How should the risks of infecting research participants with SARS-CoV-2 be assessed?

By Susan Bull, Euzebiusz Jamrozik, Ariella Binik, Michael Parker

Vaccine development processes typically take ten to twenty years. The exceptional pace of COVID-19 vaccine research has resulted in early human trials being commenced with vaccine candidates. Calls have been made to conduct controlled human infection studies (CHIs), also known as challenge studies, with SARS-CoV-2 to accelerate vaccine development pathways, and enable tests of vaccine efficacy during inter-pandemic periods. Critics have queried the value and ethical acceptability of such CHIs.

CHIs involve intentionally exposing healthy volunteers to pathogens such as SARS-CoV-2 to study mechanisms of infection and immunity and/or the efficacy of experimental vaccines or treatments. While recognising their potential value, considerations of the ethics of SARS-CoV-2 CHIs have highlighted the importance of appropriate risk-benefit profiles, careful site and participant selection, rigorous engagement and consent processes, appropriate compensation, and effective review, oversight and co-ordination. At present there is significant debate about whether SARS-CoV-2 CHIs risks can be considered proportionate, reasonable, appropriately minimised, and consistent with relevant stakeholders’ moral obligations during pandemics.

Research accelerating the development, licensure and delivery of effective vaccines for COVID-19 has the potential to be of exceptional value, prompting consideration of the levels of risk which might be justified in such research. Suggested risks limits for CHIs include a minimal risk threshold, a higher threshold that rules out risks of irreversible, incurable, or possibly fatal infections, and approaches drawing on broader norms restricting research risks in healthy volunteers. During the COVID-19 pandemic calls have additionally been made to conduct research with higher levels of risk than might otherwise be considered reasonable. However higher risk research is particularly controversial in populations or communities already facing undesirably high degrees of risk. While scientific and ethical research standards should remain unchanged during research in public health crises, engagement with local stakeholders and communities is critical to inform evaluations of the reasonableness of risks in specific contexts, and these dialogues might reasonably lead to differing courses of action in different settings.

SARS-CoV-2 CHIs would take place against a rapidly developing clinical and research data landscape, in which accelerated research and publication timelines heighten uncertainties associated with research risks. It has been suggested that the risks associated with exposing participants to SARS CoV-2 infection in CHIs may nonetheless fall within thresholds for reasonable risk in non-pandemic research with healthy volunteers. A contrasting argument is that in the absence of an effective cure for COVID-19, the risks associated with SARS-CoV-2 CHIs cannot be minimised sufficiently to be considered reasonable. However even curative treatments do not entirely preclude the occurrence of serious complications of infection amongst CHIs participants, highlighting the importance of rigorous risk management strategies during any such research.

In SARS-CoV-2 CHIs, inclusion and exclusion criteria, and site selection, are likely to play a key role in risk minimisation, given the strong age-related morality trends suggesting that infection in young adults (under 30 years of age) is associated with a hospitalisation risk of around 0.6-1% and a risk of death of around 0.007-0.03%. In the absence of an effective curative treatment for COVID-19, risk minimisation requires that provision of excellent care, including close monitoring, early diagnosis, and supportive care (including critical care if required).

It has been suggested that COVID-19 CHIs should only enrol participants with an especially high baseline probability of being exposed to SARS-CoV-2, to minimise the additional risks posed by controlled infection during research. However important questions arise about the role that such (potentially very small) risk reductions should play in decision-making, given that they may be outweighed by other ethical considerations. In particular, during pandemics, research addressing public health priorities must not adversely impact response efforts. To effectively minimise research risks, SARS-CoV-2 CHIs require specialist facilities and equipment for infection control, in addition to the expertise of highly experienced researchers, including infectious disease clinicians. In settings with a high incidence of COVID-19, health systems are being catastrophically overburdened, and the diversion of clinical resources towards research may further limit capacity to address community health needs.

Given that access to critical care has been highlighted as a key element of risk minimisation strategies in SARS-CoV-2 CHIs, some commentators have suggested that SARS-CoV-2 CHIs participants should be guaranteed access to such resources, irrespective of their scarcity in pandemic contexts. An alternative suggestion is that priority access to scarce life-saving resources should be only given to participants who have similar prognoses to patients who need them. In high incidence settings where active rationing of scarce life-saving resources has been implemented, both justifications for and effects of any guaranteed or prioritised access for participants in SARS-CoV-2 CHIS should be carefully evaluated. Such evaluations cannot only consider the implications of such access for minimising research participants’ risks, they must also consider the potential impacts on the interests of patients presenting with similar health needs.

To contribute to efforts to rapidly develop effective and safe COVID-19 vaccines, SARS-CoV-2 CHIs will need to be conducted in conjunction with other accelerated vaccine research pathways. Although there is a global need for effective COVID-19 vaccines, there are relatively few specialist sites in which SARS-CoV-2 CHIs could be conducted, and consequently few populations which may be invited to bear the risks of such research. Considerations of the reasonableness of potential risks should be informed by local stakeholder engagement and take account of heightened uncertainties, COVID-19 incidence levels, and where necessary, competing accounts of the nature and magnitude of risks that may be reasonable in the context of the pandemic.

 

Paper title: SARS-CoV-2 challenge studies: Ethics and risk minimisation in a pandemic (under review)

Authors: Susan Bull1, Euzebiusz Jamrozik2,3, Ariella Binik4, Michael Parker1

Affiliations:

1 Wellcome Centre for Ethics and the Humanities and The Ethox Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK

2 Monash Bioethics Centre, Monash University, Melbourne, Australia

3 Royal Melbourne Hospital Department of Medicine, University of Melbourne, Melbourne, Australia

4 Department of Philosophy, McMaster University, Hamilton, Canada

Competing interests: None

Social media accounts (Twitter):

Susan Bull @Susan_Bull_

Euzebiusz Jamrozik @ID_ethics

Ariella Binik @AriellaBinik

Michael Parker @michaelethox

 

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