Researchers in the United Kingdom plan to begin intentionally infecting a small batch of healthy young people with the novel coronavirus in January as part of a first “human challenge trial,” according to an announcement Monday.
The plan has not yet been approved by the Medicines and Healthcare Regulatory Agency (MHRA), which regulates clinical trials in the UK, and outside experts have had mixed reactions to the announcement so far.
Nevertheless, the UK government is planning to invest $43.4 million (33.6 million pounds) in the trials. Researchers meanwhile are preparing to recruit an initial 30 to 50 people, aged 18 to 30, who have no underlying health conditions. Those conditions include diabetes, heart disease, or obesity, all of which would put them at greater risk of the pandemic coronavirus, SARS-CoV-2, and the disease it causes, COVID-19.
The first phase of the trial will try to determine the smallest number of virus particles necessary to spark an infection. Participants will stay in a secure area of London’s Royal Free Hospital for the whole of the trial and will be monitored for weeks before release. If all goes to plan, the researchers will move forward with testing candidate vaccines and therapies in people purposefully exposed to the virus. So far, no specific experimental vaccines are lined up for the trials, though.
While the plans and the regulatory review move forward, experts have expressed both support for the effort and doubts about its usefulness.
Pros
On the one hand, human challenge trials are a firmly established tool in infectious disease and medical research. By deliberately infecting people with a dangerous germ in a controlled trial, researchers can carefully study critical aspects of infection that are difficult if not impossible to examine in real-world cases. For instance, how many virus particles does a person need to get in their nose to trigger an infection? What is the immune system up to after a hefty dose of virus but before a person gets sick—or, perhaps, doesn’t get sick?
Such trials may also offer a faster, safer way to test experimental therapies and vaccines than standard trials. To test a vaccine, for instance, researchers often recruit tens of thousands of people; some will get the experimental vaccine, and some will get a placebo. Then researchers wait for the disease to spread around as it naturally does, while tallying the number of people infected in both the vaccinated and the unvaccinated group. This process can take weeks or months, depending on the state of outbreaks and how quickly the disease is spreading in an area. In the end, if there are significantly fewer infections in the vaccinated group, it might suggest the vaccine is protective. But having a large number of people in each group is critical because researchers don’t know how many people in either group have actually been exposed to the disease. The larger group sizes reduce the chance that an outbreak just happened to expose more people in the unvaccinated group versus the vaccinated group, for instance.
A human challenge trial dodges much of this messiness. A smaller number of people can be recruited, researchers can control who is exposed to the virus and when they’re exposed, and they can then closely monitor all outcomes. And in this streamlined trial, researchers aren’t watching on the sidelines for months as disease naturally moves around a whole population, including to those most vulnerable to suffering severe disease and death.
Let’s do this?
For these reasons, some researchers have been clamoring for months to begin human challenge trials on SARS-CoV-2. In just 10 months, the virus has infected over 40 million people and caused over 1.1 million deaths globally. The need and urgency for an effective vaccine is indisputable.
“It is really vital that we move as fast as possible toward getting effective vaccines and other treatments for COVID-19, and challenge studies have the potential to accelerate and de-risk the development of novel drugs and vaccines,” Peter Openshaw, an immunologist at Imperial College London and lead researcher of the UK challenge trial plan, said in a press statement.
Cons
But other experts were wary of the plans. First and foremost is the issue of safety, which is always the most prominent concern with human challenge trials. For some infections that are mild or infections for which there are established cures, researchers can more easily address safety concerns. But COVID-19 is demonstrably deadly and no cure or “rescue” treatment exists yet. The most effective COVID-19 treatment identified so far is the steroid dexamethasone, but that only lowered the risk of death in clinical trials. It didn’t prevent all deaths.
Even though the human trial will only include young, healthy people—who have less risk of severe disease and death than those who are older or have underlying health conditions—they are not immune to severe cases of COVID-19. Some healthy young people do get severely ill and die from the disease. Researchers don’t yet understand why that is the case. And they cannot guarantee that trial participants will not die after being intentionally exposed to the virus in the trial.
This poses “a serious ethical dilemma,” said University of Leeds virologist Stephen Griffin in a statement. “The MHRA panel will have a difficult task,” of evaluating the trial, he added.
Such a risk could be ethically justified if the trial is likely to lead to effective treatments and vaccines faster than they would be otherwise. But researchers were doubtful on this point. Massive, late-stage clinical trials are already underway for at least 10 vaccines against SARS-CoV-2, and several of those trials are expected to have at least preliminary results before the end of the year. The human challenge trial, meanwhile, is not even expected to get going until January.
Moreover, with the pandemic still raging in large swaths of the planet—particularly the United States—there’s less need for deliberate infections. People in standard vaccine trials are getting naturally infected expeditiously, which throws into question how much faster the human challenge trial would move—even if it wasn’t already behind standard vaccine trials.
“Limited wider relevance”
Some experts note that efforts to maximize safety in human challenge trials end up minimizing their usefulness in assessing vaccines and treatments.
“Any studies involving the novel coronavirus will focus on those most likely to experience a mild infection—young healthy volunteers,” virologist Jonathan Ball, of the University of Nottingham, said in a statement. “Yet the people we need to protect against serious disease are more vulnerable elderly people, so what we learn from challenge studies might have limited wider relevance.”
In other words, a vaccine that protects a healthy young person may not offer the same protection to a more vulnerable one. Even basic data on the minimal dose of virus needed to spark an infection in healthy young people may not be relevant to vulnerable populations.
Other experts worried about fallout if the human challenge trial goes badly. Science policy expert Ohid Yaqub, of the University of Sussex, urged researchers and government officials to do more public engagement before beginning the trial. Even though there is only a remote possibility that a person in the trial could die or become severely ill, it still “threatens trust in research and vaccines more than necessary, because public engagement on this issue has been limited.”
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