Do controlled human infection studies put bystanders at higher risk than conventional field trials?

By Kyungdo Lee and Nir Eyal.

A dose-determining study toward the world’s first controlled human infection (abbreviated as CHI) COVID vaccine study has launched in the UK. A COVID vaccine CHI would typically enroll a few dozen young and healthy volunteers, excluding people at higher risk of severe outcomes. After admission to an isolated research facility, they would be randomized to an experimental vaccine under a certain dosing regimen vs. control (another vaccine, another dosing regimen, or a placebo). Sometime later, all would be exposed to live SARS-CoV-2, the virus behind COVID. This research design would enable researchers to gather valuable information about important questions that remain open, for example, about authorized and new vaccines’ effects on blocking infection and infectiousness against familiar or vaccine-resistant strains, the correlates and duration of vaccine protection, and more. That could be done more efficiently, and hence typically more accurately and reliably, in CHIs than in conventional field trials.

It is no surprise that CHIs for a disease that kills so many (although exclusion criteria would keep risks far lower than many imagine) have encountered ethical objections. One of us has answered many of those, but objections keep piling up.

One concern that was not thus far answered surrounds CHIs’ potential negative impact on the surrounding community. There is a surge of new interest in study effects on so-called ‘bystanders’, that is, people who are not study participants but who may be affected by research activities. Specifically, CHI opponents warn that CHIs might (1) inadvertently infect people in surrounding communities or (2) take away resources necessary for COVID response in these communities at a time of great need. Author groups who raised this concern last spring, summer, and autumn did not raise a similar concern to conducting conventional field trials, and their related demands for local community engagement as a prerequisite pertained to the former only.

Our article shows the implausibility of raising the bystander concern about CHIs and not about conventional field trials. The bystander concern makes much more sense about conventional field trial.

To give a flavor of some of our responses to warning (1) above, about inadvertent secondary transmission: whereas CHIs involve dozens of participants, conventional field trials involve tens of thousands in the field. If the same small percent engages in riskier behavior because of the trial, the potential for secondary transmission in conventional field trials is much higher. Usually, the high endemicity should make secondary transmission less alarming. But in places where some highly efficacious vaccines are already widely available, any placebo (and to some degree, experimental vaccine) arm of conventional trials there would consist of at least thousands of people who otherwise would be vaccinated with products known to be highly efficacious (probably also in reducing transmission) and who are not, because of the trial. That large group would seriously increase risk of infection for bystanders in the areas of high community spread where field trials need to take place. Those infected could include many old people and people with relevant comorbidities.

To give a flavor of our responses to point (2) above, about capture of local resources at a time of great need: the expectation of hospitalization among young and healthy CHI participants is very low. Chances are, overwhelmingly, that a CHI will not take away a single ICU bed. Even if it does, the community who is losing that bed need not be one experiencing a surge in demand for therapeutic services—the CHI research center can be located anywhere. In comparison, field trial participants are on average at far higher risk of COVID-related hospitalization and need of intensive care (simply because field trials lack CHIs’ exclusionary criteria). Field trials must take place in concurrently-surge areas and enroll at least thousands of participants in each. The impact of their prioritization on local COVID response would be far more dramatic than that of CHIs.

We doubt that preventing any adverse impact whatsoever on local communities should command the highest priority for vaccine trials during pandemic, such that these trials should not take place, or depend on prior “permission” from the local community. But if the bystander concern makes sense here, it makes sense for conventional vaccine field trials, far more than for CHIs.



Paper title: COVID-19 controlled human infection studies: worries about local community impact and demands for local engagement

Authors: Kyungdo Lee and Nir Eyal

Affiliation: Department of Health Behavior, Society and Policy, Rutgers School of Public Health, Piscataway, NJ 08854, USA; 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.

Competing interests: None.

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