Ethical Frameworks for Human Challenge Trials in Infectious Disease Research

Abstract

Human challenge trials deliberately infect healthy volunteers with a pathogen to accelerate vaccine development, and the practice moved from a research niche into public debate when a SARS-CoV-2 challenge model was proposed during the COVID-19 pandemic.
This review synthesizes the ethics literature on controlled human infection models, including the permissibility criteria built around treatable disease and scientific necessity, and the difficulty of informed consent when a study offers no direct benefit to the volunteer.
We examine the dispute over compensation, where higher payment is framed either as undue inducement or as fair recognition of risk, alongside the problem of risk to third parties who never consented, particularly for transmissible respiratory pathogens.
We also consider equity concerns raised when challenge models for diseases such as malaria and typhoid are sited in low- and middle-income countries, where the population bearing research risk may not see proportionate benefit. We conclude that no single criterion renders a challenge trial permissible alone, and that a defensible study requires treatable disease, informed consent, fair compensation, third-party risk containment, and equitable siting together, which is why most candidates still fail to qualify.