The idea of intentionally infecting volunteers to speed up development of a COVID-19 vaccine has piqued a lot of interest. But that’s not the only way human challenge trials could be used.

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The Basics: Human Challenge Trials

Human challenge trials — where healthy, consenting, adult subjects are given a vaccine and then infected or “challenged” with a live virus — date back to 1796 and the smallpox vaccine. That experiment — where physician Edward Jenner injected his gardener’s 8-year-old son with a vaccine and then exposed him to smallpox — as well as many others over the last two centuries would not pass modern ethical standards.

Over the last few decades, however, ethical oversight and scrutiny of human challenge trials has increased significantly. Researchers usually spend at least a year identifying the proper dosage and developing a study model that must be approved by an independent review board and the FDA.

More than 120 challenge trial studies were published in the last decade, with some playing an important role in new vaccines being approved. They are generally only considered an option for diseases with known treatments or which scientists know a lot about such as malaria, dengue, cholera and influenza.

The Latest: Challenge Trials and COVID-19

Even though relatively little is currently known about COVID-19, including how to effectively treat it, a growing number of scientists and policymakers think challenge trials could be a viable option to speed up development of a vaccine.

One proposal argues that scientists could save 3 to 6 months if they replaced the final step before the FDA approves a vaccine — where researchers prove the vaccine actually works — with a challenge trial. This would come after initial safety testing and be paired with an additional safety trial.

This idea has spurred more than 20,000 people around the world to volunteer for such a trial through the online advocacy group 1Day Sooner, and prompted studies of the idea by the World Health Organization and the National Institutes of Health.

The Tradeoffs: Different Uses of Challenge Trials

While using challenge trials to speed up vaccine development has captured the imagination of many in the scientific, policymaking and lay communities, it is far from universally endorsed. 

Concerns include the risks of infecting people with a virus scientists know so little about, whether the results would be generalizable to the broader population and whether participants fully understand the risks. (Even those currently opposed to challenge trials say it’s worth preparing for them now since that process will likely take 6 to 12 months and much could change that alters the tradeoffs of a challenge trial, such as a failed vaccine candidate and/or the discovery of a successful treatment.)

It is also not the only, or even the most likely, use of human challenge trials for COVID-19, according to experts.

Replace

The Idea: Replace a traditional Phase III efficacy trial with a challenge trial to prove a vaccine works.

Pros:

  • Would only require a few dozen study participants as opposed to thousands.
  • Would not have to wait for participants to be exposed in the course of their normal lives, which can take years.
  • Could speed up emergency use authorization of vaccine by 3 to 6 months, according to supporters.

Cons: 

  • FDA rarely approves vaccines without data from a large field trial.
  • Would require infecting people with deadly virus without proven treatment.
  • May not meaningfully speed up process with some traditional field trials expected to start this summer.

Prioritize

The Idea: Use challenge trials to identify the most promising vaccine candidates to advance to field trials.

Pros:

  • Could limit the number of time-consuming field trials required to identify effective vaccine.
  • Would still allow regulators access to data from large field trials before approving vaccine.

Cons: 

  • Still requires exposing volunteers to virus without known treatment.
  • Might not save as much time as replacing field trials.
  • Requires broad cooperation among vaccine producers.

Immunity

The Idea: Infect people recovered from COVID-19 to learn more about how immunity to COVID-19 works.

Pros: 

  • Identifying what makes people immune could make it easier to get people back to regular life and develop vaccines.
  • Would involve volunteers who have already recovered from COVID-19 and should be at lower risk for serious illness.
  • Would not disrupt the normal vaccine development process.

Cons: 

  • Would not as directly speed up vaccine development process.
  • Still requires exposing volunteers to virus without known treatment.
  • Lower perceived benefit may make it more difficult to recruit volunteers.

Transmission

The Idea: Test how COVID-19 passes by infecting one person and pairing them with a non-infected person.

Pros: 

  • Studying early and asymptomatic transmission is very difficult.
  • Better understanding how the virus spreads could allow more targeted public health efforts and easing of broad-based restrictions.
  • Would not disrupt normal vaccine development process.

Cons: 

  • Would not directly enhance vaccine development process.
  • Still requires exposing volunteers to virus without known treatment.
  • Lower perceived benefit may make it more difficult to recruit volunteers.

Episode Transcript and Resources

Episode Transcript

Note: This transcript has been created with a combination of machine ears and human eyes. There may be small differences between this document and the audio version, which is one of many reasons we encourage you to listen to the episode!

Dan Gorenstein: As some states start to reopen and ease physical distancing, the message from most experts remains clear: The only true way back to “normal” is a vaccine. 

In hopes of getting that as soon as possible, people around the globe are volunteering to be human test subjects — to be intentionally injected with the coronavirus. 

Now, scientists, top health officials and pharmaceutical executives are taking very seriously an option that would normally be unthinkable.

Today, from the Annenberg Studio at the University of Pennsylvania, we explore how scientists could ethically and safely infect people to speed up the fight against COVID-19.

I’m Dan Gorenstein, this is Tradeoffs.

Lehua Gray knows the risks of volunteering to be infected with SARS-CoV-2, the virus that causes COVID-19.

Lehua Gray: It is a disease that doesn’t have a cure and is something that could possibly kill you. Me. Could possibly kill me.

DG: A friend shared a journal article describing what are called human challenge trials, where healthy, young, consenting adult volunteers are intentionally infected to speed up vaccine development.

The article suggested this kind of study could shave three months off the time it would take to get a COVID-19 vaccine.

LG: Three months would be huge. Three months could save a lot of lives.

DG: The 32-year old weighed the personal cost. She weighed the larger societal benefit. And, she volunteered herself for science. 

Actually, Lehua was among the first few thousand people to sign up through the online advocacy group 1Day Sooner back in April.

As of May 17, 23,086 people have now signed up with numbers growing every day.

Seema Shah is a bioethicist at Lurie Children’s Hospital of Chicago and one of the world’s top experts on when it’s OK to put people at risk for the benefit of others. 

She says infecting volunteers for vaccine research is a common tool under certain conditions.

Seema Shah: They’re typically used when either there’s a treatment that you can give people, or we know a lot about the disease and how to manage it.

DG: Cholera, malaria, influenza. Researchers have five months of data on the coronavirus meaning little is known about how to protect Lehua or any other human test subject. 

But Seema says the need for a vaccine is so urgent, there’s a growing camp of scientists and bioethicists who think this moment warrants a break from standard protocol.

SS: We’re all looking for a way out of this pandemic, and the thought of a novel, innovative idea that even sounds a little bit crazy the first time you hear it, it sounds like it might be a way out. 

DG: Not all scientists and ethicists are on board, but that hasn’t stopped the idea from catching fire. 

In April, 35 bipartisan members of Congress urged the FDA to consider challenge trials.

Johnson and Johnson told the Financial Times the company would do challenge trials if OK’d by ethicists.

Working groups at the World Health Organization and the National Institutes of Health are now both exploring the issue.

Seema, who is part of the WHO group, says much of the excitement has centered on one particular use of intentionally infecting people.

SS: You could use challenge studies to replace the step of efficacy testing for a vaccine.

DG: Here’s the step she’s talking about replacing:

Normally, researchers recruit thousands of people, give half of them the vaccine and then let them live their regular lives to see if they’re protected from disease.

This can take years. 

Advocates of challenge trials say you can save 3 to 6 months by infecting a few dozen volunteers with the virus, giving half of them vaccine and not giving it to the other half, then seeing what happens.

If the vaccine works, and the researchers are confident it’s safe, then it’s off to the FDA.

This is the home run approach.

Sfx: Home run

DG: Or maybe the inside the park home run approach. 

Instead of the usual deliberate trot around the bases of vaccine development, scientists could sprint home going from a promising candidate to a widely distributed vaccine.

But before even stepping into the batter’s box, federal regulators have to sign off.    

In the U.S., the FDA must approve any vaccine, and Seema says they rarely do that without evidence from the big, time-consuming field trials.

SS: They’re often concerned about whether giving someone a virus in a non-natural way, who’s a young, healthy volunteer is going to tell you enough about how well the vaccine works to then feel confident it’s actually going to work in the general population.

DG: There are other concerns too.

Scientists would be infecting people with a deadly virus that we don’t have a sure-fire way to treat.

And some even question how much time this would save with some vaccines expected to start normal field trials this summer.

An FDA spokesperson said any decisions about using challenge trials will be made on a case-by-case basis. 

Most of the conversation over the first few months of the pandemic has focused on this home run approach.

But if people are going to be intentionally infected for research, there are a few other uses that experts think are more likely.

Sticking with the baseball metaphor here, if replacing field trials with challenge trials is a home run, figuring out how to prioritize the hundred plus vaccine candidates is more like hitting a double. 

Baseball announcer: That’s a sharply hit ball down the third base line.

Zeb Jamrozik: Having 100 potential vaccine candidates is great, but it also creates difficulties.

DG: Zeb Jamrozik is a physician and bioethicist at the Monash Bioethics Centre in Melbourne, Australia. We spoke to him via Zoom.

ZJ: If the first or second vaccine doesn’t turn out to work, then we need to select among the next 10 vaccines or 20 vaccines that are ready for human testing.

DG: Doing each trial one after another or even all at once would be very difficult and require tens of thousands of people across the world.

ZJ: We could test 10 or 20 vaccines in a challenge study in a short space of time and decide which three of those vaccines look the most promising. And then just test those ones.

DG: While this still saves some time, regulators would get their traditional big field trial to look at before greenlighting a vaccine for the general public.

Then there are reasons we might infect volunteers that feel even further away from finding a vaccine, approaches where scientists are just trying to get on base. 

Johns Hopkins vaccine researcher Anna Durbin has developed challenge models for a dengue vaccine and is working on one for Zika. 

She says challenge trials could help us learn more about how immunity works.

Anna Durbin: Can you develop antibodies to COVID-19 that would protect you from another infection with COVID-19 in the future?

DG: Scientists could infect people who have already recovered from COVID-19 to see if they get sick again and if they don’t, they could try and figure out what in the body is protecting them.

Or they could try to learn more about how the virus spreads.

AD: Challenge one person and then you have an unchallenged person in there, and see if that virus is able to be transmitted. And if so, is it just touching surfaces? How close do you have to be? How long do you have to be in contact?

DG: Risking your life to study how a disease spreads may feel less glamorous, more like a walk than a home run.

Scientists, regulators and especially the people volunteering to be infected would have to decide whether the possible benefit to society was worth the personal risk. 

Lehua Gray says she’d need to see a direct line between her role and some kind of game-changing breakthrough.

LG: Whatever I was volunteering for, I would want to have some confidence that it was reducing risk to everyone else.

DG: Even scientists and ethicists who are wary of challenge trials think we should start preparing for them now, so that when the time comes to actually decide if it’s worth infecting people like Lehua, we’ll be ready.

I’m Dan Gorenstein, this is Tradeoffs.

Episode Resources

Select Research and Coverage of Human Challenge Trials:

Support for Human Challenge Trials for COVID-19:

Episode Credits

Guests:

Music composed by Ty Citerman, with additional music from Blue Dot Sessions.

This episode was reported, produced and mixed by Ryan Levi.

Additional thanks to:

Tom Darton, Josh Morrison, Pieter Neels, Peter Smith, the Tradeoffs Advisory Board…

…and our stellar staff!

Ryan is the managing editor for Tradeoffs, helping lead the newsroom’s editorial strategy and guide its coverage on its flagship podcast, digital articles, newsletters and live events. Ryan spent six...