key: cord-0759842-02hunqls
authors: Spinola, Stanley M; Broderick, Camilla; Zimet, Gregory D; Ott, Mary A
title: Human Challenge Studies with Wild Type SARS-CoV-2 Violate Longstanding Codes of Human Subjects Research
date: 2020-12-28
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofaa615
sha: 9abb9cee6781c74c3dc001ceaa2d23d4a3b8ad9a
doc_id: 759842
cord_uid: 02hunqls

This manuscript explores the ethics of human inoculation experiments in young healthy adults with wild type 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.

A c c e p t e d M a n u s c r i p t 3 We are writing to discuss the ethics of human challenge experiments with SARS-CoV-2 as a tool to accelerate vaccine licensure. This approach involves randomizing healthy volunteers (18 to 25 years old) to vaccine or placebo, and then infecting all volunteers with SARS-CoV-2 to assess vaccine efficacy [1] [2] [3] . The justifications for the development of this model in young healthy adults are that the risks for morbidity and mortality in this age group are negligible, participants have a right to accept such risks "free from paternalistic overreach", and there is a "societal value of reducing the time required to identify efficacious vaccines against a disease that is creating a massive and relentless daily toll" [1, 4, 5] . Concerns expressed in opposition to this approach have centered around its utilitarian morality, the possible adverse short term and long term health outcomesincluding death -in the volunteers, the inability to manage risks associated with experimental infection, the adequacy of informed consent, the time required to develop a model, the utility of a model in accelerating vaccine development, and the reduction in confidence in the research community should adverse events occur [6] [7] [8] .

We recently published a letter voicing some of these concerns [8] . Shortly thereafter, we were invited to participate in a debate with advocates of the human challenge experiments, including 1Day Sooner, an organization that has signed up over 38,000 volunteers from 166 countries to participate in SARS-CoV-2 challenge trials, which have entered the planning stage in the United Kingdom but have yet to receive regulatory approval [9] . 1Day sooner has received significant coverage, much of it positive, in the news media, including but not limited to, stories in National Geographic, the NY Post, and CNBC [10] [11] [12] . In preparation for the debate, which was sponsored by There are three documents that have long guided human subjects research: the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report. The overarching theme of these documents is that as physicians and scientists we are obligated to protect individuals from experiments that might benefit society but harm an individual.

The Nuremberg Code, written in 1947 in response to experimentation done on prisoners in concentration camps in World War II, states that "no experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except perhaps in those experiments where the experimental physicians also serve as subjects" [15] . The Declaration of Helsinki, first published in 1964 and primarily directed to physicians, rejects even that exception [16] . The Declaration states that physicians should only engage in research that safeguards the health of participants; the goal of new knowledge "can never take precedence over the rights and interests of individual research subjects" and that "the responsibility for the protection of research subjects must always rest with the physician and never with the research subjects, even though they have given consent." The Declaration goes on to state that "physicians may not be involved in a research study involving human subjects unless they are confident that the risks have been adequately addressed and can be successfully managed." Finally, the Belmont Report, published in 1979 in response to the Tuskegee syphilis study, includes the concept of Beneficence: do no harm and maximize possible benefits [17] . For healthy people who are experimentally infected with SARS-CoV-2 or any other infectious agent, there is potential harm and no benefit. Since there is no benefit, the ethical standard for human inoculation experiments is that the disease must be entirely selflimited or there must be a curative therapy [13, 18] , which currently does not exist for SARS-CoV-2.

Those who have advocated for SARS-CoV-2 challenges have stated that the risks of morbidity and mortality in young healthy persons are negligible, based on extrapolated infection rates, and therefore such infections are permissible [1] . Those in opposition have stated that the risks of severe illness, death, protracted symptoms, and post infectious complications such as thromboembolic A c c e p t e d M a n u s c r i p t 5 events, prolonged pulmonary, cardiac, or renal dysfunction and cognitive impairment are substantial, based on the outcomes of young adults who tested positive for SARS-CoV-2 [8, 19] . For example, 2.5% of those aged 20-29 years old who were diagnosed with SARS-CoV-2 in Indiana have been sick enough to be hospitalized. However, as is discussed below, the severity of illness for many infectious agents is dose dependent. Thus, the truth of the matter is that no one can define the risks of SARS-CoV-2 human challenges because we do not know the dose of SARS-CoV-2 that causes severe infection in young healthy persons. [20] . This host effect is reproducible when the volunteers are challenged a second time [21] . For doses >150 CFU, the host effect on outcome is lost in that abscesses develop at all sites; for doses >1,000 CFU, abscesses form too rapidly to mimic natural infection [20, 22] . In some models, the infectious dose is strain dependent; for example, there is 100 fold difference in the ID 50 of two gonococcal strains used to infect male volunteers [23] . 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 x 10 2 , 1 x10 3 and 1x10 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 vs. those that cause severe disease and death in young healthy

A c c e p t e d M a n u s c r i p t

Human Challenge Studies to Accelerate Coronavirus Vaccine Licensure

SARS-CoV-2 controlled human infection models: Ethics, challenge agent production and regulatory issues

Viewpoint of a WHO Advisory Group Tasked to Consider Establishing a Closely-Monitored Challenge Model of COVID-19 in Healthy Volunteers

Coronavirus Disease 2019: Is Everything Lawful to Create an Effective Vaccine?

Severe Acute Respiratory Syndrome Coronavirus 2 Human Challenge Trials: Too Risky, Too Soon

Human Challenge Studies Are Unlikely to

Accelerate Coronavirus Vaccine Licensure Due to Ethical and Practical Issues

Britain moves closer to Covid-19 vaccine trials that infect vlounteers

Thousands sign up to be exposed to COVID after getting experimental vaccine

Volunteers in the UK will reportedly be exposed to the coronavirus to speed up vaccine development. CNBCcom: CNBC

To find a vaccine for COVID-19, will we have to deliberately infect people? . nationalgeographiccom: National Geographic

Accelerating Development of SARS-CoV-2 Vaccines -The Role for Controlled Human Infection Models

WHO Working Group for Guidance on Human Challenge Studies in COVID-19. Key criteria for the ethical acceptability of COVID-19 human challenge studies. Geneva: World Health Organization

Informed consent in human experimentation before the Nuremberg code

WMA Declaration of Helsinki -Ethical Principles for Medical Research Involving Human Subjects https

declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects

The Belmont Report. Ethical principles and guidelines for the protection of human subjects of research

The ethical challenge of infection-inducing challenge experiments

Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network -United States

Experimental infection of human volunteers with Haemophilus ducreyi: fifteen years of clinical data and experience

Differences in host susceptibility to disease progression in the human challenge model of Haemophilus ducreyi infection

Experimental human infection with Haemophilus ducreyi

Experimental gonococcal infection in male volunteers: cumulative experience with Neisseria gonorrhoeae strains FA1090 and MS11mkC

Validation of the wild-type influenza A human challenge model H1N1pdMIST: an A(H1N1)pdm09 dose-finding investigational new drug study

A Dose-finding Study of a Wild-type Influenza A(H3N2) Virus in a Healthy Volunteer Human Challenge Model

A Rush to Judgment? Rapid Reporting and Dissemination of Results and Its Consequences Regarding the Use of Hydroxychloroquine for COVID-19

We thank Byron Batteiger and Christopher Robinson for their thoughtful criticisms of the manuscript and the Rikers Debate Project, 1Day Sooner, and the Central Synagogue of Manhattan for stimulating discussion of this topic.

A c c e p t e d M a n u s c r i p t 8