Drawing on the recent seminar, this blog post addresses ethical considerations relating to justifications for, and the acceptability of, such research by outlining five key questions and possible responses.
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Infection of research volunteers with SARS-CoV-2, the virus that causes COVID-19, could be one way to accelerate and improve vaccine development, but controversy surrounds recent proposals for COVID-19 human challenge studies.
 
This blog post will summarise five key controversial questions and possible responses:
 
1. How could human challenge studies help?
2. Why not just do a standard vaccine field trial?
3. Are data from young healthy adults relevant to protecting older people and other vulnerable groups?
4. Are the risks too high?
5. What are the remaining uncertainties?
 
 
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1. How could human challenge studies help?
One type of proposal involves replacing a standard vaccine field trial with a human challenge study to provide key evidence that a vaccine protects volunteers. A challenge study would involve small numbers of volunteers, around 50-150, as compared with 5-10,000 in a vaccine field trial, so more data would need to be collected in a separate study of safety in larger numbers of volunteers. If there were enough confidence in the vaccine’s safety and efficacy based on these two studies, regulators might consider authorising use of the vaccine while more data were collected, similar to the monitored emergency use of unregistered interventions (MEURI) policy adopted for Ebola interventions. This proposal could allow manufacturing and distribution of the vaccine to begin much sooner, thus accelerating the public health benefits. However, whether there would be enough confidence in the efficacy of vaccine protection (demonstrated in the challenge study) to justify wider public health use remains controversial, and this would ultimately be a decision for regulators to make once the data are in hand.
 
A second way challenge studies could be used to accelerate vaccine development would be in conjunction with more standard Phase III field trials. Given that several (perhaps many) of the more than 100 SARS-CoV-2 candidate vaccines might ultimately need to be tested in humans, HCS would be by far the most efficient way to prioritise (or ‘select’) the most promising vaccine candidates worthy of further investigation in field trials. This could also accelerate the public health use of a vaccine or vaccines, by avoiding the need to conduct many large field trials in sequence or in parallel.
 
Third, challenges studies could help to increase the likelihood that more effective vaccines are ultimately used in public health – for example if one vaccine is shown to be 50% effective, this might raise complex questions regarding how field trials of other vaccines should be conducted. Challenge studies allow multiple vaccines to be tested in a standardised way – if this results in the identification of a vaccine that is equally safe and even 10% more effective than an alternative candidate, this could have a huge public health benefit if the more effective vaccine were used by billions of people.
 
A fourth way challenge studies could inform vaccine development would be by defining correlates of protection. Correlates of protection are biomarkers of the protection offered by vaccines. Defining well-validated correlates can help scientists develop tests that measure whether a person who has been vaccinated has developed a significant degree of immunity. This can help to simplify further testing of vaccines by testing them against the endpoint of a correlate of protection in ‘immune bridging studies’ rather than against the endpoint of being infected in a field trial or a challenge study.
 
Finally, challenge studies could be used to answer key outstanding questions related to infection, immunity, and transmission. For example, the degree to which people without symptoms pose risks of transmission of infection to others remains unknown. Being able to clarify these aspects of transmission would help to inform public health strategies, and challenge studies might also be useful for testing ‘prophylactic’ treatments – that could be given to contacts of a known case (whether symptomatic or not) to prevent further spread of the infection.
 
2. Why not just do a standard vaccine field trial?
 
Challenge studies might not be necessary for vaccine testing if there were only a few promising vaccines to test and the necessary field studies could be prepared in populations where a large epidemic is expected to occur – so that enough people in the field study become infected to estimate how much protection is offered by the vaccine.
 
However, for a standard field trial to produce results in a short period of time requires that such trials be perfectly timed with an epidemic. First, field trials cannot be done in populations that are in public health ‘lockdown’, because there is not enough disease transmission. Second, field trials also cannot be started too late in an epidemic because too many people in the population will have been infected, creating at least some degree of ‘herd immunity’ which slows transmission. The latter case occurred with Zika virus – by the time field trials for Zika vaccines were ready, the epidemic in Latin America was already over, meaning that human challenge studies are now perhaps the only way of testing a Zika vaccine candidate, besides waiting for another epidemic. Although there is significant transmission of SARS-CoV-2 in many places in the world right now, finding the right location for a field trial – where transmission will be high in future (during the trial) might not be so easy.
 
Moreover, unless one of the first few vaccines is quickly shown to be effective (either in an early field trial or human challenge study, or both), there might be many vaccine candidates to be tested – and conducting field trials with all of them could require over 100,000 research participants and months or years before results are known.
 
3. Are data from young healthy adults relevant to protecting older people and other vulnerable groups?
 
This disease needs a whole population public health strategy. Challenge studies in young adults could inform strategies to protect higher risk groups in several ways. For example, first, by developing vaccines for healthy people to provide indirect protection to the vulnerable via herd immunity from mass vaccination, just like for many other vaccines. Second, challenge studies are a powerful way to study vaccine-associated correlates of protection which, as mentioned above, can be used in ‘immune bridging studies’ and public health practice to verify whether other groups not involved in the trials (because risks to them would be too high), such as the elderly, mount a similar immune response to the vaccine.
 
4. Are the risks too high?
 
COVID-19 human challenge studies would initially involve only young healthy adults. COVID-19 is much more dangerous to older people, and those with significant medical conditions. Current estimates suggest that in younger people aged 20-29 (whether healthy or not), there is a small risk of being hospitalised with infection (0.6-1%), and an even smaller risk of fatal infection (0.007-0.03%) according to data from France and China. The risks in healthy younger people would likely be even lower. These risks are arguably comparable to some other types of research or relevant socially beneficial activities, and could potentially be outweighed by large public health benefits, especially considering that volunteers would provide informed consent. Over 20,000 people have indicated that they would be willing to participate and to accept these risks.
 
Most young healthy people in the community develop mild or asymptomatic infection with SARS-CoV-2 that would not require treatment, and risk minimization strategies including supportive or intensive care if required could reduce risks in rare severe cases. Many people might feel more comfortable if there were a specific or curative treatment for SARS-CoV-2. However, it is unlikely that any treatment developed would reduce risk to zero. For example, specific treatments are available for influenza – but these treatments don’t prevent rare complications like myocarditis (inflammation of the heart muscle) that occur in some young healthy people infected with influenza, including in at least one case in a challenge study. If specific treatments have proven benefit, these would be offered to challenge study participants if required – and, under certain conditions, challenge studies could be used to test certain types of treatment.
 
It would be extremely important to prevent risks of transmission to ‘third parties’, i.e., research staff and members of thewider community. Volunteers would thus be isolated in facilities with strict infection control procedures, including use of protective equipment by research staff. Isolation could last several weeks, during which volunteers would need to be supported – which is a consideration in many challenge studies - including for their mental health. Although volunteers would be free to withdraw from participation in the research, local public health agencies would likely require strict isolation measures – and the WHO Guidance recommends co-ordination between researchers and public health authorities, among other forms of co-ordination.
 
5. What are the remaining uncertainties?
 
Several important uncertainties remain, including but not limited to the following: first, it is not yet clear how much lower the risks of infection are in healthy young adults (as opposed to young adults in general, whether healthy or not), but more data are being collected on a daily basis. Second, it is unclear whether there are any identifiable risk factors in healthy young adults that predict rare cases severe disease – if such risk factors were known then individuals with these factors could be excluded from participation in a challenge study so as to reduce risks still further. Third, it is uncertain whether there are any lasting harms of infection in young healthy adults – as for other challenge studies, it is especially important that studies are designed to minimize such risks. Fourth, whether higher viral doses are associated with higher risks of disease is uncertain – challenge studies would need to start with low doses and any increase in dose would need to be carefully controlled.
 
Finally, there are a number of practical requirements for setting up challenge studies, including preparing an appropriate viral challenge strain and ensuring that all the facilities involved have strict infection control and biosafety practices. This will take some time, during which time standard human trials of vaccines may start to detect evidence of safety and efficacy for particular candidates. COVID-19 vaccine research is a complex set of activities involving multiple groups and types of expertise. The overall goal is to develop safe vaccines that are as effective as possible, so work should begin on the practical requirements for setting up challenge studies – in parallel with other types of research – so that in six or twelve months’ time researchers are in the best possible position to work out which vaccine candidate(s) are most likely to provide the greatest public health benefits.
 
Additional resources in the Epidemic Ethics database
 
Further resources on this topic can be found by searching the database using the keyword "challenge studies". Resources include the WHO Key criteria for the ethical acceptability of COVID-19 human challenge studies and Seema Shah et al.'s article on the ethics of controlled human infection to study COVID-19 .