It’s perhaps the most capital-R Romantic research proposal in over a century: intentionally expose some volunteers to the SARS-CoV-2 virus (the COVID-19 causing agent) in an attempt to accelerate coronavirus vaccine development.
Arm some volunteers with a promising vaccine; leave others naked and vulnerable; and intentionally introduce to them the novel coronavirus.
The benefits could be substantial, although not all scientists agree; University of Maryland vaccine researcher Myron Levine told Science that with the high infection rates out in the wild, it may not really speed up the process that much.
But facing a pandemic, those potential benefits may be worth that risk. Rutgers bioethicist Nir Eyal, Harvard epidemiologist Marc Lipsitch, and tropical epidemiologist Peter G. Smith of the London School of Hygiene and Tropical Medicine propose that it might be.
And volunteers — some 9,382 of them, as of May 1st — have agreed.
Accelerating Coronavirus Vaccine Development
A study involving purposeful exposure is known as a human challenge trial (HCT).
“They’re particularly useful when you’ve got a lot of potential products you want to test,” says Andrew Catchpole, chief scientist at hVIVO, a contract research organization.
Because an HCT guarantees infection, they can accelerate vaccine development by months. And when it comes to novel coronavirus vaccine development, these months are precious.
They can also kill their volunteers.
Because human challenge trials guarantee infection, they can accelerate vaccine development by months.
There are two main ethical considerations when considering an HCT, says Ruth Faden, founder of the Johns Hopkins Berman Institute of Bioethics.
“First and foremost, you need to have a known, proven, and effective countermeasure” to the disease, Faden says.
“What you really need to understand also is who should be in the trial in the first place. Because unless you’ve got a countermeasure that is so perfect that it’s gonna knock this thing out regardless of who gets it, there may be some people, depending on the disease, for whom it may be worse, if for whatever reason your effective countermeasure failed.”
Neither of these conditions are currently met for SARS-CoV-2.
Influenza and the respiratory virus RSV both kill people, Catchpole notes, and both are studied using HCTs. “But the risk factors for underlying health conditions are much better understood,” he says. “People could have COVID-19 risk factors we aren’t even aware of yet.”
But these ethical concerns are under normal conditions. The current pandemic is anything but.
“This is not a context in which you just throw away an idea or a proposal because we’ve never done this before,” Faden says. The proposal, right now, doesn’t fit the ethical criteria of a typical HTC for a vaccine. But it cannot be ruled out. “Is this a context where we should consider going where we otherwise would not go?”
Everyone Freethink spoke to believes that a human challenge trial will, at least, be thoroughly considered.
“I don’t know whether this idea is going to fly,” Peter G. Smith says. “But given the conversations I’ve had so far, I think it’s going to be taken very seriously.”
The Proposal
To seriously consider their idea, we need to understand the proposal’s possible benefits. Novel coronavirus vaccine development would theoretically need to follow the same three phase process as any other vaccine.
In phase 1, volunteers are given the vaccine. The idea is to make sure the vaccine per se is safe. Moderna’s RNA-based vaccine has entered phase 1 already in Seattle. Phase 2 trials are larger. They look to test vaccine safety, immune response, and side-effects. Phase 2 also checks how effective the vaccine is in natural conditions.
Phase 3 trials are larger still, sometimes encompassing tens of thousands of people and taking place over six to nine months. These are meant to examine the vaccine’s effectiveness and safety in a wide variety of people, over a long enough time that people have a chance to be exposed in the wild.
After completing phase 3, a company can apply to regulatory bodies like the FDA for permission to put the vaccine to use.
This is not a context in which you just throw away an idea or a proposal because we’ve never done this before.
Ruth Faden
The HCT would instead come in after the phase I studies. It is meant to dramatically shorten the time between clinical trials and licensure by rapidly proving how effective the vaccine is.
“What we’re suggesting is that after … finding a vaccine which appears to be efficacious in the challenge studies, then one would rapidly do what would normally be called a phase 2 study,” Smith says.
This placebo-controlled trial would be larger than the usual phase 2, around 3,000 people, to look to see that the vaccine is creating an immune system response in people — including those who are older and most at risk — and check for short-term adverse effects.
“All that will be done before we’re suggesting widespread use of the vaccine,” Smith says.
Hewed to the bone, the proposal is fairly simple. First, researchers will need a pool of volunteers who have never had COVID-19 and are fully informed about the risks they are about to take — and a realistic view of the possible benefits. The trial would then take place in a special biosafety facility — BSL-3 — so that the virus could be studied and contained as safely as possible.
For ethical reasons, the volunteers should have a low risk of severe sickness, likely young people with no underlying health conditions. They should also live in areas where they are likely to become infected anyway, like major cities. After they are observed for a period of time to make sure they aren’t already infected with SARS-CoV-2, they will be split into randomized groups. Some of them will receive a COVID-19 vaccine candidate. Others, a control group, will receive a placebo.
By purposefully challenging everyone with SARS-CoV-2, the researchers can compare the vaccine group and the control group to see if, and how well, the vaccine works. Researchers wouldn’t have to wait for the virus to infect enough people naturally in the wild to see the data they need.
Milkmaids and Mosquitos: The Dangers and Difficulties of Human Challenge Trials
The data was an eight-year-old boy.
As a medical student, country doctor Edward Jenner noticed something strange: milkmaids who had caught cowpox did not catch smallpox. In 1796, Jenner piloted a human challenge trial against one of our most feared diseases.
That May, Jenner took fluid from a cowpox blister and scratched the skin of young James Phipps, infecting him with the virus. After a brief spell of sickness, Phipps quickly recovered. In July, Jenner purposefully challenged Phipps with smallpox.
He did not develop the disease.
Over a century later, yellow fever and other tropical diseases killed more soldiers than combat did in the Spanish-American War. Determined to fell this foe, the United States Army Yellow Fever Commission was created, led by Major Walter Reed.
In the summer of 1900, the Commission used a human challenge trial with mosquitoes to prove, once and for all, Cuban doctor Carlos Finlay’s theory that female Aedes aegypti mosquitoes were the cause of yellow fever. Commission member Jesse W. Lazear was bitten by one of those mosquitoes, likely on purpose, possibly by accident. The other challenged subjects survived.
Lazear did not.
These famous examples make starkly clear their benefits and risks. When considering Eyal, Lipsitch, and Smith’s proposal for coronavirus vaccine development, one thought casts a long shadow: Are those benefits worth the risks?
“That’s the big question,” says Seema K Shah, associate director of the Bioethics Program at Northwestern’s Lurie Children’s Hospital. “And I don’t know that we have enough information to answer it yet.”
Finding the proper viral dose may be the most daunting scientific obstacle.
Answering that question means looking at the unique ethical and scientific challenges of coronavirus vaccine development. Those challenges are deeply intertwined, and they stem from the fact that SARS-CoV-2 is so new.
“Obviously, the feasibility — or the acceptability, if you like — of doing these sort of challenge studies will be greatly changed if, in the next few months, there are effective antiviral treatments developed,” Smith says.
The ability to treat volunteers who develop symptoms would lower the risk substantially; a technical solution to an ethical problem, Faden says.
Achieving those symptoms poses scientific and ethical challenges of its own. The subjects must be exposed to the SARS-CoV-2 virus enough to develop the COVID-19 disease; that’s the whole point. But it would be wrong to accidentally cause an infection more severe than they would likely get naturally, if exposing them to a higher viral load causes a more severe version of the disease.
The proper balance will need to be figured out before the challenge could begin. And before finding the viral dose, the right strain of the coronavirus to use and how to produce it would also need to be figured out.
“As far as I’m concerned, I don’t know how long that would take,” Smith says. It is perhaps the proposal’s most daunting scientific obstacle. But, Smith says, these steps could be taken while vaccine candidates are still in animal studies or phase 1.
But a properly calibrated viral challenge may still make the subjects sick. With no currently known treatments, the HCT would instead use two factors to decrease risk. One is using subjects most likely to weather COVID-19 well. This puts them at a low risk of catching a severe case and an even lower risk of dying. The other is providing them access to the finest available healthcare and constant observation.
The risks are deeply real. But so, too, are the benefits.
Providing that medical treatment is its own sticky wicket, however. Does making sure a small group of subjects and researchers have access to medical care and personal protective equipment put the community at large at risk?
“I think it’s really important that doing a challenge study doesn’t hinder the outbreak response, or prevent people from outside the research getting the treatment they need,” Shah says.
It is, like so many other elements of a COVID-19 human challenge trial, a question without a definite answer, being asked at a time when the ability to be definitive is an immense luxury.
“I think there is a very important ethical debate that needs to be had,” Catchpole, the chief scientist at research firm hVIVO, says. “Certainly, we are in unprecedented times, and in unprecedented times unprecedented measures are required.”
Beyond the bioethicists and scientists, there is one more group of stakeholders: the research subjects themselves.
The Volunteers
Josh Morrison’s got over nine thousand volunteers ready to be research subjects.
Morrison is no stranger to Good Samaritan sacrifice; he donated his kidney to a complete stranger in 2011. Moved by the experience, he co-founded Waitlist Zero — where he serves as executive director — to advocate for kidney transplant donors, patients, and policy.
Morrison helped create the COVID Challenge, a clearinghouse for volunteers to register as prospective subjects for future studies and to advocate for coronavirus vaccine development to be accelerated with HCTs.
“We asked people ‘what are your reasons for volunteering?'” Morrison says. “And it’s just really inspiring and amazing to read through these.” He has permission to share some, and their words offer a glimpse into their mindset.
“Philosophers in my tradition (Judaism) teach, ‘For anyone who saves one life, it is as if they had saved a whole world,'” reads one. “Given the opportunity to participate in a life-saving endeavor, I ought to take it. I’m young and healthy and extremely lucky in many ways, and this is a way to share my good fortune with others.”
I am absolutely down to be on the bleeding edge of getting completely BTFO by corona in the name of saving lives.
Trial participant
Others took a more pugnacious approach: “I’m the chief technical officer of a biotech company, so I am absolutely down to be on the bleeding edge of getting completely BTFO (blown the fuck out) by corona in the name of saving lives. Sign me up bro.”
And one placed their volunteering in the grander context of history, simply linking to the Wikipedia page for the famous WWI propaganda poster “Daddy, what did YOU do in the Great War?”
They have signed up with what has been minimal press so far, Morrison says. The site has been designed to be as ethical as possible, striving not to over promise on the potential benefits and ensure their candidate pool is as well informed as possible about the risks before giving their consent.
A human challenge trial with SARS-CoV-2 would require a higher bar of informed consent, Shah says. But there are methods for ensuring the volunteers go in clear-eyed.
“The data on informed consent suggests that if you do things that are pretty commonsensical, they can make a difference in improving understanding,” Shah says. Something as simple as a test to ensure they know the stakes or providing time to think through and consult with others.
Ensuring a pool of well-informed volunteers have their voice heard is important, Morrison believes. The COVID Challenge aims to not only offer subjects for researchers to potentially choose from, but give the volunteers involved that voice.
“I feel like we’re starting a conversation, and that shouldn’t hold us back from preparing to do these studies, because they could have potential benefits” Shah says. “But I don’t know if we’ve settled the question of whether they’re going to move the needle here in a way that we need to happen.”
The risks are deeply real; infection with a novel agent for a poorly understood disease can mean severe illness — with lasting impact — and even death, both during the study and in the future, as whatever long term effects may arise like Tennyson’s kraken.
But so, too, are the benefits. Every moment gained means another unlabored breath, another person who need not die alone.
“I don’t think getting a pool of informed volunteers to participate in this study would be difficult,” says Peter G. Smith, one of the proposal’s authors. And as Morrison and the COVID Challenge proves, those people are out there.
Waiting.
“Somebody’s going to have to make a call. This is not an exercise I’m doing with my students in my research ethics 101 class,” Faden, the Hopkins bioethicist, says.
“This is not a hypothetical.”
Editor’s note: this article has been updated to reflect recent volunteer numbers.
