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mRNA-1273 vaccine efficacy against SARS-CoV-2 Delta wanes over time; however, there are limited data on the impact of durability of immune responses on protection. Here, we immunized rhesus macaques and assessed immune responses over 1 year in blood and upper and lower airways. Serum neutralizing titers to Delta were 280 and 34 reciprocal ID 50 at weeks 6 (peak) and 48 (challenge), respectively. Antibody-binding titers also decreased in bronchoalveolar lavage (BAL). Four days after Delta challenge, the virus was unculturable in BAL, and subgenomic RNA declined by ∼3-log 10 compared with control animals. In nasal swabs, sgRNA was reduced by 1-log 10 , and the virus remained culturable. Anamnestic antibodies (590-fold increased titer) but not T cell responses were detected in BAL by day 4 post-challenge. mRNA-1273-mediated protection in the lungs is durable but delayed and potentially dependent on anamnestic antibody responses. Rapid and sustained protection in upper and lower airways may eventually require a boost. [Display omitted] • Protection from severe lung disease 1 year after mRNA-1273 vaccination in macaques • Protection in the lungs is coincident with a local anamnestic antibody response • Protection in upper airway is limited 1 year after mRNA-1273 vaccination • Neutralizing responses to Delta are low to undetectable 1 year after mRNA-1273 vaccination A study looking at immunity against the SARS-CoV-2 Delta variant one year after mRNA vaccination found durable but delayed anamnestic antibody responses in the lung but limited protection in the upper airway and low neutralizing responses, thus advocating for booster shots for sustained upper and lower airway protection. [ABSTRACT FROM AUTHOR]

The 2005 Immunity paper by Karikó et al. has been hailed as a cornerstone insight that directly led to the design and delivery of the mRNA vaccines against COVID-19. We asked experts in pathogen sensing, vaccine development, and public health to provide their perspective on the study and its implications. [ABSTRACT FROM AUTHOR]

Coronaviruses make use of a large envelope protein called spike (S) to engage host cell receptors and catalyze membrane fusion. Because of the vital role that these S proteins play, they represent a vulnerable target for the development of therapeutics. Here, we describe the isolation of single-domain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spikes. These VHHs neutralize MERS-CoV or SARS-CoV-1 S pseudotyped viruses, respectively. Crystal structures of these VHHs bound to their respective viral targets reveal two distinct epitopes, but both VHHs interfere with receptor binding. We also show cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S and demonstrate that this cross-reactive VHH neutralizes SARS-CoV-2 S pseudotyped viruses as a bivalent human IgG Fc-fusion. These data provide a molecular basis for the neutralization of pathogenic betacoronaviruses by VHHs and suggest that these molecules may serve as useful therapeutics during coronavirus outbreaks. • VHHs isolated from a llama immunized with prefusion-stabilized coronavirus spikes • Structural characterization of VHHs reveals conserved mechanism of neutralization • SARS-CoV-1 S-directed VHH cross-reacts with SARS-CoV-2 S • Bivalent VHH neutralizes SARS-CoV-2 pseudoviruses Using llamas immunized with prefusion-stabilized betacoronavirus spike proteins, Wrapp et al. identify neutralizing cross-reactive single-domain camelid antibodies, which may serve not only as useful reagents for researchers studying the viruses causing MERS, SARS, and COVID-19, but also potential therapeutic candidates. Crystal structures further reveal how these antibodies bind spike proteins to prevent virus entry into cells. [ABSTRACT FROM AUTHOR]

Current influenza vaccines predominantly induce immunity to the hypervariable hemagglutinin (HA) head, requiring frequent vaccine reformulation. Conversely, the immunosubdominant yet conserved HA stem harbors a supersite that is targeted by broadly neutralizing antibodies (bnAbs), representing a prime target for universal vaccines. Here, we showed that the co-immunization of two HA stem immunogens derived from group 1 and 2 influenza A viruses elicits cross-group protective immunity and neutralizing antibody responses in mice, ferrets, and nonhuman primates (NHPs). Immunized mice were protected from multiple group 1 and 2 viruses, and all animal models showed broad serum-neutralizing activity. A bnAb isolated from an immunized NHP broadly neutralized and protected against diverse viruses, including H5N1 and H7N9. Genetic and structural analyses revealed strong homology between macaque and human bnAbs, illustrating common biophysical constraints for acquiring cross-group specificity. Vaccine elicitation of stem-directed cross-group-protective immunity represents a step toward the development of broadly protective influenza vaccines. [Display omitted] • Broad group 2 protective immunity was induced by H10-based group 2 HA stem immunogen • Co-immunization with group 1 and 2 HA stem immunogens elicits cross-protective antibodies • A bnAb isolated from an immunized NHP neutralizes both group 1 and 2 influenza A viruses • A common mode of HA recognition via the D H gene-encoded motif among NHP and human bnAbs Current vaccine-induced influenza immunity targets the hypervariable HA head, requiring frequent vaccine reformulation. Moin et al. show that co-immunization with HA stem immunogens of group 1 and group 2 influenza A viruses broadly elicits cross-protective antibodies in animals and leads to the discovery of a cross-group protective monoclonal antibody in a macaque, offering a blueprint for broadly protective influenza vaccines. [ABSTRACT FROM AUTHOR]

Viral pandemics and epidemics pose a significant global threat. While macaque models of viral disease are routinely used, it remains unclear how conserved antiviral responses are between macaques and humans. Therefore, we conducted a cross-species analysis of transcriptomic data from over 6,088 blood samples from macaques and humans infected with one of 31 viruses. Our findings demonstrate that irrespective of primate or viral species, there are conserved antiviral responses that are consistent across infection phase (acute, chronic, or latent) and viral genome type (DNA or RNA viruses). Leveraging longitudinal data from experimental challenges, we identify virus-specific response kinetics such as host responses to Coronaviridae and Orthomyxoviridae infections peaking 1-3 days earlier than responses to Filoviridae and Arenaviridae viral infections. Our results underscore macaque studies as a powerful tool for understanding viral pathogenesis and immune responses that translate to humans, with implications for viral therapeutic development and pandemic preparedness., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Immunization with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike elicits diverse antibodies, but it is unclear if any of the antibodies can neutralize broadly against other beta-coronaviruses. Here, we report antibody WS6 from a mouse immunized with mRNA encoding the SARS-CoV-2 spike. WS6 bound diverse beta-coronavirus spikes and neutralized SARS-CoV-2 variants, SARS-CoV, and related sarbecoviruses. Epitope mapping revealed WS6 to target a region in the S2 subunit, which was conserved among SARS-CoV-2, Middle East respiratory syndrome (MERS)-CoV, and hCoV-OC43. The crystal structure at 2 Å resolution of WS6 revealed recognition to center on a conserved S2 helix, which was occluded in both pre- and post-fusion spike conformations. Structural and neutralization analyses indicated WS6 to neutralize by inhibiting fusion and post-viral attachment. Comparison of WS6 with other recently identified antibodies that broadly neutralize beta-coronaviruses indicated a stem-helical supersite-centered on hydrophobic residues Phe1148, Leu1152, Tyr1155, and Phe1156-to be a promising target for vaccine design., Competing Interests: Declaration of interests The authors declare no competing interest., (Published by Elsevier Ltd.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization from coronavirus disease 2019 (COVID-19) when administered early. However, SARS-CoV-2 variants of concern (VOCs) have negatively affected therapeutic use of some authorized mAbs. Using a high-throughput B cell screening pipeline, we isolated LY-CoV1404 (bebtelovimab), a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody. LY-CoV1404 potently neutralizes authentic SARS-CoV-2, B.1.1.7, B.1.351, and B.1.617.2. In pseudovirus neutralization studies, LY-CoV1404 potently neutralizes variants, including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved, except for N439 and N501. The binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The broad and potent neutralization activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants., Competing Interests: Declaration of interests Eli Lilly and Company provided resources for this study. AbCellera Biologics Inc. received funding from the U.S. Department of Defense, Defense Advanced Research Projects Agency (DARPA) Pandemic Prevention Platform, agreement D18AC00002. This research was funded in part by the U.S. Government (the views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the U.S. Government). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract DE-AC02-06CH11357 (https://www.aps.anl.gov/Science/Publications/Acknowledgment-Statement-for-Publications). Use of the Lilly Research Laboratories Collaborative Access Team (LRL-CAT) beamline at Sector 31 of the Advanced Photon Source was provided by Eli Lilly and Company, which operates the facility (http://lrlcat.lilly.com/). This work was supported by the Intramural Program at the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Vaccine Research Center (to B.S.G. and J.R.M.). Operations support of the Galveston National Laboratory was supported by NIAID/NIH grant UC7AI094660. D.F., P.V., A.P., J.H., J.M.S., R.W.S., J.C., I. H., J.J.F., S.H., H.C.P., B.R., B.A.H., R.W.S., J.C., J.M.S., R.E.H., N.K., and B.E.J. are employees and/or stockholders of Eli Lilly and Company. K.W., S.Ž., M.W., E.L., L.K., Y.H., K.J., R.G., M.A.S., D.W.C., D.P., P.X., V.d.P., R.v.d.L., M.R., L.D., C.P., I.L., L.A., P.S., T.L.F., C.L.H., E.F., and B.C.B. are employees and stockholders of AbCellera Biologics Inc. AbCellera Biologics Inc. and the National Institutes of Health have filed patent applications related to the work described herein (US patent application 17/192243 and international patent application PCT/US21/20843, both titled “Anti-Coronavirus Antibodies and Methods of Use”)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-matched vaccines would enhance protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing titers against D614G were 4,760 and 270 reciprocal ID 50 at week 6 (peak) and week 41 (preboost), respectively, and 320 and 110 for Omicron. 2 weeks after the boost, titers against D614G and Omicron increased to 5,360 and 2,980 for mRNA-1273 boost and 2,670 and 1,930 for mRNA-Omicron, respectively. Similar increases against BA.2 were observed. Following either boost, 70%-80% of spike-specific B cells were cross-reactive against WA1 and Omicron. Equivalent control of virus replication in lower airways was observed following Omicron challenge 1 month after either boost. These data show that mRNA-1273 and mRNA-Omicron elicit comparable immunity and protection shortly after the boost., Competing Interests: Declaration of interests K.S.C. is an inventor on U.S. Patent no. 10,960,070 B2 and International Patent Application no. WO/2018/081318 entitled “Prefusion Coronavirus Spike Proteins and Their Use.” K.S.C. is an inventor on U.S. Patent Application no. 62/972,886 entitled “2019-nCoV Vaccine.” A.R.H., L.W., W.S., Y.Z., E.S.Y., J.R.M., P.D.K., M.R., N.J.S., and D.C.D. are inventors on U.S. Patent Application no. 63/147,419 entitled “Antibodies Targeting the Spike Protein of Coronaviruses.” L.P., A.V.R., B.N., D.V., A. Cook, A.D., K.S., H.A., and M.G.L. are employees of Bioqual. K.S.C., L.W., W.S., and Y.Z. are inventors on multiple U.S. Patent Applications entitled “Anti-Coronavirus Antibodies and Methods of Use.” G.-Y.C., G.S.-J., I.R., Y.-T.L., A.M., K.W., A. Carfi, and D.K.E. are employees of Moderna. M.S.S. serves on the scientific board of advisors for Moderna and Ocugen. The other authors declare no competing interests., (Published by Elsevier Inc.)

Current coronavirus (CoV) vaccines primarily target immunodominant epitopes in the S1 subunit, which are poorly conserved and susceptible to escape mutations, thus threatening vaccine efficacy. Here, we use structure-guided protein engineering to remove the S1 subunit from the Middle East respiratory syndrome (MERS)-CoV spike (S) glycoprotein and develop stabilized stem (SS) antigens. Vaccination with MERS SS elicits cross-reactive β-CoV antibody responses and protects mice against lethal MERS-CoV challenge. High-throughput screening of antibody-secreting cells from MERS SS-immunized mice led to the discovery of a panel of cross-reactive monoclonal antibodies. Among them, antibody IgG22 binds with high affinity to both MERS-CoV and severe acute respiratory syndrome (SARS)-CoV-2 S proteins, and a combination of electron microscopy and crystal structures localizes the epitope to a conserved coiled-coil region in the S2 subunit. Passive transfer of IgG22 protects mice against both MERS-CoV and SARS-CoV-2 challenge. Collectively, these results provide a proof of principle for cross-reactive CoV antibodies and inform the development of pan-CoV vaccines and therapeutic antibodies., Competing Interests: Declaration of interests C-L.H. and J.S.M. are inventors on U.S. patent application no. 63/188,813 (“Stabilized S2 Beta-coronavirus Antigens”). This research was, in part, funded by the U.S. Government. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the U.S. Government. S.R.L., K.H.D., and R.S.B. have a pending patent for recombinant SARS-CoV-2 MA10 used in this study., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Vaccine-associated enhanced respiratory disease (VAERD) was previously observed in some preclinical models of severe acute respiratory syndrome (SARS) and MERS coronavirus vaccines. We used the SARS coronavirus 2 (SARS-CoV-2) mouse-adapted, passage 10, lethal challenge virus (MA10) mouse model of acute lung injury to evaluate the immune response and potential for immunopathology in animals vaccinated with research-grade mRNA-1273. Whole-inactivated virus or heat-denatured spike protein subunit vaccines with alum designed to elicit low-potency antibodies and Th2-skewed CD4 + T cells resulted in reduced viral titers and weight loss post challenge but more severe pathological changes in the lung compared to saline-immunized animals. In contrast, a protective dose of mRNA-1273 induced favorable humoral and cellular immune responses that protected from viral replication in the upper and lower respiratory tract upon challenge. A subprotective dose of mRNA-1273 reduced viral replication and limited histopathological manifestations compared to animals given saline. Overall, our findings demonstrate an immunological signature associated with antiviral protection without disease enhancement following vaccination with mRNA-1273., Competing Interests: Declaration of interests O.M.A., K.S.C., and B.S.G. are inventors on pending patent applications related to coronavirus vaccines. S.R.L. and R.S.B. have pending patents on recombinant viruses used in this study. A.T.D., D.K.E., and A.C. are current employees and shareholders of Moderna, Inc. Other authors declare no competing interests., (Published by Elsevier Inc.)

Biotin-labeled molecular probes, comprising specific regions of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike, would be helpful in the isolation and characterization of antibodies targeting this recently emerged pathogen. Here, we design constructs incorporating an N-terminal purification tag, a site-specific protease-cleavage site, the probe region of interest, and a C-terminal sequence targeted by biotin ligase. Probe regions include full-length spike ectodomain as well as various subregions, and we also design mutants that eliminate recognition of the angiotensin-converting enzyme 2 (ACE2) receptor. Yields of biotin-labeled probes from transient transfection range from ∼0.5 mg/L for the complete ectodomain to >5 mg/L for several subregions. Probes are characterized for antigenicity and ACE2 recognition, and the structure of the spike ectodomain probe is determined by cryoelectron microscopy. We also characterize antibody-binding specificities and cell-sorting capabilities of the biotinylated probes. Altogether, structure-based design coupled to efficient purification and biotinylation processes can thus enable streamlined development of SARS-CoV-2 spike ectodomain probes., Competing Interests: Declaration of Interests The authors declare no competing interest., (Published by Elsevier Inc.)

Middle East respiratory syndrome coronavirus (MERS-CoV) emerged into the human population in 2012 and has caused substantial morbidity and mortality. Potently neutralizing antibodies targeting the receptor-binding domain (RBD) on MERS-CoV spike (S) protein have been characterized, but much less is known about antibodies targeting non-RBD epitopes. Here, we report the structural and functional characterization of G2, a neutralizing antibody targeting the MERS-CoV S1 N-terminal domain (S1-NTD). Structures of G2 alone and in complex with the MERS-CoV S1-NTD define a site of vulnerability comprising two loops, each of which contain a residue mutated in G2-escape variants. Cell-surface binding studies and in vitro competition experiments demonstrate that G2 strongly disrupts the attachment of MERS-CoV S to its receptor, dipeptidyl peptidase-4 (DPP4), with the inhibition requiring the native trimeric S conformation. These results advance our understanding of antibody-mediated neutralization of coronaviruses and should facilitate the development of immunotherapeutics and vaccines against MERS-CoV., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)