Recently, the UK announced that they would begin recruiting young patients for a COVID-19-19 challenge study to observe the course of the disease, assess “rescue treatments” for the disease, and test the effectiveness of vaccines. I remain highly concerned about these challenge studies because I think they test the limits of ethics.
As I have written previously, I think that the data could be valuable, but this UK COVID-19 challenge study could be dangerous. And I am unconvinced that it will actually provide us with any information that could be otherwise determine from scientific research.
What is a challenge study?
A challenge study is a controlled infection in which healthy volunteers are intentionally “challenged” with an infection, in this case, the SARS-CoV-2 virus. Although there are a lot of reasons to perform a challenge study, it has been mainly considered recently for COVID-19 for a few reasons:
- It requires fewer participants to gauge the safety and effectiveness of vaccines because researchers do not have to “wait” for patients to become naturally infected with SARS-CoV-2. This can lead to the faster development of a new vaccine.
- We can get information about SARS-CoV-2, including how it causes COVID-19, the course of the disease, infectivity, the immune response over time to the infection, and other scientific information that we are lacking regarding this disease.
Usually, these vaccine challenge studies use animal models, specifically, chimpanzees. However, they have been done with other diseases and vaccines in the past.
Unfortunately, there are stories that can be scary with regard to challenge studies.
The hepatitis B vaccine development started with a preclinical challenge study, which is typical of vaccine development. 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 story doesn’t imply that the proposed UK challenge study for COVID-19 is unethical, but it tells us that the history of these types of studies has included numerous ethical lapses. And that’s why vaccine challenge studies are extremely rare and difficult to start.
A vaccine challenge study proposal for COVID-19 was 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.
The proposed study was outlined by this figure found in the article:
They proposed 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 outlines the this 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.
Now, this challenge study was proposed to speed up the vaccine research timeline, but of course, we did that without a challenge study. We have several COVID-19 vaccines already launched, or about to be launched, so the need for a challenge study seems a bit suspect.
What is the UK COVID-19 challenge study?
The study intends to include up to 90 healthy adults, ages 18-30 years. The study intends to include two areas of research:
- Test the varying amounts of virus to determine the smallest amount of virus which will cause an infection and generate a subsequent immune response. The researchers hope that they can then determine how an infected person transmits the virus into the environment.
- Then various COVID-19 vaccine candidates would be administered to some of the volunteers to determine whether the immune response is sufficient to protect individuals from reinfection while also determine which vaccine(s) are the most effective.
The UK COVID-19 challenge study is being run by the UK’s Vaccines Taskforce, Imperial College London, the Royal Free London NHS Foundation Trust, and the clinical research company (CRC) hVIVO Plc. The UK government is contributing £33.6 million (about US$47 million) to the research. Each volunteer will be paid about £4500 for their time, which will include a substantial amount of time in isolation.
This study is not risk-free, but the researchers are trying to do everything they can to protect both the volunteers and the outside world. The participants would be isolated on a hospital floor, so they won’t be able to pass their COVID-19 infection to anyone.
The participants will be monitored 24 hours a day (insert innuendo here) with top-notch medicare. Any participants infected with SARS-CoV-2 who develop COVID-19 will be treated with the antiviral drug remdesivir as soon as the disease is confirmed.
My thoughts about challenge studies
I’m just going to list my thoughts on what I think about this UK COVID-19 study. I’m sure smarter people than I contributed to the decision by the four entities involved with the study, but here are my worries about this study specifically, but for any challenge study that may happen.
- Volunteers. This study will only include healthy, young-ish, volunteers. Researchers will not include any who have comorbidities, like obesity and diabetes, This does not represent a broad cross-section of those at risk of serious COVID-19 outcomes.
- 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.
- Risks. Even though the volunteers are going to get the best healthcare possible, there are no “cures” for the disease. And there is a small but significant number of long-term issues that arise from the disease, even to those who are younger.
- Public response. Because this research will be public (I’m sure everyone who’s included in the study will post an Instagram photo), one serious event, like a death, during the vaccine studies will be overblown by the anti-vaccine world. That one person, if it happens, will be the star of every anti-vaccine meme out there.
I know that a lot of people would volunteer for these types of studies, especially for the cold hard cash provided by the UK government. Some will do it just because they want to help humanity.
But I am concerned about the ethics of the UK COVID-19 challenge study – I believe that it is unethical, even if the volunteers are volunteers, and I don’t think it will provide anything useful about the disease.
However, smarter people than I have moved this forward. And they certainly did not ask my opinion of these types of studies. I hope it tells us something about COVID-19. I hope it can help us understand the effectiveness of vaccines. But science isn’t based on hope, and I am concerned that this is a good use of science.
- 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.