Unnecessary hesitancy on human vaccine tests—Response

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Science  10 Jul 2020:
Vol. 369, Issue 6500, pp. 151
DOI: 10.1126/science.abc9380

Eyal contends that the expected social value of controlled human infection studies (CHIs) conducted in an effort to find vaccines and treatment for coronavirus disease 2019 (COVID-19) will be high enough to justify the risks to participants. We are concerned that Eyal and others (1) underestimate the uncertainties inherent in making such a determination. CHIs could take too long to be sufficiently valuable or may even hinder vaccine uptake and introduce risks that are not well understood. Because of these uncertainties, our Policy Forum supports laying the groundwork for CHIs but not deploying them to address COVID-19 until there is greater confidence that their value can justify the risks.

Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) CHIs can be integrated into a highly dynamic vaccine development pipeline is an open question. It takes months to develop a challenge strain (2), even under a highly compressed schedule, and additional time to establish an appropriate challenge model. If SARS-CoV-2 transmission continues at a relatively high rate, other vaccine trials might speed ahead and produce efficacy data before CHIs could be launched (3). On the other hand, if field trials are not feasible because of declining transmission, SARS-CoV-2 CHIs could provide crucial efficacy data about candidate vaccines and would have much higher and clearer social value.

Potential implementation challenges also make the social value from SARS-CoV-2 CHIs highly uncertain. For example, if CHIs feed distrust among the public, they could exacerbate challenges in vaccine roll-out (4) and delay uptake of an effective vaccine. Given these uncertainties, it is difficult to determine whether there is a credible case that CHIs are likely to save substantial time in vaccine development. Although there are other possible reasons to conduct SARS-CoV-2 CHIs, as we have argued, such as identifying correlates of immune protection, whether they will have high social value is also currently uncertain.

It is difficult to predict whether risks to participants will be better understood or further reduced by the time CHIs could be implemented. For example, investigators might be able to identify with greater confidence individuals at substantial risk of severe and potentially long-term symptoms and exclude them from participation. If new evidence reveals that SARS-CoV-2 CHIs pose lower risks than those currently estimated, they would require less social value to justify. These major uncertainties as to whether, why, and how to conduct SARS-CoV-2 CHIs should not be disregarded in a rush to judgment.

We also disagree with Eyal's assessment that the overall risk from study participation is already lower than the limits proposed for research with consenting adults. Not enough is known about the risks of serious and chronic complications other than mortality. Given that current estimates of mortality risks—which remain contentious—are in the upper range of what might be acceptable, emerging risks of long-term, serious complications, including kidney damage and strokes (5, 6), could push the risk estimates above acceptable limits. Even trials with low risks of severe outcomes can only be justified by a reasonable chance of sufficient benefit.

We maintain our stance of open-minded, cautious consideration of SARS-CoV-2 CHIs rather than unwavering advocacy. To be clear, continued debate and rapidly evolving evidence should not delay technical development (including challenge agent manufacture), stakeholder coordination efforts, and broader public engagement to determine, for example, whether such studies would be widely acceptable. The balance between social value and individual risk should be formally assessed as soon as feasible and reassessed if and when CHIs are ready to launch.

References and Notes

Competing Interests

The opinions expressed in the article are the authors' and do not reflect the views of organizations with which the authors have affiliations, including the National Institutes of Health, the Department of Health and Human Services, or the United States government. The authors receive support from a Making a Difference Grant from the Greenwall Foundation (S.K.S., A.R., R.P., D.D.), the Wellcome Trust (S.K.S., E.J., D.K., M.K., R.P., M.J.S., V.V.), Brocher Foundation (S.K.S., A.R., R.P., D.D., T.C.D., H.F.L., E.J., N.S.J., D.K., J.K., D.M., S.C.M., T.L.R., M.R., A.S., M.J.S., V.V.), and NIH Clinical Center Department of Bioethics (A.R.).

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