Characterising the benefits and risks of vaccines approved through accelerated pathways

Alternative regulatory pathways for vaccine licensure without traditional Phase III efficacy trials are of increasing priority for epidemic pathogens. Using IXCHIQ, a chikungunya virus vaccine licensed through an accelerated pathway, we demonstrate that prior understanding of disease risk from infection can inform risk-benefit assessments for new vaccines. The mass deployment of IXCHIQ during an ongoing outbreak in La Réunion was suspended in those aged 65y+ following three deaths in vaccine recipients, although two appear unlikely to have been vaccine-linked. For individuals aged 18-64y, we find the vaccine benefits outweigh risks across epidemiological settings. In those aged 65y+, we estimate a net benefit in large outbreaks, which includes the La Réunion outbreak, and endemic settings. There is insufficient evidence of a net benefit in smaller outbreaks or in travellers. Our generalizable approach can help guide trial recruitment, inform vaccine implementation, and provide a foundation for weighing potential benefits against vaccine-associated risks.