The path to an RSV vaccine

•Maternal immunization provides a path to early infant protection against RSV.•Structure-based engineering overcomes the biochemical challenges of the RSV F antigen.•Improved animal models for RSV vaccine-mediated disease enhancement are needed.•A self-amplifying RNA vaccine platform has been designed for safe infant immunization.•Infant RSV vaccines aim for high neutralizing titers and a non-Th2-biased response.

Respiratory syncytial virus (RSV) is the greatest remaining unmet infant vaccine need in developed countries and an important unmet infant vaccine need worldwide. More than 40 years of effort have yet to result in a licensed RSV vaccine for humans. Key challenges to RSV vaccine development include a peak of severe disease at 2–3 months of age, problematic biochemical behavior of key vaccine antigens, a history of vaccine-mediated disease enhancement, and reliance on animal models that may not accurately reflect human disease processes. Potential paths to overcome these challenges include maternal immunization, structure-based engineering of vaccine antigens, the design of a novel platform for safe infant immunization, and the development of improved animal models for vaccine-enhanced disease.