Two years ago, the possibility of deliberately infecting fully informed volunteers with COVID-19 to aid in vaccine research and development was controversial. Us and much others argued that the risks were justifiable, and the reservations of some bioethicists did not deter almost 40,000 people from more than 160 countries to express interest in volunteering for this research, called human challenge trials. However, in the end, while they have been widely done in the UK, there were no such studies in the US.
We have made great strides against the COVID-19 disease in the form of vaccines and treatments, but there are still thousands of deaths in the United States every week. Even as COVID-19 moves toward endemicity, it remains”pretty brutal” in the words of journalist David Wallace-Wells, and it can still be especially serious in the unvaccinated.
Thus, many experts agree: we need new vaccines to limit the spread of the virus. The current generation of vaccines offer strong protection against serious illness and death, but their advantage has been weakened against new variants and they do not always prevent infection and transmission of the virus.
The White House hosted a summit on the subject in July, showcasing the myriad ways researchers are developing new vaccines. exist hundreds of candidates in early stages around the world, but resources devoted to COVID-19 vaccine research are a fraction of what they were 2 years ago. Human challenge trials can greatly accelerate the selection of the most promising candidates in this field, providing scientific and economic benefits over uniform reliance on large field studies.
Ideally, the next generation of COVID-19 vaccines will substantially reduce transmission of the virus and protect against variants of concern. Research in pursuit of these targets is critical for an eventual vaccine that protects against all sarbecoviruses, the subgroup that includes SARS-CoV-2 and the original SARS virus, and perhaps also future coronaviruses.
Vaccines administered intranasally it will likely be key to reducing the transmission of COVID-19. They could induce an immune response at the site of infection, the mucosa of the upper respiratory tract. This would prevent the virus from taking hold in the body and reduce its spread to others, especially in the asymptomatic phase.
The use of human challenge tests offers the most promise for testing intranasal vaccines for their ability to reduce infection and transmission. In the case of a live attenuated vaccine, something as simple as a regular nasal swab can reveal how much live virus is present in the nose over time, and how much would spread when a patient sneezes, for example.
By contrast, a field study can only reveal whether or not participants eventually contract COVID-19. But without measuring participants’ viral load, little information could be discerned about how well a vaccine reduces infectiousness. In theory, this could be done in a field test through regular and massive testing of all participants, but that would be extremely difficult and expensive to carry out. Not surprisingly, then, that as early as 2020, intranasal vaccine developers have expressed interest in human challenge trials for COVID-19.
Obviously, there are risks to COVID-19 challenge studies, and it was for these reasons that initial proposals for such research faced opposition. However, the risk of death is now lower than it was at the beginning of the pandemic given the better immune protection gained from both vaccination and natural exposure, and various treatment options further reduce the risk.
Of course, the long duration of COVID is still important, but this risk can also be controlled by selecting trial participants with a lower risk of severe disease, as more severe disease from COVID-19 is more severe. correlated with persistent post-COVID symptoms. Ultimately, if COVID-19 becomes endemic, the long duration of COVID may well be a threat to everyone, whether or not they enroll in a challenge trial; All the more reason we must act quickly to develop vaccines that stop transmission.
We believe that volunteers are perfectly capable of rationally considering these risks. Those who decide to make a potential sacrifice for the good of humanity should be commended, not dismissed as naive. (Notably, A study of the nearly 40,000 potential volunteers organized by 1Day Sooner showed that their tolerance for risk was the same as that of a control group, and they were motivated primarily by altruistic motivations).
Challenge trials will also be critical in the development of a pan-coronavirus vaccine, covering all members of the viral family that cause disease in humans. An easy first step in that process would be human challenge trials with the common cold coronaviruses, four species that have long circulated in the population, causing mild illness. David Morens, MD, Jeffery Taubenberger, MD, PhD, and Anthony Fauci, MD, argued in January in the New England Journal of Medicine that challenge studies with these species would likely be important in guiding the development of a coronavirus vaccine. This relatively close at hand fruit should appeal even to those still hesitant about COVID-19 challenge trials on young, healthy volunteers.
Beyond aiding in vaccine development, COVID-19 and other coronavirus challenge trials may also provide unique insights into immunity. We know that immunity against COVID-19 declines over time, but quantifying this decline after vaccination and after infection is difficult outside the context of a challenge trial.
Challenge tests can also further our understanding of correlates of protection. Antibodies correlate with protection against infection, for example, but we need more information on cellular immunity mechanisms such as T cells, which may be the best correlates for predicting disease severity if infection occurs. Once these correlates are definitively known, they could be used to confirm the immune response to a new vaccine before any field trials, speeding up research and potentially leading to regulatory approval after safety is proven.
The White House summit on next-generation vaccines was a good start, but a clear administration endorsement for COVID-19 challenge trials, like those already completed safely in Britain, would help speed things up even further. plus these efforts.
Dr Stanley Plotkin, He is a professor emeritus of pediatrics at the University of Pennsylvania, a veteran vaccinologist, and a board member of 1Day Sooner, an organization that advocates for challenge trial volunteers. Josh Morrison, JD, is co-founder and president of 1Day Sooner, and founder of Waitlist Zero and the Rikers Debate Project.
Plotkin has consulted on COVID-19 for Merck, Sanofi, Moderna, Novavax, NTx, Valneva, Vaxart, VBI, Meissa, Rational, and Bionet. He is a board member of 1Day Sooner, an organization that advocates for challenge test volunteers.