP-S Omicron variant vaccines utilised for primary immunizations or boosting efficiently elicit humoral and cellular immunity. The described induction of systemic and mucosal immunity has the potential to reduce infection and transmission., Funding: This work was partially funded by the NIAIDCenters of Excellence for Influenza Research and Response (CEIRR) and by the NIAID Collaborative Vaccine Innovation Centers and by institutional funding from the Icahn School of Medicine at Mount Sinai. See under Acknowledgements for details., Competing Interests: Declaration of interests The Icahn School of Medicine at Mount Sinai has filed patent applications entitled “RECOMBINANT NEWCASTLE DISEASE VIRUS EXPRESSING SARS-COV-2 SPIKE PROTEIN AND USES THEREOF” which names P.P., A.G.S, F.K. and W.S. as inventors. Mount Sinai is seeking to commercialise this vaccine; therefore, the institution and its faculty inventors could benefit financially. I.G.D. has co-chaired at the ninth ESWI Influenza conference, which has no competing interest with this work. The M.S. laboratory has received unrelated research funding in sponsored research agreements from 7Hills Pharma, ArgenX N.V., Moderna and Phio Pharmaceuticals, which has no competing interest with this work. F.K. has consulted for Merck, Seqirus, Curevac and Pfizer, and is currently consulting for Pfizer, Third Rock Ventures, GSK and Avimex. The FK laboratory is also collaborating with Pfizer on animal models of SARS-CoV-2. The A.G.-S. laboratory has received research support from GSK, Pfizer, Senhwa Biosciences, Kenall Manufacturing, Blade Therapeutics, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories and Merck. A.G.S. has consulting agreements for the following companies involving cash and/or stock: Castlevax, Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, CureLab Oncology, CureLab Veterinary, Synairgen, Paratus and Pfizer. A.G.S. has been an invited speaker in meeting events organised by Seqirus, Janssen, Abbott and Astrazeneca. A.G.S. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York. Specifically, A.G.S., a member of the faculty of the Icahn School of Medicine at Mount Sinai (Mount Sinai) is an inventor of a novel COVID-19 vaccine currently being investigated in clinical trials. Mount Sinai is advancing the development of this vaccine and related technologies for potential commercial use. Mount Sinai has created CastleVax Inc., a Mount Sinai company, and has licensed the applicable IP to it. Mount Sinai will receive financial compensation from CastleVax Inc. pursuant to that license if vaccine development proceeds and as an owner of the company subject to the sale of its ownership interest in the future. Subject to Mount Sinai receiving such financial consideration, A.G.S. will receive a portion of that consideration pursuant to the terms of the Mount Sinai Intellectual Property Policy. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

In patients with lung cancer (LC), understanding factors that impact the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-spike antibody (SAb) titers over time is critical, but challenging, due to evolving treatments, infections, vaccinations, and health status. The objective was to develop a time-dependent regression model elucidating individual contributions of factors influencing SAb levels in LC patients using a prospective, longitudinal, multi-institutional cohort study initiated in January 2021. The study evaluated 296 LC patients-median age 69; 55% female; 50% stage IV. Blood samples were collected every three months to measure SAb levels using FDA-approved ELISA. Asymptomatic and unreported infections were documented through measurement of anti-nucleocapsid Ab levels (Meso Scale Discovery). Associations between clinical characteristics and titers were evaluated using a time-dependent linear regression model with a generalized estimating equation (GEE), considering time-independent variables (age, sex, ethnicity, smoking history, histology, and stage) and time-dependent variables (booster vaccinations, SARS-CoV-2 infections, cancer treatment, steroid use, and influenza vaccination). Significant time-dependent effects increasing titer levels were observed for prior SARS-CoV-2 infection ( p < 0.001) and vaccination/boosters ( p < 0.001). Steroid use ( p = 0.043) and chemotherapy ( p = 0.033) reduced titer levels. Influenza vaccination was associated with increased SAb levels ( p < 0.001), independent of SARS-CoV-2 vaccine boosters. Prior smoking significantly decreased titers in females ( p = 0.001). Age showed no association with titers. This GEE-based linear regression model unveiled the nuanced impact of multiple variables on patient anti-spike Ab levels over time. After controlling for the major influences of vaccine and SARS-CoV-2 infections, chemotherapy and steroid use were found to have negatively affected titers. Smoking in females significantly decreased titers. Surprisingly, influenza vaccinations were also significantly associated, likely indirectly, with improved SARS-CoV-2 titers.