Story at a glance
- Human challenge studies could accelerate Phase 1 of vaccine clinical trials, but relative to the whole timeline of development may not shorten the time horizon by much.
- These types of studies are experiments where a candidate vaccine is given to participants followed by a known amount of the pathogen the vaccine is thought to protect against.
- Although there may be ethical ways to conduct challenge trials, we may not get to that point with the coronavirus.
Dozens of research groups are moving forward with vaccine development for SARS-CoV-2, the coronavirus that causes COVID-19. With the need for a vaccine feeling urgent, some people are considering whether to accelerate vaccine development by deliberately exposing vaccine trial participants to the coronavirus.
And people are lining up to say they want to take part. A new advocacy group named 1 Day Sooner has sprung up to gather volunteers who would like to participate in so-called human challenge studies, which involve purposely exposing people to the virus. As of today, more than 24,000 people in 102 countries have signed up. But is it smart to consider such a move, or is it mostly wishful thinking?
What are human challenge studies?
Human challenge studies are vaccine trials in which people are given the vaccine and then inoculated with the pathogen that the vaccine is trying to prevent against. These are controlled experiments where experts give a known amount of vaccine and a known amount of pathogen and then observe the study participants.
Current vaccine trials in humans involve giving people candidate vaccines and then letting them go about their normal lives. This should be done in conjunction with a control placebo group. In this case, the researchers are relying on the prevalence of the coronavirus in the population to expose study participants to the virus. This could become a problem as the number of new cases drops and the coronavirus is not circulating as widely.
The goal of a human challenge study is to test for the efficacy of the candidate vaccine and to measure whether there is an immune response. “The whole idea of human challenge trials is to accelerate development,” says Seema Yasmin of Stanford University, who is a clinical assistant professor in medicine. Its main purpose is to get a candidate vaccine through Phase 3 clinical trials quicker than such trials would normally go. The people you would recruit for a challenge study are the least vulnerable to the disease. This often means young, healthy people between the ages of 18 and 30 or so.
These types of studies are controversial because people are exposed to a pathogen and could get seriously ill. In most cases when this approach has been tried in the past, there was a therapeutic treatment available to give to the study participant if they got sick. This is currently not the case with COVID-19. There are no treatments or antiviral drugs that can reliably help someone recover from the coronavirus, although researchers are exploring the possibilities with remdesivir and other drugs.
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However, before one can even consider starting such a study, a model has to be established, says vaccine and immunology researcher Beth Kirkpatrick at the University of Vermont. The model sets up the baseline for how much virus to give to people and what signs of disease to look for.
Developing the model is in itself another set of trials that could take about a year. You have to set up a model for how much virus should be given and what clinical outcome you want to see in the recipient. You don’t want them to get sick, but you want some sign that the virus is replicating and causing disease. And you need that to be reproducible and reliable. Otherwise, you can’t be sure that the vaccine is doing anything in the study participants’ bodies.
You have to first decide what version of the virus to use and then that has to be grown under good manufacturing principles and approval by the FDA, says Kirkpatrick. And then you need to make sure it's pure, safe and the concentration you want. Then you figure out the dosage. This means testing it out by giving small, known amounts of virus to people and observing what happens to them. If a small amount of virus doesn’t result in symptoms, then you move on to giving more virus. Researchers would also try different methods of administering the virus, including oral and intranasal methods.
And none of this is as simple as getting a shot and heading home. Because of the danger of the virus becoming airborne, study participants would need to stay in isolation units for weeks while being observed, according to Kirkpatrick.
A short history of past challenge studies
Human challenge trials are not a new idea. It’s been considered or done with past diseases like Ebola in West Africa, Zika virus and cholera. Researchers conduct challenge trials to test pesticides and drugs. In some cases, challenge trials are done to try to develop better vaccines for diseases that have existing vaccines. In some cases, researchers use an attenuated, or less virulent, version of the virus, such as with smallpox and polio.
However, there is a history of human challenge studies that were done unethically. For example, starting in 1946, U.S. researchers conducted syphilis and other sexually transmitted disease experiments in people in Guatemala. The people in the study did not give informed consent and at least 1,308 people were infected between 1946 and 1948. In 1955, a group of researchers conducted hepatitis studies at Willowbrook State School in a group of mentally disabled children.
What it could mean for the COVID-19 response
If human challenge studies could be done safely and effectively, it could potentially speed up the vaccine development process. It could shorten the Phase 3 portion of clinical trials, according to Kirkpatrick. Human challenge studies could demonstrate if there is an immune response to the candidate vaccine.
One of the advantages of these types of studies is that you know how much virus the participants are exposed to and you can gather a lot more data. “You're gonna get a lot more scientific and medical attention than the average person is by a modern clinical trial,” says Yasmin.
Human challenge studies really could speed up the process, says Frederic Bushman of the Perelman School of Medicine at the University of Pennsylvania. But that is relative to the lengthy vaccine development process overall and there are a lot of caveats that come with attempting to move forward with one. It’s important to fully commit to doing clinical trials right and doing it well. “You don't know anything ‘til you really do a clinical trial,” says Bushman. “You don't know if your medication’s hurting somebody unless you do that. It could be making things worse.”
Why experts are wary
Although 1 Day Sooner has gathered thousands of volunteers, human challenge studies could be performed with much fewer people, potentially giving some hope for people waiting for a vaccine.
“Now we’re in an epidemic situation...It is frustrating to think about trying to do things, one at a time, one vaccine at a time,” says professor of law and bioethics R. Alta Charo at the University of Wisconsin-Madison.
In theory, human challenge studies for SARS-CoV-2 vaccine development are possible. However, many experts think that the risks are still too high even to do a small study with about 100 people.
The biggest concern from experts who spoke to Changing America is that we don’t know enough about the disease and the virus. We’re still learning about how the virus attacks our bodies and how they may be affecting children and young people. Doctors are still learning about how to treat people suffering from severe cases of COVID-19.
“We're still finding out new things about the way this virus affects our bodies,” says Charo. “It would make it difficult to do a challenge study, not only because we don't know how to make a more benign version of the virus but because we don't really understand the full range of effects on the body.”
If researchers choose only some milder symptoms to watch for, it's difficult to ensure that it’s also an indicator of more severe forms of the disease. To put it simply, researchers can’t currently tell who will react mildly to the virus and who will react more severely, and without being able to make that prediction, it's difficult to determine who is least at risk to participate in a challenge study.
Bioethicists have written about human challenge studies often over the years, and also have picked up the conversation in recent months because of the coronavirus. Some bioethicists are pushing for human challenge trials, but many are wary. A 2001 paper published in Clinical Infectious Diseases lays out a systematic framework for considering human challenge experiments. The conditions for doing a human challenge trial include needing an acceptable scientific justification, acceptable risks, and having vulnerable groups that are protected. These have not been established yet for COVID-19.
In addition, in a paper published in Science Translational Medicine in July 2019 titled “Design of vaccine efficacy trials during public health emergencies,” the authors state, “In the context of a disease outbreak, vaccine evaluation also provides a way to give access in the affected communities to the most promising experimental vaccines and potentially to help control the outbreak should the vaccine prove to be effective...Conducting vaccine evaluation in public health emergencies is associated with methodological and operational challenges. The epidemiology of an infectious disease, sociocultural aspects, and outbreak circumstances affect the choices that must be made when designing a vaccine trial or study.”
A remaining concern with COVID-19 surrounds informed consent. Even if a volunteer gives verbal or written consent, that does not necessarily equate to informed consent, says bioethicist Kelly Hills. Because the coronavirus pandemic has affected so many peoples’ lives and livelihoods, this brings in the unseen external social and financial pressures that could make a person feel like they need to do something to help bring a vaccine to market faster.
“We're encouraged to think about the social dimension of challenge studies, what is feeding into social perception, what kind of pressures exist socially,” says Hills. “There's concern that we have to think about those kinds of pressures whether or not it's an accurate understanding of how medical research works or how medical experiments work.”
The ideal situation
The leadership of 1 Day Sooner is aware that it could take a long time to get to the point that human challenge studies are viable, and researchers may not ever be able to conduct such studies.
However, in the case that it does move forward, researchers want to be ready with names of potential study participants, says Josh Morrison of 1 Day Sooner, who is also the Executive Director of Waitlist Zero, an advocacy group for living organ donors. Advocates want to be in the position to be able to help researchers recruit study participants if it comes down to it.
To stay engaged with their community of volunteers, they send out newsletters and speak with them individually. The group is also collaborating with researchers to conduct studies on motivations to volunteer and pro-social or altruistic behavior. So at the very least, they could learn something about this group that has volunteered to get infected with SARS-CoV-2.
Ideally, however, we get to a point where we know enough about COVID-19 and what it does to our bodies and how it spreads in our populations. That knowledge will keep informing how we need to respond to the outbreak and what we can do to prevent more deaths.
The current situation
There are some ongoing vaccine trials that have already administered vaccine candidates to people. One trial at Moderna is reported to show promising results in terms of safety and being able to stimulate an immune response, although the data has not been released and the trial is ongoing.
We may not ever be able to move forward with human challenge studies for a SARS-CoV-2 vaccine. Not only do we not know enough about how it’s affecting people, there’s more and more evidence that it’s affecting groups of people that we thought were less vulnerable. There’s the mysterious Kawasaki-like illness in children that may be linked to COVID-19. There’s also reports of strokes in people in their 30s and 40s. We just don’t know enough about the disease.
Because COVID-19 does seem to be affecting children and young adults, that means there may not be a low risk group of people who would be eligible to participate in a challenge study. The risks are too high, even for children and young adults. But lawmakers are urging the Health and Human Services and the Federal Drug Administration to speed approvals so that human challenge trials could go forward if it makes sense.
It may be wishful thinking that we will get a vaccine for SARS-CoV-2 in the next year or two. Candidate vaccines that are currently in Phase 1 trials may not make it to Phase 2 or 3. Not to mention, Phase 3 trials require thousands of study participants to see if there are any uncommon adverse effects of the vaccine. The reality may be that it may take much longer than we’d like with or without human challenge studies, if the momentum keeps up at all. Although there’s a lot of talk now, funding and interest could drop off, like it has in the past with SARS and MERS.
“I don't think challenge studies are inherently unethical,” says Charo. “But I just think they are absolutely a last resort.”
For up-to-date information about COVID-19, check the websites of the Centers for Disease Control and Prevention and the World Health Organization. For updated global case counts, check this page maintained by Johns Hopkins University.
You can follow Chia-Yi Hou on Twitter.
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