The past, present, and future of human challenge trials

Anna M. Romanov* and Jeongpyo Hong

Edited by Steven S. Cheng and Grant A. Knappe

Article | Aug. 29 2022


DOI: 10.38105/spr.6zwl7hims5


  • Human challenge trials are advantageous for studying emerging disease and vaccine efficacy but have a controversial history
  • Challenge trials for COVID-19 began in 2021 and invigorated the debate around the ethics of intentionally exposing trial participants
  • Few regulations currently exist for challenge agents, possibly limiting implementation in future epidemics

Article Summary

Human challenge trials (HCTs) have the potential to lay groundwork for critical advances in medicine. For centuries, physicians and researchers have intentionally infected human subjects to study disease transmission and design life-saving vaccines and treatments. Historically, many controlled infections occurred without informed consent from participants, but in the last century, several HCTs have been conducted which included full risk assessment, informed consent, and patient compensation. The COVID-19 pandemic has elevated the topic of establishing human challenge trials to accelerate the design and testing of protective vaccines. Thousands of people have expressed willingness to be infected with SARS-CoV-2, risking their health to help the global effort of ending the pandemic. Conducting such a study during a pandemic involves additional scientific and ethical precautions to minimize the risk to volunteers and to prevent community transmission; however, HCTs are not directly regulated. Here, we assess the scientific, ethical, and regulatory considerations of implementing HCTs for infectious disease models, particularly in pandemic settings.

Open Access


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Anna M. Romanov

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

Jeongpyo Hong

Department of Health Policy and Management, Harvard T.H. Chan School of Public Health, Boston, MA, USA