Strategic and scientific contributions of human challenge trials for vaccine development: facts versus fantasy.

The unprecedented speed of delivery of SARS-CoV-2 pandemic vaccines has redefined the limits for all vaccine development. Beyond the aspirational 100-day timeline for tomorrow's hypothetical pandemic vaccines, there is a sense of optimism that development of other high priority vaccines can be accelerated. Early in the COVID-19 pandemic, an intense and polarised academic and public discourse arose concerning the role of human challenge trials for vaccine development. A case was made for human challenge trials as a powerful tool to establish early proof-of-concept of vaccine efficacy in humans, inform vaccine down selection, and address crucial knowledge gaps regarding transmission, pathogenesis, and immune protection. We review the track record of human challenge trials contributing to the development of vaccines for 19 different pathogens and discuss relevant limitations, barriers, and pitfalls. This Review also highlights opportunities for efforts to broaden the scope and boost the effects of human challenge trials, to accelerate all vaccine development.

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Declaration of interests Y-NA is supported by a National Health and Medical Research Council (NHMRC) and Heart Foundation PhD scholarship. EJ is supported by the Wellcome Trust and the Moh Family Foundation. JO is supported by an NHMRC Investigator grant and Melbourne Children's Campus Clinician–Scientist fellowship. ACS is supported by an NHMRC Investigator grant and Viertel Senior Medical Research fellowship. JSM is supported by an NHMRC Investigator grant. All authors are Human Infection Challenge Network for Vaccine Development members. The authors declare no competing interests.