The respiratory mucosal interface plays a crucial role in preventing respiratory infections. Secretory IgA (SIgA) antibodies are vital components of this defense, but the extent to which mRNA vaccination induces antigen-specific mucosal SIgA responses in humans remains unclear. SARS-CoV-2, the causative agent of COVID-19, infects respiratory tract epithelia. SIgA antibodies, found in the upper and lower respiratory tracts, are thought to be critical in preventing infection by neutralizing pathogens before they penetrate the epithelial barrier. These antibodies are produced in mucosal-associated lymphoid tissue (MALT) and transported to mucosal surfaces. While IgA antibodies have been detected in COVID-19 patients' serum and saliva, the ability of intramuscularly administered mRNA vaccines to induce SIgA responses is uncertain. This study aims to determine if mRNA vaccination induces antigen-specific SIgA responses and if prior SARS-CoV-2 infection influences this response.

Previous research highlights the importance of SIgA antibodies in preventing respiratory infections, particularly in the context of influenza and other viruses. Studies have shown that IgA antibodies are rapidly produced in response to SARS-CoV-2 infection and can be detected in serum and saliva. However, the impact of vaccination, especially intramuscular mRNA vaccines, on the generation of SIgA antibodies remained unclear prior to this study. The existing literature suggests that IgA responses may be important for protection, but the mechanism by which intramuscular vaccines induce mucosal immunity wasn't fully understood. The authors cite several studies on influenza and other respiratory viruses to establish the context of mucosal immunity and the role of SIgA.

The study utilized longitudinal serum and saliva samples from 29 adult participants in the PARIS study, with 18 having a history of SARS-CoV-2 infection and 11 without. Participants received two doses of either the Moderna or Pfizer-BioNTech mRNA vaccine. Samples were collected at multiple time points before and after vaccination. Enzyme-linked immunosorbent assays (ELISAs) were used to measure anti-SARS-CoV-2 spike binding IgG titers in serum and anti-SARS-CoV-2 spike IgG, SIgA, and mucinoglobulin (M) SIgA titers in saliva. Total IgA concentration in saliva was also measured and used for normalization of SARS-CoV-2-specific SIgA titers. The methodology included considerations to account for the presence of monomeric IgA and IgG from serum that might leak into saliva. Statistical analyses involved Mann-Whitney tests, one-way ANOVA with Kruskal-Wallis tests, and Spearman's rank tests to compare antibody titers and assess correlations between different antibody responses. Recombinant SARS-CoV-2 proteins (spike, RBD, and nucleoprotein) and those of common human coronaviruses (HCoV-OC43 and HKU1) were produced using a mammalian cell expression system for ELISA assays. The detailed ELISA protocols for serum IgG, salivary SIgA and IgG are described in the methods section, including steps for coating, blocking, antibody incubations, washing, substrate addition, and optical density measurement. A five-parameter logistic fit was used to analyze standard curves for IgA concentration in saliva.

The study found a significant increase in anti-SARS-CoV-2 spike serum and mucosal antibody titers after vaccination in the seropositive group (those with prior infection), with higher titers compared to the seronegative group. While the seronegative group also showed increased serum and saliva anti-spike IgG titers, they were lower than in the seropositive group. Notably, some individuals in the seronegative group exhibited a peak in anti-spike SIgA titers. Correlation analyses revealed a strong correlation between saliva IgG and serum IgG anti-spike titers, but a weaker correlation between saliva SIgA anti-spike titers and serum IgG titers. Mucosal SIgA antibody titers were significantly higher in seropositive individuals compared to seronegative individuals before vaccination and at various time points post-vaccination. The increase in mucosal SIgA antibody titers after vaccination was significantly higher in the seropositive group than in the seronegative group. In seropositive individuals, baseline anti-SARS-CoV-2 saliva SIgA titers were significantly higher in those who showed detectable SIgA post-vaccination. However, no significant difference in baseline SIgA titers was observed between those with detectable and undetectable SIgA in the seronegative group. Pre-vaccination SIgA levels showed no correlation with the fold-increase in SIgA levels post-vaccination. There was no evidence suggesting that cross-reactive immunity to seasonal coronaviruses contributed significantly to the observed SIgA response. Individuals in the seropositive group who had detectable SIgA after vaccination also exhibited significantly higher peak serum anti-SARS-CoV-2 spike IgG titers.

The findings demonstrate that prior SARS-CoV-2 infection significantly enhances the mucosal SIgA response to mRNA vaccination. This suggests that pre-existing immunity plays a crucial role in shaping the immune response to vaccination. The study does not fully elucidate the mechanisms behind SIgA induction by intramuscular vaccination but provides valuable insight into the influence of prior infection. The more robust SIgA response in previously infected individuals may contribute to enhanced protection against future SARS-CoV-2 infection. The findings highlight the importance of considering prior infection status when evaluating vaccine efficacy and immune responses, particularly in relation to mucosal immunity.

This study shows that prior SARS-CoV-2 infection enhances the mucosal SIgA response to mRNA vaccination. The robust SIgA response in previously infected individuals may offer enhanced protection against reinfection. Further research should investigate the underlying mechanisms and explore the long-term implications of these findings for vaccine strategies and overall immune response.

The relatively small sample size might limit the generalizability of the findings. The study focused on a specific population and time frame, which may not be fully representative of broader populations or different viral variants. The study's observation period might not capture the full dynamics of the long-term mucosal immune response. The methods used for measuring SIgA were not entirely without bias, as it's acknowledged that small amounts of serum IgA can leak into saliva.