Why does rotavirus vaccine effectiveness vary around the globe?

Rotavirus vaccines have transformed the prevention of severe childhood diarrhea globally, yet their effectiveness remains markedly lower in low- and middle-income countries (LMICs), where rotavirus mortality is greatest. Understanding the biological and environmental determinants of this disparity is critical for optimizing existing vaccination strategies and informing next-generation vaccine development. This review examines the factors contributing to variable rotavirus vaccine effectiveness across different settings, with a focus on maternal antibodies, infant gut health, co-infections, co-vaccinations and human genetic polymorphisms. Maternal antibodies, transferred transplacentally and through breast milk, can inhibit vaccine replication in the infant gut. Maternal antibody interference may be exacerbated in LMICs due to higher maternal antibody levels, driven by increased rates of natural rotavirus exposure and prolonged breastfeeding. Malnutrition, disruption of the gut microbiome, and environmental enteric dysfunction collectively impair intestinal immune responses, with their relative contributions also varying by geography. Co-administration of the oral poliovirus vaccine and concurrent enteric infections represent additional sources of interference that are more prevalent in resource-limited settings. Host genetic factors, particularly polymorphisms in fucosyltransferase genes governing histo-blood group antigen expression, further modulate vaccine immunogenicity across populations. These factors do not act in isolation; rather, they interact to shape the gut environment and collectively limit oral vaccine replication. Addressing rotavirus vaccine inequity will require context-specific strategies that combine optimized vaccine scheduling, nutritional and microbiome-targeted interventions, and the development of novel vaccine platforms capable of overcoming the unique immunological challenges of LMICs.