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      Original antigenic sin responses to Betacoronavirus spike proteins are observed in a mouse model, but are not apparent in children following SARS-CoV-2 infection

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          Abstract

          Background

          The effects of pre-existing endemic human coronavirus (HCoV) immunity on SARS-CoV-2 serologic and clinical responses are incompletely understood.

          Objectives

          We sought to determine the effects of prior exposure to HCoV Betacoronavirus HKU1 spike protein on serologic responses to SARS-CoV-2 spike protein after intramuscular administration in mice. We also sought to understand the baseline seroprevalence of HKU1 spike antibodies in healthy children and to measure their correlation with SARS-CoV-2 binding and neutralizing antibodies in children hospitalized with acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome (MIS-C).

          Methods

          Groups of 5 mice were injected intramuscularly with two doses of alum-adjuvanted HKU1 spike followed by SARS-CoV-2 spike; or the reciprocal regimen of SARS-Cov-2 spike followed by HKU1 spike. Sera collected 21 days following each injection was analyzed for IgG antibodies to HKU1 spike, SARS-CoV-2 spike, and SARS-CoV-2 neutralization. Sera from children hospitalized with acute COVID-19, MIS-C or healthy controls (n = 14 per group) were analyzed for these same antibodies.

          Results

          Mice primed with SARS-CoV-2 spike and boosted with HKU1 spike developed high titers of SARS-CoV-2 binding and neutralizing antibodies; however, mice primed with HKU1 spike and boosted with SARS-CoV-2 spike were unable to mount neutralizing antibodies to SARS-CoV-2. HKU1 spike antibodies were detected in all children with acute COVID-19, MIS-C, and healthy controls. Although children with MIS-C had significantly higher HKU1 spike titers than healthy children (GMT 37239 vs. 7551, P = 0.012), these titers correlated positively with both SARS-CoV-2 binding (r = 0.7577, P<0.001) and neutralizing (r = 0.6201, P = 0.001) antibodies.

          Conclusions

          Prior murine exposure to HKU1 spike protein completely impeded the development of neutralizing antibodies to SARS-CoV-2, consistent with original antigenic sin. In contrast, the presence of HKU1 spike IgG antibodies in children with acute COVID-19 or MIS-C was not associated with diminished neutralizing antibody responses to SARS-CoV-2.

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          Most cited references24

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          Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans

          Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10-15 d after the onset of COVID-19 symptoms. However, due to the recent emergence of SARS-CoV-2 in the human population, it is not known how long antibody responses will be maintained or whether they will provide protection from reinfection. Using sequential serum samples collected up to 94 d post onset of symptoms (POS) from 65 individuals with real-time quantitative PCR-confirmed SARS-CoV-2 infection, we show seroconversion (immunoglobulin (Ig)M, IgA, IgG) in >95% of cases and neutralizing antibody responses when sampled beyond 8 d POS. We show that the kinetics of the neutralizing antibody response is typical of an acute viral infection, with declining neutralizing antibody titres observed after an initial peak, and that the magnitude of this peak is dependent on disease severity. Although some individuals with high peak infective dose (ID50 > 10,000) maintained neutralizing antibody titres >1,000 at >60 d POS, some with lower peak ID50 had neutralizing antibody titres approaching baseline within the follow-up period. A similar decline in neutralizing antibody titres was observed in a cohort of 31 seropositive healthcare workers. The present study has important implications when considering widespread serological testing and antibody protection against reinfection with SARS-CoV-2, and may suggest that vaccine boosters are required to provide long-lasting protection.
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            Preexisting and de novo humoral immunity to SARS-CoV-2 in humans

            Antibodies predating infection Immunological memory after infection with seasonal human coronaviruses (hCoVs) may potentially contribute to cross-protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Ng et al. report that in a cohort of 350 SARS-CoV-2–uninfected individuals, a small proportion had circulating immunoglobulin G (IgG) antibodies that could cross-react with the S2 subunit of the SARS-CoV-2 spike protein (see the Perspective by Guthmiller and Wilson). By contrast, COVID-19 patients generated IgA, IgG, and IgM antibodies that recognized both the S1 and S2 subunits. The anti-S2 antibodies from SARS-CoV-2–uninfected patients showed specific neutralizing activity against both SARS-CoV-2 and SARS-CoV-2 S pseudotypes. A much higher percentage of SARS-CoV-2–uninfected children and adolescents were positive for these antibodies compared with adults. This pattern may be due to the fact that children and adolescents generally have higher hCoV infection rates and a more diverse antibody repertoire, which may explain the age distribution of COVID-19 susceptibility. Science, this issue p. 1339; see also p. 1272
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              • Record: found
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              A systematic review of antibody mediated immunity to coronaviruses: kinetics, correlates of protection, and association with severity

              Many public health responses and modeled scenarios for COVID-19 outbreaks caused by SARS-CoV-2 assume that infection results in an immune response that protects individuals from future infections or illness for some amount of time. The presence or absence of protective immunity due to infection or vaccination (when available) will affect future transmission and illness severity. Here, we review the scientific literature on antibody immunity to coronaviruses, including SARS-CoV-2 as well as the related SARS-CoV, MERS-CoV and endemic human coronaviruses (HCoVs). We reviewed 2,452 abstracts and identified 491 manuscripts relevant to 5 areas of focus: 1) antibody kinetics, 2) correlates of protection, 3) immunopathogenesis, 4) antigenic diversity and cross-reactivity, and 5) population seroprevalence. While further studies of SARS-CoV-2 are necessary to determine immune responses, evidence from other coronaviruses can provide clues and guide future research.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Data curationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Formal analysisRole: Funding acquisitionRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                27 August 2021
                2021
                27 August 2021
                : 16
                : 8
                : e0256482
                Affiliations
                [1 ] Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States of America
                [2 ] Center for Childhood Infections and Vaccines, Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, United States of America
                [3 ] Yerkes Primate Center, Emory University, Atlanta, GA, United States of America
                [4 ] Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States of America
                University of South Dakota, UNITED STATES
                Author notes

                Competing Interests: E.J.A. has received personal fees from AbbVie, Pfizer, and Sanofi Pasteur for consulting, and his institution receives funds to conduct clinical research unrelated to this manuscript from MedImmune, Regeneron, PaxVax, Pfizer, GSK, Merck, Novavax, Sanofi-Pasteur, Janssen, and Micron. He also serves on a safety monitoring board for Sanofi- Pasteur and Kentucky BioProcessing, Inc. C.A.R.’s institution has received funds to conduct clinical research unrelated to this manuscript from BioFire Inc, GSK, MedImmune, Micron, Janssen, Merck, Moderna, Novavax, PaxVax, Pfizer, Regeneron, Sanofi-Pasteur. She is co-inventor of patented RSV vaccine technology unrelated to this manuscript, which has been licensed to Meissa Vaccines, Inc. These do not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                https://orcid.org/0000-0001-9321-7839
                https://orcid.org/0000-0001-8439-0592
                Article
                PONE-D-21-10490
                10.1371/journal.pone.0256482
                8396729
                34449792
                d1c6aced-1ef7-4360-a432-5bc56348ed50
                © 2021 Lapp 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.

                History
                : 30 March 2021
                : 6 August 2021
                Page count
                Figures: 4, Tables: 1, Pages: 13
                Funding
                Funded by: Center for Childhood Infections and Vaccines of Children's Healthcare of Atlanta and Emory University School of Medicine
                Award ID: CCIV
                Award Recipient :
                Funded by: Emergent Ventures at the Mercatus Center at George Mason University
                Award Recipient :
                This work was funded by a Center for Childhood Infections and Vaccines (CCIV) pilot award from Children’s Healthcare of Atlanta and Emory University School of Medicine (to C.A.R.) and a Fast Grant from Emergent Ventures at the Mercatus Center at George Mason University (to A.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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