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Blog 6: Testing Covid-19 vaccinesAre we up for the challenge?On May 6th, The World Health Organisation (WHO)1 cautiously endorsed the possibility of deliberately infecting human volunteers with Covid-19 to test the protective potential of new Covid-19 vaccines. For many, the first reaction to the idea of intentional infection of healthy persons with a potentially deadly virus is likely to be one of surprise or even disbelief. But many scientists think that these investigations, often called microbial challenge studies, could be justified and may be critical to facilitating the development of the vaccines on which so much importance is justifiably placed. A careful consideration of all arguments, for and against, is needed. Among the major recommendations in the WHO’s recent publication is the imperative that this form of research should be “……informed by consultation and engagement with the public”. All too often, that good intention is compromised because people are not informed, nor given an opportunity to make their views known. So, this blog offers an opportunity for discussion among my followers.Currently, around 100 Covid-19 vaccine research projects are underway world-wide. Around 10 of these have advanced to the stage where testing in conventional clinical trials is currently underway. I have mentioned the Oxford vaccine project, but it’s only one of several that are leading the charge in what is a massive global effort. To achieve this goal, it’s important to face up to a potential problem: the feasibility of demonstrating vaccine protection using conventional clinical trials. Simply put, in so many of the countries where these trials are being done, the number of infections is declining. Therefore, volunteers enrolled in trials may be increasingly less likely to be exposed to the virus, risking the possibility that there will be an insufficient number of infections in the comparison group to provide clear evidence of protection. This provoked one of the senior investigators of a Covid-19 trial to say: “We’re the only people in the country who want the number of new infections to stay up for another few weeks, so we can test our vaccine.” This concern is why human challenge studies deserve serious consideration. The idea of human challenge studies is not new. In its darkest times, it recalls the despicable and unacceptable experiments associated with the holocaust. But, in the past decades, many responsible and highly beneficial human challenge studies with pathogens that include malaria, typhoid and influenza have been carried out. It is now widely accepted that microbial challenge studies in humans are justified if the risk of harm is minimal and the studies have the potential to confer benefits to many people. These studies might not only accelerate COVID-19 vaccine development, but also make it more likely that the vaccines ultimately deployed are more effective. To carry out human challenge studies, approval by formal, independent ethical committees is mandatory. A key guiding principle for ethical committee approval is that there is a strict limit to the amount of harm inflicted by an investigational study, irrespective of the benefits conferred. In a sense, there is a ‘cap’ on the amount of harm, but defining this limit is often elusive because the required information to make this decision may not be known. This poses difficulties in that another important principle is that participants must be fully informed and able to understand the risks of harm to them as well as to those with whom volunteers may be in contact. Prior studies using selected strains of influenza virus are the closest precedent to the proposed challenge studies with Covid-19. But for either influenza or Covid-19 viruses, there is currently no highly effective treatment. Although the severity of Covid-19 disease in healthy, young volunteers is usually mild, the very rare occurrence of serious even fatal infection is an undeniable possibility. So, are challenge studies with Covid-19 feasible? In healthy volunteers, aged 20-30 years, natural infection with Covid-19 results in less than one fatality in every three thousand persons. As argued by Professor Stanley Plotkin2, an eminent vaccine expert, society endorses kidney donation for transplantation where the immediate risk to life for the donor is comparable. Indeed, individuals in sound mind and health have the right to determine their involvement in a whole range of activities that carry substantial risk (think of F1 drivers and other extreme sports). There may well be tensions between the rights of an individual to participate in what they perceive to be a major contribution to society and an ethical committee’s determination of minimal risk. Yet, at the present time, many may argue that deliberate infection with Covid-19 would exceed the threshold of minimal risk. However, science is advancing at an exceptional pace. Given the huge progress already achieved in just a few months, who can say what we’ll know about the biology of Covid-19 in the very near future? Effective treatments may soon be available; drugs, infusions of protective antibodies or other various forms of immunotherapy. We may soon learn much more about who is at risk of serious disease through genetic studies. All of these could substantially lower the risk of serious outcome in challenged volunteers. It would therefore seem important and sensible to keep the possibility of challenge studies very much on the table. Indeed, the advantages are not just their utility in accelerating progress towards a vaccine. Human challenge studies could also provide vital information on the biology of the virus about which we still have so much to learn. World Health Organisation. Key criteria for the ethical acceptability of COVID-19 human challenge studies 6 May 2020. Plotkin SA, 2020. Extraordinary diseases require extraordinary solutions. Vaccine. 38.3987-88I am grateful to Professors Andrew Pollard and Tony Hope for helpful discussions. Copyright Richard Moxon 19.05.20 ................
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