Objective: Little is known about the interplay between gut microbiome and SARS-CoV-2 vaccine immunogenicity. In this prospective observational study, we investigated associations between the gut microbiome, habitual dietary fibre intake, and mRNA vaccine-elicited immune responses, including anti-Spike IgG, avidity, and ACE-2 competition (surrogate neutralization). Design: 16S rRNA sequencing and short-chain fatty acid analyses were undertaken using stool samples collected from 48 healthy individuals at baseline and twelve-weeks after 1st BNT162b2 SARS-CoV-2 vaccine dose. Associations between gut microbiome data and SARS-CoV-2 spike and RBD IgG levels, competitive binding antibodies, and anti-SARS-CoV-2 spike total relative fractional avidity assays were evaluated. A validated dietary fibre intake food frequency questionnaire was also used to correlate habitual dietary fibre intakes with vaccine responses. Results: Our data revealed several baseline bacterial taxa, including Prevotella, Haemophilus and Veillonella (p<0.01), associated with BNT162b2 vaccine responses. Several Bacteroides spp. (p<0.01) as well as Bifidobacterium animalis, (p=0.003), amongst others, were positively associated with antibody avidity. Conversely, concentrations of isovaleric and isobutyric acid were higher in individuals with the lowest SARS-CoV-2 vaccine responses (p<0.01). Classifying participants based on habitual dietary fibre intake identified distinct avidity responses. Conclusion: We showed associations between baseline gut microbiota composition and immunogenicity of BNT162b2 vaccine responses, particularly avidity maturation. We also demonstrate that branched-chain fatty acids and habitual dietary fibre intakes are associated with BNT162b2 vaccine immunogenicity. Together these findings indicate a link between gut microbiome, diet and antibody immunity to SARS-CoV-2 spike protein, suggesting interventions which modulate the gut microbiome could enhance COVID-19 vaccine responses.

The authors have declared no competing interest.

This study was funded by Weston Family Microbiome Initiative (Grant ID GR018179)

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Clinical Research Ethics Board of the University of British Columbia gave ethical approval for this work

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors