Yesterday, I discussed the difficulty of developing a new coronavirus vaccine. However, vaccine challenge studies may be one way to speed up the timeline for us to get a vaccine for COVID-19.
But, and there’s always a but, vaccine challenge studies test the limits of biomedical ethics and quality of results.
Because it is important to review all aspects of coronavirus vaccine development, I wanted to spend a few moments of your time discussing this method of clinical testing of a new vaccine.
What are vaccine challenge studies?
As I discussed in my article about the challenges of vaccine clinical trials, one of the time-limiting factors are phase 2 and 3. Although many of you think they are straightforward, just inject a vaccine and wait, it’s more than that. Unless the SARS-CoV-2 virus is circulating in the area where the patients are located, it becomes difficult to determine if the vaccine is effective.
If the level of COVID-19 is very low, then the control and vaccinated groups will show the same effectiveness – very low levels of disease. Furthermore, we will need time to determine how long the vaccine effectiveness lasts, and if the virus isn’t prevalent, then we can’t tell if it works after a few weeks or months or years.
To speed up clinical trials for COVID-19 vaccines, researchers have proposed vaccine challenge studies. Essentially, these studies intentionally expose the control and vaccine groups to the virus.
Usually, these vaccine challenge studies are done with animal models, specifically, chimpanzees. The hepatitis B vaccine development started with this type of preclinical studies. But Paul Offit examined the history of hepatitis vaccine development, which included doing a hepatitis challenge study on mentally disabled children at the Willowbrook State School in NY. The parents were essentially coerced into signing consent forms, or their child wouldn’t be allowed at the school.
That doesn’t mean proposed vaccine challenge studies for coronavirus would do something so unethical, but it tells us that the history of these types of studies has included numerous ethical lapses.
A vaccine challenge study for COVID-19 was recently published in the Journal of Infectious Diseases by Nir Eyal, a bioethicist at the Center for Population-Level Bioethics, Rutgers University; Marc Lipsitch, Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard T. H. Chan School of Public Health; and Peter G Smith, MRC Tropical Epidemiology Group, London School of Hygiene & Tropical Medicine, London, UK.
This study is outlined by this figure found in the article:
They propose that after the Phase 1 study, which usually includes around 100 healthy patients (that is, they have no comorbidities and generally lack any chronic health conditions) all of whom receive the vaccine, they would move to vaccine challenge studies.
The authors proposed the following study design:
- The volunteers would be relatively young (20-45), healthy (no chronic health conditions), and never been infected with SARS-CoV-2. They will be isolated from the world for 2 weeks prior to the start of the study.
- All participants will receive a more thorough informed consent than for most clinical studies as participants must fully comprehend the unusual risks involved in this type of study.
- Before the challenge study itself starts, a group of volunteers would be required for a dose-escalation study to selected a dose of viral exposure at which most recipients become infected. In other words, this first group will be intentionally infected without any chance of receiving the vaccine.
- The next step is that volunteers would be randomized to receive the candidate vaccine or placebo. After an interval to permit a full immune response (which should have been established in the Phase 1 trial), the participants will receive a controlled exposure to the SARS-CoV-2 virus.
- Following the virus challenge, the participants will be carefully followed in the clinical isolation facility. Various endpoints could be measured including viral load, antibodies, time to first clinical symptoms, and other immunological monitoring.
Once the human challenge study shows that the vaccine candidate is safe and effective, a regular randomized, placebo-controlled Phase 3 study, involving at least 6000 individuals. This will provide data for both short-term safety and immunogenicity post-vaccination.
This proposed study should cut several months, maybe a year, off the coronavirus vaccine development timeline. It probably won’t move it to just 12-18 months, but making the vaccine available sooner will save lives.
My thoughts about vaccine challenge studies
I’m just going to list my thoughts on what I think about these studies. They are considerations anyone should have.
- Volunteers. This study will only include healthy, young-ish, volunteers. Even though many people think only seniors and others with chronic diseases are at risk of death, that’s not quite true. Young, healthy people do die from COVID-19. Even if the vaccine works, two groups of unvaccinated people will be challenged by the virus – the dose-escalation participants and the placebo group. You don’t get to choose to just be in the vaccine group, since that would invalidate the randomization.
- Institutional Review Board. IRB’s are the ethics reviewers at almost all medical and research institutions that determine if they will allow a study to proceed. Intentionally putting volunteers at risk of dying of COVID-19 may cause them to not agree to this study design. I can imagine that the IRB discussion for such a study will be long and stressful.
- Value of data. These challenge studies will only include healthy young people who are at the lowest risk of harm from the disease. This may not give us much information about how the vaccine works in the most vulnerable individuals.
To the author’s credit, they listed out the reasons why this type of study can minimize risk to the volunteers:
- They are only recruiting patients from groups that are at the lowest risk of severe disease and death following SARS-CoV-2 infection.
- The participants in the vaccinated group will have some non-zero level of protection from the vaccine candidate.
- In the absence of a vaccine, a high proportion of these individuals will probably be infected eventually.
- Only individuals who have the highest baseline risk of getting exposed during the trial period because they are at a high risk of being exposed during or soon after the trial begins. For example, healthcare workers would be good volunteers because we would expect them to be eventually infected.
- Volunteers would receive some of the best available healthcare if needed.
- By the time the vaccine candidates are being tested, some therapeutic drugs may be available, further reducing the risks from the disease.
I thought about whether I would volunteer for these studies. At first, I thought that vaccine challenge studies would be unethical and dangerous. I worried that the data wouldn’t really tell us much. I wondered if any Institutional Review Board would approve this type of study (and they may not).
Then I recalled a quote from the Talmud, made famous in the movie Schindler’s List:
He who saves the life of one man saves the entire world.
Maybe if I joined such a clinical trial, I would save the life of one person. Maybe if this challenge study brings us the vaccine even one day faster, then how many lives could be saved if I participated?
- Beasley RP. Development of hepatitis B vaccine. JAMA. 2009 Jul 15;302(3):322-4. doi: 10.1001/jama.2009.1024. PubMed PMID: 19602694.
- Eyal N, Lipsitch M, Smith PG. Human challenge studies to accelerate coronavirus vaccine licensure. J Infect Dis. 2020 Mar 31;. doi: 10.1093/infdis/jiaa152. [Epub ahead of print] PubMed PMID: 32232474.
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