Viewpoint of a WHO Advisory Group Tasked to Consider Establishing a Closely-monitored Challenge Model of Coronavirus Disease 2019 (COVID-19) in Healthy Volunteers

Abstract

WHO convened an Advisory Group (AG) to consider the feasibility, potential value and limitations of establishing a closely-monitored challenge model of experimental SARS-CoV-2 infection and COVID-19 in healthy adult volunteers. The AG included experts in design, establishment and performance of challenges. This report summarizes issues that render a COVID-19 model daunting to establish (SARS-CoV-2’s potential to cause severe/fatal illness, its high transmissibility, and lack of a “rescue treatment” to prevent progression from mild/moderate to severe clinical illness) and it proffers prudent strategies for stepwise model development, challenge virus selection, guidelines for manufacturing challenge doses, and ways to contain SARS-CoV-2 and prevent transmission to household/community contacts. A COVID-19 model could demonstrate protection against virus shedding and/or illness induced by prior SARS-CoV-2 challenge or vaccination. A limitation of the model is that vaccine efficacy in experimentally challenged healthy young adults cannot per se be extrapolated to predict efficacy in elderly/high-risk adults.

Low-dose and oral exposure to SARS-CoV-2 may help us understand and prevent severe COVID-19

“…The ethical validity of such studies depends in large part on whether the anticipated public health benefit (and/or individual benefit to study participants) outweighs the risk of contracting severe COVID-19, as such studies must induce sufficiently severe disease to be relevant for the evaluation of vaccine efficacy. Detailed discussion and quantitation of those risks, and how they compare to risks in other CHIM studies or other societal risks, have been detailed extensively by a World Health Organization Advisory Group (Levine et al, 2020) and others (Deming et al, 2020;Eyal et al, 2020;Plotkin and Caplan, 2020) with no need to recapitulate them here.…”

Prioritizing second-generation SARS-CoV-2 vaccines through low-dosage challenge studies

“…Others have recently explored different potential scientific applications of low-dosage challenge studies to COVID-19, for a host of non-vaccine-related uses (Hausdorff and Flores, 2021). We explore the advantages and potential disadvantages of low-dosage challenge over conventional challenge designs in the particular role of developing second-generation vaccines: as an initial efficient test of experimental vaccine efficacy that determines which candidates proceed to standard phase 3 testing (herein, 'field trials') (Jamrozik and Selgelid, 2020;Douglas and Hill, 2020;Levine et al, 2020). The advantages and disadvantages are summarized in Table 1 below.…”

“…By enabling control of the timing of infection, challenge studies excel at demonstrating vaccine efficacy against asymptomatic infection and transmission. Specific challenge designs can also permit rigorous testing of the duration of vaccine protection and generate other information for improved control measures (Douglas and Hill, 2020;Levine et al, 2020;. Challenge studies may also help to refine dosing regimens of existing vaccines and determine the degree of protection against particular viral variants.…”

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

“…1Day Sooner has received significant coverage, much of it positive, in the news media, including but not limited to stories in National Geographic , the New York Post , and CNBC [ 10–12 ]. In preparation for the debate, which was sponsored by the Rikers Debate Project and the Central Synagogue of Manhattan and can be viewed at https://youtu.be/v1XpQK8nkFg , we realized that although there had been a great deal written concerning the ethics of such experiments [ 2 , 3 , 13 , 14 ], there had been little direct discussion of whether human challenges with SARS-CoV-2 are compatible with longstanding ethical codes of human subjects research.…”

“…For the initial human trials done with coronavirus 229-E in 1967, the infectious dose that caused common colds in 66% of the volunteers was only 10 1.2 to 10 1.5 50% tissue culture infectious dose (TCID 50 ). Some have advocated that initial dose-ranging experiments for SARS-CoV-2 challenges should include doses of 1 × 10 2 , 1 × 10 3 , and 1 × 10 4 TCID 50 [ 2 , 3 ], which are 3 logs lower than the doses used in recent influenza challenge models [ 24 , 25 ]. However, if SARS-CoV-2 operates in a very low and narrow dose range similar to coronavirus 229-E, we may not be able to easily distinguish between doses that lead to asymptomatic or mild infection versus those that cause severe disease and death in young healthy volunteers.…”