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Abstract

To reduce the global burden of the COVID-19 pandemic, there is an urgent need to develop a safe vaccine. Vaccine development usually takes many years as it goes through several different phases. To hasten COVID-19 vaccine development, it has been suggested that the final stage could be replaced with a human challenge trial (HCT). Volunteers would be intentionally infected with SARS-CoV-2 to see how the vaccine candidate works. To intentionally infect a healthy human being with a potentially deadly virus is contrary to the highest ethical standards in medical research. This article highlights the benefits and risks of COVID-19 HCTs and summarises what research ethics committees (RECs) need to consider during the ethical assessment of such trials including risk reduction, strict containment measures, specific informed consent measures and avoiding high monetary inducements.

Keywords

COVID-19 human challenge trial vaccine development ethical review research ethics committees ethical standards

Introduction

The COVID-19 pandemic is a major challenge for billions of people and countries worldwide. Impacts upon health, the economy, society and everyday life are extreme. The hope of returning to normalcy rests largely upon discovery of a safe vaccine and/or effective treatments for severe cases of COVID-19. Although more than 120 vaccine candidates are in development (BBC, 2020), it could still take a long time until a safe vaccine is discovered and made available. For the testing the effectiveness of a trial vaccine, vaccinated participants must come into contact with the disease and usually, this is dependent upon a large number of research participants having contact with persons who are infected. However, the statistical chances of being infected with the SARS-CoV-2 virus are currently very low. Even in countries with high infection rates, only a small fraction of the population carries the virus and it is likely that most of those infected are in quarantine, wearing masks or practising social distancing. This poses a scientific dilemma. Human challenge trials (HCTs) have been posited as a potential solution to this dilemma.

Human challenge studies involve the intentional infection of research participants and can accelerate or improve vaccine development by rapidly providing estimates of vaccine safety and efficacy. Human challenge studies of low virulence coronaviruses have been done in the past and human challenge studies with severe acute respiratory syndrome coronavirus 2 have been proposed (Jamrozik and Selgelid, 2020: 1).

The authors of 1Day Sooner a worldwide initiative, set up to find volunteers for COVID-19 HCTs provide a brief timeline of challenge trials that were instrumental in the development of vaccines for deadly infectious diseases, for instance smallpox, cholera and malaria (1Day Sooner, 2020). However, the history and record of HCTs is not outstanding. Metzger et al. (2019) outline historical aspects of HCTs. They explain how knowledge about infectious diseases has been gained through experiments in humans going back to the 18th and 19th centuries. Numerous fully unacceptable and unethical studies have been conducted in this endeavour. In addition to the experiments of the Nazi concentration camps, others include a study (1950–1965), in ‘Willowbrook’ a school for mentally disabled children in the United States, where children were injected with hepatitis virus to test passive vaccination. Parents were not truthfully informed about the risks of the investigations, and children were involved with the prospect of harm rather than benefit (Metzger et al., 2019: 1386). Furthermore, there is scant reliable information available on vaccine HCTs, leading to successfully and extensively applied vaccines. Taking this into account, the risks and benefits of COVID-19 HCTs need to be reviewed very carefully.

Human challenge trials and their benefits in combatting COVID-19

During an HCT, a group of volunteers are intentionally infected with a contagious agent to determine whether a vaccine candidate is effective or not. For the novel coronavirus, two groups would be intentionally infected with the virus. First, those who received the candidate vaccine, and second, those who are in the placebo-controlled arm of the study. In cases where no vaccine is currently available for a disease, a placebo-controlled study is considered the only way to obtain reliable answers on the effectiveness of the candidate vaccine (Rid et al., 2014: 4709). This approach has two advantages over the method of waiting for a random infection (Eyal et al., 2020; Jamrozik and Selgelid, 2020; Shah et al., 2020):

(1) Researchers can determine whether a vaccine candidate is effective or not more quickly, and

(2) a smaller group of participants is needed.

According to 1Day Sooner (2020), one day of speedier vaccine development would save 7,120 lives. If they are correct, speeding up vaccine development by three months would save over half a million lives.

The calculations of 1Day Sooner are based on two assumptions, which cannot be taken for granted. First, the successful vaccine can be manufactured in large enough numbers to satisfy demand. Second, people are willing to take the vaccine, which depends largely on the question of how safe it appears and how communication with the public is handled. We shall leave these two issues aside for the purpose of this paper.

Human challenge trials for COVID-19 – an overview of the ethical issues

From an ethical perspective, infecting healthy individuals with a potentially fatal disease for which there is no treatment is not justifiable. COVID-19 has led to a large number of deaths worldwide, including unexplained deaths that cannot be attributed to existing health conditions.¹ It is estimated by the UK National Health Service that of those who needed hospitalisation for COVID-19, 45% will require additional, potentially long-term care after discharge from hospital; 4% will require rehabilitation and 1% will require permanent nursing home care (NHS, 2020: 27). Hence, HCT involvement could be very dangerous for research participants; they could die or suffer permanent damage to lungs, brain or other organs.

This worst-case scenario of permanent damage or death cannot be ignored. However, COVID-19 infections can also occur with very mild or even without symptoms. Eyal et al. (2020) state that it may seem impermissible to allow people to take the risk of severe, possibly long-term illness or even death, but they note that such risk-taking is permissible in other life situations. For instance, we do not stop firefighters from running into burning buildings and relatives are permitted to donate organs, which could result in their death (Eyal et al., 2020). More importantly, according to Eyal et al. (2020), volunteers can autonomously give their informed consent to take these risks. This aligns with the view of Chappell and Singer (2020: 2), who write:

If it is permissible to expose some members of society (e.g. health workers or the economically vulnerable) to a certain level of ex ante risk in order to minimize overall harm from the virus, then it is permissible to expose fully informed volunteers to a comparable level of risk in the context of promising research into the virus.

The question remains, however, of just how informed consent can be in a COVID-19 HCT given that knowledge about the novel virus is scarce and constantly changing. In particular, the long-term effects remain unclear. Therefore, volunteers cannot know the full extent of what they are consenting to. The risks of an intentional infection are unpredictable and risk assessment is challenging. Those arguing that consent is sufficient for exposing volunteers to a potentially deadly virus would need to explain precisely how this informed consent will be obtained.

Furthermore, risks are not limited to research volunteers. If research participants are infected with the highly virulent SARS-CoV-2, they pose a risk to externals, i.e. those they are in contact with their relatives as well as health care staff and researchers. However, this is not unique to HCTs; it also applies to other studies with serious pathogens.

What research ethics committees need to consider when assessing COVID-19 HCTs

HCTs have been suggested for COVID-19 vaccine development (e.g. Chappell and Singer, 2020; Eyal et al., 2020), which means that research ethics committees (RECs) might have to review this kind of research in the near future.

Globally recognised standards and operational guidelines beyond legal requirements for ethical reviews are formulated for example in the Declaration of Helsinki (WMA Declaration of Helsinki, 2013), the Good Clinical Practice Guideline (ICH Topic E 8, 1998) and in the CIOMS guidelines (Council for International Organizations of Medical Sciences (CIOMS), 2016). With these and other documents, such as institutional or national standards, RECs would have to decide whether research proposals for COVID-19 HCTs should be rejected, or whether special requirements can be formulated under which they can be conducted in an ethically sound way.

On the one hand, the accelerated development of a safe vaccine could lead to benefits like significantly fewer COVID-19 deaths, and significantly lower social and economic burdens globally. On the other hand, the risks to research participants are uncertain with a possibility of being extremely grievous, plus additional risks might be encountered by third parties (e.g. relatives of research participants, health care workers or researchers). This divergence between very high potential benefits for society and very high potential risks to research participants/third parties makes the ethical review of COVID-19 HCTs extremely challenging. Three essential points must be addressed:

Minimising risks

Appropriate informed consent

Avoiding high monetary inducements

Minimising risks

Three groups have to be considered when minimising risks. First, the research participants who receive an active vaccine candidate, second, the research participants who receive a placebo and third, all third parties who are in direct contact with the first two groups.

The three main physiological risks for the vaccine group are side-effects of a candidate vaccine, infection with COVID-19 and vaccine-enhanced COVID-19.² The placebo group will not suffer from side-effects or vaccine-enhanced COVID-19, since they will not receive the vaccine candidate. However, they will be infected with SARS-CoV-2 and therefore, the chances are high that they will develop some form of COVID-19. What this infection means for each research participant remains unclear with possibilities ranging from no symptoms at all to death. Finally, there is a third group that is at risk of contracting COVID-19 from direct contact with research participants.

To reduce risks to third parties associated with the research participants, RECs can consider restricting studies to inpatient settings for the time during which virus transmission can occur (Jamrozik and Selgelid, 2020). In this case, it would be important to ensure that early withdrawal from a study and leaving the inpatient unit does not create risks for third parties. In addition, RECs must insist on full protective equipment for health care workers and researchers.

To minimise risks for both groups of research participants, there are at least three strategies that RECs need to be aware of:

1) Inclusion and exclusion criteria must be stipulated such that only participants who belong to a low-risk group can be included.

2) Measures could be taken to infect volunteers with an attenuated³ challenge strain or a low viral load, which might reduce overall risks.

3) Early diagnosis and access to immediate high-quality medical care could reduce risks further.

In addition, compensation for harm incurred during a study must be available for all research participants.

Include only participants that belong to a low-risk group

Experiences during the pandemic and early research studies have shown that older people, and people of all ages with pre-existing medical conditions (such as diabetes, high blood pressure, heart disease, obesity, lung disease or cancer) appear to develop serious symptoms more often than others (World Health Organization (WHO), 2020a). It has also been shown that the vast majority of young persons, without previous illnesses, who are infected with COVID-19, develop no or only weak symptoms of the disease (Bialek et al., 2020). Early estimates of infection fatality risk in 20- to 29-year-olds set it at 0.007–0.031% (Jamrozik and Selgelid, 2020). Hence, young people, without health issues or background conditions, seem best suited to be involved in HCTs. However, given that research into COVID-19 is still in its infancy, many features of the disease are not fully understood, and it is currently not possible to define a low-risk group with certainty. Unexplained cases of young, healthy people dying from COVID-19, while rare, have been reported (Proto, 2020). At the time of writing this paper, there is insufficient evidence to draw firm conclusions about why some groups are symptom-free and others are not. Research findings from studies of low-risk groups must be monitored to ensure that discovered risk factors for seemingly young and healthy people are immediately accounted for with regard to exclusion and inclusion criteria. Importantly, potential volunteers must undergo thorough health checks before inclusion in an HCT.

At the same time, this approach has inherent weaknesses. Even if a vaccine is shown to effective in one age group, it cannot be guaranteed that this vaccine will be effective in all other age groups (Bialek et al., 2020). Hence, a stepped approach would be needed to test the vaccine candidate, which proved effective in young volunteers, in other age groups.

Consider lower risk trials

There are two main ways of lowering risks in HCTs that can be built into the design. First, attenuated, weakened strains of SARS-CoV-2 could be developed and used in the HCT. Second, HCT volunteers could be infected with low viral loads. Developing attenuated challenge strains is highly time-intensive (Jamrozik and Selgelid, 2020) and could invalidate the reason for running HCTs in the first place. Hence, they are not given further consideration here. Alternatively, volunteers could be exposed to such a small dose of the virus that they are unlikely to get ill or only develop mild symptoms (as has been demonstrated in an influenza HCT by Sherman (2019). The WHO recommends that initial challenges should be ‘conducted one by one, with careful titration of viral dose’ (World Health Organization (WHO), 2020b: 8). To help minimise risks, close monitoring of the viral load and related symptoms in the very first participants is required. Subsequent participants can only proceed when there is sufficient confidence that the infection in the previous participants will gradually subside without unexpected or unacceptable adverse events. Only when more is known about the pathophysiology of viral infection might it be appropriate to proceed more expediently (World Health Organization (WHO), 2020b). However, there are two problems with this approach: First, it remains scientifically unproven that a small SARS-CoV-2 viral load will cause only mild COVID-19 symptoms (Caddy, 2020; Jones et al., 2020; Yu et al., 2020). Second, a high viral load might be necessary to find out whether a vaccine candidate is fully effective. Hence, whilst this approach will reduce risks to research participants, it might also reduce the possibility of accelerating effective vaccine design, the main reason for considering HCTs in the first place.

Access to early diagnosis and immediate high-quality medical care

Drugs for the treatment of COVID-19 are being tested in clinical studies worldwide. The anti-inflammatory drug Dexamethasone, the virus inhibitor Remdesivir and the cancer drug Ruxolitinib appear to be promising (European Medicines Agency (EMA), 2020; Horby et al., 2020; Neubauer et al., 2020; Vfa. Die forschenden Pharma-Unternehmen, 2020). They have shown, in individual cases, that the treatment phase could be shortened, but there is currently still no cure in sight that can preclude severe and/or fatal consequences for all. Nevertheless, immediate access to diagnosis and high-quality medical care for all involved in the HCT is likely to contribute to risk reduction. This being the case, HCT studies should be undertaken predominantly in high-income countries and not in resource-poor settings, where facilities are urgently needed for clinical care.

Appropriate informed consent

To date, more than 30,000 people have registered as volunteers for COVID-19 HCTs on 1Day Sooner. However, it is unlikely that all understand fully what they volunteered for. HCT volunteers should receive a very detailed description of risks that is fully up-to-date with current scientific knowledge. At present, this would include these four essential points:

1) The long-term effects of a COVID-19 infection remain unclear.

2) COVID-19 infection can be fatal.

3) Research participants need to fully disclose their medical history to determine their risk exposure.

4) Research participants may not be able to withdraw immediately from a study that is set in an inpatient setting.

Methods to evidence that potential research participants fully understand these four points need to be developed by the researchers and reviewed by the RECs.

Avoiding high monetary inducements

Setting COVID-19 HCTs in high-income settings with high-quality inpatient medical care facilities reduces the concern of undue inducement. However, it is essential that payments for time spent in the inpatient facility (if chosen) do not exceed coverage for time lost (Gelinas et al., 2018; Grady, 2019; Resnik, 2015). Given the uncertainty of risks, monetary incentives must be excluded. Otherwise, vulnerable people will put themselves at risk for money.

Public engagement

In their ethical assessment of COVID-19 HCTs, Jamrozik and Selgelid (2020) attribute high priority to public opinion and commitment of the community in which such studies are to be conducted. This is to promote transparency but also public acceptability. However, such an approach should be handled very carefully from the perspective of ethics committees. As much as RECs are seen as intermediary bodies between science and society, for HCTs, they must focus on the protection of the healthy volunteers. Against the backdrop of a pandemic crisis, public pressure is not always the best guide for well-considered ethical decisions. Public majority opinion is important for societal discourse but cannot suffice as justification for favourable opinion of an HCT by a REC.

Conclusion

In theory, COVID-19 HCTs could accelerate vaccine development when compared with standard vaccine field trials. Furthermore, highly effective, traditional public health measures (e.g. social distancing, masks, quarantine) pose a challenge for standard vaccine field trials as the numbers of participants needed would be unfeasibly high. COVID-19 is a pandemic with gigantic health, social and economic costs and delivering a vaccine earlier could yield significant societal benefit. However, this cannot be done at any cost. The quest for a vaccine must comply with established standards in research ethics, in particular, the principle of do no harm.

It is often a challenge for RECs to decide whether the benefits of a medical trial can justify the risks and whether the risks to research participants are acceptable. However, even in the context of the most challenging REC work, the prospect of COVID-19 HCTs stands out. Healthy volunteers are to be intentionally infected with a potentially lethal agent for which no known treatment is available, also posing potential risks to third parties.

The Council of Europe advises that a REC must be convinced that the participation of healthy volunteers in a research project does not lead to unacceptable risks and burdens for the participants (Council of Europe, 2012: 6.C.4; Council for International Organizations of Medical Sciences (CIOMS), 2016: 10). Given the gaps in scientific understanding of COVID-19, at the time of writing this paper there is no assured way of reducing the risks for participants appropriately. Consequently, COVID-19 HCTs cannot currently be conducted in an ethically sound manner. However, this might change in the light of new research and new risk minimising options. The considerations of RECs should be guided by three aspects: the possibility of reducing risks through very specific inclusion/exclusion criteria; the consideration of alternative study designs; and ensuring that the study is located in and environment where there is immediate access to high-quality health care, preferably in a high-income setting, where it does not constitute a drain on medical resources.

Footnotes

Acknowledgements

Thanks to Prof. Doris Schroeder and Dr Kate Chatfield for editorial input and reviewer comments. Also, thanks to the members of the European Network of Research Ethics Committees for sharing their views on HCTs; in particular, to Prof. Dr. Joerg Hasford.

Funding

All articles in Research Ethics are published as open access. There are no submission charges and no Article Processing Charges as these are fully funded by institutions through Knowledge Unlatched, resulting in no direct charge to authors. For more information about Knowledge Unlatched please see here:

ORCID iD

Dirk Lanzerath

Notes

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COVID-19 human challenge trials – what research ethics committees need to consider

Abstract

Keywords

Introduction

Human challenge trials and their benefits in combatting COVID-19

Human challenge trials for COVID-19 – an overview of the ethical issues

What research ethics committees need to consider when assessing COVID-19 HCTs

Minimising risks

Include only participants that belong to a low-risk group

Consider lower risk trials

Access to early diagnosis and immediate high-quality medical care

Appropriate informed consent

Avoiding high monetary inducements

Public engagement

Conclusion

Footnotes

Acknowledgements

Funding

ORCID iD

Notes

References