As the number of COVID-19 cases continues to increase, it is clear an effective vaccine is urgently needed. With experts predicting 12 to 18 months before a vaccine is available, some scientists are considering unconventional ways to speed up the process. One highly debated method involves injecting healthy adults with live coronavirus.
This strategy — called a challenge trial — would normally never be considered to test a deadly virus for which there is no effective cure, but these are extraordinary times.
Vaccine trials are usually slow and cumbersome because researchers have to recruit thousands of patients and then wait for some of those people to be exposed to the virus naturally in their communities.
In a challenge trial, healthy adult volunteers are divided into two groups. One group receives a placebo and the other receives the potential vaccine. After enough time has passed for the vaccine to cause the appropriate protective immune response, both groups are then injected with the virus, revealing whether or not the vaccine offers some level of protection.
“If all that you care about are outcomes — how many people are exposed to the pathogen in question and then are either infected or protected by the vaccine? — then challenge studies look like a shorter and easier way to get to the same outcome,” said Dr. Alex John London, the Clara L. West professor of ethics and philosophy and the director of the Center for Ethics and Policy at Carnegie Mellon University.
Some scientists propose that after phase I and II trials to determine the proper dosage and initial safety of a potential vaccine, the traditional phase III could be skipped in favor of a challenge trial. Considering that the challenge trial is one of two steps proposed to replace phase III, experts are debating how much time would actually be saved with this plan.
“It would be important to understand how much time a challenge trial could save to understand whether it's justified — given risks for participants,” said Dr. Jennifer Miller, Ph.D., an assistant professor at Yale School of Medicine and founder of Bioethics International and the Good Pharma Scorecard. “How much time needs to be saved in order to justify the risks to participants? A month probably isn't long enough, but what about five months?”
Only healthy adults with no underlying conditions would be permitted to undergo the virus challenge in the first step designed to test the effectiveness of a coronavirus vaccine. The next step, designed to test the safety of the vaccine, would enlist the help of the adults who are most at risk to severe symptoms of COVID-19, including the elderly and people with underlying medical conditions. During this phase, volunteers would be given either a placebo or the potential vaccine, but would not be injected with the virus. The aim would be to determine if there were any side effects associated with the vaccine. Once the potential vaccine proved safe in this more vulnerable group, it would be green-lit to go to market.
Challenge trials have been used before, but usually in the context of a disease for which there is already a cure, like malaria. There is no proven cure for the novel coronavirus, adding to the risk associated with a challenge trial. Giving volunteers the live virus could result in severe consequences.
“We need to think through approach, trial and implications with guidance before we move quickly and have unintended consequences from a challenge trial,” said Dr. Jay Bhatt, former medical chief at the American Hospital Association and an ABC News contributor. “This trial can lead to individuals having severe infection, complications and even death. Young, healthy individuals may be at lower risk, but it isn't zero.”
London agreed, adding, “In a challenge study, researchers are directly infecting people and many people feel uncomfortable with the idea that some people are going to be sick and potentially injured or even die because researchers infected them with a particular pathogen. So one danger is that in challenge studies we are doing things to people that some people find objectionable — knowingly exposing them to pathogens that can harm them.”
The matter is an ethical dilemma. Should fully informed adults be allowed to risk their lives for the good of society? Doctors, nurses, firefighters, police and military members routinely choose to risk their safety for the benefit of others. Is this any different? The website 1 Day Sooner is already recruiting volunteers who are willing to take that risk.
“A scientifically rigorous and responsibly designed trial could have high social value — notwithstanding, the risks to trial participants should be minimized,” said Miller, noting that volunteers should only include people who are least likely to die of infection.
“Trials, including challenge trials, should be responsive to a population's needs,” she said. “In this case, trial participants should be those at high risk of contracting the coronavirus, independent of participating in the trial — for example, because they live in a virus hotspot. This is critical.”
Bhatt echoed, “When doing a trial like this, we need to consider the implications for justice. This trial has to be conducted in a fair, equitable and ethical way. … I would be very concerned about the vulnerable who struggle with literacy, or are poor, or are with their backs against the wall being taken advantage of. Health equity is also an ethical imperative here.”
History is littered with examples of unethical experiments on human beings.
In 1932, the Public Health Service and Tuskegee Institute set out to observe the natural course of syphilis. They enrolled 600 black men who were told they were being treated for “bad blood.” While they received some compensation for participating — free medical exams, free meals and burial insurance — they never did receive proper treatment for their disease.
Even when penicillin, the cure for syphilis, became available in 1947, the researchers failed to offer it to the participants. An advisory panel declared the Tuskegee Study “ethically unjustified” and shut it down 40 years after it began. A couple years later, the Belmont Report was published, one of the cornerstones for ethical principles in human research.
Today, safeguards such as institutional review boards protect the welfare and rights of study participants to ensure such atrocities against medical volunteers are never repeated. Likewise, the three phases of clinical trials required by the Food and Drug Administration before a drug or vaccine is approved are designed to protect us.
Nevertheless, proponents of challenge trials maintain that participants would be protected. Selected participants would be young, healthy adults with low risk of severe response to infection if they were naturally exposed to the novel coronavirus in the course of their everyday lives. They also argue that participants would receive close monitoring and the best treatment available if they were to become sick — not withstanding a shortage of treatment resources due to a health care system overwhelmed past surge capacity. Some researchers have also recommended that the volunteers not only be protected but financially compensated as well.
According to the 1 Day Sooner website, “There is a consensus among ethicists that trial participation should in no way cost participants money. Therefore, participants should be compensated for travel expenses, lost work time, injuries, follow-up care, and the like.”
“Ethicists debate the ethics of paying research subjects, partly out of worries about exploitation and undue inducement,” Miller said. “In my judgement, assuming the trial has been IRB approved, reasonable compensation for participation is likely both fair and appropriate.”
“On the one hand, we often do give people hazard pay for taking jobs that have more risk. So some people think we should pay people a lot for being willing to contribute to science in this way. On the other hand, being a subject in a challenge study isn't like most other kinds of work. They aren't paying you to do something, they are paying you to let them do something to you,” added London. “Rather than working a lab, the idea is that your body is the lab and some people feel uncomfortable with the prospect of paying people for the privilege of using their bodies in this way.”
The dilemma that challenge trials present, aside from possibly being more expedient, could also cause scientists to miss out on a deeper or better understanding of the virus.
“Challenge studies may be a quick way to answer the question of whether a vaccine candidate provides protection against a particular pathogen, but that is only one of the many questions that are important in drug development,” said London. “And when candidates fail to show protection we can learn a lot from those failures and that knowledge cycles back into the way that we develop other vaccines for the same condition. And often, these are things that we need to know in order to develop something that is both effective and safe. So, challenge studies may offer a faster path to answering one question, but traditional designs may do a better job of filling in broader details that we ultimately need to produce something we are confident in rolling out to millions of people.”
Angela N. Baldwin, M.D., M.P.H., is a pathology resident at Montefiore Health System in the Bronx and a contributor to the ABC News Medical Unit.