key: cord-0981600-84n6nvfz authors: Kirchhelle, Claas; Vanderslott, Samantha title: Editorial: The Need for Harmonised International Guidelines ahead of COVID-19 Human Infection Studies date: 2021-01-29 journal: Public Health Rev DOI: 10.3389/phrs.2021.1603962 sha: 25db25d184be2227a278f165c772ca4f49b021bd doc_id: 981600 cord_uid: 84n6nvfz nan vaccines, it is, however, unclear how much additional scientific value these studies-which will be limited to healthy young volunteers aged between 18 and 30-will generate over largescale ongoing phase III vaccine trials and post-rollout phase IV studies with tens of thousands of volunteers from all age groups across the world. Ethically, COVID-19 infection studies are at the edge of what may be acceptable for CHIMs. Challenge studies require knowledge of the appropriate infectious dosage with which to test a vaccine and usually require a 'rescue remedy' if participants fall ill. The British CHIM proposal will gradually increase viral exposure to assess the minimum dose needed for an infection. However, there is still no known cure for SARS-CoV-2. The rescue-therapy Remdesivir has been found ineffective by the WHO's 'Solidarity Trial' published in October (www.who.int/ emergencies/diseases/novel-coronavirus-2019/global-researchon-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments). Historically, CHIMs were never employed for incurable diseases like rabies or Ebola [6] . In the case of the far less deadly Zika virus, US funders only recently decided that it was premature [6] to conduct CHIM-based vaccine studies. Some commentators argue that the current pandemic context justifies a revaluation of existing ethical limitations for COVID-19 CHIMs because of the comparatively low mortality risk for young adults. However, they remain vague on the cut-off point at which mortality risks become unacceptable-thus opening the door to a potentially dangerous weakening of existing ethical frameworks for CHIMs. Proponents have so far also failed to sufficiently address emerging research on 'Long-COVID', which indicates that the virus can cause long-term health damage in a significant group of survivors-including formerly young, healthy adults [7] . Deciding how to select participants will be of critical importance for the global acceptability of any future COVID-19 CHIM-regardless of where it takes place. The long and troubled history of medical experimentation on vulnerable populations calls for caution. In the 19th and 20th centuries, imperial powers trialled new vaccines and treatments on colonial subjects. Prisoners and racially and economically marginalized groups were also used as human guinea pigs. During the 1940s, US researchers infected four hundred prisoners with malaria to test potential treatments. In Nazi Germany, doctors conducted infection studies on concentration camp inmates [8] . Even after the 1947 Nuremberg Code established the principles of informed consent, voluntary participation, and freedom to leave a study, CHIMs in US prisons continued until 1976 [8] . Ensuring that COVID-19 CHIM participants fully understand both the mortality and morbidity risks resulting from a deliberate exposure to SARS-CoV-2 will be a major challenge. Whether and how to reward participants is an equally difficult question. A recent survey at Oxford's Typhoidland exhibition (www.typhoidland.org) indicated that visitors favoured higher payments for CHIMS involving high-risk diseases. However, there are concerns about unduly influencing volunteers with high financial rewards and whether payments should be allowed to vary between identical CHIMs in high and lowincome contexts. Despite their chequered past and these important ethical questions, there is no harmonised international regulatory framework for CHIMs. In Britain, challenge agents are not considered drugs and studies do not require regulatory approval in addition to local ethics approvals if they do not include an investigational medicinal product. In the US, trials are subject to more stringent oversight by the Food and Drug Administration (FDA). In India, concerns about the 'offshoring' of clinical trials to poorer countries has led to clinical trials restrictions but legalising strictly controlled CHIMs is now [8] . The COVID-19 crisis offers an opportunity for the global community to rethink the patchwork approach to CHIMs. Properly designed CHIMs are an incredibly useful tool to aid medical research. The sheer scale of the current crisis justifies serious considerations of whether compromising the health of a small number of courageous volunteers is an acceptable trade-off for vaccines that will aid billions. Websites are asking for volunteers, and one group, '1Day Sooner' (www.1daysooner.org) claims to already have found nearly 40,000 volunteers to take part in a CHIM against SARS-CoV-2. However, in addition to the personal risks for volunteers, there is a danger that rushed, badly designed, or exploitative CHIMs can undermine wider trust in medical research. Past experiences like the 2019 CRISPR-baby scandal [9] show that weak standards in one place can bring disrepute on an entire community. Perceptions of divergent standards and rushed research can also undermine confidence in COVID-19 vaccines. While it is important to be wary of long-standing Western biases against research conducted by non-Western entities, allegations of a lack of transparency and insufficient or patchy trial data have marred the in-country launch of Russia's 'Sputnik V' vaccine and the reputation of China's vaccines (www.reuters.com/article/healthcoronavirus-vaccines-attitudes/exclusive-international-covid-19vaccine-poll-shows-higher-mistrust-of-russia-china-shots-idUSL 8N2JQ17C). Avoiding similar problems regarding CHIMs for COVID and other diseases is crucial. With the geographic locations of biomedical research becoming more diverse, the likelihood of pandemic events increasing, and the number of CHIMs rising since the 1990s, developing a common international framework for human challenge studies is highly desirable. Although local needs and constraints will vary, the WHO's eight criteria [1] for SARS-CoV-2 challenge studies, which include scientific justification and ethical assessment based on risks and potential benefits, are an important first step in what will hopefully become a wider push for harmonised global CHIM guidance. Trial participants, developers, and vaccine and therapy recipients in low-, medium-, and high-income contexts have much to gain from a more transparent global CHIM framework. Key criteria for the ethical acceptability of COVID-19 human challenge studies Jenner and the history of smallpox and vaccination Straight back to barbarism": antityphoid inoculation and the Great War The human viral challenge model: accelerating the evaluation of respiratory antivirals, vaccines and novel diagnostics The utility of human challenge studies in vaccine development: lessons learned from cholera When could human challenge trials be deployed to combat emerging infectious diseases? Lessons from the case of a Zika virus human challenge trial Covid-19 vaccines: Should we allow human challenge studies to infect healthy volunteers with SARS-CoV-2? human challenge studies in endemic settings The CRISPR-baby scandal: what's next for human gene-editing As concerns surge after a bombshell revelation, here are four questions about this fast-moving field CK and SV conceived the idea for the paper, wrote and approved the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We would like to thank Prof. Andrew Pollard for commenting on the draft.