Abstract
Objective. To systematically evaluate the interface between vaccination and the gut-brain axis (GBA) in both directions of effect: first, whether vaccines or their components alter GBA biology, including microbiome composition, barrier integrity, cytokine responses, and mitochondrial function; second, whether pre-existing GBA state modifies the response to vaccination; and third, whether either direction bears on neurodevelopmental outcomes or on the adverse events recorded in trials and surveillance. Data Sources. PubMed and Google Scholar were searched directly, and the Walden University Library federated discovery service was used to search its subscribed collections, including MEDLINE, Embase, Cochrane, CINAHL, Scopus and ScienceDirect, from inception to 5 September 2025. Eligibility Criteria. Human and animal studies examining licensed vaccines or vaccine components with measurable outcomes in GBA domains, neurodevelopmental endpoints, or post-marketing adverse events. Results. Of 3,047 records, 60 studies met inclusion criteria in the primary search, with a further 7 identified through a targeted supplementary search to September 2026, giving 67 included studies, listed in Appendix A. Microbiome composition influenced vaccine immunogenicity: higher Bifidobacterium abundance predicted stronger infant antibody responses, and neonatal antibiotic exposure reduced antibody titres to several infant vaccines measured at 7 months of age. Evidence on whether vaccination itself alters the microbiome is limited: one longitudinal adult cohort reported compositional stability, pediatric data are close to absent, and transient shifts have been observed in mice. Animal maternal immune activation models implicated IL-6 and IL-17A pathways in neurodevelopmental alterations, whereas maternal vaccination showed no such association. Cohorts exceeding one million children found no association between autism and the vaccine exposures they measured, principally measles-mumps-rubella vaccination, thimerosal and cumulative antigen count, consistent with a 2025 Danish cohort of aluminium-adsorbed vaccine exposure and a December 2025 WHO advisory reaffirmation. No study identified examined DTaP, hepatitis B or varicella in relation to neurodevelopmental outcomes. Few eligible studies directly assessed barrier or mitochondrial endpoints. Active surveillance quantified specific adverse events, including febrile seizures, intussusception, immune thrombocytopenic purpura, myocarditis (lower with 2023-2024 mRNA formulations), and anaphylaxis. Conclusions. The two directions of effect at this interface are supported to very different degrees, and that asymmetry is the principal finding. Evidence that gut microbiome state modifies vaccine response is moderate in certainty. Evidence on whether vaccination alters gut-brain axis biology, the direction the causal hypotheses in this field assert, is thin rather than negative: barrier, mitochondrial and paediatric data are essentially absent, and the single relevant longitudinal cohort concerns adults receiving COVID-19 mRNA vaccines. Large-scale epidemiology does not support vaccine-attributable increases in autism risk for the exposures those cohorts measured, principally measles-mumps-rubella vaccination, thimerosal and cumulative antigen count; it does not address the microbiome pathway. Several rare adverse events are quantifiable through active surveillance, whereas others remain uncertain signals. Continued active surveillance and transparent risk communication remain essential.