Subclinical SARS-CoV-2 Infections and Endemic Human Coronavirus Immunity Shape SARS-CoV-2 Saliva Antibody Responses

SUMMARY This study characterized antibody responses induced by COVID-19 mRNA vaccination and SARS-CoV-2 infection in saliva. Utilizing multiplex microsphere-based immunoassays, we measured saliva anti-SARS-CoV-2 spike IgG, IgA, and secretory IgA in 1,224 saliva samples collected from healthcare workers in the Prospective Assessment of SARS-CoV-2 Seroconversion study between August of 2020 through December of 2022. By spring of 2022, most individuals had detectable spike-specific antibodies in saliva. Longitudinal measurements of saliva anti-SARS-CoV-2 nucleocapsid IgG revealed that most spike-specific IgA and secretory IgA detected in saliva was driven by subclinical and clinically-evident infections, rather than by vaccination alone. In contrast, saliva anti-SARS-CoV-2 spike IgG was strongly induced by vaccination and exhibited improved durability with hybrid immunity. Baseline levels of saliva antibodies to the endemic human coronaviruses positively correlated with post-vaccination anti-SARS-CoV-2 spike IgG levels. This study provides insights for development of vaccines that generate mucosal antibodies to respiratory pathogens. HIGHLIGHTS Saliva anti-spike antibodies were present in > 90% of participants by spring 2022 Saliva anti-spike IgA was driven by subclinical and clinically evident infections COVID-19 mRNA vaccination alone was a weak inducer of saliva IgA antibodies HCoV immunity correlates with post-vaccine anti-spike saliva antibody levels