Is NIAID Exploring Human Challenge Studies as an Alternative or Complement to Large Clinical Trials?

Is NIAID Exploring Human Challenge Studies as an Alternative or Complement to Large Clinical Trials?

A number of media recently reported that the National Institutes of Allergy and Infectious Diseases (NIAID) communicated that government scientists are developing a strain of coronavirus that may be used in ‘human challenge studies.’ That is where volunteers sign up to be deliberately infected by the virus to determine if a vaccine can work or not. The primary source for the government agency statement originates from Reuters. NIAID now is on the record considering the prospective need for human challenge studies for full access to vaccines for therapeutics for SARS-CoV-2; and that the agency now studies up on the technical and ethical issues associated with this class of research. Human challenge studies have been used for a long time, and in many cases, successfully. Underlying success criteria include the conditions that A) there is a large pool of healthy and young volunteers willing to participate in the human challenge trial and B) that the lab-developed virus is premised on a deep and thorough understanding of the underlying pathogen. In more open and democratic societies, controversy can arise when a novel and dangerous pathogen, such as SARS-CoV-2, is involved. Hence authorities must be incredibly transparent about intentions, the process, and the underlying details, including risks and benefits, and a disclosure and full debate of the ethical considerations. The NIAID understands this and hence shares information as it becomes relevant. In more command and control societies, human challenge studies may just be mandated. For example, TrialSite speculates that the incredibly fast development and approval of the Gamaleya (SputnikV) vaccine in Russia was at least in part the result of human challenge studies.

What are Human Challenge Studies?

As defined by the World Health Organization (WHO), Human Challenge studies “are trials in which participants are intentionally challenged (whether or not they have been vaccinated) with an infectious disease organism.” The challenge organism may be close to wild-type and pathogenic, adapted and/or attenuated from wild-type with less or no pathogenicity, or genetically modified in some manner. See the WHO link for details. WHO has established criteria for human challenge studies.

Have Human Challenge studies been used before with vaccines?

Yes. Plenty of available literature shares the benefits of this approach in select circumstances. Investigations where infectious organisms administered to healthy adult volunteers with the intent to deliberately induce infection have occurred for centuries. 

Moreover, useful applications have arisen from these investigations, such as the “provision of evidence of microbial pathogenicity and the identification of key virulence factors.” Two University of Maryland authors, Debbie-Ann T Shirley and Monica A. McArthur, reported, “Challenge studies have also played an important role in the evaluation of preliminary efficacy of potential vaccine candidates.” The authors suggest that a number of both living and nonliving attenuated cholera vaccines were made possible by this approach.

What kinds of groups support human challenge studies for COVID-19 vaccines?

Groups such as 1Day Sooner, as reported in Science Magazine, have signed up over 30,000 volunteers from 140 countries. Co-founded by a 22-year old, it authored an open letter that was even signed by 15 Nobel laureates and 100 prominent researchers, ethicists, and philosophers. The letter was sent to NIH Director Francis Collins back on July 15, urging the U.S. government “to undertake immediate preparations for human challenge trials” in young, healthy people who face a lower probability of risk from COVID-19.

Does the Government have a current POV on this topic?

Yes. TrialSite has introduced the National Institutes of Health (NIH) ACTIV group, which oversees all COVID-19 research using federal dollars moving forward. ACTIV stands for National Institutes of Health’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) Working Group. ACTIV ongoing is assessing the pragmatic factors and elements, as well as prerequisites for employing what they term “controlled human infection models” (CHIMS), which are a possible way to implement human challenge studies to support SARS-CoV-2 vaccine development.

Has ACTIV or its Members published on the topic?

Yes. Some ACTIV members authored in a Perspective for the New England Journal of Medicine introduce “practical considerations and prerequisites for using “CHIMS,” which again can be deployed for human challenge studies. In this study, the authors introduce an important perspective on CHIMS and convey such an effort is probably two years away. Presently, ACTIV’s vaccine working group position is that large, randomized clinical trials with healthy volunteers are the way to go. However, ACTIV does posit that “parallel development of CHIMS may provide complementary tools” in supporting an investigation into critical issues such as “duration of immunity” and “correlates of protection.” The authors also address the ethics of such human challenge studies.

Does NIAID and the NIH Favor Human Challenge Studies?

No. Right now, they are on record that large, randomized clinical trials with volunteers are the way to go. These “Phase 3” clinical trials are underway in the United States, including vaccines from Moderna (mRNA-1273) and Pfizer/BioNTech (BNT162), as expressed in a statement emailed from NIAID to Reuters.

Are there different kinds of Human Challenge Studies?

Yes. As reported by Reuters, small challenge studies include “small isolation units to control the virus,” while larger studies could include at least 100 people with the actual study conducted in multiple locations, which would add considerable time to the endeavor.

Why are there critics of this current approach?

Groups such as 1Day Sooner are critical of the current approach because the vaccine trials rely on “inadvertent infection” as those that sign up and volunteer may or may not be exposed to the pathogen. As societies become smarter about avoiding COVID-19 (e.g., wearing masks, social distancing, hand washing, and other measures), it could take far longer to develop a successful vaccine. Moreover, in many other nations, the infection rate is either low or declining.

Are there drug makers on record that would consider Human Challenge studies?

Yes. According to the recent Reuters piece, AstraZeneca and Johnson & Johnson would both consider such trial methods should they be needed.

What is the NIAID formal position based on the communication to Reuters?

NIAID wrote in an email to Reuters, “Should there be a need for human challenge studies to fully assess candidate vaccines or therapeutics for SARS-CoV-2, NIAID has begun investigations of the technical and ethical considerations of conducting human challenge studies.” NIAID is currently on record that the research agency prefers the existing approach of large, randomized controlled trials (e.g., Phase 3 clinical trials).

What ethical considerations?

The Hastings Center, founded in 1969, helped contribute to the field of bioethics. A nonpartisan and nonprofit organization consisting of research scholars from multiple disciplines researching and publishing on relevant topics. TrialSite offers a link to their Human Challenge Studies for COVID-19 Vaccine: Questions about Benefits and Risks.” Author Ruth Macklin, a distinguished university professor emerita at Albert Einstein College of Medicine and Hastings Center fellow, provides an important topic to consider: “The situation has all the earmarks of a quintessential ethical dilemma: Is it permissible to intentionally inflict serious harm on a few for possible benefit to many? With several vaccines already in the pipeline, along with worries about a disproportionate number of minorities and poor people likely to enroll, I conclude that a rush to begin human challenge vaccine trials for a grave disease lacking an effective treatment is ethically unjustifiable.”

Of course, the other side could argue that if participation is controlled to ensure the poor and minority groups are not at all exploited that this ethical risk could be mitigated. But is it that simple?