Human genetics of susceptibility to live-attenuated viral vaccines

Alongside the development of antibiotics, vaccination is the medical innovation with arguably the greatest impact on human health. Testament to its success is the eradication of infectious diseases, such as smallpox, that devastated human populations for almost 4000 years. Live-attenuated vaccines (LAV), which retain the capacity for infection and replication, were the first to be developed and remain highly efficacious, underpinning successful human vaccination campaigns (e.g. polio virus, measles virus, yellow fever virus). The cost of this success is the capacity of LAVs to cause disease in a small proportion of recipients, typically owing to overt or previously unappreciated immunodeficiency. From the careful investigation of such rare events, major clinical and scientific lessons about human antiviral immunity have been drawn. Here, we review features of pathogenic LAV dissemination, which continue to inform our understanding of critical steps in the immune control of LAVs. We discuss recent data on specific variants identified in geographically isolated populations and reflect on more common phenocopies of these monogenic defects, with potential implications for vaccine practice and policy. Collectively, these insights may inform approaches to the growing population of individuals rendered more vulnerable to LAVs by aging, multimorbidity or medical intervention. They also serve to highlight the clinical need for therapeutic strategies to combat pathogenic LAV dissemination.