Preface

By the turn of the twentieth century, yellow fever had caused multiple epidemics and killed more than 100,000 people in the United States alone (Patterson, 1992). Yet scientists did not understand what caused the deadly disease to spread. To that end, Dr. Walter Reed was appointed to lead a special commission to study yellow fever (Lederer, 2008). Reed planned to investigate two competing theories about how yellow fever could be transmitted. One theory was that yellow fever was spread through contact with the bodily fluids of people who were sick; the alternative was that mosquitoes transmitted the disease from person to person. To settle this debate, Walter Reed’s research team set up a site in Cuba and ran several risky experiments (Reed, 1902). These experiments required doing something that seems contrary to the central purpose of medicine—they were trying to make healthy people sick. The most famous of these experiments involved randomly assigning volunteers to stay in one of two uninviting conditions. One hut was filled with bedsheets and surfaces covered in fluids that came from yellow fever patients. Others were assigned to stay in a tent filled with mosquitos that had just fed on yellow fever patients. When the volunteers became sick from mosquitos but not from bodily fluids, the experiment definitively settled the question of how yellow fever was transmitted. This discovery led to near elimination of yellow fever in countries that could rid themselves of mosquitoes that carried it and saved countless lives—a tremendous public health achievement (Sutter, 2016). At that time in history, research ethics was in its infancy. Indeed, Walter Reed’s experiment was followed by decades of studies involving intentional infection that were ethically problematic or even “ethically impossible” (Presidential Commission for the Study of Bioethical Issues, 2011). Yet Walter Reed’s team had an unusual sensitivity to the ethics of their research. Although the level of risk that volunteers undertook was much higher than what would likely pass muster with an ethics review board today, volunteers were given an early contract that was essentially an informed consent document—which was not standard practice at the time. The researchers paid participants in gold and promised to pay additional funds to the relatives of anyone who died in the study (Lederer, 2008). In this respect in particular, the ethics of this study were remarkably advanced. Despite several bioethics commissions recommending that research participants receive compensation if they are injured by research, compensation for research-related injury is still not required in the United States today (Pike, 2014). These yellow fever experiments provide an early example that demonstrates both the potential power and ethical complexity of exposing people to pathogens for science—not to mention the way that this unusual type of research can spur innovation in ethics, which is a central theme of this book. I first became interested in controlled human infection (CHI) research in 2014, when I was at the Department of Bioethics at the National Institutes of Health, serving as a liaison to the National Institute of Allergy and Infectious Diseases (NIAID). In that role, I was asked to help moderate a debate at NIAID on whether CHI research could be ethically acceptable. The leaders of the two divisions within NIAID took opposing positions on the topic, and I presented an ethical analysis that I intended to provide a more balanced view. At the time, I was fortunate to receive advice from the first two ethicists who had written a manuscript focused on the ethics of CHI research—Frank Miller and Christine Grady—and I drew heavily on their seminal work. What I did not realize at the time, though, was how much more work needed to be done. In 2016, after I had moved to another institution, I was asked to chair a National Institutes of Health (NIH) panel on ethical considerations for CHI research with Zika virus, which was then emerging. I was reluctant to take on this role, recognizing how controversial the topic was at the time, but felt confident that we could rely on the existing ethical analyses in the literature and simply apply it to the case of CHI research with Zika virus. As illustrated in Chapter 5, I could not have been more wrong. This book is the product of more than a decade of work to address the challenging and sometimes unresolved ethical questions raised by CHI research. Before providing an overview of what this book sets out to accomplish to add clarity to the ethics of CHI research, however, I will briefly address terminology, which is a surprisingly complicated issue. In CHI research, researchers intentionally expose small numbers of participants to pathogens to gain scientific insights. CHI research is a particularly powerful way to learn about interactions between diseases and hosts and/or test experimental vaccines or treatments (Roestenberg et al., 2018). CHI research is known by different names, including human challenge studies, trials, or models and voluntary infection studies. In fact, the Wellcome Trust commissioned a report focused exclusively on the terminology used for these studies (Marsh, 2018). In this book, I use the term “controlled human infection (CHI)” research as an umbrella term that covers both CHI models and CHI studies. Developing a CHI model is the first step in the process; only once a CHI model has been shown to be safe and reliable can it be used in CHI studies to test interventions like vaccines and treatments. I further explain the difference between CHI models and studies in Chapter 3, when it becomes important for understanding what makes this research unique and how this research can be conducted ethically—for example, it will help clarify when extra oversight is needed. While I will use this approach to terminology in most of the book, the only exception is when I discuss historical examples of studies, in Chapter 1 and throughout the book, that were conducted before the modern oversight system for research was developed. In those instances, I will use the terminology used at the time the studies were conducted: “human challenge trials.” CHI research has been integral to ground-breaking scientific achievements. In addition to the discovery that yellow fever was transmitted by mosquitoes, discussed at the start of the introduction and in greater depth in Chapter 1, a smallpox challenge conducted by Edward Jenner proved the concept of vaccinology (Riedel, 2005). With the advent of increased ethical safeguards for research in the 1980s, CHI studies have been powerful tools for accelerating the development of new treatments and vaccines. To date, more than 15,000 people have participated in human challenge studies for at least 30 pathogen models (Abo et al., 2023). A traveler’s cholera vaccine and a typhoid vaccine were recently approved, relying heavily on data from CHI research. The use of CHI studies is a standard part of the testing of any new interventions for malaria, including a recently approved malaria vaccine (Roestenberg et al., 2018). Yet the exciting scientific promise of these studies can be tempered by their potential for ethical abuses and controversy. For example, to prove the concept of vaccination, Jenner enlisted his gardener’s 8-year-old son without clearly obtaining consent and exposed him to cowpox and then smallpox (Riedel, 2005). Greater ethical clarity is also sorely needed regarding how to use CHI research ethically to address emerging infectious disease threats. As mentioned above, in 2017, I was invited to chair an expert panel of ethicists, clinicians, and researchers that was convened by the National Institute of Allergy and Infectious Diseases to determine whether it was ethical to develop a CHI model with Zika virus. Our panel recommended pausing the proposed CHI research involving Zika virus based on two ethical issues we could not resolve at the time: the unclear value of the research and concerns about risk to third parties outside of the study who could not give their consent (Shah et al., 2018). The panel struggled with this decision, as discussed in Chapter 5. Some thought too little was known about the virus to conduct such studies ethically, especially in terms of how to protect members of the public from being infected by volunteers participating in the study. On the other hand, since Zika virus was spreading rapidly, others felt that any tool should be used to prevent the peril involved, including deliberately infecting people with Zika virus in research. In fact, in an article published in the New York Times, our recommendation to pause the study was described as having “slammed the door on progress” (Baumgaertner, 2018). Controversy involving the Zika CHI model persisted for a time, but, as more evidence about transmission of Zika virus emerged and the ethical issues could be addressed, the Zika CHI model was allowed to proceed (Vannice et al., 2019). Before it could be resumed, however, the nascent global debate over CHI research was taken to another level. During the COVID-19 pandemic, research involving deliberate human infection with a pathogen was hotly debated as a way to respond to the spread of this new disease that had stopped the world in its tracks (Eyal et al., 2020; Kahn et al., 2020; McPartlin et al., 2020). The potential use of CHI research to accelerate the development of a vaccine against the novel coronavirus captured the public’s imagination, not to mention the attention of ethicists. After decades of the ethics of CHI research being a niche topic, in 2020, there was an explosion of papers on the subject, with more than 100 ethics papers written in the first year of the pandemic—more than ever before or since (Katzer et al., 2023). In addition to the unprecedented scholarly attention to CHI research, a new organization called “1Day Sooner” ran such a successful advocacy campaign for CHI research that they were vaulted into the public consciousness. 1Day Sooner established a registry that ultimately included more than 38,000 willing volunteers and drummed up media interest in the topic, in addition to generating several open letters that were signed by prominent academics and other figures (1Day Sooner, 2020). Their efforts interested members of Congress, who asked Dr. Anthony Fauci to respond about why the NIH was not conducting these studies. Despite the fact that CHI research with COVID-19 has now been conducted in the United Kingdom, with more research being planned (Rapeport et al., 2021), this research was not done in the United States and other countries in part due to ethical concerns (Gupta et al., 2020). The sharp divides that arose during the COVID-19 pandemic are less surprising when viewed in context, however. Ethical concerns about CHI research have persisted throughout its long, complex history (Bambery et al., 2016) and are worthy of further examination. This book seeks to make two key contributions. The first is to advance the debate about CHI research by focusing attention on when it requires additional ethical scrutiny. Scholars have typically treated CHI research in one of two ways: either it is seen as raising unprecedented ethical questions that always require extra scrutiny, or it has been considered no different from other types of research. I will demonstrate that CHI research is not monolithic and falls on a wide spectrum of value, risk, and uncertainty. I will further show that CHI research has surprising similarities to other types of research but will argue that CHI research is ethically distinct because it can raise several difficult, unresolved ethical issues at the same time. When CHI research raises this unusual set of unresolved ethical issues, extra scrutiny can be helpful to ensure the research is conducted ethically, if it is justifiable to conduct it at all. Importantly, I will make an ethical distinction between CHI models and studies. As will be explained later, a CHI model for how to infect people reliably and safely is just the first step in the process. Creating a new CHI model therefore involves making several decisions that will affect any studies that will be done with the model in the future. I will argue in Chapter 4 that, as a general rule, CHI models should have extra scrutiny and specialized review, whereas CHI studies can go through standard review processes and be evaluated by an Institutional Review Board or Research Ethics Committee. In that chapter, I also provide a framework to help guide the ethical conduct of CHI research. Use of this framework will help make clear when CHI research should be treated the same as other types of research and when it requires specialized review to rigorously evaluate the difficult and unresolved issues this type of research can raise. My goal is to take the temperature down for certain types of CHI research and increase ethical caution surrounding others. This framework will also help clarify how CHI research should proceed when moving into new populations. For example, as India contemplates conducting its first CHI research, for example, beginning with established CHI studies that pose lower risk and less uncertainty than new models will help build the capacity and public trust needed to support more of this research in the future. A second contribution is to clarify how CHI research can be used ethically and effectively. CHI research suffers from an abundance of hype and a lack of clarity about how and why it can be valuable for society in the first place. Indeed, in considering whether to use CHI research during the COVID-19 pandemic, many focused on whether CHI studies should play a primary role as the final phase of vaccine testing or none at all. The other ways that CHI research can be and has been useful—for example, by yielding fundamental insights about diseases or playing supporting roles in vaccine and treatment development—received less attention. I will argue that CHI research should generally be seen as a long-term investment in accelerating the development of new vaccines and treatments rather than a last-minute shortcut. In Chapter 5, I show how CHI research during the COVID-19 pandemic was ethically problematic precisely because it was sold as a “quick fix” to make vaccines available at least one day sooner. Using a longer-term lens to evaluate CHI research can help to avoid such mistakes in the future. Finally, it is also worth noting that, although this book is written primarily for an academic audience, I have attempted to write it in a way that will be accessible to members of the public and policymakers, to illuminate the unique role that these studies can and, most importantly, should play. In recognition of the many important perspectives on CHI research, each chapter begins with a quote from someone who has volunteered to participate in a CHI model or study, drawn from the largest set of qualitative data from potential volunteers for challenge studies, which was gathered through a collaboration with the organization 1Day Sooner. This book proceeds in three parts. First, I set the stage for an analysis of CHI research. Next, I provide an ethical framework to guide the evaluation of CHI research. Finally, I look ahead to implications of this analysis for future studies in other contexts, with new populations, or in future pandemics. I close by considering the implications of this analysis more broadly. I begin by providing a historical overview of CHI research in Chapter 1. There have been several exploitative and unethical studies involving CHI research, including studies that exposed people to high risks with limited chances of social or personal benefit, and research in which participants were never asked for their consent. This history of ethically questionable research colors the conduct of CHI research to this day. This history also reveals that CHI research usually provides value by demonstrating why some people are better protected from disease than others, how transmission of infections occurs, and how correlates of protection can be used as proxy to to There are examples of CHI research being used to provide the primary data for of vaccines or which was the CHI research much attention during the COVID-19 Chapter 1 provides historical that can explain why it is for CHI research to be conducted to the scientific and ethical to not the mistakes of the and to support the public trust that CHI research to be In Chapter I address what have to as a with these studies. In other people to the of CHI research as Although have that CHI research is not ethically distinct as the work public trust in research, I take this to the question in greater depth and argue to the I research the to better understand why people to CHI research in this including considering whether different types of challenge studies can raise higher than others. Finally, I explain why we should take the even it not and I a way to address it In Chapter 3, I build on this analysis to into a key that has not the treatment it whether CHI research is ethically The of this chapter will be to whether there are to CHI research from other types of research or other or whether and make CHI research ethically I ultimately argue that CHI research is unusual because of the set of complex and/or unresolved ethical issues it particularly when on research that intentionally to a pathogen for the first time, that can extra ethical scrutiny. In the second part of the book, I provide an ethical framework to guide the evaluation of CHI research that will help clarify when CHI research can go through standard review processes and when additional scrutiny be needed. In Chapter I out the ethical in existing Health as as an ethical framework I have with a to for the use of challenge studies. I first the framework within ethics literature and for CHI research to provide a of the of on CHI research. I then out the framework and show how the framework with the distinction between CHI models and studies in can help risk and in the use of CHI research as as illuminate that should not be I then apply this framework to CHI research on emerging infectious diseases in Chapter 5, given the high level of uncertainty in infecting people with a disease that is I examples of a CHI model for Zika virus and CHI research conducted in the United during the COVID-19 pandemic and out for the use of CHI research in pandemic I argue that CHI research as a is generally ethically and will not provide a on To help avoid such mistakes in the CHI research should be considered just one part of a longer-term research to develop vaccines and treatments. In the final part of the book, I look ahead to how CHI research should be used in the future and what it can about the ethics of research in general before in the final In Chapter I the of CHI research into new populations, such as the use of CHI research in and CHI research is being used in and countries and to address diseases that have higher in these countries Some have even there is an to conduct CHI research in and safeguards are in if it can help accelerate to treatments and vaccines to address the disease by these countries CHI research in and countries can also raise concerns about and global particularly in of a to global health and these concerns additional attention. I also the of CHI research into different that be at higher such as and ethical and have against of these or it should be I to clarify how it can be ethical to these in certain of CHI research but important to from others. Next, I the implications of this analysis for CHI research in and human research in general in Chapter CHI research raises a set of issues that are unresolved in research ethics, analysis should for in these important The research ethics literature has not questions as as how to the social value of research, what can be on the to how to address and how to the for public trust in research when studies. For example, the advocacy by research participants during the COVID-19 pandemic reveals a to the of participating in research. Research participants have typically public attention when they have been or in research. for example, the 8-year-old famous for having been exposed to smallpox by Edward or who died in a that was to ethical The of CHI research and the of the advocacy organization during the COVID-19 pandemic an to the with research and greater respect for research participants and their to scientific et al., 2023). The final chapter the throughout the book to provide a overview of the ethics of intentionally infecting in research. CHI research into the question of when it is ethically to expose some people to risk for the of others. My is that into the ethics of this and controversial research can help illuminate the to the ethical use of CHI research in the future and advance the of research ethics the