Abie Rohrig

TB human challenge studies could accelerate TB vaccine development by reducing uncertainty in early-stage vaccine testing, selecting promising vaccine candidates for large-scale field trials, and identifying an immune correlate of protection. However, ethical concerns regarding the exposure of trial participants and bystanders to significant risk have been a limiting factor for TB human challenge models. We analyze the expected social value and risks of different types of TB human challenge models, and conclude that given the massive public health burden of TB, challenge models with even scant probabilities of expediting TB vaccine authorization have enormous expected humanitarian value, saving between 33,000 and 1,375,000 lives over the next ten years. We argue that attenuated M.tb challenge trials can be conducted ethically, and discuss the benefits and drawbacks of conducting virulent M.tb challenge trials.

The world’s first COVID-19 human challenge trial using the D614G strain of SARS-CoV-2 is underway in the United Kingdom. The Wellcome Trust is funding challenge stock preparation of the Beta variant (B.1.351) for a follow-up human challenge trial, and researchers at Imperial College London are considering conducting that trial. However, little has been written thus far about the ethical justifiability of human challenge trials with SARS-CoV-2 variants of concern. While vaccine resistance as such does not increase risks for volunteers in COVID-19 challenge trials, we explore two specific characteristics of some variants that may initially be thought to make such trials unethical and conclude that SARS-CoV-2 variant challenge trials can remain ethical.

Ongoing and anticipated COVID-19 human challenge studies in the UK may advance our understanding of COVID-19 and facilitate the licensure of safe, effective, and easily deployable next-generation COVID-19 vaccines and boosters. We argue that international volunteer recruitment for COVID-19 human challenge trials can help promote diversity in these trials and ensure a sufficient number of eligible volunteers, both of which will increase the benefits of challenge research. We explore the ethical ramifications of dealing with unfair background conditions of global vaccine injustice to expand medical research, and conclude that international recruitment for COVID-19 human challenge trials can be conducted ethically provided that several robust protections are in place for volunteers.

We extend recent conversation about the ethics of human challenge trials to tuberculosis (TB). TB challenge studies could accelerate vaccine development, but ethical concerns regarding risks to trial participants and third parties have been a limiting factor. We analyse the expected social value and risks of different challenge models, concluding that if a TB challenge trial has between a 10% and a 50% chance of leading to the authorisation and near-universal delivery of a more effective vaccine 3–5 years earlier, then the trial would save between 26 400 and 1 100 000 lives over the next 10 years. We also identify five important ethical considerations that differentiate TB from recent human challenge trials: an exceptionally high disease burden with no highly effective vaccine; heightened third party risk following the trial, and, partly for that reason, uniquely stringent biosafety requirements for the trial; risks associated with best available TB treatments; and difficulties with TB disease detection. We argue that there is good reason to consider conducting challenge trials with attenuated strains like Bacillus Calmette-Guérin or attenuatedMycobacterium tuberculosis.