Breakthroughs and insights: A comprehensive review of yellow fever vaccine breakthrough infection across 8 decades

The yellow fever vaccine 17D is one of the most successful live-attenuated vaccines ever developed, controlling mosquito-borne yellow fever virus and yellow fever disease worldwide. Introduced in 1937, 17D never underwent rigorous phase III clinical trials to evaluate safety or efficacy, and while protection in the field was quickly established, no prospective evaluation of vaccine efficacy has ever been conducted. One important measure of vaccine efficacy is breakthrough infection resulting from vaccine failure. Yellow fever breakthrough infection was previously formally evaluated in a policy-changing report conducted by the Advisory Committee on Immunization Practices in 2015 but has not been reviewed since despite several recent outbreaks in South America and Africa. To address this knowledge gap, we conducted a literature search and reviewed 19 papers documenting breakthrough yellow fever infection between 1944 and 2023. There were up to 7793 suspected and up to 773 confirmed breakthrough cases reported in the literature, including thirteen cohort studies, four case reports, and two case series, which we summarize, evaluate the approaches used, and identify strengths and weakness. This review provides an important and much needed update on the topic of yellow fever breakthrough infection, drawing from recent outbreaks, highlighting limitations, and suggesting future approaches to further advance the field.