ABSTRACTStudies have shown that probiotics can decrease the symptoms of respiratory tract infections as well as increase antibody responses following certain vaccinations. We examined the effect of probiotic supplementation on anti-SARS-CoV-2 specific antibody responses upon SARS-CoV-2 infection as well as after COVID-19 vaccination. In this randomized, triple-blinded, placebo-controlled intervention study with a parallel design, 159 healthy adults without prior SARS-CoV-2 infection or COVID-19 vaccination and any known risk factors for severe COVID-19 were randomly allocated into two study arms. The active treatment arm consumed a probiotic product containing a minimum of 1 × 108colony-forming units ofLimosilactobacillus reuteriDSM 17938 + 10 μg vitamin D3 twice daily for 6 months. The placebo arm consumed identical tablets containing only 10 μg vitamin D3. Anti-SARS-CoV-2 specific antibodies and virus neutralizing antibody titers were analyzed from blood samples collected at baseline, after 3 months, and after 6 months. Differences in serum antibody titers between the two study arms were tested with independent t-test using log-transformed values. In the intention-to-treat (ITT) analysis, SARS-CoV-2 infected individuals in the active treatment arm (n= 6) tended to have higher serum anti-spike IgG (609 [168–1480] BAU/ml vs 111 [36.1–1210] BAU/ml,p= 0.080) and anti-receptor binding domain (RBD) IgG (928 [212–3449] BAU/ml vs (83.7 [22.8–2094] BAU/ml,p= 0.066) levels than individuals in the placebo arm (n= 6). Considering individuals who were fully vaccinated with mRNA-based COVID-19 vaccines, the active treatment arm (n= 10) exhibited significantly higher serum levels of anti-RBD IgA (135 [32.9–976] BAU/ml vs 61.3 [26.7–97.1] BAU/ml,p= 0.036) than the placebo arm (n= 7) >28 days postvaccination. Supplementation with specific probiotics might improve the long-term efficacy of mRNA-based COVID-19 vaccines via enhanced IgA response.