SCIENCE sciencemag.org 10 JULY 2020 • VOL 369 ISSUE 6500 151
practice, carries a similar mortality risk of
<0.03%. An alternative suggestion cited
by Shah et al. would limit risk to below a
1% death rate ( 3 ), but that threshold is far
higher than their own estimate of 0.03%.
Further mitigating the overall risk, CHI
participation could reduce participants’
relative risk—i.e., their risk in the trial
minus their risk if they decline to partici-
pate ( 4 , 5 )—and improve their treatment
access ( 4 ). Shah et al. agree that recruiting
in “locations with high community spread
of SARS-CoV-2 could be an acceptable way
to reduce relative risks for participants”
( 6 ). CHIs should also guarantee partici-
pants critical care [which most young
COVID-19 patients survive (7–9)] and any
novel therapeutics. Those may be scarce
in some locations with high community
spread ( 6 ), even absent economic or racial
injustices that might create ethical com-
plications ( 5 ). These factors push overall
risk further below limits.
Shah et al. question the social value
of CHIs because of the necessary “coor-
dination of stakeholders,” but no trial
guarantees coordinated delivery. Even a
fairly moderate chance at substantially
curbing colossal ( 10 , 11 ) mortality through
an accelerated vaccine rollout would imbue
CHIs with high expected social value.
Nir Eyal
Center for Population-Level Bioethics and
Department of Philosophy, Rutgers University,
New Brunswick, NJ 08901, USA, and Department
of Health Behavior, Society and Policy, Rutgers
School of Public Health, Piscataway, NJ 08854,
USA. Email: [email protected]
REFERENCES AND NOTES
- R. Verity et al., Lancet Infect. Dis. 20 , 669 (2020).
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- N. Eyal, Ethics Hum. Res. 10.1002/eahr.500056 (2020).
- N. Eyal, M. Lipsitch, P. G. Smith, J. Infect. Dis. 221 ,
1752 (2020). - Intensive Care National Audit & Research Centre
(ICNARC), “ICNARC report on COVID-19 in critical care
08 May 2020” (ICNARC, London, UK, 2020). - G. Grasselli et al., JAMA 323 , 1574 (2020).
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and strategies for mitigation and suppression,” (WHO
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COMPETING INTERESTS
N.E. is funded by National Institute of Allergy and Infectious
Diseases grant R01 AI114617-01A1.
10.1126/science.abc8264
Response
Eyal contends that the expected social
value of controlled human infection stud-
ies (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 valu-
able or may even hinder vaccine uptake
and introduce risks that are not well
understood. Because of these uncertain-
ties, 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 syn-
drome 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 chal-
lenge 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 chal-
lenges also make the social value from
SARS-CoV-2 CHIs highly uncertain. For
example, if CHIs feed distrust among
the public, they could exacerbate chal-
lenges 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 protec-
tion, 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, investiga-
tors might be able to identify with greater
confidence individuals at substantial risk
of severe and potentially long-term symp-
toms 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 disre-
garded in a rush to judgment.We also disagree with Eyal’s assessment
that the overall risk from study partici-
pation is already lower than the limits
proposed for research with consenting
adults. Not enough is known about the
risks of serious and chronic complica-
tions 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 com-
plications, including kidney damage and
strokes ( 5 , 6 ), could push the risk esti-
mates above acceptable limits. Even trials
with low risks of severe outcomes can only
be justified by a reasonable chance of suf-
ficient 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 evolv-
ing 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 indi-
vidual risk should be formally assessed as
soon as feasible and reassessed if and when
CHIs are ready to launch.
Seema K. Shah*, Franklin G. Miller, Thomas C.
Darton, Devan Duenas, Claudia Emerson, Holly
Fernandez Lynch, Euzebiusz Jamrozik, Nancy S.
Jecker, Dorcas Kamuya, Melissa Kapulu, Jonathan
Kimmelman, Douglas MacKay, Matthew J. Memoli,
Sean C. Murphy, Ricardo Palacios, Thomas L. Richie,
Meta Roestenberg, Abha Saxena, Katherine Saylor,
Michael J. Selgelid, Vina Vaswani, Annette Rid
*Corresponding author. Email: seema.shah@
northwestern.edu
The list of author affiliations is available at
http://www.sciencemag.org/cgi/content/full/science.
abc1076/DC1.REFERENCES AND NOTES- S. A. Plotkin, A. Caplan, Va c c i n e 38 , 3987 (2020).
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when a coronavirus vaccine finally arrives: Sobering
lessons from the history of the polio vaccine,” The New
York Times (2020). - A. A. Divani et al., J. Stroke Cerebrovasc. Dis. Aug. 29,
104941 (2020). - A. B. Docherty et al., BMJ 369 , m1985 (2020).
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.).10.1126/science.abc9380