Introduction: Gut dysbiosis has been associated with suboptimal antibody response after vaccination. We aimed to evaluate the oral microbiome immunity formula (SIM01) in enhancing immunogenicity after SARS-CoV-2 vaccination in vulnerable populations.

Methods: We report findings from a randomized clinical trial of 453 subjects aged ≥ 65 years or with type 2 diabetes mellitus (T2DM) to receive SIM01 or placebo within one week of SARS-CoV-2 vaccine (CoronaVac and BNT162b2) for three months. Shotgun metagenomic sequencing was performed to assess gut microbiota composition in stool samples of 283 SARS-CoV-2 vaccinees at baseline and three months after the second dose of vaccination. We also measured the SARS-CoV-2 surrogate virus neutralization (sVNT), anti-spike receptor binding domain (RBD) IgG levels in plasma samples and determined the proportion of IFN-γ⁺ CD4⁺ and CD8⁺ T cells in peripheral blood against wild-type strain of SARS-CoV-2 using flow cytometry with peptide pools at baseline, 1 month, and 6 months after vaccination (Fig 1A). Wilcox test and Spearman correlation were used to evaluate the association between intervention/engraftment effectiveness and vaccine immunogenicity enhancement.

Results: A total of 283 SARS-CoV-2 vaccinees (50.88% females; mean age: 67.5 years) were randomly assigned in a 1:1 ratio to receive either SIM01 (147 participants) or placebo (136 participants) and enrolled in the metagenomic and vaccine immunity index analysis. Subjects receiving SIM01 were significantly more likely to transition into Bifidobacterium enriched-gut microbiome enterotypes 3 months after the second vaccination (Fig 1B). Of note, the increase of three bifidobacterial species, especially B. adolescents, after 3-month SIM01 intervention was positively correlated with the level of neutralizing antibodies to BNT162b2 vaccine at 6 months (n = 82, R = 0.24, p < 0.05), and associated with vaccine adjuvant-related pathways Bifidobacterium shunt (P124-PWY) (p < 0.05, FDR < 0.25) (Fig 1C). Importantly, SIM01 engraftment, evaluated by StrainPhlAn strain profiling, was associated with a higher level of IFN-γ⁺ CD8⁺ T cell proportion in BNT162b2 vaccinees.

Conclusion: We for the first time demonstrated that SIM01 serves as a new adjuvant through CD8⁺ T cell activation to boost the immunogenicity of SARS-CoV-2 BNT162b2 vaccines for 6 months. Our findings have implications on the management of vaccine efficacy through gut microbiome modulation. Further studies are warranted to explore the beneficial effects of SIM01 in other conditions such as pneumococcal disease.

Acknowledgment: The study was supported by the Health Bureau and the Government of the Hong Kong Special Administrative Region (COVID19F07). Authors affiliated with MagIC are partially supported by InnoHK, The Government of Hong Kong, Special Administrative Region of the People’s Republic of China.

Chris KP Mok

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