What is a Human Challenge Study?

In a human challenge study (also called a human challenge trial, controlled human infection model (CHIM), or controlled human infection study (CHIS)), healthy, adult participants volunteer to be exposed to a disease. This is usually done to test a vaccine, but can also test treatments or reveal other important information about a disease.

While they may sound strange, they are hardly rare. Between 1980 and 2021, over 15,000 people have participated in a human challenge study for one of over two dozen different diseases — with zero recorded deaths, and only a handful of cases requiring emergency medical care (Adams-Phipps et al. 2023). Today, human challenge studies are done with ethical scrutiny and oversight to make sure they are scientifically useful and don’t involve unnecessary risk for participants.

In the past, however, medical testing (whether a challenge study or other type) often denied patients —particularly ones who are poor, female, or people of color — the right to informed consent and could be horrifically unethical. Mistreatment of medical volunteers has not disappeared from the world, either. 1Day Sooner is dedicated to the support of ethically conducted medical research, and will advocate for volunteers first and foremost, keeping in mind the imperative to avoid the serious mistakes of the past and to prioritize volunteer consent, autonomy, and safety.

Some Past Challenge Trials

Smallpox

Influenza

Cholera

Malaria

Zika

The first-ever vaccine, for smallpox, was developed by deliberately exposing people to infection. Physician Edward Jenner created this early version of a vaccine in 1796 by taking samples from a cowpox sore and putting it into the skin of James Phipps—his gardener's eight-year-old son. Jenner then exposed Phipps to smallpox, but the child did not become infected. Jenner went on to vaccinate around 6,000 other people using the same technique and tested the effectiveness of his method by exposing them to smallpox. Jenner’s vaccine allowed us to eradicate smallpox from the global population 200 years later.

Eradicating smallpox is one of humanity's greatest achievements, but how the first vaccine was developed—by exposing an eight-year-old boy to the disease—was unethical, and would never be allowed today.

The first well-described influenza challenge study was published in 1937 and involved the inhalation of a human influenza virus. Because only a small number of volunteers (20%) developed mild disease, this model was used across studies for many decades. These challenge studies allowed us to understand more about the human immune response to influenza and test preventative and therapeutic measures.

After the 2009 H1N1 pandemic, researchers at the United States National Institute of Health (NIH) began using human challenge models to investigate and develop countermeasures against influenza A. They began with a dose-finding study in 46 participants, which led to the development of a challenge virus. This virus was subsequently used to challenge participants who had received a broad-spectrum influenza vaccine candidate, FLU-v. The results of this challenge trial demonstrated the FLU-v vaccine was safe, and induced a long-lasting immune response.

In 1976 the U.S. National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, began conducting challenge studies with cholera, which allowed scientists to realize that their leading vaccine candidate was not going to work. These studies also gave us a better understanding of effective immune responses and identified a new vaccine candidate. This candidate, known as Vaxchora, is the first vaccine approved by the US Food and Drug Administration (FDA) for prevention against cholera infection. The approval process relied heavily on the results of the cholera challenge studies conducted at NIAID.

Malaria challenge studies have played a key role in speeding up the development of malaria candidate vaccines for many years now and are routinely used in the United Kingdom, United States and the Netherlands to accelerate the process of vaccine testing. In these studies, healthy adult volunteers have either been exposed to the bites of infectious mosquitos or injected with the blood-stage of the malaria parasite, in a highly controlled environment. They are then monitored regularly for signs of infection and treated with antimalarial drugs if they develop a malaria infection. The malaria vaccine currently being deployed in three countries in Africa was developed using malaria challenge studies.

In 2016, researchers suggested using a human challenge study where healthy volunteers would be intentionally exposed to the Zika virus, which was a new and growing public health concern at the time. The plan was to use the study as an opportunity to understand the early stages of Zika infection and test whether vaccines would offer protection. The trial was supposed to run in the United States, using healthy volunteers who would not otherwise be exposed to Zika. However, two potential funders of the trial—the NIAID and the Walter Reed Army Institute of Research—had ethical concerns. An independent ethics committee of relevant experts in 2017 offered an early ethical framework for the Zika trial and decided that Zika challenge studies could be ethically justified, but that it was too early to conduct one at the time. Their two main concerns were that (i) researchers did not have a good enough understanding of how the virus was transmitted, which meant it would be difficult to protect non-volunteers, and (ii) existing studies were looking at Zika so it was not clear whether a Zika challenge study was needed to speed up vaccine development.

Less than two years later, however, the Zika epidemic had subsided, and it was clear that it was no longer possible to conduct field trials to test vaccines. Additional research also made the nature of transmission more clear, and Baltimore, MD researchers began conducting Zika challenge trials in 2022.