The microbiome-metabolite-vaccine axis: context-dependent modulators of immunogenicity and durability

Vaccine responses vary markedly between individuals, yet age, genetics, prior antigen exposure, comorbidity, nutrition and vaccine platform explain only part of this heterogeneity. The intestinal microbiome is a candidate modulator through microbial metabolites and parallel non-metabolic signals. Human studies link microbial features to vaccine outcomes, but taxa rarely replicate across geography, age and platform. Small randomised antibiotic studies identify effects of treatment assignment, not necessarily microbiome mediation; infant microbial rescue has been demonstrated in mice rather than infants. Amongst the pathways considered, short-chain fatty acids have the largest mechanistic evidence base, predominantly preclinical, but acetate, propionate and butyrate differ in targets, exposure and direction of effect, and direct human vaccine mediation remains unestablished. Null findings for BNT162b2 in microbiota-depleted mice and for overall antibody responses in an older-adult probiotic trial argue against universal microbiome dependence or probiotic benefit. We organise the evidence around a microbial function-mediator-exposure-immune-checkpoint-endpoint chain, retaining a primary focus on metabolites. Vaccine take, peak antibody, decay and recall are distinguished from clinical protection. We also separate microbiome-modifying probiotics from antigen-delivery platforms. A decision-gated workflow links signature discovery, source and target verification, independent validation, randomised intervention and demonstrated clinical utility. Microbiome-guided vaccination remains a research strategy rather than an established clinical practice.