Vaccines are a cornerstone of modern medicine, significantly reducing morbidity and mortality worldwide. Their administration in infants requires consideration of physiological maturity. Cytochrome P450 (CYP450) enzymes, crucial for drug metabolism, are underdeveloped at birth and mature over the first two to three years of life. While vaccines are not directly metabolized by CYP450 enzymes, emerging evidence suggests that certain excipients-such as polysorbate 80 and gelatin-could interact with CYP450 pathways, particularly in genetically susceptible infants. This study integrates pharmacogenetics and epidemiology to examine how CYP450 immaturity and variability may influence vaccine excipient metabolism, immune activation, and infant health outcomes. A systematic review of peer-reviewed literature, pharmacogenetic data, and epidemiological studies was conducted to assess CYP450 enzyme activity in infants, potential metabolic interactions with vaccine excipients, and temporal associations between vaccination and sudden infant death syndrome (SIDS). Gaps in postmortem investigations were also evaluated for their impact to identify metabolic vulnerabilities. CYP450 enzymes exhibit developmental immaturity in infants and genetic polymorphisms-particularly in CYP2D6 and CYP3A5-may affect vaccine excipient clearance. While epidemiological evidence shows temporal clustering of some SIDS cases post-vaccination, causality remains unproven. Inflammation-induced suppression of CYP450 enzymes raise questions about potential metabolic vulnerabilities, which current postmortem protocols often fail to capture. This study highlights the need for further research into the influence of CYP450 variability on vaccine-related outcomes. Incorporating genetic and metabolic profiling into postmortem protocols may improve our understanding of metabolic contributions to SIDS and refine vaccine safety assessments. Developmental immaturity and genetic variability in CYP450 enzymes may affect vaccine excipient metabolism and interact with immune activation. This interplay could influence metabolic vulnerabilities in infants, particularly with inflammation-induced CYP450 suppression. Genetic and metabolic profiling before vaccination could identify at-risk infants, while postmortem analysis may enhance SIDS understanding and vaccine safety assessments.