Suppose you were offered $200 in gold to expose yourself to a deadly disease in an important scientific experiment: Would you do it?
Almost 120 years ago, a handful of volunteers took up the offer in American-occupied Cuba, including a 25-year-old nurse from the United States, Clara Louise Maass. The man in charge of the experiment was Army Major Dr. Walter Reed. His goal was to determine the cause of yellow fever, a leading killer in tropical climates.
Today, nearly 29,000 volunteers from around the globe have expressed their willingness to be exposed to the world’s current viral threat, COVID-19, if vaccines against it were to be tested by giving “challenge” doses of live coronavirus to participants. The hope is that such experiments might trim months off the clinical trial process, saving lives and livelihoods.
Scientists at Fred Hutchinson Cancer Research Center, which has hosted human challenge studies in malaria research, are playing a pivotal role in the roll-out of massive COVID-19 vaccine trials overseen by the National Institute of Allergy and Infectious Diseases, but as of now they do not include challenges with live virus.
Reed’s offer in 1900 would be worth $8,000 today, rising to $20,000 if a participant became ill. Not for the faint-hearted, the trial assigned one group to sleep in the soiled bedclothes of previous yellow fever victims; members of another were injected with a patient’s blood; while a third group was assigned to be bitten by mosquitoes. In a final phase of the study, four of 10 volunteers assigned to mosquitos died of yellow fever, including nurse Maass.
Reed’s research proved that yellow fever was transmitted by mosquitoes. It led to the draining of swamps near Havana, freeing the city from the scourge. Mosquito control was critical to the successful completion of the Panama Canal by the U.S. Army Corps of Engineers in 1914 — decades after France abandoned their dig after losing 22,000 workers to yellow fever.
The acclaimed Walter Reed National Military Medical Center, in Bethesda, Maryland, was dedicated in his honor in 1909, and the New Jersey hospital where Maass trained was renamed the Clara Maass Medical Center in 1952.
Now, faced with the worst outbreak of respiratory disease since the influenza pandemic of 1918-1919, Dr. Anthony Fauci, director of NIAID, is considering whether to add controlled human infection trials to support COVID-19 vaccine development.
Leading a popular charge to bring about COVID-19 challenge studies is Josh Morrison, a 34-year-old former corporate attorney and founder of 1 Day Sooner. His New York City organization advocates human challenge trials to speed up the process, not only to determine if a vaccine is effective, but also to identify biomarkers in volunteers that correspond with immunity — so- called correlates of protection — to inform other vaccine trials and help compare different candidates.
Within weeks of establishing a website to recruit potential participants in such trials, 1 Day Sooner had gathered the names of thousands of potential volunteers from 102 countries.
Researchers say challenge studies would enroll between 15 and 150 participants and would likely yield definitive results in about six weeks. The planned 30,000-person Phase 3 vaccine efficacy trials, which do not involve deliberate infection, are likely to take six months, even on the accelerated timescale sought by Operation Warp Speed, the Trump administration’s crash program to test, manufacture and distribute effective vaccines.
But Morrison said that if a successful challenge study could reduce vaccine development time by a single month, it could save hundreds of thousands of lives. Results from a challenge trial could convince vaccine makers to drop poorly performing candidates or to ramp up production early if evidence suggests their big trials will succeed.
“We don’t see challenge studies as a replacement for Phase 3 trials,” Morrison said. “What we’d like to see is having them during smaller Phase 2 trials, or alongside Phase 3. The aim is primarily to compare different vaccines against each other.” [Learn more about vaccine development and clinical trial phases.]
Morrison, who became interested in medical altruism when he donated a kidney to a stranger in need eight years ago, co-founded Waitlist Zero, an organization to encourage others to do the same. “That’s my day job,” he said.
He has parlayed that experience and his connections into an effort to raise $10 million to finance a COVID-19 vaccine challenge trial. Much of its focus would be to develop a strain and dosage of live COVID-19 virus that could pass regulatory scrutiny and be administered in a quarantined facility — a critical step expected to take three to four months.
Challenge trials have been critical to the success of vaccines for cholera and typhoid fever. A team of Fred Hutch scientists led by Dr. Jim Kublin and colleagues at the Seattle-based Center for Global Infectious Disease Research have conducted several challenge studies to test vaccines for malaria.
Such studies, carefully designed under Institutional Review Board guidance to balance risk and value to society, have demonstrated that controlled human infection trials can be done safely and ethically. But Kublin is concerned that that our understanding of the coronavirus, which was first identified only six months ago, make human challenge studies for COVID-19 problematic for now. “Our overall philosophy is ‘first, do no harm,’ and the best we can do to adhere to that is to have a very good idea what the risks are,” he said.
COVID-19 challenge trials must also clear some practical hurdles that raise questions about whether they can be completed any sooner than the large-scale conventional trials already beginning to queue up.
“Challenge studies have their limitations. They’re going to have an assessment of their scientific value, but the reality is that they take time,” said renowned virologist and former Hutch president and director Dr. Larry Corey.
As head of the Hutch-based operations center for NIAID’s COVID-19 Prevention Network, Corey will lead coordinated efforts to roll out large-scale clinical trials for at least five vaccine candidates on a compressed timescale. The first of these giant trials, of the experimental vaccine produced by Moderna Inc., is set to begin next month. In an interview published in JAMA, NIAID chief Fauci said he hopes trials will show efficacy for at least one vaccine candidate as early as November or December.
— Dr. Jim Kublin
There are several ways to reduce the risks of controlled human infection trials for COVID-19 vaccines, but they all come with drawbacks. A common technique in human challenge trials is to develop an attenuated strain of disease-causing virus so that if the participants get sick, they have less risk of serious illness. But in the high-stakes race for a COVID-19 vaccine, would a vaccine that stops a weakened virus still perform against the wild strain?
“There are groups working on an attenuated form that would be attractive for these kinds of studies,” said Hutch vaccine researcher Kublin. “I’d be more intent on entertaining these kinds of studies should we overcome those hurdles.”
Kublin has carried out malaria human challenge trials with the naturally occurring pathogen that can cause death, but he had at his disposal medicines that could cure the disease in participants as soon as signs of infection emerged. There are no such “rescue medicines” available for COVID-19 trials.
“As we currently entertain these challenge studies we are focused on the potential benefits, but there are also risks and consequences, and I am afraid that currently there is just too much uncertainty about them to make an informed decision,” Kublin said.
The most obvious way to reduce risk in a COVID-19 challenge trial is to limit participants to young adults, who for unknown reasons are statistically far less likely to die from this new disease. If such trials are launched, they would likely target healthy adults aged 20-29, whose risk of death in the pandemic has been 0.03%, comparable to that of donating a kidney. But will a vaccine that protects young people in a challenge study still protect senior citizens, who are most at risk for death?
Ethicists say it is important for volunteers in these trials to recognize the risks are real. For example, most vaccines that reach clinical trials fail. That means participants should not assume it is going to work. And in these carefully designed trials that infect volunteers with a live virus, they have an equal chance of receiving a potentially ineffective vaccine or a surely useless placebo.
“Even though the fatality rate for COVID-19 among young people is low, it is not zero,” said Dr. Ben Wilfond, director of the Treuman Katz Center for Pediatric Bioethics at Seattle Children’s Research Institute. Young volunteers should also be aware of recent research showing that those who survive serious bouts with COVID-19 may suffer long-term neurological or cardiac deficits.
Professor Seema Shah, a bioethicist at Lurie Children’s Hospital of Chicago, said that she believes controlled human infection trials can be designed to limit risk and provide significant social benefit to justify them.
“Let’s suppose we have a new vaccine this fall, but it is not perfect. It is not safe enough, or doesn’t work in certain populations, or is very expensive. We’d want to quickly prepare another one. A challenge study could be one way to bridge the data to the next trial,” she said.
Shah is the lead author of an influential article in Science, published in May, which laid out a framework for ethical challenge trials for COVID-19. The authors even addressed the question of whether volunteers should be paid, as is standard in most such trials — not in gold as in Walter Reed’s day, but in dollars. To compensate for their time in quarantine, it could amount to “several thousand dollars,” they wrote.
“Participants should be compensated for their time and effort, rather than being asked to subsidize the research. Fortunately, available data suggest that payment doesn’t compromise the ability to understand risks,” Shah said.
Ethicists such as Shah, and clinical trial researchers like Kublin at Fred Hutch, will be watching carefully as new studies provide added information about the biology and epidemiology of COVID-19.
“How our research community balances these complex equations of risk and benefit, timing and projected societal costs, will determine when and how these challenge studies begin — and end,” Kublin said.
Sabin Russell is a staff writer at Fred Hutchinson Cancer Research Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT, and a freelance writer for the New York Times and Health Affairs. Reach him at firstname.lastname@example.org.
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