Covid-19 human challenge trials: frivolous risk or practical solution?

Credit: Keystone/Gaetan Bally

While most of us hope that if we can just get one vaccine to market that will be enough to solve our global Covid-19 matrix – the controversial ‘human challenge’ studies now getting underway highlight how many more twists and turns we are likely to face before we finally get out of the pandemic maze. 

On Tuesday, London’s Imperial College sent ripples of both excitement and protest through the Covid research community, announcing that it would embark on the first “human challenge” trials of Covid-19 vaccines – involving the deliberate infection of healthy, young volunteers with the potentially deadly SARS-CoV-2 virus.

The first stage of the project, scheduled to begin in January 2021, will expose the volunteers to the coronavirus in controlled, gradually increasing doses, in order to determine the smallest amount of virus that it may take for a person to develop the disease. In a second stage, researchers aim to use that newfound knowledge to test different vaccine alternatives more rapidly and efficiently than could be done in conventional large-scale clinical trials – including by administering a vaccine to volunteers, and then infecting them with infectious doses of the virus.

Why is this important? Even if a couple of the leading vaccine candidates from Moderna, Pfizer, AstraZeneca and Johnson & Johnson make it to the market by early 2021, the world faces a myriad of other problems in deploying the new tools to actually stop the pandemic. Among the barriers:

  • Limited vaccine supplies. As low-income countries have pointed out over and over, over 50 per cent of the supplies created by the front-runners, which are expected to become available in 2021, have already been bought up by rich countries. This includes not only the United States but also the United Kingdom, the European Union and a big new preorder by Switzerland (5.3 million doses from AstraZeneca) in just the past week. This is on top of a previous Swiss pre-order of 4.5 million doses from Moderna.

  • Unsuitability of some vaccines in some places or for some populations. The AstraZeneca vaccine, for instance, requires cold storage at extreme temperatures; its trials also have been marred by a series of adverse events -including the death Wednesday of a 28-year-old trial participant in Brazil from Covid-19, although it was not clear if he had received the vaccine or a placebo. In addition, some vaccines may be more or less effective in older people, than others.

  • Limited vaccine acceptance. A new study of vaccine hesitancy covering 18 OECD countries indicates that only about 72 per cent of people would even use a vaccine, at this stage, even if one is proven safe and available. More vaccine testing leading to more choices also might, indirectly, help build public support.

So while hardly a panacea, proponents of so-called human challenge trials say that their approach could help cull out other effective vaccines among the 40-odd candidates still in the research and development pipeline, making more vaccine choices more widely available to more people around the world.

Proponents note that human challenge trials are, in fact, not unusual; they have been used in the past to rapidly test and scale up new types of vaccines for other deadly infectious diseases like cholera and typhoid, the fairly unique aspect of these trials is the fact that they will be undertaken before any known treatment or cure exists for Covid-19.

But sceptics point out that while the UK study would recruit healthy, young volunteers (18-30 years) with no previous history or symptoms of Covid-19, no underlying health conditions and no known adverse risk factors for Covid-19 such as heart disease, diabetes or obesity, the SARS-CoV-2 virus has proven to be a particularly tricky one, causing a weird array of unexpected side effects from neurological impacts to heart disease – even in some presumably, young and healthy people. Some of them lasting for months, or longer – a phenomenon described as “long Covid.”  In light of the still unknown factors that cause some people to fare much worse than others,  and the fact that there is no known treatment, let alone cure, the ethical challenges posed by human challenge trials of this particular virus are particularly vivid.

Critics of the human challenge trial approach include Dr Ken Kengatharan, co-founder and chairman of the California-based biotech firm Renexxion, who told us the following:

"A Covid-19 challenge study is as dumb and dangerous an idea as it gets considering the fact that SARS-CoV-2 is an atypical coronavirus (without any comparable out there or historically) and we are just learning about its MOA [mode of action] plus acute and chronic effects in all age groups with or without co-morbidities. Even the mechanism by which the virus causes, cytokine storm or SIRS (systemic inflammatory response syndrome), multi-organ failure, sepsis orseptic shock is very different.”

A recent study published in Lancet Respiratory Medicine vividly describes the distinctive quality of that immune response and dangerous over-response, in words and in graphics.

Cytokine Storm .jpg
Lancet Respiratory Medicine - mapping of immune over-reaction to SARS-CoV-2 as compared to other viruses

Human Challenge studies may be very useful to get rapid answers, Kengatharan adds:

“If there are no large participants’ pool. These studies should be used once you know a lot about the virus; there aren't that many people in the world to test; the vaccines have an expected efficacy of greater than 90 per cent especially if the virus does not have long-lasting effect; and when there is a way to treat people using drugs once they develop the disease (useful, if the vaccine does not work in a particular person), for example, Zika.”

He adds that the biggest costs around late-stage vaccine development involve the length of time required to recruit large numbers of patients. This in turn depends on infection numbers and thus how many stand to benefit from a vaccine.

So when there is a potentially small number of available vaccine users, challenge studies will be useful to know if a vaccine is safe and efficacious using a small number of patients which means shorter timeline and lower cost.

But in the case of Covid-19, where we have exceeded 41 million cases worldwide, “we have Covid-19 hot spots around the world, one can do the vaccine Phase 3 studies as fast as challenge studies!

“If there are many participants available, and one wants to test vaccines that are likely to have lower efficacy e.g. less than 80 per cent, and the virus has long lasting effects, then these challenge studies are not advisable. They don't and won't compress the length of Phase 3 trials!

“Besides, challenge studies [involving limited number of participants in just one setting] won't tell you much about the effect of vaccines on heterogeneous populations with different co-morbidities. Already we know SARS-CoV-2 affects different people in different ways.”

So are human challenge studies both reckless and a waste of time? A number of top global bioethics experts, who spend their careers pondering the pros and cons of these kinds of ethical dilemmas, put a much more positive spin on the Imperial College initiative and the relevance of the human challenge concept to Covid-19.

Dr Arthur Caplan, founding head of the division of medical ethics at NYU School of Medicine, notes that right now, there may be sufficient numbers of people ready to volunteer for the classically designed randomized controlled trials (RCTs) which need 30,000 to 50,000 participants to determine whether infection rates are really lower in those receiving the vaccine than those who received a placebo, without subjecting anyone deliberately to extra risks. That may soon change.

What happens, he asks, after the first vaccine hits the market? People may be far less willing to sign up for such trials en masse. And at that point, Human Challenge trials may become more critical to tease out the benefits of different types of Covid-19 vaccines, particularly in light of the more than 40 vaccines are currently in various stages of R&D. Caplan:

"As vaccines get approved for emergency use or licensed many [clinical] trials may collapse as subjects demand unblinding, or refuse to sign up for new studies and seek access to an approved, albeit not great vaccine.

“Challenge studies will enable comparator trials among promising vaccines to help determine which is best... Challenge studies may be the only way forward if large RCTs are not feasible for next in line vaccine candidates. Risks and unknowns are real but if brave volunteers consent the benefit to the world will be enormous."

Nir Eyal, head of the Rutgers Center for Population-level Bioethics and author of a recent paper on the ethics of human challenge trials, is even more emphatic.

He calls the planned British studies “very important”, saying that they can eventually provide more nuanced data, more rapidly, on what vaccines are safer and more effective:

“Even if and when a vaccine like the ones currently being tested is proven safe and efficacious, we would still need to test others. These others may yet prove even more efficacious (e.g. for blocking infections and reaching vaccine-derived herd immunity, and thus helping us end this pandemic), as well as safer, easier to deliver, cheaper, or simply available outside a few countries that are hoarding the global vaccine supply.

“A challenge trial would provide fast, reliable answers, much more than more rounds of slower conventional trials.

“Challenge trials save some time compared to conventional trials when all goes well in the latter, because in challenge trials, there is no need to wait for enough natural infections to accrue. When all does not go well, and specifically when the outbreak moves elsewhere, challenge trials can save a lot of time.”

That, he says, is what we are seeing with Covid-19, which is proving to be a moving target with infection rates rising, declining and hotspots constantly shifting.

And what about the risks to the brave volunteers recruited to this mission? Any benefits, he asserts, will still far outweigh the risks:

  • It is true, he concedes, that a challenge trial carries risks to volunteers, but those risks can be dramatically suppressed simply by selecting volunteers at low risk. But compared to the dramatic humanitarian value of a challenge trial, these risks to volunteers are “ethically acceptable.” Some other common medical practices such as live kidney donation involve commensurate risks.

“If a challenge trial helps shorten the pandemic by a mere one month (and it may shorten it more), it will have averted the loss of at least 720,000 years of life and 40 million years in dire poverty worldwide (an estimate by development economist Pedro Rosa Dias, global health leader Ara Darzi, and myself).”

  • Crucially, just like live kidney donation, challenge trials (and the dose-escalation study that will precede them) must be performed only with the “truly informed consent of the study volunteers, who prove their comprehension of all risks and uncertainties,” he underlines. “Just as the consensual nature of kidney donation helps justify risks to kidney donors, so does the challenge volunteer’s autonomous consent to being put at risk, for the greater cause of ending the pandemic earlier.”

Eyal’s big regret, in fact, is that the US didn’t pursue such studies early on, as was proposed at one stage to the National Institutes of Health.

“Such an early study would have saved even more time and accelerated vaccine development even more than the UK study will do.” He says an ill-informed report to the National Institutes of Health put the US public authorities off of the idea, saying it would take one to two years to set up, “an impression that will be refuted when the Brits conduct a challenge study earlier.”

The World Health Organization’s take. Like many other thorny pandemic issues it has faced, WHO doesn’t exactly endorse challenge trials. But it’s fairly obvious that the organisation sees them as a potentially legitimate mode of research – even in the Covid-19 context – having drawn up two weighty volumes of guidance about the issue.

In a press briefing this week, WHO Spokesperson Margaret Harris said that the organisation’s guidance includes a report by a WHO working group on the key criteria for the ethical acceptability of COVID-19 human challenge studies and another draft document by a WHO Advisory group on the feasibility, potential value and limitations of challenge studies.

In a nutshell, says Harris: 

"There are very important ethical considerations to take into consideration if you are planning to do such a trial. We have developed guidance on this… We have identified eight principles that need to be followed, one of them being that they must be overseen by an ethics committee. They must also have full consent. You will be challenging people with a virus that we don't have a treatment for. Generally, these were done in the past when we had a specific treatment... You must ensure that everybody involved understands what is at stake... and the informed consent is rigorous.”

That’s not an unqualified ‘‘yes’’. But it isn’t a ‘‘no’’ either.