mRNA COVID-19 vaccination induces minimal IgA in saliva in the absence of prior clinical or subclinical infection

In this prospective cohort study, we analyzed saliva IgA and IgG antibody levels over the first two years of the pandemic after COVID-19 mRNA vaccination and infection. Generally healthy adult healthcare workers with no evidence of prior SARS-CoV-2 infection were enrolled into the Prospective Assessment of SARS-CoV-2 Seroconversion (PASS) study between August of 2020 and March of 2021. Utilizing multiplex microsphere-based immunoassays, we measured saliva anti-SARS-CoV-2 spike IgG, IgA, and secretory IgA in 1224 saliva samples collected from 266 individuals between August of 2020 through December of 2022. By the summer of 2022, 45.2% of the cohort had tested positive for SARS-CoV-2 by antigen or PCR test at least once and another 42.2% had evidence of prior subclinical infection as denoted by a doubling in saliva anti-SARS-CoV-2 nucleocapsid (N) IgG level. While many individuals had elevations in saliva spike-specific antibodies by spring of 2022, analyses revealed that most elevations in saliva spike-specific IgA and secretory IgA were driven by subclinical and clinically evident infections. Removal of saliva samples after positive COVID-19 testing or evidence of subclinical infection revealed that two doses of BNT162b2 induced only minimal (1.6-fold) increases in saliva anti-spike IgA levels at one month after the second vaccination. In contrast, saliva anti-spike IgG was strongly induced by vaccination and exhibited improved durability with hybrid immunity. We also observed that females produced higher levels of saliva anti-spike IgA and IgG antibodies than males in response to mRNA vaccination, that the half-life of anti-spike IgG in saliva after two mRNA vaccine doses is ∼90 days, and that in the setting of hybrid immunity saliva anti-spike IgA levels are greater when infection follows vaccination than when vaccination follows infection. This study demonstrates that intramuscular mRNA vaccines are weak inducers of IgA antibodies in saliva. • COVID-19 mRNA vaccination alone is a weak inducer of IgA antibodies in saliva. • Saliva anti-spike IgA is driven by subclinical and clinically evident infections. • Females produce more saliva anti-spike IgG and IgA after vaccination than males. • Saliva anti-spike IgG half-life is ∼90 days after 2 mRNA doses & ∼160 after 3 doses. • By July 2022 almost all participants had had either a clinical or subclinical infection.