 Good afternoon, everybody. I'm delighted to welcome you to today's lecture in the series on ethics in the COVID-19 pandemic, medical, social and political issues. We're delighted that our speaker today is. Seema Shah, who is JD, and is the Founders Board Professor of Medical Ethics and the Associate Director of Research Ethics programs at the Lurie's Children's Hospital under Northwestern. Professor Shaw is an expert in the field of pediatrics and global health research ethics, as well as on ethical issues in the determination of death. Professor Shaw attended Stanford University, both for her undergraduate and law degrees, and completed a fellowship in bioethics at the National Institutes of Health Clinical Center. Dr. Shaw, Professor Shaw clerked in Federal District Court in Sacramento, California. Previously, Professor Shaw had been on the faculty at the University of Washington Seattle's Children's Hospital, as well as at the NIH Clinical Center Department of Bioethics. Professor Shaw has chaired an NIH committee on ethical considerations in conducting Zika virus human challenge trials, and served as an expert member of the World Health Organization working group to develop key criteria for human challenge trials to address COVID-19. I'm stunned by the number of international locations in which she, Dr. Professor Shaw has presented the ethics of clinical research work. It includes South Africa, the Netherlands, Vietnam, Japan, Indonesia, Brazil, Zimbabwe, and it goes on from there. Dr. Shaw's research is focused around the following question, when is it ethically and legally acceptable to expose some people to risk for the benefit of others. She's examined this in a number of different medical domains, including HIV AIDS, pediatric research, and the COVID-19 area. Today, the title of Professor Shaw's talk will be Ethics of Controlled Human Infection to Address COVID-19. It's an honor to introduce you to Professor Seema Shaw, Professor Shaw. Thank you for that kind introduction. It's an honor for me to be here with you. I will, let me go ahead and start my, okay. So what I'll be talking to you about today is the ethics of challenge studies or controlled human infection studies to address the COVID-19 pandemic. And this is really an opportune time. Lady Ross and I were just talking about how she couldn't have planned a better time for this talk if you've been following the news, but I'll get to that in just a moment. So first, what are controlled human infection studies also known as human challenge trials or controlled human infection models? So these are studies that are highly counterintuitive. The basic idea is that researchers deliberately expose people to pathogens. These pictures demonstrate two different models for controlled human infection. The first, the picture to my left, is a picture of a man in a cholera human infection study that was conducted at the University of Maryland. And what's really nice about this picture is it illustrates the burden that these studies can involve. So this man was deliberately infected with cholera, and he recovered and was treated into just fine. But the reason he's holding up a sign that says 26 is because he needed 26 liters of intravenous fluid to fully recover after having experienced the disease. The next picture is a picture of someone in a controlled human infection study with influenza. And this was conducted at the NIH. And so in this study, you see a droplet being placed into his nose, and this is basically a common approach that's used for respiratory viruses. In this study, this participant did okay, although he had a couple of months of sequelae from the controlled human infection study and was then ultimately fine. But these studies, I think, although they're deeply counterintuitive, they can be quite safe. I think the common, one common denominator is that participants really do experience quite significant burdens. They're often followed for days, up to something like 42 days where they have to come in each day to the clinic site, they might need to be confined into a specialized facility. And they are fundamentally exposed to a disease as part of their research participation. So these histories have a very long scientific history. And when you look at that long scientific history, it's sort of startling that there's been limited ethical analysis along the way. Probably the first recorded controlled human infection study occurred in 1796. And this was also the start of moderate vaccination. And this was when Edward Jenner challenged James, James Phipps, his gardener son, with smallpox. So he knew that dairymates were not as likely to get smallpox. And the practice of variation or exposure to cowpox was this interesting idea that he wanted to test. And what he did was he exposed Phipps first to cowpox and then to smallpox and was able to show that Phipps did not become infected with smallpox so that you could inoculate people to give them protection against future exposure to disease. There were other challenges that were conducted, although less prominently, but in probably the next most prominent challenge was in the 1900s. Walter Reed famously conducted yellow fever experiments in Cuba. And at this time, there was a sort of scientific debate going on about how yellow fever was transmitted. There were people who believed it was transmitted through fomites and people who thought it might be transmitted through vectors like mosquitoes. So Walter Reed conducted this experiment in Cuba where yellow fever was highly endemic and randomized people to live in one of two huts. One hut was filled with fomites and the other was filled with mosquitoes. And he, despite his prior belief in the fomite theory of infection, actually proved that yellow fever was transmitted by mosquitoes, that then led to really important developments in public health to reduce yellow fever transmission significantly. And it even led to the U.S. government being able to conduct construction on the Panama Canal without losing all of their workers to yellow fever. In the 1950s, there was probably sort of the first tentative discussion of ethics of these studies. So at the Willowbrook State Institution and New York Pediatric Challenge studies with hepatitis were conducted. These studies ultimately proved that there were, at the time they discovered two forms of hepatitis, hepatitis A and hepatitis B. And these studies were criticized so much in the literature, including by Henry Beecher that the researcher himself actually published a defense of his study. But despite this long history, the first article that really tried to present an ethical framework or a series of considerations for these types of studies was only published in 2001 by Frank Miller and Christine Grady. And since that time, quite a lot of catching up has happened in the ethics world. When I first became interested in control tumor infection studies was really around the time of the Zika virus pandemic. So at this time, although it feels a little bit like a distant memory to all of us today, Zika was spreading around the world and there was a lot of concern about where it would go and what would happen. Researchers were conducting trials as quickly as they could, recognizing the devastating effects of Zika virus on particularly infants who had congenital Zika syndrome and microcephaly that was really different than it is often experienced with other types of diseases, much more profound loss of function associated with it. So at that time, researchers proposed to conduct a controlled human infection study with Zika virus. And they were really interested in doing this, they obtained funding for this study through the NIH and IRB approval. But then, before the study was to launch, people raised concerns at the NIH about conducting this trial. And that's when I first became involved. So the NIH decided to create a special panel to address the question of whether a Zika virus human challenge trial could be ethically justified. And if so, under what conditions. And this was, I was the chair of this panel. This was one of the more difficult things I've done because people had such strong views, but they were diametrically opposed. So some people thought Zika virus was so terrible that it was a no braider that we should use every tool in our arsenal to address it, including challenge trials. And others thought that, you know, given the uncertainty about Zika and its potentially devastating effects on fetuses, there was no way that such a trial could be ethically justified. Our panel ultimately decided that Zika virus human challenge trials could be ethically acceptable in principle, but there were significant unknowns that related to work that needed to be done in ethics. And that included unknowns about social value and third party risks. So more specifically, a big question was how was a Zika virus human challenge trial going to make a difference? At the time, many researchers were conducting phase two trials in the field. They were moving pretty quickly. And nobody indicated that they were going to stop or pause their trials or change them in any way based on results from a human challenge trial. So one of the big questions is where in the development of vaccines would this trial actually fit in and make a difference? The second problem was the issue of third party risks. So if people in the study were infected with Zika virus, at the time the CDC recommended that those people could be infectious for up to six months. And it was unclear to us how researchers could control the behavior of those participants to make sure that they couldn't transmit it through the many ways in which Zika was transmitted, including sexual transmission. So we paused the study or we recommended that the study be paused and then National Institute of Allergy and Infectious Diseases did so. But shortly after this, a few months after a report came out, signals started to emerge that Zika virus vaccine trials weren't going to be successful in the field. Zika virus epidemiology was changing, so it was becoming much more sporadic. Outbreaks were harder to predict and it was very difficult to launch trials in the sites where outbreaks would move or occur. So even though the World Health Organization didn't think that Zika virus would go away, it still was no longer an emergency and it was very difficult to conduct these trials. Additionally, the new guidance emerged suggesting that people could only transmit Zika virus for about 30 days after infection, suggesting that then precautions research participants would need to take were much more minimal and shorter in duration than we had thought. So ultimately, challenge trials were planned to proceed as clearly socially valuable and able to manage third-party risk with this new knowledge. As far as I know, however, these trials haven't yet been conducted, I think, due to the COVID-19 pandemic. But at this time, it was really interesting to look to the ethics literature about the ethics of challenge trials and really all of these articles you see here are pretty much what was available. There were a couple of other reports. You know, I naively, when I agreed to chair the panel, thought I would rely heavily on the Miller and Grady framework and that would be sufficient, given the respect I have for both of those authors. But I think while it was really important, there's so much more work that needed to be done. What people agreed upon was that controlled human infection studies, even though they've sort of raised the ick factor and they seem very counterintuitive, they're not ethically distinct. So like phase one trials and healthy volunteers, the basic balances that people in these studies are taking on risks for the benefits of others in society and not for their own benefit. Additionally, some controlled human infection studies were considered too risky to permit and people often relied on proxies for risk. So, you know, whether there was a curative treatment available or whether the disease was what people refer to as self limiting and likely to resolve with no lasting consequences. That was, those were considered the criteria for deciding when controlled human infection studies could be ethically justifiable and international ethical guidelines actually refer to controlled human infection studies as examples of research that's beyond the upper limit of risk. So in the Council for International Organizations in the medical sciences guidelines, the World Health Organization's ethics guidance. They say that a controlled human infection study with anthrax ribola would not be ethically acceptable and that's, you know, their attempt to demarcate an upper limit of risk. What's interesting about these, this sort of tentative consensus that existed is that influenza controlled human infection studies have been going on for a long time, and there's arguably no curative treatment. We know a fair amount about influenza, but the way that one of the researchers who conducts these studies regularly says that there's nothing really controlled about infecting people with influenza. That once the disease is in the body of participants, he doesn't know what's going to happen. He has to monitor them closely and watch, but it isn't really controlled. So additionally, people also believe that there were several other ethical considerations to apply, but that these were essentially no different than standard research ethics criteria. Now, I think what was missing from this literature is that although controlled human infection studies are not ethically unique, they do raise a constellation of difficult and unresolved research ethics issues that have been longstanding challenges in research ethics that we've never solved. And for that reason, they're especially hard, but also a critical area for making progress in other areas of research ethics. So for instance, when there's a controlled human infection study, one big question is what the upper limit of risk in that research might be? And that is a perennial issue. We know that if you look at the regulations, the U.S. federal regulations don't provide an upper limit of risk. Very few ethics guidelines actually do. The most guidance really refers to the idea of balancing the benefits to society against risks to individuals. And unless you're talking about a vulnerable population, adults are freely able to consent to almost any level of risk. And yet most ethicists agree that there is some level of risk, that people can't just sacrifice their interests in research completely. So this is sort of this perennial challenge where there's a big debate and yet no clear answer. The second issue is default exclusion. So for a long time, participants have been enrolled into research with the idea that research is something that poses risks to people and burdens, and therefore people should be protected from it. But that default policy of excluding people from research led to children having about 75% of the drugs that are given to them not being tested even for basic safety and efficacy. That number, as Laini Ross knows well, has changed a little bit over the recent years, but not as much as it needs to. Additionally, pregnant women have been excluded from a lot of research. We've seen this in the COVID-19 pandemic where vaccines were not had no information about how they would act in pregnancy. And this default of exclusion, while it may protect individuals leads to big problems for those populations down the road, where it's not really clear how the benefits of research apply to them. Additionally, third party risk in research is an area that the regulations say nothing about. So third party risk is the idea that people who are not enrolled in the study who don't consent to their involvement could be exposed to risk by virtue of being connected to participants, could also have research staff being exposed to risk through participants. And this is an area where there's extremely limited guidance. And finally, the right to withdraw is held out to be an inviolate right where participants can withdraw freely from research at any time. And this is really an important way to ensure voluntariness of participation. And yet in a challenge study, if somebody is deliberately infected with a disease and they want to withdraw, that could expose other people outside the study to risk, or it could expose that individual to risk of death, which could create challenges for that research study. So all of this made me really keen to explore these ethical issues and develop a more rigorous comprehensive ethical framework for controlled human infection studies. So with funding from the Greenwell Foundation and the Rochette Foundation and the Welcome Trust, we can convene a group of people who were half and half ethicists and challenge study researchers. And you see us here gathered pre-pandemic in Switzerland with some babies to help us work together over the course of a few days to try and develop an ethical framework for controlled human infection studies. And really was illuminating I think the challenge study researchers didn't realize how much ethicists have debates about various issues and how heated those debates can get. And similarly, I think a lot of us who were ethicists didn't realize that things, the types of guidance that we sometimes provide that other researchers who were actively involved in the field don't actually find that useful. So then the COVID-19 pandemic hit, we were just wrapping up our framework and had gotten to a point where we had a pretty good draft of the framework when the pandemic hit. And people started very early in the pandemic as early as March questioning whether a controlled human infection study should be conducted to address this pandemic, whether people should be deliberately exposed with SARS-CoV-2, the virus that causes COVID-19. When we thought it was really important to rapidly repurpose the work that we had been doing to try and address this question, but it was really interesting because the amount of attention that was focused on this issue was very different than in the Zika virus pandemic. In the Zika virus pandemic, people were passionate about doing controlled human infection studies, but it was still a pretty small group of people. And in the COVID-19 pandemic, it felt like the world was watching because the pandemic had touched just about everyone. So we saw an explosion of articles and interest in controlled human infection studies. In fact, more articles were written about controlled human infection studies and the ethics thereof in the year 2020 that had ever been written before. What was also really interesting is an organization called One Day Sooner started a website where people could sign up to participate in human challenge trials that no one had actually launched at that time. And there are now about 38,000 people who've signed up on this website. So it's been a really interesting journey to see all of this interest in controlled human infection studies, but I think a lot of this discussion has really had important limitations that I'll get to in just a moment. There are now also public plans for controlled human infection studies. There are also a few private plans, so there's some information that I can't share or that other people are keeping pretty close to the best. But essentially the NIH has developed strains for SARS-CoV-2 challenge trials in case they are needed. But Tony Fauci has indicated this is not even a plan B, it's a plan C or plan D. And his thought is that if vaccine trials had not succeeded, then they would have these strains to do more testing of vaccines now that we've seen approval of vaccine candidates that's very unlikely to happen. By contrast, the UK government and Oxford researchers have received approval to conduct a challenge model. Their idea is to use it to complement phase three trials and they should be launching it really any day now. So this has been also very interesting to see. There are some, there's also some indication that challenge trials will be launched in Belgium as well, and I think there are likely a few other actors who are interested in moving forward, although it has, most of those plans are non-public. So our group, as I mentioned, rapidly repurposed our ethical framework and published that in science. I also collaborated with the World Health Organization to serve as part of this expert working group in developing key criteria for the ethical acceptability of these challenge studies. And in, at the same time, we had planned as part of our project to have a special issue of the journal Bioethics where each article and the special issue had input from an ethicist and a researcher to address some of these key questions that are unresolved and unanswered for controlled human infection studies. And that was really an interesting experience where in the first year, it didn't work very well to ask people to collaborate across disciplines and it was, you know, sort of people were just speaking different languages. But in the second year, it really came together nicely and led to some fascinating collaborations and conclusions. So we ultimately developed this ethical framework for controlled human infection studies. And I will tell you what this framework is, but I'm going to focus in on part of it because I don't think we have time to go through all of it. But our framework first requires justifying these studies by ensuring they have sufficient social value and a reasonable risk benefit profile. Then, ensuring there's context specific community engagement, which may vary, of course, depending on the community we're talking about in its form or also its goals. Fair participant selection, suitable site selection to make sure there's capacity and ability to treat participants and conduct studies safely, robust informed consent, of course, and proportionate payment. And, you know, this is similar to a lot of other research ethics frameworks, but I think it's separate and it's specific to controlled human infection studies and the way we try to lay it out. So I won't walk you through all of these, but I will also just note that there is an actual report on the effects of paying people for challenge studies that Holly Lynch led. That's a really nice description of the issues involving payment. And a lot of people are really interested in that because challenge studies do involve high amounts of payment ranging from about $2,300 to $6,500. It's actually interesting that I've talked to challenge study researchers who say that they have trouble sometimes enrolling participants because phase one studies pay more than that. So that's their competitor, but it is usually payment that's based on the amount of time that people spend in these challenge studies, which then adds up to quite a bit of money over time. So I want to focus in on these justificatory elements of the framework. And first, it's important to ensure that studies have sufficient social value. So social value is of course ensuring that they're the magnitude distribution and likelihood of the health benefits from research for populations is sufficient. And this is important. Usually it's sort of a threshold determination that IRBs will make and researchers as well. Where there's this question, should this research be conducted? Is it likely to produce, are the methods rigorous enough to answer a scientific question that's still important to answer? Sometimes that can mean replicating research that other people have done, but that's still important in science. So generally this is sort of an ad hoc calculation that people do in not a very rigorous way. But I think that the high risk and potential controversy from doing a SARS-CoV-2 challenge trial or control tumor infection study requires being more rigorous here and actually being able to delineate a path from conducting these studies to achieving certain clear health benefits. And there are different potential paths to social value for vaccine testing. Now, I think the one that has gotten the most airtime is a proposal that was put into the literature in March of 2020 by Nearyall, Peter Smith and Mark Lipschitz. And their proposal was that controlled human infection studies could replace vaccine efficacy testing. The idea specifically was they thought you could take phase three of testing vaccines and do a challenge trial instead, which would have a much smaller number of participants. It would be somewhere between 15 and 150 as compared to tens of thousands of people. And then there might need to be some additional safety testing of about 3,000 volunteers, but after that was done, their thought was that vaccines could be authorized. This was an interesting idea and it had high potential social value if it could work. It's also sort of an easy to understand idea. So if you don't know a lot about how vaccine testing works, everyone can at least understand the idea that efficacy testing that you can learn really quickly. If you randomize people to a vaccine or a placebo and then you challenge them with a disease, you can tell if the vaccine protects them. Now, there are a couple of problems with this. The first is that regulators wouldn't necessarily accept these data to authorize vaccines. Because if you take small numbers of young, healthy people and prove that a vaccine works in them, it's not really clear that it's going to work for the broader population and for the people who are at higher risk of disease. Relatedly, another challenge is that in a controlled human infection study, people are selected to have more mild disease in order to decrease the risk. And then what trials are doing is they're testing for who becomes infected on a regular basis. So trials might be able to tell you if a vaccine works to protect against infection, but it wouldn't necessarily tell you if a vaccine works to protect people against severe disease. And what's interesting about the vaccines that we have now is that many of them are highly efficacious against severe disease. One of the biggest advantages of the vaccines that we now have, almost regardless of strain, is that they seem to protect people from severe disease and death. And that is something that you couldn't necessarily see in a challenge trial. So challenge trials might rule out vaccines that do still have some number of infections, but actually do prevent severe disease, which is something we still really care about. Now, of course, the second problem is timing. And what happened with the COVID-19 pandemic is that certain governments are included did such a terrible job of controlling the pandemic that vaccine trials moved incredibly quickly. There was also, to be fair, really thoughtful approaches to moving vaccine testing along as quickly as possible, starting to manufacture vaccines before they were actually authorized and overlapping phases of clinical trials in a way that didn't decrease what we could learn, but did increase financial risk where companies were testing vaccines at later stages than they would otherwise earlier, not knowing if they necessarily would have passed other tests. So what ended up happening is that we're now in a situation where we have vaccines that are authorized in the United States, some that are approved, mostly in other countries where they've received full approval. And many other vaccine candidates in the pipeline. And the big challenges, of course, that we're facing are making sure that everybody is willing to take the vaccine and challenges of supply and distribution. So we're in a very different place than a lot of people thought we would be. And the idea of using a challenge trial to accelerate vaccine development doesn't seem like such a good idea, especially when you consider that challenge trials take several months to set up. Additionally, just to note, every time I give this talk, I always have to check the news in the morning and add something. And this is what I added for this talk that the FDA just had their independent panel review, the Johnson and Johnson coronavirus vaccine. And it, the FDA review found it was favorable in terms of safety and efficacy, meaning that it's likely to be authorized very soon. So this first idea of why to do a challenge study, what value it could bring us really didn't end up panning out. But that doesn't mean that there aren't other potential uses of challenge studies. One of the most interesting is the idea that challenge studies could help identify correlates of protection. So these are ways to tell when people are protected against infection. And as you may know, most of the ways that people have been thinking about correlates of protection are related to neutralizing antibodies to systemic immune protection. But there might be other correlates of protection that are related to say mucosal immunity that are equally, if not more important for protecting people against SARS-CoV-2. And depending on what's learned from challenge studies, they could produce correlates that are useful for future vaccine research, either to create new endpoints that could make it easier to conduct the research, or to determine that there's a different and more promising way of developing vaccines to address how immunity actually works. Additionally, we could learn more about transmission, which could help improve public health guidance. Another possibility is learning about infection and reinfection, whether people who've been infected previously can be infected if they're exposed again, and if so, if they're likely to have less or more symptoms. And finally, using these studies could be one way to prioritize vaccine candidates. We have still about 200 or more in the pipeline. And most people agree that the first generation vaccines that we've seen be approved are not perfect for lots of reasons. One big problem is, of course, that some of the early vaccines require two doses and cold chain storage, ultra cold chain in some cases. And although the Johnson & Johnson vaccine doesn't have those requirements and does just have one dose, there still are these questions about where will we get to the optimal kind of vaccine, and how will we have enough vaccine to treat everyone, to use for everyone in the world. So once the social value is set, then we have to turn to the question of the risk benefit profile. I'll just say one last thing, which I'd love to discuss this with you more afterwards. As I've been talking to researchers just in the past week, it's been really interesting to have this conversation about the social value of controlled human infection studies. And a lot of what I'm hearing is that these studies are somewhat analogous to basic science research, where they produce value and insights that are really hard to get any other way that you couldn't really see in a field trial. But how those insights will ultimately be translated is often unclear. And it often will take some degree of time. Another big problem is that when you launch a challenge study, you need to have a strain that's selected, purified, tested, and manufactured according to good manufacturing standards. So the strain that the UK government is using is the one that's been circulating in the UK since March, not the UK variant, as some people call it, or the South African variant. So there's always this approach of playing catch up and that really can't be solved, even if the trial was, if they shifted immediately to trying to work on these new variants, it would still take time to produce the strain and in that time other variants might emerge. So there's always this problem of doing this basic science research and predicting where we will be in some time. And then seeing where the value might lie, but the potential for value is pretty significant. If you think about all the different ways that challenge studies could inform a public health response or future vaccine research, which really poses this hard question for research ethics where we haven't had strong and solid ways of assessing social value like this. Okay, so assuming that there is enough social value to proceed, at least in the abstract, the next question is whether there's a reasonable risk benefit profile for enrolling people in the study and deliberately exposing them to COVID-19. And in this case, this means that the risks and benefits to participants should be systematically identified, evaluated, minimized, and below some upper limit of risk, which as I mentioned earlier, there isn't a clear consensus on what that upper limit of risk is, but most people agree that there is some upper limit. So what people are proposed to do is to enroll young, healthy adult participants at the lowest risk. So people from between the ages of 18 and 30. A conservative estimate of the risk that these people would be exposed to is about a 1 in 1000 chance of hospitalization and a lower risk of death would be lower than that. These participants would be monitored closely and provided with the standard of care. It isn't clear that rescue therapy would be required if enough is known about minimizing risks. And people have argued that this level, sorry, there's also this QCOVID resource where you can go onto this website and determine your risk based on your risk factors. And the researchers doing the study are relying on the QCOVID tool to determine who would be at lowest risk to enroll in their trials. This paper that I've listed below is really a systematic assessment of the risks associated with these controlled human infection studies. And their claim is that if you, even taking conservative estimates, it appears that these studies are lower than the risks you would see in influenza challenge studies, and also risks that occur for people in car accidents, or sorry, the general risk we all face with regard to car accidents. The one challenge is, of course, there's still a lot of uncertainty. So there are longer term complications that we still don't fully understand and they occur even with mild infection. You may have heard of these people who some people refer to as long hollers or people with long COVID who experienced symptoms for many months. Some data suggests that those symptoms usually resolve within about four months, but it's still not entirely clear because this is a disease that we've been living with for about a year and a half. And humanity just doesn't know what that long experience might be. There are also no treatments that are proven to reliably avoid severe complications or deaths. Remdesivir does appear to have positive results in some trials, but not in others. Monoclonal antibodies may reduce the likelihood of hospitalization and the duration of symptoms to some degree, but not to zero. And dexamethasone seems to prevent mortality, given during severe illness. So there's some data to suggest how participants should be treated. There are obviously other things about supportive care and pruning different ways to treat patients. And the people running these trials are planning to administer the highest standard of care. And in some cases even have an expert panel of clinicians who would be consulted on what the protocol should be for treating anyone who becomes sick. But there's still a lot of uncertainty about these risks that can't fully be resolved. A second type of risk, as I alluded to earlier, is risk to third parties. So third parties in research could be infected with COVID-19. Now, unlike Zika virus controlled human infection studies, there's not the worry about sexual transmission. And this is a respiratory illness that we know a fair amount about how it is transmitted. Participants could be confined in a highly secure facility for up to three weeks, or maybe less than that depending on whether they're able to test negative. Personal protective equipment could be insured for personnel. But one tricky thing is that isolation really can't be legally enforced in most places. So in the UK and certainly in the US, there isn't a clear form of isolation that's required. So if somebody decided to leave the study early and wanted to leave, there wouldn't be any legal authority on the part of the researchers. It's not clear that the UK government could actually force that person to remain home and away from others. One protection could be ensuring people don't have anyone who's immunocompromised or at higher risk in their home. But that doesn't necessarily prevent them from being able to go to the pub and transmit it to someone there. So finally, I think one key question that lives in the background of these studies is this issue of public trust. And some many people have argued Jonathan Kimmelman and Alex London have done this really eloquently that risky research can inadvertently undermine forms of broader longer term collaboration that sustain the production of socially valuable medical knowledge. Given the long and troubled history of clinical drug trials and controlled human infection studies in particular, there's a lot of reason to worry about what would happen if such a trial was done. We've seen that there's still a fair amount of vaccine hesitancy in the United States, although it appears to be going down somewhat as the different studies have progressed over the course of the pandemic. There are a lot of people who still don't know or say they won't actually get vaccinated. And one study interestingly found that people were really worried about the rushed pace of testing for a new COVID-19 vaccine and that it would fail to detect potential side effects or dangers. So if these trials were used to be the primary way we evaluated new vaccines, that might diminish people's trust in those vaccines. And 73% of the people asked about the statement actually agreed with it. The thing that I'm worried about a little bit more is almost an off target effect. And it's the idea that doing these types of trials could somehow be a part of public opinion in a way that's unpredictable. And it could be someone dies in a trial. It could be the people think that the COVID-19 vaccine is likely to infect them. But the reason I worry about this is because of how Tuskegee has played out in the public imagination. So we all know that the Tuskegee syphilis study was a really terrible and unethical study that was done as a natural history study where black men were followed for years to determine how syphilis manifested in black people. Allegedly the researchers wanted to know how it was different in black people than white people, but they didn't enroll any white people. And they felt it was the last opportunity to have a natural history study that they would have after treatments were discovered. So they just withheld those treatments from those men and let the descendants of those men be infected. And this study is a horrible statement in our history, but it's also important to recognize that it was a natural history study. And yet many people think of it as a controlled human infection study or a challenge trial. And there have been a couple of articles written recently about the UK challenge study that actually referred to Tuskegee as such as a challenge study. And this participant from this study really put it nicely and I think that over time the legend of Tuskegee is more palpable than what people know about what went down. I think I've always known, but I've always known that the government gave people syphilis and this is not true. So, you know, there are lots of interesting questions here about sort of the nature of truth and what leads people to form beliefs. But what I think is really interesting about this is that it's not clear exactly how the public receives information and what gets translated into our story about research and vaccines. And one worry I would have is that conducting these challenge trials could particularly if something goes wrong, but even if it doesn't affect public trust in some really detrimental way. So what I'd like you to take away is that the potential social value and risk of these controlled human infection studies is very dynamic. And it's also hard in some ways to pin down and understand if you're really thinking about how control human infection studies fit into a larger portfolio of research or a long term effort at pandemic preparedness. I mean, it could be that these trials could inform our preparation for the next coronavirus pandemic since we've already had three in my lifetime. So it's worth investing in these controlled human infection studies, but I think it's still a close question on whether they're ethically justified. And in my mind, that's primarily due to their potential social benefits and harms, which are fairly uncertain and present. One issue is that there hasn't been as much transparency as I think there could be. So this controlled human infection study being done in the UK, they haven't yet published a protocol. It appears they're sort of holding certain things close to the best, even though other people are likely to do these studies and having at least the same metrics across studies and agreement and perhaps sharing of strains would be valuable. But ultimately, I think the big challenge is there are lots of other ethical considerations to keep in mind. And the challenge of remaining trustworthy while conducting studies like this is a significant and important challenge that we need to take seriously. So I would like to acknowledge our incredible team. My co-investigator Annetta Ridd was really critical in helping all of us come to pass, but we also had just wonderful collaborators from around the world. And of course my funders. And then I'd love to hear any questions you have or comments or thoughts about all of these fascinating developments. Thank you. Thank you very much. Absolutely great. So as I told you before we started your talk, the first question I'm going to ask is why now and but by that I mean why now at this time and already have several vaccines available. We have new strains coming out. Why now is the UK or should the UK be doing this challenge trial? Right. And you know, I think the answer of why now is complicated because there's kind of a like a pragmatic answer, right? And then there's the ethical answer. So pragmatically, I think some of it is probably they've been planning this challenge trial for some time. They've invested in their infrastructure. They wanted to be the first to do this and science often rewards the first person who are the first group who does something bold, even if there are lots of ethical questions about it. And I also think that, you know, some of the reasons for doing this, there are people who are really committed to addressing the COVID-19 pandemic in whatever way possible. So that's part of it too. I think some of the challenge study researchers I've spoken to, they sort of just want to do something to help. In terms of the real, you know, why now and does it make sense. On the social value side, I do think that there are interesting possibilities about doing these studies that could lead us to valuable insights. So, you know, I do think that the point about how much does mucosal immunity matter or what kinds of correlates of protection might we be able to find that could be really useful if we're still testing vaccines down the road in order to get to a better vaccine, maybe even one that prevents infection completely a sterilizing one induces sterilizing immunity. And if we want to do that when you can't run placebo controlled trials any longer, challenge studies might be a really important way of selecting between existing vaccine candidates and trying to get to the best ones before you test them in people. So I think there are reasons to do these trials. I still don't know, especially because there are these unknowns about long COVID and, you know, why some young healthy people still die, and we don't have great treatments in our arsenal yet, whether it's actually justified. So that's a, you know, maybe not the most satisfying answer to your question but in my mind it's, you know, a mix of reasons and I think reasonable people can disagree about whether now is the right time to start these trials. I had a request from the audience that you can stop sharing your screen and I'm going to read a comment from Parth Modi. Does the calculus regarding the ethics of challenge trials take into account the risk of the subject becoming infected outside of a trial. That is a high prevalence community infection rate might make a given challenge trial more ethically acceptable than a rare disease that one has a low chance of acquiring this may also have implications for where in the country such a child might be more or less ethical to carry out. Yeah, that's a great question. I think in the past, I've just been doing this historical review of different challenge studies, and a lot of people in the past have justified their challenge studies on the basis that there's a high baseline risk of infection. So they've used this argument to say, look, people are already at a high risk in the Willowbrook hepatitis studies or claims that, you know, people are about a 60% chance of being infected. And in the challenge trial, there's somewhere between a 70 to 100% chance of infection. So there is a way to say this relative risk is lower for people if they're already exposed to risk outside of the trial. There are a couple of problems with that. One is that if you think some of the risk that people are exposed to is due to underlying injustice, then researchers should not exploit existing injustice in order to justify exposing people to higher risk in their trials. So if you were to take a community that's been really hard hit by COVID-19 and say, we should do this in, you know, the south and west sides of Chicago, because that's where people are already at high risk, and we'll select exclusively from those groups rather than from the northern parts of Chicago, that would clearly be problematic. That would be researchers profiting from injustice. And I think that's one of the big challenges is assuring that there's a normative baseline of risk that people are exposed to that is something that we think is a risk that can't necessarily be eliminated, but it's not for ethically problematic reasons. So that to me is really the key. Some people argued early in the pandemic that if we were to take healthcare workers and exclusively draw from healthcare workers that that could be an interesting way to look at conducting a challenge trial. In the United States where we've seen, you know, very different distribution of PPE across the country and in some places where the government really wasn't stepping up to ensure availability of PPE, you might still make an argument about injustice driving higher rates of infection. But I think if you could develop a normative baseline where people were exposed to higher levels of risk, and there wasn't some injustice behind it, that could be a way to justify recruiting from that population. So an interesting issue is that both England and Belgium that are thinking of doing the challenge trials both have a national health insurance and then it tends to have a safety net for these participants if bad things were to happen. Do you think that matters and do you think that's a reason not to even consider doing challenge trials in the US. I think it matters a lot. So as you know Lady the although every national commission of bioethics that's looked at the issue is always recommended we should have a system of compensation for research related injury. We don't in this country have any requirements that researchers have to compensate people for research related injury. The federal regulations that you just have to tell people whether or not you're going to compensate them you don't have to actually provide compensation. And while you know most people looked at the issue it seems that researchers will often provide shorter term treatment for their participants. What happens to people down the road is a lot less clear. And in a country where we don't provide universal access to health care that could mean that people are enrolled in studies suffer these long lasting harms and have no recourse to address them. So I do think that the fact that these two countries have a national commitment to making sure everybody has access to health care is relevant. I, at the same time there are other kinds of harms, including you know loss of wages if you're experiencing long COVID and you can't do your job any longer. So I think it's probably not sufficient as a condition for ensuring that it's acceptable to enroll people in these studies. Eric Wilde asked, you know, of any government that has hired its citizens to participate in challenge studies or other research trials as a service to their country similar paying people to serve in the military, trying to make it more of a job service to treat them the participants receiving a reward incentive for their volunteering in the trial. That's an interesting way to conceive about it. So there are some papers about whether we should make service and research compulsory just a slightly different question than what you asked but you know Alan Rothheimer famously looked at this issue of should we have something like a draft for research. And he used that to really illustrate why consent was important because it is important for ensuring public trust. I think there's also this question about what it looks like when the government runs a challenge study so you know I wonder in the United States, the idea of the government endorsing it and running it as part of what's keeping it from happening here. However, I think in countries where there's a greater emphasis on solidarity, you could see governments saying something like you know we were trying to get people to really believe in the value of what they can offer to others and contribute to society and that's why we're doing this challenge study. And it would be interesting to think about you know what kind of process should you have to really make sure that this is something that reflects national values and is appropriate for the government to do. So I think it's a really interesting thought. And the final thing I'll say about it is, it does seem to me that one big problem we have with research ethics in general is that participants are more often remembered for having experienced a serious adverse event in research or for being exploited so you know we know Henrietta Lacks' name, but we don't know the names of many of the people who participated in COVID-19 vaccine trials. And that to me is a disservice that we're doing where we don't honor research participants and recognize what they're doing as a form of service to others. And that's something that I hope that we can change to kind of rehabilitate the image of research participation and make it clear why we all should be willing to do it. Maybe not in challenge trials, but certainly more broadly. That said, just sort of following up on that a little bit. Have there been any studies or analyses of the motives of individuals who participate in these trials, or the ones that have signed up I think you said a headline that had 14,000 people that signed up. What were the motives of these individuals and how does that alter or affect how you conduct and construct these trials? Right, so there have been a few studies. I actually, we did a study of about 16 volunteers in a control team in a malaria infection study in Seattle and it was really fascinating to talk to them. They split into three groups in our analysis. So one set of people really was mostly motivated by money. The second set of people were they had some knowledge of people, someone they knew somebody who had experienced malaria in the past or they knew about the toll of malaria. And so they were really interested in helping others. So it was a strong motivation based on altruism. Then there was this third group that had this kind of curiosity slash experiential motivation. And they were people who said things like I've never been infected with malaria before, so I'd like to try it. But after I'm enrolled in this study, I would never do it again because then it's not a new experience anymore. So it was really interesting to see how that played out. And then of course, you know, as is true with other studies of volunteers, they're definitely mixed motivations. So some people had, you know, some monetary motivations, but also had the motivation to do it for altruism. And then there are other people who had really pure motives like people who said I would have done it for nothing. I thought it was really important and that's why I did it. Interesting. I'm currently working with One Day Sooner to analyze. We have a data set of 1200 of their, they're actually 38,000 volunteers and they're looking to understand their motivations. And you know, we don't have any preliminary data yet, but it does seem that altruism is really a strong motivation. Some of that might also be where they got their information out to people. There's this huge group of effective altruists who you may have heard of. And these are people who really, they're consequentialists primarily who really believe that our actions should be designed to benefit others. And many of them were really motivated by some of the early literature and news articles about child studies and felt like this was one of the most important things they could do to make a vaccine available one day sooner. So that I think altruism is a big driving factor for people in these studies. There are also interestingly, I think some questions about how much we should worry about money being a motivator. And what's interesting is when you look at the data on people who are primarily motivated by money, it does appear that people who are primarily motivated by money pay more attention to risk. So they're actually better informed about risks than others because they see higher payments as a signal that something is going to happen to them that may set back their interests. So that is one reason why even though there are some people who do these studies primarily for the money, that is, you know, we might not always need to be concerned about it. And then the last thing I'll say is there is this other, maybe even I don't know how large this proportion is. But there are super altruists who enroll in these studies. So some typhoid studies in England, for instance, they found that people who enrolled in the studies donated a portion of the money that they got to charity. So not only were they, you know, trying to help the world by participating in a challenge today, then they also wanted to double their impact. So that I think is a really fascinating group that would be interested to learn more about. I want to read one comment and then ask a question by from Beanie Meadow but the comment was from Lauren Robinson who mentions operation white coat from 1954 to 1973 was a seven day Adventist conscientiously objected to war and volunteer to undergo infectious studies in the U.S. Armed Forces to fever Cops yellow to the U.S. government in place of serving in the armed forces. So getting back to that whole point that was raised by one of our former people. You can comment on that but also then comment on Beanie Meadow said were there ever thoughts of doing CHI and young healthy people as an attempt to reach herd immunity. There are. So there is a paper by I can't, I actually now can't remember if this is published or if I saw a preprint or something like that, but there definitely was a discussion of doing controlled human infection, not to test vaccines, but to try and reach herd immunity and you know, some people are arguing if you were going to try and use herd immunity you could start with younger healthy people in the population and try to get to shift the infections. The idea was that if you gave it to enough younger healthy people you could get closer to herd immunity without infecting people were more likely to die. And I think there are this idea although you know it's interesting there are a lot of problems with it. I mean one is that you're infecting young healthy people at scale would be very complicated. Just being able to vaccinate people is a huge logistic operation. So you know I don't necessarily have a lot of confidence that the government if it were our government at least if it were to try to do something like this could do it in a way that was perceived as equitable and acceptable. A second problem is that it isn't clear that you know it's not entirely clear what level we need to reach to get to herd immunity and the more that you let an epidemic run rampant, the more that new variants might emerge. So it's possible that you know that strategy could backfire, if especially if we ultimately will need something like 85% herd immunity. So I don't think, although it's an interesting idea I don't think it was ever something that that was comparable to the strategy of trying to vaccinate the population in order to get to herd immunity. The comment comes from Jeff DeSousa he says thank you very much Dr. Seema Shah for an excellent presentation. I was wondering whether you'd be willing to elaborate a bit on the fair selection participation principle. Does this include exclusion of certain group those individuals for example from lower socioeconomic communities. I recently attended a session where bioethicist audits unfair to be targeting the 18 to 30 year old group because this generation has experienced a lot already as a result of COVID-19. Jeff that's a really interesting question. So I think when it comes to you know trying to exclude people from studies, there are lots of good reasons to exclude people from challenge studies, and they primarily relate to risk. So I think you know, excluding people who have comorbidities or have a BMI above a certain percentage or have a prior history of COVID, because that would interfere with the scientific aims right these are good reasons for inclusion exclusion criteria. So the challenge when it comes to thinking about excluding people based on socioeconomic status is that it's not really clear what it is we're trying to protect against some challenge studies in fact in the past that were conducted in low and middle income countries. They actually tried the excluded people on the basis of education or literacy. So they actually decided in some cases to try and enroll medical students there's a dang a human challenge trial being proposed in Vietnam where that's part of the inclusion exclusion criteria and they're deliberately trying to only enroll medical students so they can get people who are really informed about the study. But I think part of it is, you know, it may be sort of worries about voluntariness and informed consent that are misplaced. To the extent that you can have a robust informed consent process, people should be able to across educational gaps and literacy gaps should still be able to understand what the study involves. And to me that sort of challenge of communication that researchers face is it shouldn't be solved by just saying we're going to take people who are already well educated. If money really serves as if being motivated by money really serves as a signal for risk, it may be that people who are from who are motivated by money whether or not they come from low socioeconomic status. Those people might be better informed about the risks involved and more careful to look at it. So it isn't clear to me that people should be excluded on that basis. And then the last thing I'll say is, with regard to the comment that people have suffered so much that, you know, they shouldn't be asked to do this. I think it's so hard to know what will help people in this pandemic. We're all struggling with different problems. I mean, some people much more so than others. And it isn't, it's really hard to understand what exactly someone is experiencing and then what will make them feel better, or at least, you know, help them cope. And I don't know for sure whether they're, you know, 18 to 30 year olds as a group, how they would react to being enrolled in a challenge study but I certainly talked to some of the members of one day center who say that it would help them feel better to be able to do something to have control to contribute to something bigger than themselves. So I do think it's very personal to know, you know, what the effect of being in a challenge study will be for somebody what it will mean for them, and whether for some people it would actually be very meaningful and a way to take back some of the control that the pandemic has taken away from them. But that said, you know, I think you still need to have really good justification for doing the study in the first place before you invite anyone to participate. And even all that we're learning now about long haulers and even in people who are, quote, asymptomatic or minimally symptomatic at the time of disease that change the risk benefit calculation and should the UK be rethinking their decision. Yeah, it's interesting. I mean the researchers who look at those data, their claim is that if you look at long, you know, studies that really do have large cohorts and try to follow them, that most symptoms resolve at four months. So people can have extended symptoms, but they do resolve. They also, I think, will claim that long haulers have a range of symptoms right so it's not clear that all of them have really terrible symptoms. So it's different than thinking about mortality risks. While that's true, I do think, you know, first it suggests that if a trial is done that this idea of compensation for harm that's that people experience is really important. So one debate that's been going on in the literature is about do you compensate people for risk upfront or harm afterwards. And some people have been arguing that we should pay people a lot to participate in challenge studies, because some of them will experience harms, and that way you sort of offset that harm. Other people argue, well, if only some people experience harms, it's better to actually compensate them when they experience those harms and make sure that they are made whole, rather than compensating everybody upfront for risk. So I tend to think that at a minimum, it should be factored into the plan to take care of people in the longer term, and how they receive payment or compensation. But it also does raise a lot of questions in my mind about whether it's acceptable or whether the idea of enrolling people 18 to 30 really does cab in the risks efficiently. I think it's a tough question. I suspect that people could make a reasonable argument that based on what we've permitted and other types of research, including influenza control human infection studies or phase one studies, that it's still within the bounds of what we generally permit. But there's still this argument about uncertainty and what would happen if something bad were to happen to these participants. And that's where to me that that's really where the rubber hits the road, what are the longer term effects and doing such a study in terms of social harms. One question was what is the view of researchers regarding using an attenuated virus to study a pathogen. So that's another really interesting question. Challenge studies, they actually range quite a bit in risk. Some people use attenuated viruses. The dengue model actually uses a vaccine candidate that failed, but it's an attenuated form of dengue. Polio vaccine, the live attenuated vaccine is another thing that's been used in challenge studies. And then if you go down, there's still these questions about developing the strain. For the most part in SARS-CoV-2, what people have been talking about is using a strain that is actually circulating. And the reason is because that would maximize the information that you get. And if you really want to know if a vaccine protects people and, you know, it may be that the protection is about diminishing symptoms rather than sterilizing immunity, then a better way to see that is to use the strain that's actually circulating. But it's interesting there are some researchers who are proposing taking a different approach, which would answer different questions. So their approach is actually to take people who have been infected with COVID. And try and reinfect those people. And the idea is that they will already have some protection. So that's a way of diminishing risk. But we'd also learn a lot more about reinfection. One of the big challenges in the pandemic has been this issue of, you know, is it the case that people who have been infected with COVID, how long does their immunity last? And are they likely to become more or less sick? And early in the pandemic, some of the first confirmed cases of reinfection actually went in both directions. So it was unclear what reinfection can cause. So that's, I think, an interesting question that could be addressed in a way that decreases the risk. The challenge is, of course, it's, you know, depending on the design or whether you use an attenuated strain or an actual strain, that will change the questions that you can answer. So the last question I'm going to take, and then I'm going to turn it back to Mark to say thank you is from Janice Benson and she says, does Dr. Schaff special concerns about the current COVID vaccine research in children? Are there certain ages most concerning? That's a great question. I think with that COVID-19 vaccine research in children, it's been interesting to follow it. Early on, I don't think that pharmaceutical companies really factored in the need to test the vaccine in children. Initial development plans, as you all may or may not know, were to just test it all the way through in adults. So to wait two years after vaccines started testing to start trials in children. And then I think part of that was because everyone initially thought children were at much lower risk, which they were, but people didn't factor in the costs of not having children in school. So the many different kinds of indirect harms that children have experienced in this pandemic were things that we were slow to realize. In my mind, one of the biggest ethical problems is that we haven't moved a little bit faster in conducting these trials. I think it is really, you know, there are all sorts of mental health effects of the pandemic on children. There are lots of just smaller losses that children have experienced. And so it does seem to me that at least for the vaccines that have been proven to be safe and effective in adults and also other vaccine candidates where there's a long history of using the platform in children. There are good reasons to try and use those to accelerate testing in children. In terms of age, what's usually happening in these trials is age de-escalation, although often what I've been surprised to see in Laney, I'm actually curious what you think about it, is that people tend to open things up in bands that are pretty big. So it's sort of down to 16 and then down to 12, then down to six in some cases, and they aren't being as careful with age de-escalation and at least some of the trials I've seen as we usually are. I do think that, you know, one of the big questions is sort of how do we accelerate vaccine testing in children without exposing children to additional and unjustified risk. But I'm curious since you're here, Lady, a few thoughts about that. I'm just in 30 seconds or less, I share your concerns about the indirect impact of COVID-19 on the children, the mental health issues, the school loss, and I think that the school loss is exacerbated in poorer and lower socio-economic communities. And so I'm very worried about that as well as our kids who are English language learners and kids with disabilities. So it's a huge issue. I'm not talking about some of that in May, but I'm not here to promote my own talk. I'm here to say thank you very much. That was a fabulous talk. You were great with the questions and answers. Mark, do you have any last words before we say goodbye? And you have to get off mute. You have to get off mute. I agree with everything that Laney said about what a spectacular talk it was and how wonderfully you responded to the questions that were raised. It was very moving and very wonderful. I had one simple question to ask. Go back 50 years or thereabouts, let's say to Willowbrook and thereafter, what is the mortality risk of the challenge approach to vaccines or to other standards? I mean, has that been looked at and written about? Yes. So I think most people have left out in terms of the analysis. Most people leave out the trials that were done in the 50s and 60s, the trials that were done by the Nazis, because a lot of those had unacceptable risks of mortality. And participants really weren't followed in some cases. So the Guatemala studies the US government conducted, they didn't really follow people. But over the last few decades, the challenge studies have been done, there's been about four serious adverse events out of, you know, thousands and thousands of volunteers. So the risk of mortality is actually pretty low. And some of that is because the models that are used are generally safe ones like malaria where people are infected with something where there's a curative treatment and no danger of long lasting symptoms. There's still, they're interesting questions about whether all of the adverse events are actually published, you know, when you get in a room with challenge study researchers, they'll talk about the time when a malaria challenge study research participant left the country to go to a funeral and they had to frantically try to track them down using Interpol and other resources, but and those things are not in the literature. So I'm not sure that we have a full handle on it, but the record has been very safe for many years. Well, thank you. So we're so happy that you're in Chicago. So happy that you're at Lurie's Northwestern, a great institution, and so happy that you could join us today. Absolutely, my pleasure. Thank you so much. Thank you very much. Bye everyone. Bye bye thank you. Bye bye.