By Melinda Young

The most pressing research goal in decades is the race to produce a vaccine to cure COVID-19.

The United States — with more than 2 million COVID-19 cases and deaths exceeding 120,0001 — has pushed to expedite vaccine research. In May, President Trump launched Operation Warp Speed, with the goal of producing a COVID-19 vaccine by January 2021.2

While that short timeline might prove impossible, bioethicists and researchers say it may be possible to shorten the typical 15-year-plus vaccine timeline through a challenge trial. In this model, participants receive the study vaccine, the are deliberately exposed to SARS-CoV-2. Safety and efficacy are important, but the risk-benefit balance for study participants is weighed more heavily in favor of the greater public good.

“The entire plan for the development of a vaccine candidate needs to be evaluated to ensure it provides sufficient evidence of both safety and efficacy that potentially hundreds of millions of otherwise healthy people will be willing to be vaccinated,” says Alex John London, PhD, Clara L. West professor of ethics and philosophy and director of the Center for Ethics and Policy at Carnegie Mellon University.

“There are many organizations and companies with vaccine programs underway. More than 100 companies are trying to produce vaccines, and we’ve never had 100 companies working at the same time on a single disease,” said Arthur Caplan, PhD, professor of bioethics at NYU Langone Medical Center. Caplan spoke about the challenges of developing vaccines and treatments for COVID-19 at a May 13 web conference sponsored by WIRB-Copernicus Group.

“The goal of having a vaccine available quickly is one I don’t think is going to happen, even with massive effort and money poured in,” Caplan explained. “The usual timeline for getting a vaccine developed is closer to 15 to 20 years, and the fastest is six years. It takes a long time.”

Vaccine research sometimes lasts for decades and fails. “We’ve tried for 30 years to get an HIV vaccine, and they haven’t proven safe and effective,” noted Walter A. Orenstein, MD, FIDSA, FPIDS, fellow with the Infectious Diseases Society of America (IDSA), and professor and associate director of the Emory Vaccine Center. He spoke at an IDSA web conference on May 1.

“One of the advantages we have is there are many candidates, including eight vaccines in clinical trials and more than 90 vaccines in pre-clinical stages,” said Orenstein, professor in the department of medicine, division of infectious diseases at Emory University School of Medicine, and director of the Emory-UGA Center for Excellence for Influenza Research and Surveillance.

‘What Is Indefensible Becomes Defensible’

In a SARS-CoV-2 challenge trial, researchers would not wait for study participants to become infected. Instead, investigators would deliberately expose participants to the disease after attempting to immunize them, and study what happens.

“To put it mildly, that is ethically controversial,” Caplan said. “Is it worth taking the risk of compromising subjects to deliberately give them a disease?”

Caplan argued that because COVID-19 is killing so many people and years of waiting for a vaccine might result in many more deaths across the world, the benefits outweigh the risks of a challenge study.

“The stakes are so high and the impact on the world is so huge that, morally, what is indefensible becomes defensible,” Caplan stated.

There is no consensus among stakeholders, including ethicists, IRBs, and researchers, on the potential benefits of a challenge trial, says Karen J. Maschke, PhD, research scholar and editor of Ethics & Human Research with The Hastings Center in Garrison, NY.

“For example, the World Health Organization [WHO] says in its draft ethical framework for COVID-19 challenge trials — released on May 6, 2020 — that ‘It must be reasonable to expect that the potential benefits of SARS-CoV-2 challenge trials outweigh risks,’” Maschke explains.

When evaluating potential risks and benefits, research organizations should consider how these affect research participants, society, and third-party contacts of participants, she says.

Other ethicists have noted it is difficult to determine the potential benefits of a challenge vaccine trial because no one knows the degree and duration of naturally acquired and vaccine-derived immunity for those who receive the vaccine, Maschke explains. Also, most vaccines that are tested prove to be ineffective. Instead, IRBs and researchers should focus on the risks to participants and potential benefits to society of a SARS-CoV-2 vaccine, she adds.

The risks of a SARS-CoV-2 vaccine trial are predictable, and they include risks to bystanders, as well as the study’s volunteers, says Jonathan Kimmelman, PhD, James McGill professor and director of the biomedical ethics unit in the department of social studies of medicine at McGill University in Montreal.

“One additional variable to consider here is the uncertainty about complication and fatality,” Kimmelman says. “COVID-19 is still a new condition, and we don’t have a clear sense of mortality rates and risk factors for complications.”

Since the available information will change with time, IRBs should be asking whether the research community knows enough now to assess the risk, he adds. (See story on methods of reviewing a challenge vaccine trial in this issue.)

“Or, does it make sense to wait until that knowledge, and the knowledge about rescue medication, becomes available?” Kimmelman asks.

Any challenge studies involving SARS-CoV-2 should have sufficient social value to justify the study design. “But I don’t think the social value of a challenge study can be determined solely from looking at the protocol for that study alone,” London says. “In particular, proponents argue that the main advantage of such a study would be the prospect that it will shorten the timeline for vaccine development. But I am not persuaded that it will do that.”

With unknown benefits to participants and better-known risks of a challenge vaccine trial, transparency is paramount. “If research regulators permit one or more challenge trials to go forward, they should be transparent about what risk-benefit assessment they applied, and about how they determined which individuals should be eligible to participate,” Maschke says.

In addition to questions about safety to research participants and those around them, there also is a question of whether a challenge study would produce enough information about a potential vaccine’s safety and efficacy in the populations most at risk of serious illness and death from COVID-19. For instance, no one would propose purposely enrolling at-risk people to participate in a challenge trial for the vaccine because it would endanger their lives. But, if they are not part of the vaccine trial, how will any vaccine be shown to be effective for those populations?

“We cannot skimp on the assessment of safety, including the safety profile of the vaccine in older people and other people in high-risk categories,” London says. “Because other approaches will generate this information in the course of testing vaccine efficacy, I am not convinced that challenge studies will save time once all things are considered.”

WHO recommends a specialized, independent committee — at the national or international level — review challenge studies in conjunction with local ethics boards, Maschke notes.

“I support a heightened approach to ethical review, which should be independent of the funding bodies, the researchers, and the institutions where the trials will be conducted,” she says. “Of note, the WHO framework says that research participants should be compensated for any study-related harms.”

This compensation might include access to critical care services, free treatment, and compensation for research-related injury. “My view is that from an ethical standpoint, trial participants who become ill should be treated for free and receive some type of compensation for injuries related to their research participation,” Maschke says. “However, to my knowledge, no one has said who should pay for injury-related harms or for medical treatments if diagnosed with COVID-19. In my view, the trial sponsors/funders should bear these costs, as well as the costs associated with the need for extra hospital beds, personal protective equipment, and medical support staff dedicated to the study.”

This is so the clinical trial is not competing for access to these resources during an ongoing medical response to the pandemic, Maschke explains.

“In addition, a detailed containment, contact tracing, and medical care plan should be in place in the event that the research staff or other third parties become infected,” she says.

REFERENCES

  1. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19) cases in the U.S., June 15, 2020. https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html
  2. Department of Health and Human Services. Trump administration announces framework and leadership for ‘Operation Warp Speed,’ May 15, 2020. https://www.hhs.gov/about/news/2020/05/15/trump-administration-announces-framework-and-leadership-for-operation-warp-speed.html