Human Challenge Study Design for Covid-19 Vaccine Clinical Trials?

The world is desperate to develop vaccines for Covid-19. Pharmaceutical and biotechnology companies are racing to start the clinical trials for Covid-19 vaccines. With the traditional phased approach for drug development (no exception for vaccine development), after the early phase clinical trials, a pivotal phase III study with thousands of volunteer subjects will need to be conducted to demonstrate the efficacy and safety of the vaccine. It is a very lengthy process that may not be successful. With the Covid-19 pandemic and the urgent situation, an alternative approach is desired to expedite the Covid-19 vaccine development. This is why we see the discussions about 'human challenge studies' heating up recently. On October 20, 2020, we saw the news release that the UK starts the first human challenge study of COVID-19 vaccine "Expert partnership to explore and establish Human Challenge studies of COVID-19 in the UK". The study plans to enroll up to 90 volunteers - much smaller in sample size than the COVID-19 vaccine studies with traditional designs. 

• Dozens to be deliberately infected with coronavirus in UK ‘human challenge’ trials
• Volunteers to Be Infected With Coronavirus in Vaccine-Effectiveness Trials in U.K. - Controversial ‘human challenge’ trial would require injecting healthy humans with virus to gauge effectiveness of vaccines
• U.K. Preparing COVID-19 Vaccine Trials That Deliberately Expose Study Subjects

The Human Challenge Studies may be also called "controlled human infection (CHI) studies". In human challenge studies, volunteer subjects were intentionally infected with the virus or other pathogen. It is supposed to shorten the time of the vaccine development program so that we know the results earlier if a vaccine works or not.   

• Infecting Subjects May Speed Covid Vaccine Studies, WHO Says
• Should scientists infect healthy people with the coronavirus to test vaccines?
• Is it worth risking lives to speed up a coronavirus vaccine?
• Infect volunteers with Covid-19 in the name of research? A proposal lays bare a minefield of issues
• Studies that intentionally infect people with disease-causing bugs are on the rise

When I see the discussions about the human challenge studies, I immediately ask myself: is it ethical to intentionally infect people just to speed up the vaccine development program? Some infamous studies came to my mind: Guatemala syphilis experiments, Holmesburg Prison, Tuskegee syphilis experiment even though the ethical issues with these studies were mainly lack of informed consent. 

However, human challenge studies were not new and had been used in other vaccine developments. Here are some examples: 

• Collins et al (2015) First Human Challenge Testing of a Pneumococcal Vaccine Double-Blind Randomized Controlled Trial - Healthy adults were randomly assigned to pneumococcal conjugate vaccine (PCV) or hepatitis A (control) vaccination, and then inoculated with Streptococcus pneumonia (pathogen causing pneumonia)
• Cohen et al (2002) Randomized, Controlled Human Challenge Study of the Safety, Immunogenicity, and Protective Efficacy of a Single Dose of Peru-15, a Live Attenuated Oral Cholera Vaccine - Volunteers were randomly assigned to receive a single oral dose of either vaccine Peru-15 or placebo; and then 3 months later, inoculated with vibrio cholerae, the bacterium that causes cholera.
• Balasingam and Wilder-Smith (2016) Randomized controlled trials for influenza drugs and vaccines: a review of controlled human infection studies - 26 studies with human challenge design were included in the review. In these studies, healthy volunteers were inoculated with influenza A and/or influenza B virus

Human challenge studies were also mentioned in FDA guidance for industry:

• Clinical Data Needed to Support the Licensure of Pandemic InfluenzaVaccines 

"To date, prospectively designed studies to evaluate the effectiveness of influenza vaccines have not identified a specific HI antibody titer associated with protection against culture-confirmed influenza illness. Some studies of influenza infection, including human challenge studies following vaccination, have suggested that HI antibody titers ranging from 1:15 to 1:65 may be associated with protection from illness in 50% of subjects and that protection from illness is increased with higher titers. Evaluations of seroconversion and GMT have been used as measures of vaccine activity." 

• General Principles for the Development of Vaccines to Protect Against Global Infectious Diseases 

"B. Human Challenge Studies
In some situations, it may be possible to conduct challenge studies in human subjects during early development or in lieu of clinical trials in an endemic area. Such studies may be conducted to demonstrate “proof of concept” of the vaccine antigen early in clinical development (e.g., Plasmodium falciparum sporozoite challenge of malaria-naïve U.S. volunteers previously administered a candidate malaria vaccine). Human challenge studies may also be conducted to demonstrate the efficacy of the vaccine. For example, in 1993 and 1998, the Agency convened the Vaccines and Related Biologics Products Advisory Committee meetings to consider whether data from human challenge studies in U.S. subjects could be sufficient to demonstrate efficacy of a cholera vaccine in travelers to endemic areas, who are at high risk for contracting the disease. In 1998, the committee agreed that human challenge studies could suffice to demonstrate efficacy of a cholera vaccine provided that studies were adequate and well-controlled and conducted under the provisions of GCP (Ref. 13). Of note, use of challenge studies to demonstrate efficacy does not preclude the requirement for adequate safety data. As human challenge studies may present unique considerations, we recommend that the sponsor discuss its development plan with CBER prior to initiation of such studies for either proof of concept or vaccine efficacy."

What does a human challenge study for Covid-19 vaccine look like? 

Here are the excerpts from the article "A Challenge to Accept The FDA should allow testing Covid-19 vaccines through deliberate human infection" to describe what the conventional phase III trial and the human challenge trial look like:

"In Phase III trials, thousands of volunteers get the vaccine or a placebo, are checked for immediate adverse reactions to the vaccine, and then are tracked for a few months as they go about daily life, to ascertain the vaccine’s efficacy. Once enough trial participants have been infected, if a large enough difference in infection rates exists between the vaccinated and control groups, then the vaccine can enter general use. This comparison, the Times notes, is especially difficult to make once the spread of a disease has slowed: “The scientists [making the vaccine] would declare victory,” the Times says, “if as many as a dozen participants who are given a placebo become sick with Covid-19 compared with only one or two who receive the inoculation.” But if too few test subjects get infected to make a valid comparison, the researchers will simply “have to try again elsewhere,” repeating the time-consuming process."

 "In human-challenge trials, volunteers are given either a candidate vaccine or a placebo and then deliberately infected with the disease that the vaccine should prevent, and closely monitored, often in medical isolation. Such trials have been conducted in exigent circumstances for several diseases, including cholera, malaria, typhoid, and dengue fever."

In another article "Human challenge trials,” where healthy volunteers would be exposed to Covid-19, explained", the human challenge study for Covid-19 vaccine was described as the following:

A human challenge trial replaces that process with one in which all of the trial volunteers are exposed to the virus that causes Covid-19 after being dosed with a vaccine or placebo. That way, you get a much clearer sense of how the vaccine performs when actually confronted with the disease it’s intended to guard against.

"To allow for a high portion to get exposed, the standard trial would have to take at least several months," Eyal, the bioethicist who co-authored the Journal of Infectious Diseases article calling for human challenge trials, told me. "By contrast, in a coronavirus challenge ... the success or failure of the vaccine to protect against the disease becomes apparent much faster."

What’s more, a human challenge trial could be conducted with fewer people than a standard Phase III trial. A Covid-19 vaccine being developed at Oxford, for instance, aims to have 5,000 volunteers for Phase III. A human challenge trial, Eyal argues, could happen with only about 100 people. The total number of participants needed would likely be higher than that, since (among other reasons) multiple vaccine candidates need to be tested, but the total would be much lower compared with a conventional study.

I drafted two diagrams to illustrate what the conventional design and the human challenge study design look like (for illustration only, SARs-Cov-2 is the virus that causes Covid-19).

Will the human challenge study be feasible for Covid-19 vaccine studies? 

There are people who push for conducting human challenge study to speed up the vaccine development - the argument is to sacrifice the few for the many.

• Infecting healthy people in vaccine research can be ethical and necessary
• First, do harm
• Volunteers Are Lining Up to Be Infected With the Coronavirus

However, the human challenge studies that had been done so far were for those pathogens that the resulted diseases were either not severe enough (for example influenza) or could be treated or cured (for example, cholera).

For Covid-19, the human challenge study design is not feasible for the following reasons:
Safety: currently there is no effective treatment for Covid-19. For healthy volunteers who are inoculated with SARs-Cov-2, they could end up in ICU or death.

• Ethical issue: even though the subjects sign the informed consent to participate in the human challenge study voluntarily, inoculating the subjects with the deadly and extremely contagious virus of SARs-Cov-2  
• Uncertainties about SARs-Cov-2: for human challenge studies, extensive modeling needs to be performed to understand the characteristics of the virus and appropriate virus load (sort of dose level) to be used for inoculation. 
• Timeline: it is arguable if it is true that using human challenge design will actually speed up the vaccine development. Covid-19 is new and a lot of unknowns need to be learned. Significant leading time may be needed to do the modeling to decide what the appropriate virus load for inoculation before the study can be initiated. 
• Recruitment: it is still uncertain whether there will be difficulties in recruiting the volunteers to participate in the human challenge study knowing that the volunteers will be infected with the potentially deadly virus that has no effective treatment so far. There is a website "one day sooner" that tracks the volunteers who are willing to participate in human challenge study for Covid-19. At the time I check, 14183 volunteers from 102 countries have signed up. 
• Generalization: if the human challenge study is conducted in volunteers who are young adults, the results may not be generalized to the vulnerable groups (elderly, with underlying diseases).  

In a digital event organized by STATNEWS.com, Tal Zaks, chief medical officer, Moderna answered the question about the human challenge study design. He argued against the use of human challenge design in Covid-19 vaccine development for issues in practicality, timeline (may not save time), and ethical (justification the risk for the benefit we gain).