Human Challenge Studies With Wild-Type Severe Acute Respiratory Sydrome Coronavirus 2 Violate Longstanding Codes of Human Subjects Research

Abstract

This manuscript explores the ethics of human inoculation experiments in young healthy adults with wild-type severe acute respiratory sydrome coronavirus 2 (SARS-CoV-2) as a tool to evaluate vaccine efficacy in the context of the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report, and in the context of dose-response relationships with infectious agents. Despite societal pressure to develop a SARS-CoV-2 challenge model to evaluate vaccines, we argue that there are substantial risks that cannot be adequately defined because the dose of SARS-CoV-2 that causes severe disease in young adults is unknown. In the absence of curative therapy, even if a volunteer consents, longstanding ethical codes governing human subjects research preclude the conduct of such experiments.

Early SARS-CoV-2 dynamics and immune responses in unvaccinated participants of an intensely sampled longitudinal surveillance study

“…Human challenge studies using SARS-CoV-2 could overcome some of the practical limitations of observational clinical studies as participants would be closely monitored in a controlled setting. However, given our limited understanding of COVID-19 and the potential for significant morbidity associated with acute disease presentation as well as persistent, long-lasting symptoms (i.e., so-called “long-COVID”), human challenge studies involving SARS-CoV-2 are controversial and face an ethical dilemma that has been the subject of considerable debate 10 – 14 . Controlled infection models also suffer from a number of scientific limitations borne out of their inherent artificial nature, such as the choice of the viral strain, the size of the viral inoculum, the mode of inoculation, and the age of the participants, as only young and healthy subjects typically can be enrolled.…”

Ethical Requirements for Human Challenge Studies: A Systematic Review of Reasons

“…If disagreements persist about key ethical requirements of HCS, this may raise the further question of how these disagreements influence decisions about particular types of HCS. This question is especially relevant in the context of the COVID‐19 pandemic, as the idea of conducting SARS‐CoV‐2 HCS was highly controversial among ethicists 28–34 . The decision to initiate COHVIC, the first SARS‐CoV‐2 HCS, and the ethical review of this study were supported by a consensus document developed by the WHO early in the pandemic 66,67 .…”

“…Alternatively, HCS should pose no more than “minimal risk,” understood as risks similar to those associated with activities of everyday life (E10). The main reasons given for these positions relate to provisions in influential research ethics documents 34 and expected public reactions against more risky studies 20 . Others, however, have argued that the threshold of acceptable risk should be higher; in particular, it should be similar to the risk that is generally accepted in other altruistic activities, such as living organ donation or firefighting (E13).…”

“…As a result, a number of ethical aspects of HCS still remain unclear or controversial. This became particularly evident when severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) challenge studies were proposed at the beginning of the COVID‐19 pandemic, and scholars responded to this idea in a wide variety of ways 28–34 . Scholars have also emphasized that the existing ethical guidelines for clinical trials pay little attention to the specific issues that arise in HCS 5,26 .…”

Elucidating the Early SARS-CoV-2 Dynamics and Concomitant Immune Responses in Unvaccinated Participants of an Intensely Sampled Longitudinal Surveillance Study

“…Human challenge studies using SARS-CoV-2 could overcome some of the practical limitations of observational clinical studies as participants would be closely monitored in a controlled setting. However, given our limited understanding of COVID-19 and the potential for significant morbidity associated with acute disease presentation as well as persistent, long-lasting symptoms (i.e., so-called "long-COVID"), human challenge studies involving SARS-CoV-2 are controversial and face an ethical dilemma that has been the subject of considerable debate [10][11][12][13][14] . Controlled infection models also suffer from a number of scientific limitations borne out of their inherent artificial nature, such as the choice of the viral strain, the size of the viral inoculum, the mode of inoculation, and the age of the participants, as only young and healthy subjects typically can be enrolled.…”