Student reflection on Human Challenge Trials
Timothy Keith Hung MBBS 2026
For the past two months, I have been working as a research assistant at QMH, investigating the reactogenicity and immunogenicity of COVID-19 vaccines in adolescents. While looking at relevant studies and articles, one topic caught my eye — human challenge trials.
Human challenge trials are just as the name suggests — experimental trials involving humans as test subjects. Most clinical trials are done on animals, but results must often be extrapolated to estimate the effects on humans. Historically, human challenge trials have been used to aid and significantly speed up the development of vaccines for cholera, typhoid, seasonal flu, and other infections. However, as one might expect from experiments involving humans, the ethical issues are controversial.
To date, there have been three different types of human challenge trials that were proposed as the pandemics progressed. Back in 2020, when the mechanisms and effects of Covid-19 were still unknown, human challenge trials were called for to enhance our knowledge to increase our ability to treat the disease, e.g., testing the transmitting rate and reinfection rate. However, urges for them were soon put on hold due to the surging number of cases worldwide. The second time human challenge trials were called for was during the development of vaccines to speed up testing for rare side effects and efficacies. Most recently, people started proposing another round of human challenge trials to quickly validate and legalize new vaccines so that more vaccines can be distributed to countries in need of them.
By today’s standards, most human challenge trials of the past would be considered wholly unethical, and with good reason. Their notoriety is well earned as most of the well-known human trials of the past involved exposing subjects to inhumane conditions, resulting in something more resembling torture than experiment. These include German and Japanese experiments during World War II, US sexually transmitted disease experiments in Guatemala after the war, the Willowbrook hepatitis experiments that only ended in 1972, and far more sprinkled throughout history.
So, coming back to the modern human challenge trials, how are they different from their predecessors, and are covid-19 human challenge trials justified? Some say that human challenge trials are justified as while a few are exposed to some amount of risk, a far greater amount of benefit can be reaped by society, more so than conventional studies. This justification espouses a more utilitarian world view, believing that the end can justify the means.
Adding on to that, urgency is also an essential factor in the justification of human challenge trials. I believe that, in an ideal world, with enough time and testing, even the most rudimental study model can gather enough data to be clinically relevant. But the world is rarely ideal, and time is often a huge constraint.
Some bioethicists argue that in some cases, with great urgency, human trials are warranted. Using the Covid-19 pandemic as an example, cases grew exponentially by the hour; scientists did not have the luxury of developing a vaccine conventionally, which would usually take 3–4 years. They argue that if people are highly likely to contract the virus in the wild, why not inoculate them in a lab where they can be treated and observed?
As with other trials, the basic ethical requirements for clinical studies still apply, i.e., Respect for persons, beneficence, and non-maleficence — though more of a gray area in the context of challenge trials, justice, informed consent, etc. Added with the two justifications from above, we can get a feel for how the proposed Covid-19 challenge trials differ from some of its infamous predecessors.
Let’s look at the German Nazi experiments first, which from the name, already sounds ungodly. According to the US Holocaust Museum, the goal of German Nazi experiments was to “[improve] the survival and rescue of German troops; [test] medical procedures and pharmaceuticals; and experiments that sought to confirm Nazi racial ideology.” From the get-go, these challenge trials did not ask for the subjects’ consent, and there was no respect for the subjects — no autonomy was given nor the ability to withdraw from the trials at any point in time. Additionally, these human trials only benefit a very niche population; the number of people exposed and harmed potentially more than those who benefitted, so even from a utilitarian viewpoint, these trials are not justified. The urgency of the trials can also be called into question, as most of the trials can be done on animals with similar results. So regardless of how you look at it, the German Nazi experiments are not justified.
Turning to the Willowbrook experiment, which involved children’s exposure to strains of hepatitis in the 1950s. This experiment was quintessential to discovering the different types of hepatitis virus and paved the way for Hepatitis vaccines; however, the circumstances under which the experiments were performed were highly controversial. Over fourteen years, the experiment was conducted in an institution for developmentally disabled children; the experiment involved infecting subjects with hepatitis through serum transfusions and mixing fecal matter into their food. Krugman, the investigator, argued that this experiment was justified. There was over a 90% chance that admitted children would contract hepatitis sometime during their stay and that the subjects would be under close medical observation.
This scenario is similar to the debate behind the Covid-19 human challenge trials. It also calls to mind the trolley problem — whether to risk the lives of a few to save the lives of many — which, to be frank, can also be applied to most other human challenge trials, but that is a discussion for another day. The Willowbrook experiment differs from the Covid-19 challenge trials where the latter calls for informed consent directly from mentally component adults, the subjects in the Willowbrook experiment were mentally impaired children. Consent was only obtained from their parents, and most children were not aware that they were in a study and incapable of withdrawing from the experiments.
Moreover, as the Willowbrook state school was one of the few institutions for mentally retarded children, there was an excess demand for admission. Many parents were coerced into giving consent as joining the study was often one of the conditions for admission. This was the most common concern stated by the study’s critics. A critique I rarely see is that the hepatitis virus was not isolated when specimens were synthesized from fecal matter, and as a result, could contain other pathogens. This places the subjects at unnecessary risk and could also affect the experiment results.
Nevertheless, this could have been due to a lack of technological advancements rather than malintent or carelessness. In defense of the study, though, human immunogenicity is challenging to replicate in animals, unlike some of the Nazi experiments mentioned above, which could have been done on animals. And while there could have been better approaches and study designs, human challenge trials yielded tremendous benefits in the Willowbrook experiment.
After looking at some of the challenge trials of the past and comparing them to the current Covid-19 challenge trials, I believe that current ethical standards are a lot higher than before. All the subjects will be mentally competent adults who have Informed consent, and they will be compensated for their sacrifice. Additionally, they will be allowed to drop out of the trial at any time as long as it is deemed medically safe. So, without coming to any conclusions, we can objectively say that the Covid-19 challenge trials are a great deal more ethical than their predecessors. But then again, to err on the side of caution, only time will tell if these challenge trials were indeed necessary and justified.
