The Challenges of COVID-19 Human Challenge Trials
by Stephanie Holden, PhD | November 23rd, 2020
Would you be willing to voluntarily get infected with a virus for the chance to help advance a vaccine? COVID-19 has killed over a million people worldwide, spurring vaccine development at an unprecedented pace, but for many it still doesn’t feel fast enough. If you’re relatively young and healthy, this may be all the more reason to contribute to a vaccine study. But in the absence of a treatment, the risks may appear daunting. Maybe you’re still hesitant because you know a few people who have gotten sick and they still haven’t fully recovered, or you’re an essential worker and you can’t take time off to quarantine for a study, or you’re just afraid of the unknowns – including the small but real chance of severe illness or death.
The many unknown outcomes and personal factors of such an undertaking make volunteer participation in challenge studies a complex decision, one that may come sooner than expected for some, as the first COVID-19 human challenge trials (HCTs) will be carried out in the U.K. early next year. Human challenge trials, which involve infecting healthy adult volunteers with a pathogenic agent, are intended to test the efficacy of a vaccine or other therapeutic intervention. The hope is that HCTs will help shed light on how people react to the virus and accelerate COVID-19 vaccine development.
However, with the guiding principle in medicine of “first do no harm”, how do we ensure that such challenge trials are done within an ethical framework? To think more deeply about this question in the context of our current global pandemic, it helps to understand how challenge trials have played a role in medical history. With the first challenge trials on the horizon, it may be a good time for each of us to explore our thresholds for risk, our definition of informed consent, and how far we are willing to go for the health and safety of humanity.
The history of challenge trials and vaccine development
Many medical advances in history, including the first vaccine experiments, were made under controversial ethical circumstances. For instance, the first scientific attempt at a “vaccine” is typically attributed to English physician Edward Jenner in 1796. Jenner infected a young child with cowpox after learning that dairymaids, who were often exposed to cowpox while milking cows, were protected from smallpox. When the child was subsequently inoculated with smallpox, no disease developed, and Jenner concluded that his experiment was successful. However, the infected child and his family, who worked for Jenner, likely did not give consent to be part of this experiment. This type of free-wheeling experimentation would not pass muster with modern medical regulatory agencies.
Since then, the development of vaccines for other diseases, including cholera, typhoid, and influenza, have been aided by human challenge trials. Generally, challenge trials are safest with illnesses that can be rapidly and completely cured, or with diseases that are known to not have long-term adverse health effects. Typhoid fever is one such example – it can now be treated with orally-administered antibiotics, but a vaccine was needed because children have trouble swallowing pills and some strains of typhoid are antibiotic resistant. Typhoid is caused by bacteria spread in food and water, and can cause intestinal and heart problems. A vaccine challenge trial carried out in 2015-2016 was tested in healthy adult volunteers and was shown to be 87 percent effective before being tested in children. This saved a significant amount of time, as without the challenge trial, researchers would have had to track children for three to four years before knowing if the vaccine worked.
In the United States, drug and vaccine testing must go through several different stages, called phases, before they can be approved by the FDA and distributed to patients. Phase 1, which typically requires an average of 50 participants, is intended to assess safety and vaccine doses that can be tolerated. Phase 2 expands upon Phase 1, involving hundreds of people, to get more safety information and learn about immunogenicity, or how a vaccine can promote an immune response. Phase 3 trials are large-scale efficacy trials, which require recruiting tens of thousands of people (in the case of COVID-19, an estimated 30,000-50,000) who will receive the vaccine and go about their normal lives, with the expectation that some of them will be exposed to the disease of interest. This phase requires enough infections to show that the vaccine works better than the placebo, which can often take several years to determine. Spontaneous infection rate is often very low to start with, and people typically take precautions to avoid getting sick in their day-to-day lives. HCTs could accelerate this process because they involve infecting every participant in a controlled study, eliminating the need to wait for people to get infected and reducing the number of participants needed.
“Efficacy is something that you can measure in these challenge trials very well,” said Dr. Melanie Ott, a virologist at the Gladstone Institutes and the University of California, San Francisco. “It’s faster than in larger trials where you wait for spontaneous infection to see who is protected or not, but I think the important part is that these trials have to capture the different risk groups that we have in SARS-CoV2.” This will be an important consideration for clinical researchers – early trials will likely recruit healthy young adults, a relatively low-risk group, but their response to the virus or to a vaccine may not be representative of all people.
To add further precautions, groups like the World Health Organization (WHO) have outlined many regulatory considerations for human challenge trials. In an article published in 2016, they advised that virulent or attenuated organisms with a high case fatality rate and/or no existing therapies may not be appropriate for human challenge trials. Since the COVID-19 outbreak, the WHO published an updated document in May 2020 which slightly revised their position on virulent organisms with no therapies to adapt to our need for a COVID-19 vaccine. This new article suggests that challenge studies could be used to validate tests for immunity, identify correlates of immune protection, and investigate risks of transmission. Their current estimates suggest that HCT participation would be the least risky for young healthy adults (ages 18-30). The document also outlines eight (non-exhaustive) criteria for COVID-19 challenge studies, which include factors such as scientific justification, assessment of risks and potential benefits, participant and site selection, and informed consent.
Amidst the discussion about HCTs, researchers have been diligently developing COVID-19 vaccine candidates since March 2020. There are currently around 200 vaccines in development, many of which have already entered various human trials. The New York Times estimates that there are 12 vaccines in Phase 3 or large-scale efficacy tests, but 0 approved for full use.
Weighing the risks and benefits
1Day Sooner is an organization recruiting and advocating for volunteers for COVID-19 human challenge trials. A lot of volunteers are young adults, including Abie Rohrig, a U.S. college student who has taken a gap year to dedicate more time to 1Day Sooner’s efforts. The organization has put a lot of thought into the potential risks and benefits of human challenge trials for COVID-19, with the goal of helping potential volunteers be as informed as possible.
Human challenge trial advocates believe that challenge trials would reduce the number of individuals needed to test a vaccine, while also reducing the time to vaccine licensure. Although challenge trials would likely not accelerate first generation vaccines such as those in development at Moderna, AstraZeneca, and Pfizer, as these are already entering and generating results from Phase 3 trials, they could perhaps aid with testing the second generation of vaccines.
“Historically, the first is not necessarily the best vaccine,” Rohrig said. He explained that vaccines leading the pack right now are typically hard to distribute in the U.S., let alone in the developing world, as they need to be kept at temperatures lower than common refrigerator temperatures, as cold as -80°C. Second generation vaccines may overcome such limitations.
Typical vaccine testing, particularly Phase 3, relies on individuals becoming naturally infected in their day-to-day lives. This requires tens of thousands of participants, especially if the infection rate is relatively low or if individuals typically take precautions to not get sick. In these studies there is also no control over who gets exposed to the virus, so naturally-infected individuals could include higher-risk populations like the elderly or immunocompromised. In contrast, human challenge trials require fewer volunteers because they would expose all participants to the virus in a controlled environment and monitor them for symptom development. And importantly, to reduce risk as much as possible, all the participants would be consenting, healthy, young adults.
Because human challenge trials allow for such a high degree of scientific control, data gleaned about COVID-19 from these studies could be broadly applicable to development of vaccines and treatments. For instance, the exact viral dose would be controlled, and researchers would observe participant reactions from the moment they are exposed to track the course of the disease. Such controlled studies could also provide more information such as correlates of infection, which are signs (other than viral or antibody tests) that a person has contracted a virus.
“There’s also an enormous social value because young people are a common vector of the virus, and many are essential workers. A vaccine that works for them could help with things like herd immunity and opening the economy,” Rohrig said.
One of the greatest concerns about COVID-19 in general is that the long-term health risks of COVID-19 are still unknown, leading some to argue that fully informed consent is not possible. Although healthy young adults are usually recruited for challenge trials, it could still be fatal or cause other long-term health problems.
Rohrig offers a counter-argument: “Informed consent could be described as complete understanding between a researcher and the research subject. As long as there is utter transparency about the known and unknown risk, that can qualify as informed consent,” he said. Researchers may not be required to know every single aspect of a disease before they can make medical advances. For example doctors were not fully aware of the long-term health risks before the first living kidney donation, but it was still a worthwhile endeavor.
Many volunteers also argue that exposure to COVID-19 may, in the long-term, be inevitable. For some, getting infected in a controlled setting such as a challenge trial, where volunteers have access to medical care, could be safer than getting sick at home, while also having altruistic effects.
“Nobody’s consenting to getting sick right now, so why not give it to people who are volunteering, and who are informed about how much we don’t know,” said Gavriel Kleinwaks, another 1Day Sooner volunteer based in the United States. “Informed medical consent is an incredibly important principle. Sometimes people object to challenge trials on this basis…but everyone else is still not consenting to getting [COVID-19], so why don’t we step forward to prevent as much non-consensual contraction of the virus as possible?”
It’s also possible that the vaccines tested in challenge trials may not be fully effective, or may be far more effective in healthy young adults than in risk-prone populations like children, elderly, or the immunocompromised. However, Rohrig claims that even if the data from a challenge trial cannot be directly generalized to other populations, it could lead to indirect benefits like understanding biomarkers of the disease or markers of immunity.
To Rohrig and many other volunteers at 1Day Sooner, one of the greatest risks is not simply an adverse event in a challenge trial like serious illness or death, but the public response to such an adverse event. They worry that a serious adverse event could lead to negative societal perceptions of challenge trials in the future.
A drive for altruism
Given all the unknowns, one might imagine volunteers to be scarce, but nearly 40,000 volunteers have already registered on the 1Day Sooner website. About half of these volunteers are from the United States, and nearly a quarter are from Brazil.
Henrique Esteves, a 1Day Sooner volunteer in Brazil, explained, “We [Brazil] are a little bit negligent in some aspects…we didn’t perform any shutdown or any real measures to keep people at home.” But he also sees hope and altruism in the number of Brazilians who have signed up as volunteers. “People want to help, it’s a general feeling here,” said Esteves.
Kleinwaks considers volunteering to have multiple positive outcomes. She is frustrated that the pandemic has kept people like her elderly grandmother stuck at home. “We are saving people’s lives through the production of a vaccine…but there’s also something to be said about saving people’s lives by reducing the amount of time that we have to be isolated,” Kleinwaks said.
There are over 2,000 1Day Sooner volunteers in the U.K., including Alastair Fraser-Urquhart, who has been helping to contact every volunteer to inform them about vaccine development progress and potential risks. Part of 1Day Sooner’s advocacy work also includes investigating the capabilities of governments and hospitals to support a challenge trial. They were concerned that existing facilities were not large enough, so Fraser-Urquhart started a petition to the U.K. government asking for the creation of a Challenge Study Center with enough biocontainment capacity to quarantine 100-200 volunteers.
Fraser-Urquhart’s outreach efforts have become all the more important, as the U.K. recently announced that the first COVID-19 challenge trial will be carried out at the Royal Free Hospital in London starting in January 2021. This trial will be run by Imperial College London and a company called hVivo, which specializes in challenge trials. In the first stage, scientists are trying to determine the smallest possible dose of the virus that infects people, which will be tested on up to 90 participants between the ages of 18-30. Once a dose is decided, perhaps by late spring, vaccine candidates can be compared, though the vaccine candidates have not yet been announced.
A cautious optimism
In the right circumstances and with careful study design, challenge trials can be useful for advancing vaccine development. However, the ethical considerations behind challenge trials are complicated and many factors, including risks vs. benefits, informed consent, and scientific justification, need to be considered before moving forward with challenge trials for any disease, including COVID-19.
Whether or not HCTs continue, most experts agree that safety should remain the top priority for vaccine development.
“I think what we have learned from current vaccine trials is there are considerable safety concerns that we should not ignore,” said Ott. “My personal opinion is that we should not accelerate vaccine trials at any costs, because we might pay a huge cost in the future if we produce a non-safe or non-fully effective vaccine.”
Ott is still cautious when it comes to volunteering for human challenge trials. “Would I recommend my children participate? Probably not – I am worried because of the risk. Young people fare better, but there are still children that develop complications. From a personal standpoint, I would probably not participate. From a scientific standpoint, I admire people who do, because it can lead to important accelerated development,” she said.
Fraser-Urquhart and Rohrig are a little bit more optimistic – through their advocacy work, they have met people of all ages and all stages of health who have been willing to help advance vaccine development.
“The fact that there are so many people [volunteering] is really heartening, and there’s not a lot of historical precedent for potential trial participants banding together for something that hasn’t even happened yet,” Rohrig said.