Non-specific effects of vaccines on all-cause mortality: a meta-analysis of randomized controlled trials (RCTs) 2012-2025

BackgroundEarly observational studies reported substantial reductions in all-cause mortality, suggesting that childhood vaccines might influence health in ways beyond their targeted disease. Such Non-Specific Effects (NSEs) of vaccines could potentially have important implications for the Expanded Programme of Immunization (EPI). In 2014 World Health Organization (WHO) Strategic Advisory Group of Experts (SAGE) commissioned a review of the NSE evidence, which called for more Randomized Controlled Trials (RCTs). We aimed to review all RCTs published after this WHO-commissioned review. MethodsFollowing PRISMA guidelines, we searched systematically for RCTs published during 2012-2025. Inclusion criteria: children under 5 years and all-cause mortality as the primary outcome for any vaccine intervention. Risk estimates were pooled using a random effects model, reflecting the underlying hypothesis: that live-attenuated vaccines greatly reduce, and inactivated vaccines increase all-cause mortality. ResultsWe identified seven RCTs that fit the inclusion criteria, all of them of live-attenuated vaccines (Bacillus Calmette-Guerin, measles, and oral polio vaccine). In total, 52,596 participants were included across these studies. Five were conducted in Guinea-Bissau, one in Guinea-Bissau and Burkina Faso, and one in India. The RCTs were not blinded, and no placebo was used, consistent with a moderate risk of bias. Our meta-analysis found no significant evidence of NSEs (vaccine effectiveness 5%; -16% to 22%). One study of low birthweight newborns admitted to neonatal intensive care units in India found a small but statistically significant NSE (17%; 2% to 31%); interestingly the effect primarily played out in the first 3 days of the study, raising concern of bias. DiscussionThe meta-analysis of seven RCTs of live-attenuated vaccines found no evidence of significant NSE on all-cause mortality. This was also true when adding RCTs from before 2012 studying NSEs. In conjunction with the WHO-SAGE review, the current body of evidence on NSEs on all-cause mortality does not warrant a paradigm shift, nor does it provide a rationale for changing vaccine programs.