Preexisting immunity restricts mucosal antibody recognition of SARS-CoV-2 and Fc profiles during breakthrough infections
Kevin J. Selva, … , Stephen J. Kent, Amy W. Chung
Kevin J. Selva, … , Stephen J. Kent, Amy W. Chung
Published September 22, 2023
Citation Information: JCI Insight. 2023;8(18):e172470. https://doi.org/10.1172/jci.insight.172470.
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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 4

Ancestral imprinting limits cross-reactive responses against VoCs elicited by COVID-19 mRNA vaccination.

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Ancestral imprinting limits cross-reactive responses against VoCs elicit...
Bar graphs display the salivary (n = 9) (A) and tear (n = 6) (B) Fcγ3a responses against WT SARS-CoV-2 or the VoC spike 1 antigens in COVID-19–recovered individuals following 2 doses of mRNA vaccines. Fold-changes listed above the bar graphs were calculated for postvaccination responses (purple) over their respective prevaccination responses (gray) for each antigen. The numbers of individuals with detectable responses above the assay threshold (dotted line; pre-pandemic or 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. Heatmaps illustrate the VoC-specific Spike trimer (ST) salivary (n = 10) (C), plasma (n = 10) (D), and tear (n = 6) (E) antibody responses postvaccination (dose 1 or 2) for COVID-19–recovered individuals. Bar graphs describe VoC-specific ST salivary IgA responses in COVID-19–recovered individuals (n = 10) after 1 (F) or 2 (G) vaccine doses. The median antibody response for each VoC spike was described as a fold-change to the WT spike. Statistical significance was calculated using Friedman’s test followed by Dunn’s test for multiple comparisons and where significant or trending significance, P values were reported (*P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001).