Infectious Disease · Medical Literature
Effect of probiotics on humoral responses to COVID-19 vaccination in older adults: a randomized, placebo-controlled trial (PIRATES-COV study).
Abstract
Although COVID-19 vaccination has reduced morbidity and mortality, adults aged 65 y old and older are at high risk of complications from COVID-19. The evidence suggests that probiotics may enhance immune responses when co-administered with influenza vaccination. However, few studies have evaluated the potential benefit of probiotic supplementation in this context in this high-risk population. This study was a randomized controlled trial recruiting adults between 65 and 89 y of age living in Quebec, Canada, who received an mRNA booster (Pfizer-BioNTech or Moderna). Probiotic supplementation (Lacticaseibacillus rhamnosus Rosell®-11 and Lacticaseibacillus paracasei Rosell®-215, 1x 6 x 109CFU per capsule) versus placebo was administered from 15 d pre- to 15 d post-vaccination. Participants provided dried blood spot samples at baseline, at 3- and 6-month post-vaccination. The primary outcome was the proportion of participants without detectable anti-S1-receptor binding domain (anti-S1-RBD) antibodies at 6 months post-vaccination. Secondary outcomes included longitudinal anti-S1-RBD and anti-nucleocapsid (anti-N) antibody responses across the three timepoints. 592 adults were enrolled. At 6 months post-vaccination, anti-S1-RBD antibodies were comparable between groups, and the percentage of participants with undetectable antibody response in the placebo and probiotic groups (1.2% vs 1.6%) was comparable. Anti-N seropositivity was lower in the probiotic group at 6 months (OR 0.6, 95% CI 0.4-0.9; p = 0.02) and marginally lower at 3 months after adjustment. Self-reported COVID-19 infection incidence was 16.5% overall (19.1% placebo vs 13.9% probiotic; p = 0.134). Probiotic supplementation administered around COVID-19 vaccination did not change the proportion of seronegative participants for anti-S1-RBD antibodies at 6 months. However, in the probiotic group, anti-N antibody levels were lower, while self-reported COVID-19 infections also tended to be reduced, although this difference was not statistically significant. They may be consistent with earlier control of infection and reduced exposure to the nucleocapsid antigen, but this interpretation remains speculative. #NCT05195151.
Clinical relevance
Older adults aged 65–89 years represent a high-risk population for severe COVID-19 outcomes despite mRNA vaccination, and immunosenescence may blunt vaccine-induced humoral responses in this cohort. This RCT addresses a clinically relevant gap by evaluating whether perioperative probiotic supplementation can augment anti-spike antibody responses following mRNA booster vaccination. The findings are timely given ongoing booster campaigns and growing interest in gut-immune axis modulation as an adjunctive strategy in vulnerable populations.
Key findings
1. No significant difference in the primary endpoint: the proportion of participants with undetectable anti-S1-RBD antibodies at 6 months post-vaccination was comparable between groups (placebo 1.2% vs. probiotic 1.6%), indicating probiotics did not meaningfully alter seronegative rates for the spike antigen. 2. Anti-nucleocapsid (anti-N) seropositivity was significantly lower in the probiotic group at 6 months post-vaccination (OR 0.6, 95% CI 0.4–0.9; p = 0.02), suggesting reduced SARS-CoV-2 infection or attenuated nucleocapsid antigen exposure in the probiotic arm. 3. Anti-N seropositivity was also marginally lower in the probiotic group at 3 months post-vaccination after covariate adjustment, suggesting a consistent directional trend across the follow-up period. 4. Self-reported COVID-19 infection incidence was 16.5% overall, with a numerically lower rate in the probiotic group (13.9%) versus placebo (19.1%); however, this difference did not reach statistical significance (p = 0.134). 5. The study enrolled 592 adults aged 65–89 years receiving mRNA booster vaccination (Pfizer-BioNTech or Moderna), with the probiotic regimen consisting of Lacticaseibacillus rhamnosus Rosell-11 and Lacticaseibacillus paracasei Rosell-215 (6 × 10⁹ CFU/capsule) administered from 15 days pre- to 15 days post-vaccination. 6. Longitudinal anti-S1-RBD antibody responses across all three timepoints (baseline, 3 months, 6 months) were comparable between groups, confirming that peribooster probiotic use does not impair vaccine-induced spike-specific humoral immunity.
Practice implications
Clinicians should not routinely recommend this specific probiotic formulation (L. rhamnosus Rosell-11 / L. paracasei Rosell-215) as an adjunct to mRNA COVID-19 booster vaccination in adults ≥65 years with the intent to augment anti-spike humoral immunity, as the primary endpoint was not met. The lower anti-N seropositivity in the probiotic group is a biologically plausible signal warranting further investigation, possibly reflecting reduced viral replication or mucosal infection control rather than a vaccine-immunogenicity effect, but this interpretation remains speculative and should not drive prescribing decisions at this time. Future adequately powered trials should prospectively capture virologically confirmed COVID-19 infections, mucosal IgA responses, and T-cell immunity as co-primary endpoints to more fully characterize any protective benefit of probiotic co-administration in immunosenescent populations.