Preexisting immunity restricts mucosal antibody recognition of SARS-CoV-2 and Fc profiles during breakthrough infections
Kevin J. Selva, Pradhipa Ramanathan, Ebene R. Haycroft, Arnold Reynaldi, Deborah Cromer, Chee Wah Tan, Lin-Fa Wang, Bruce D. Wines, P. Mark Hogarth, Laura E. Downie, Samantha K. Davis, Ruth A. Purcell, Helen E. Kent, Jennifer A. Juno, Adam K. Wheatley, Miles P. Davenport, Stephen J. Kent, Amy W. Chung
Kevin J. Selva, Pradhipa Ramanathan, Ebene R. Haycroft, Arnold Reynaldi, Deborah Cromer, Chee Wah Tan, Lin-Fa Wang, Bruce D. Wines, P. Mark Hogarth, Laura E. Downie, Samantha K. Davis, Ruth A. Purcell, Helen E. Kent, Jennifer A. Juno, Adam K. Wheatley, Miles P. Davenport, Stephen J. Kent, Amy W. Chung
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Research Article COVID-19

Preexisting immunity restricts mucosal antibody recognition of SARS-CoV-2 and Fc profiles during breakthrough infections

Abstract

Understanding mucosal antibody responses from SARS-CoV-2 infection and/or vaccination is crucial to develop strategies for longer term immunity, especially against emerging viral variants. We profiled serial paired mucosal and plasma antibodies from COVID-19 vaccinated only vaccinees (vaccinated, uninfected), COVID-19–recovered vaccinees (recovered, vaccinated), and individuals with breakthrough Delta or Omicron BA.2 infections (vaccinated, infected). Saliva from COVID-19–recovered vaccinees displayed improved antibody-neutralizing activity, Fcγ receptor (FcγR) engagement, and IgA levels compared with COVID-19–uninfected vaccinees. Furthermore, repeated mRNA vaccination boosted SARS-CoV-2–specific IgG2 and IgG4 responses in both mucosa biofluids (saliva and tears) and plasma; however, these rises only negatively correlated with FcγR engagement in plasma. IgG and FcγR engagement, but not IgA, responses to breakthrough COVID-19 variants were dampened and narrowed by increased preexisting vaccine-induced immunity against the ancestral strain. Salivary antibodies delayed initiation following breakthrough COVID-19 infection, especially Omicron BA.2, but rose rapidly thereafter. Importantly, salivary antibody FcγR engagements were enhanced following breakthrough infections. Our data highlight how preexisting immunity shapes mucosal SARS-CoV-2–specific antibody responses and has implications for long-term protection from COVID-19.

Authors

Kevin J. Selva, Pradhipa Ramanathan, Ebene R. Haycroft, Arnold Reynaldi, Deborah Cromer, Chee Wah Tan, Lin-Fa Wang, Bruce D. Wines, P. Mark Hogarth, Laura E. Downie, Samantha K. Davis, Ruth A. Purcell, Helen E. Kent, Jennifer A. Juno, Adam K. Wheatley, Miles P. Davenport, Stephen J. Kent, Amy W. Chung

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Figure 3

Improved salivary antibody-neutralizing activity from COVID-19–recovered vaccinees.

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Improved salivary antibody-neutralizing activity from COVID-19–recovered...
Bar graphs depict the plasma (A–C) and salivary (D–F) inhibition of RBD-ACE2 interactions against the ancestral wild-type (WT) SARS-CoV-2 or the VoCs (α, Alpha; δ, Delta; β, Beta; σ BA.1, Omicron BA.1; σ BA.2, Omicron BA.2) by vaccinated only (n = 10) (A and D) and COVID-19–recovered individuals (n = 10) (B, C, E, and F). Fold-changes listed above the bar graphs were calculated for post-booster (green) and postvaccination responses (blue, purple) over their respective pre-booster (yellow) and prevaccination responses (gray) for each cohort and antigen. The numbers of individuals with detectable responses above the assay threshold (arbitrary 20%; dotted line) at either time point were listed under the bar graphs in their respective colors. Significant differences between both time points were calculated using the 2-tailed Mann-Whitney U test, followed by Bonferroni-Dunn’s test for multiple comparisons. Where significant or trending significance, P values were reported (*P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001).