Boosting of cross-reactive antibodies to endemic coronaviruses by SARS-CoV-2 infection but not vaccination with stabilized spike

Elife. 2022 Mar 15:11:e75228. doi: 10.7554/eLife.75228.


Preexisting antibodies to endemic coronaviruses (CoV) that cross-react with SARS-CoV-2 have the potential to influence the antibody response to COVID-19 vaccination and infection for better or worse. In this observational study of mucosal and systemic humoral immunity in acutely infected, convalescent, and vaccinated subjects, we tested for cross-reactivity against endemic CoV spike (S) protein at subdomain resolution. Elevated responses, particularly to the β-CoV OC43, were observed in all natural infection cohorts tested and were correlated with the response to SARS-CoV-2. The kinetics of this response and isotypes involved suggest that infection boosts preexisting antibody lineages raised against prior endemic CoV exposure that cross-react. While further research is needed to discern whether this recalled response is desirable or detrimental, the boosted antibodies principally targeted the better-conserved S2 subdomain of the viral spike and were not associated with neutralization activity. In contrast, vaccination with a stabilized spike mRNA vaccine did not robustly boost cross-reactive antibodies, suggesting differing antigenicity and immunogenicity. In sum, this study provides evidence that antibodies targeting endemic CoV are robustly boosted in response to SARS-CoV-2 infection but not to vaccination with stabilized S, and that depending on conformation or other factors, the S2 subdomain of the spike protein triggers a rapidly recalled, IgG-dominated response that lacks neutralization activity.

Keywords: SARS-CoV-2; antibodies; conformation; epitope; human; immunology; infectious disease; inflammation; microbiology; neutralization; vaccine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Antibodies, Viral / immunology*
  • Antibody Specificity / immunology
  • COVID-19 / prevention & control*
  • COVID-19 Vaccines / immunology*
  • Cross Reactions / immunology*
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunoglobulin A / immunology
  • Immunoglobulin G / immunology
  • Immunoglobulin M / immunology
  • Neutralization Tests
  • SARS-CoV-2 / immunology*
  • Spike Glycoprotein, Coronavirus / immunology*
  • Vaccination


  • Antibodies, Viral
  • COVID-19 Vaccines
  • Immunoglobulin A
  • Immunoglobulin G
  • Immunoglobulin M
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2