Ethics and future of human challenge trials with SARS-CoV-2 to speed vaccine development

ABSTRACT

Introduction: Early in the COVID-19 pandemic, human challenge trials with SARS-CoV-2 were proposed as a way to develop a vaccine faster, and thereby save lives. But would such trials in fact speed vaccine development? Is it ethical to infect healthy volunteers with wildtype SARS-CoV-2? And going forward, what should be the role of human challenge trials in the development of SARS-CoV-2 vaccines? This 60-min panel session, chaired by Professor Seema Shah, will explore scientific and ethical issues in SARS-CoV-2 human challenge trials. The panel brings together key stakeholders, including scientists working with a variety of challenge models, research ethicists, and a member of the advocacy group 1Day Sooner who recently participated in a challenge trial. The panel comprises five talks followed by a 10- to 15-min discussion period. Background: The origins of human challenge trials can be traced back to efforts in the 1790s to determine whether cow pox inoculation protected against smallpox. In the last 50 years, human challenge trials have enrolled thousands of healthy volunteers to be exposed to dozens of diseases, from the common cold to cholera. Challenge trials are used to better understand how a pathogen causes disease, how it is transmitted (and how transmission may be mitigated), and whether a vaccine candidate confers protection against it. In vaccine challenge trials, healthy participants are randomized to receive either vaccine or placebo, and they are subsequently exposed to the infectious agent. If less people who received the vaccine, compared to those who received placebo, become infected, this provides evidence that the vaccine is efficacious. Challenge trials have played important roles in developing vaccines for cholera, typhoid, and malaria. To protect volunteers, in the modern era, scientists have generally restricted their use of such trials to diseases that are well-understood, or for which there is curative treatment. In the face of the global COVID-19 pandemic, human challenge trials with SARS-CoV-2 were proposed as a means to speed vaccine development and save lives. But are such trials ethical? There are risks associated with COVID-19, including in young people, such as myocarditis, stroke, long COVID, and death. Proponents argue ethical norms are too conservative and may be set aside in a pandemic, provided informed volunteers are willing to participate. What should be the role of challenge trials in the development of a SARS-CoV-2 vaccine? While challenge trials were initially proposed as a substitute for phase 3 efficacy trials for vaccines, challenge trials take time to set up and did not keep pace with dramatically accelerated vaccine development in the COVID-19 pandemic. They also have limitations, including generalizability to older adults or people with comorbidities, since they test vaccine efficacy in 15-150 healthy young adults. Nevertheless, challenge trials could test the second round of vaccine candidates, which is important if the first vaccine approved is not very efficacious or safe or to ensure widespread global access of vaccines. Our panel comprising a healthy volunteer, scientists working with a variety of challenge models, and research ethicists will explore and discuss these ethical and scientific issues. Talk 1 Human challenge trials with SARS-CoV-2 Meta Roestenberg (Leids Universitair Medisch Centrum, The Netherlands) will introduce human challenge trials and their use in vaccine development. She will discuss the development of a SARS-CoV-2 challenge model, and the role of challenge trials in the development of second-generation SARS-CoV-2 vaccines. Bio https//www.lumc.nl/org/parasitologie/medewerkers/ metaroestenberg Talk 2 The volunteer experience in a SARS-CoV-2 challenge trial Alastair Fraser-Urquhart (1Day Sooner) participated in the UK SARS-CoV-2 challenge trial in Spring 2021, and he will describe his experience in the trial. 1Day Sooner is a grass roots organization that has gathered over 38,000 people globally who have expressed a willingness to participa e in SARS-CoV-2 challenge trials. Bio https//1daysooner.org/ Talk 3 Developing ethical guidance for SARS-CoV- 2 challenge trials Seema Shah (Northwestern University Feinberg School of Medicine, USA;session co-chair) will describe the development of ethical guidance for SARS-CoV-2 challenge trials published in Science and Vaccine in 2020 and the World Health Organization's key criteria document. She will outline the main ethical considerations in such trials and explain the most compelling potential social value they could provide. Bio https//www.feinberg.northwestern.edu/faculty-profiles/ az/profile.html?xid = 42926 Talk 4 A critical perspective on the ethics of SARSCoV- 2 challenge trials Charles Weijer (Western University, Canada;session co-chair) will examine critically the case for SARS-CoV-2 challenge trials. He will focus on the social value of challenge trials, whether benefits are justified by risks to volunteers, the use of high-risk groups in such trials, and their impact on public trust in a SARS-CoV-2 vaccine. Bio https// www.charlesweijer.com/about-me Talk 5 The future of challenge trials in SARS-CoV- 2 and future pandemics Gagandeep Kang (Christian Medical College, India) will consider the future of challenge trials in the future of SARS-CoV-2 vaccine development and, indeed, their role in future pandemics. The pace of vaccine development and clinical trials in the COVID-19 pandemic is unprecedented. Does this undermine the need for challenge trials? If not, what ought to be their role in vaccine development? Bio https//en.wikipedia.org/wiki/Gagandeep-Kang Format This 60-min panel session will be chaired by Professor Seema Shah. Each of the talks will be 8- to 10-min in duration and they will cover the volunteer experience, the science of challenge trials, and ethical issues. The five talks will be followed by a highly interactive 10- to 15-min discussion period. The discussion will be divided into two sections. The first half of the discussion will explore the ethics of SARS-CoV-2 challenge trials. The second half will discuss the future role of challenge trials in vaccine development.