Impact of systemic SARS-CoV-2 vaccination on mucosal IgA responses to subsequent breakthrough infection.

Abstract

Background: Mucosal IgA responses are central to protection against SARS-CoV-2 infection and viral transmission. While systemic immunity following SARS-CoV-2 infection and vaccination is thoroughly investigated, we have limited understanding of factors affecting the generation and boosting of mucosal IgA.

Methods: In this cohort study, we investigated factors influencing mucosal SARS-CoV-2 IgA responses among 879 healthcare workers enrolled in the longitudinal COMMUNITY study. Blood samples and clinical data were collected from all participants every four months since April 2020. SARS-CoV-2 immune histories are well characterized through national vaccine and infection registries along with regular monitoring of seroconversion of spike and/or nucleocapsid antigen. Regression models were developed to assess the influence of vaccinations and prior infections on the magnitude of SARS-CoV-2 spike-specific IgA in nasal secretions collected from the cohort in October 2022.

Findings: Mucosal SARS-CoV-2 spike-specific IgA was detected in 81% of participants, with a positive association with number of prior infections, indicating a booster effect by reinfection. The increased odds ratio of detectable mucosal IgA remained for at least 22 months post infection. There was a strong association between repeated systemic vaccinations and a lower magnitude of mucosal IgA responses. Moreover, the temporal sequence of infection and vaccination influenced mucosal IgA responses, with higher levels among participants with infection prior to systemic vaccination as compared to those with breakthrough infection as the first viral encounter.

Interpretation: The observation that repeated mucosal exposures elicit enhanced and long-lasting mucosal IgA responses strengthens the rationale for developing effective mucosal vaccines. While systemic vaccination remains essential for preventing severe disease, our findings suggest that it may influence subsequent generation of mucosal IgA trough a reduction of viral load and inflammation in the mucosa. This is highly relevant for both understanding the development of population immunity and for optimizing the timing of a sequential systemic and mucosal vaccination approach.

Funding: This study was supported by grants from Region Stockholm, and SciLifeLab and the Knut and Alice Wallenberg Foundation, SSMF and European Research Council. We thank the Public Health Agency of Sweden for support.