Immunological Lessons from Respiratory Syncytial Virus Vaccine Development

Respiratory syncytial virus (RSV) has eluded active vaccination efforts for more than five decades and continues to cause substantial morbidity and mortality in infants, the immunocompromised, and older adults. Although newer approaches of passive antibody-mediated protection show promise, vaccines aimed at eliciting fusion protein (F)-targeting antibodies have repeatedly failed to meet pre-established, modest-efficacy goals. Newer candidates, including protein-based vaccines, live-attenuated viruses, and gene-based delivery platforms, incorporate structurally defined and stabilized versions of the prefusion form of the F glycoprotein and are advancing rapidly into critical efficacy studies in susceptible target populations. This review discusses the storied history of RSV vaccine development, immunological lessons learned along the way, and critical findings about protein structure that remodeled our understanding of protective immunity to this important pathogen. In this review on respiratory syncytial virus vaccines, Ruckwardt et al. discuss immunological lessons learned through five decades of RSV vaccine development and testing. Seminal studies of fusion protein structure and immunogenicity have modified our understanding of protective immunity to RSV and led to precision vaccine approaches that elicit increasingly potent antibodies targeting prefusion F.