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 5

COVID-19 breakthrough infections induce salivary FcγR engagement and IgA responses.

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COVID-19 breakthrough infections induce salivary FcγR engagement and IgA...
Paired saliva and plasma samples were serially collected from individuals over the course of their Delta (n = 8) or Omicron BA.2 breakthrough infections (n = 10) (A). Circles depict the time points where serial paired plasma and saliva samples were collected in the presence (open circles) or absence (closed circles) of a nasal swab sample. Bar graphs describe the salivary (B and C) inhibition of RBD-ACE2 interactions against the ancestral 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 individuals with Delta (n = 8) (B) and Omicron BA.2 breakthrough (n = 10) (C) infections. Similarly, bar graphs depict the engagement of FcγR3a by salivary (D and E) antibodies by individuals with Delta (n = 8) (D) and Omicron BA.2 breakthrough (n = 10) (E) infections. Fold-changes listed above the bar graphs were calculated for responses 2 weeks after symptom onset (Delta: red; Omicron BA.2: green) over respective responses earlier during infection (gray; ≤5 days after symptom onset) for each cohort and antigen. The numbers of individuals with detectable responses above the assay threshold (dotted line) (RBD-ACE2: arbitrary 20%; FcγR3a: uninfected, unvaccinated healthy control average) 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. Heatmap illustrates the VoC-specific ST salivary antibody responses for Delta (n = 8) and Omicron BA.2 breakthrough (n = 10) cohorts 2 weeks after symptom onset (F). The median antibody response for each VoC spike was described as a fold-change from the WT spike. Statistical significance was calculated using Friedman’s test followed by Dunn’s test for multiple comparisons. Where significant, P values were reported (*P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001).