Published 30 March, 2023. Last updated 30 March, 2023.
Human challenge trials for vaccines involve giving volunteers vaccine candidates, then deliberating exposing them to the disease, to test the efficacy of a vaccine candidate more quickly than standard vaccine trials.
Challenge trials are not a technological temptation which has been fully resisted: they have been used for dozens of diseases, including some recently. They have been significantly slowed in response to ethical concerns.
For COVID-19, if challenge trials had been done faster, we estimate that they could have allowed vaccines to be developed a few months more quickly, which could have saved trillions of dollars and hundreds of thousands or millions of lives lost.
This case study is part of the resisted technological temptations project. The goal of this project is to understand situations where some actor might have expected to capture substantial value from pursuing a technology, but did not as a result of concerns about downsides that would not directly affect that actor.
Traditional Phase 3 trials for vaccines involve giving thousands of volunteers a vaccine candidate, or a placebo, and comparing how frequently the two groups naturally catch the disease. By deliberating exposing the volunteers to the disease, challenge trials reduce the number of volunteers needed and the amount of time the trial takes. Phase trials typically take years, or at least many months, while challenge trials can be done in two months.1)
Along with testing vaccine efficacy, challenge trials can also be used to better understand how the disease spreads and how the immune system responds to the disease.
Certain preparatory steps are done before a challenge trial. Protocols are written, approval from the institutional review board (IRB) or other regulatory agency is secured, and various parties are coordinated. Some time is needed to learn to produce the virus under Good Manufacturing Practice, so a particular dose can be given to the volunteers. The dose to be given is determined using an escalation study: different volunteers are given small doses, then increasingly larger doses, until they develop minor but not severe symptoms. Biocontainment units, which include access to the highest standard of care, for the volunteers are prepared to keep the disease from escaping from the study into the community. This preparation typically takes at least 12-18 months,2) although it could be done in as few as 8 months.3)
The history of vaccines typically begins in 1796, with Edward Jenner’s use of cowpox to protect against smallpox.4) Jenner was not the first to discover or use cowpox this way,5) but he did the first scientific investigation that publicly established it. He exposed an eight year old boy, first to cowpox, then to smallpox, to show that the boy had been made immune.
During the 1800s, challenge trials for various diseases were done with varying ethical and scientific standards. Some were done on the physician himself or on other medical practitioners, who presumably knew what they were doing to themselves. Others were done on children, prisoners, or hospital patients.6) If people died in these studies, there was often significant public and professional backlash.7) In 1900, Walter Reed developed the first written consent form which included a statement of the study’s risks for challenge trials involving yellow fever in Cuba for the US Army. This study showed that mosquitoes transmit yellow fever, but 4 participants died, including the only woman and one of the doctors conducting the studies.8) Public outcry in the US terminated the study.
During the 1900s, the scale of medical research often increased more quickly than the ethics of medical research. The worst abuses of challenge trials were done during WWII by Germany and Japan. In response, the Nuremberg Code of 1947 established the first international rules for medical research involving human subjects.9) There was also some unethical research done in the West during and after WWII. For example, hepatitis challenge trials at the Willowbrook School from 1954-1971 were done on mentally disabled children.10) In the early 1970s, concern about unethical medical research, including the Willowbrook study, Tuskegee Syphilis Study, Fernald State School trials, and Jewish Chronic Disease Hospital case,11) led Congress to pass the National Research Act of 1974 which created IRBs.12) IRBs review all potential medical research and determine if it is ethical to proceed.
Dozens of human challenge trials have been approved by IRBs, including for malaria,13) influenza,14) cholera,15) typhoid,16) dengue,17) and others.18)
The recent pandemic caused discussion about all aspects of vaccines to dramatically increase, including debates about human challenge trials. Even before they became available, vaccines were widely seen as an extremely powerful tool for fighting the pandemic. Anything that could speed up the development of the vaccine would be extremely valuable.19) An organization named 1DaySooner found 38,000 people in 166 countries who wanted to volunteer to be part of COVID-19 challenge trials.20) One challenge trial was eventually done, but not until after several vaccines had already been approved using traditional trials.21)
How much time in vaccine development could have been saved if fast challenge times were done?
To estimate this, we could assume that challenge trials replace phase 3 trials, in conjunction with a larger safety trial, and that all of the preparatory work could have been done by July 2020, when the phase 3 trials for Pfizer and Moderna began. Challenge trials could have been completed in two months.22) The actual phase 3 trials took four months.23) We will estimate that challenge trials could have sped up vaccine development by two months.
A more aggressive (and speculative) strategy would be to skip the preparatory work. You do not need to manufacture the virus or figure out the right dose of virus if the challenge trial involves directly exposing the volunteers to someone who is currently sick with COVID-19. This is significantly more risky for the dozens of volunteers involved in the study, but it would make the process much faster. Once the scale of the crisis became apparent in March 2020, we could have decided to ignore medical ethics and adopt this strategy. We would have known which vaccines work two months later, in May 2020, 6 months earlier than what actually happened. This is a very speculative estimate because (1) I have not found a counterfactual plan describing the details of how this might have worked, (2) scaling up the manufacturing of the vaccine might have taken long enough for us not to have been able to realize these gains, and (3) public acceptance of the vaccine might have been lower if the vaccine development had seemed more rushed.
In April 2022, the Institute for Progress estimated that the total cost of the pandemic to the US was \$10-22 trillion, including 1.1-1.4 million deaths.24) If this were spread evenly over the 25 months since March 2020 and challenge trials shortened the pandemic by 2 [or 6] months, this would have saved \$0.8-1.8 trillion [$2.4-5.3 trillion], including 90,000-110,000 deaths [260,000-340,000] deaths. This is likely an underestimate because the vaccine became widely available just after the worst part of the pandemic for the US.
Another way to estimate how many lives would have been saved if the vaccine had come sooner is to compare the number of deaths before and after the vaccine. This is also an underestimate because the vaccine is not the only thing that changed: new variants arose and people took fewer precautions, partially in response to the vaccine and partially because they were tired of social distancing. During the first year of the pandemic, between March 15, 2020 and March 15, 2021,25) 540,000 people died from COVID-19 in the US. During the second year of the pandemic, 430,000 people died from COVID-19 in the US.26) There were about 10,000 fewer deaths per month with the vaccine than without the vaccine. If the vaccine were available 2 [or 6] months earlier, there could have been 20,000 [60,000] fewer deaths.
For a rough estimate of the global amount of value resisted by slowing vaccine challenge trials, we could multiply the financial cost for the US by a factor of 4,27) and the number of deaths by a factor of 6.28) The result is trillions of dollars and hundreds of thousands or millions of lives lost.
The main actors which decide how quickly vaccine challenge trials occur are pharmaceutical companies and institutional review boards (IRBs).
The two leading COVID-19 vaccine developers, Pfizer and Moderna, each had tens of billions of dollars of revenue from their COVID-19 vaccines29) and had profit margins of 25%-60% during the pandemic.30) If one of them were able to roll out their vaccine two months earlier, they probably could have made billions of dollars of additional profit. They had a substantial incentive to make vaccines faster.
Trials can be slowed or stopped by IRBs, which have very different incentives. This is a description of the situation in the US; similar ethics committees exist in other countries as well.
There are two types of IRBs: 'Central' or 'independent' IRBs are for profit enterprises which charge investigators for reviewing their proposed research. 'Local' IRBs are associated with the institution where the research is done and seem to be significantly more common.31) Oversight of IRBs is done by the Food and Drug Administration (FDA) and the Office for Human Research Protections (OHRP). Their audits encourage detailed documentation of all parts of the investigation.32) Other than these audits, there are few incentives acting on IRBs, especially local IRBs. They do not have to justify their decisions and their decisions cannot be appealed.33) If research results in an important discovery, the research institution and investigators gain prestige, but this is rarely shared with the IRB which approved it. The IRB is much more likely to gain infamy if it approves research which is considered unethical. The result is a form of asymmetric justice: IRBs face more criticism for their mistakes than praise for their successes.34) In these circumstances, it is not surprising that IRBs are often cautious and insist on justifying and documenting everything.
During the pandemic, there was also significant political pressure to make vaccines available faster. Operation Warp Speed provided funding for vaccine research and preordered hundreds of millions of doses of promising vaccine candidates so vaccine manufacturing could scale up before the vaccines were approved.35) These efforts probably shortened the time until vaccines were widely available by months. However, the FDA and Pfizer proved to be effective at resisting political pressure to get the vaccines approved before Election Day.36)
While pharmaceutical companies and the public have incentives that encourage them to quickly approve human challenge trials, and vaccines more generally, IRBs and the FDA are insulated from these incentives. This allows them to slow or block challenge trials, partially resisting the technological temptation.
Here are a few key takeaways from this technological temptation:
Primary author: Jeffrey Heninger.