Science/Nature

Infecting individuals with COVID-19 may velocity vaccine trials. Is it price it?

The world waits with bated breath for a COVID-19 vaccine, which could effectively end the pandemic once it’s widely available. Until then, more people will die from the disease, and economies will struggle to fully recover.

With such intense pressure
to get a vaccine quickly, many experts are contemplating a controversial shortcut
to the usual vaccine testing protocol: human challenge trials.

Instead of vaccinating
hundreds to thousands of people and waiting to see if they naturally catch the
virus, scientists would purposely infect a smaller number of vaccinated volunteers
with COVID-19 in a controlled setting to see if a vaccine offered protection.
If successful, such studies could fast-track vaccine evaluation, as well as our
understanding of COVID-19 immunity.

However, doctors and
researchers don’t all agree on whether it’s ethical to infect people with a
disease that remains poorly understood, and for which there is currently no
reliable treatment. That leaves it to those bioethicists, researchers and
regulators to weigh the pros and cons.

If scientists stick to the
usual playbook, a licensed vaccine is at least 12 to 18 months away, experts
say. That’s not because it takes long to develop possible vaccines — dozens are already in the testing stage (SN: 5/20/20) — but because of the time that it
takes to be sure a vaccine is safe and actually works.

The final and most involved
stage of this process, Phase III clinical trials, requires thousands of volunteers
to get the vaccine or a placebo. Then, scientists track them over months to see
whether vaccinated people are less likely to get sick compared with
unvaccinated people.

And it could take longer now
that lockdowns and social distancing have flattened the curve of new cases.
“You can only test vaccine efficacy if incidence [of the disease] is high
enough,” says Helen McShane, a vaccine biologist at the University of Oxford.
The less the disease is spreading, the longer traditional Phase III trials will
take.

Challenge trials might shave
months off the process. “Human challenge trials have been done for hundreds of
years,” says Seema Shah, a bioethicist at Northwestern University Medical
School in Chicago. “They come with a lot of promise, but also with serious
ethical concerns.”

For example, in 1796, English
physician Edward Jenner, an earlier popularizer of vaccination, demonstrated
that inoculation with cowpox worked as a vaccine against smallpox by injecting
his gardener’s 8-year-old son with cowpox and then exposing him to the disease.
“Clearly, that’s problematic,” Shah says.

Nowadays, challenge trials
are typically done on diseases about which scientists know a lot, and for which
there are numerous treatment options, such as influenza or malaria. But there’s
currently no established drug safety net for COVID-19, though some drugs show promise (SN: 4/29/20).
And much still remains unknown about the virus, including all the risk factors for severe disease (SN: 4/22/20).
Consequently, most advocates are calling for such trials to be done only on
young and healthy volunteers, who seem least at risk for serious illness.

Still, researchers,
clinicians, bioethicists and policymakers are debating the ultimate utility of
human challenge trials for COVID-19. The ethical calculus could change as we
learn more about the virus and continue developing treatments, but some experts
are already putting out rough plans for how to minimize risk to participants.

Here are two perspectives on
the issue, from scientists weighing both the risks and potential benefits.

Human challenge trials could help us have a vaccine quicker and save lives.

“We face a worldwide
epidemic with a high mortality, and the only thing likely to stop it is vaccination,”
says Stanley Plotkin, a vaccine developer at the University of Pennsylvania.
Human challenge trials have the potential to get us an effective vaccine sooner
and thus save lives, Plotkin says, and we should start planning how to do them
ethically now.

Stanley Plotkin
Stanley Plotkin, a vaccine developer at the University of Pennsylvania, says that a COVID-19 vaccine could be accelerated by purposefully infecting humans with the coronavirus in what’s known as a human challenge trial.S. Plotkin

“I would, of course, not
want to subject anyone to harm, but the fact is that harm is accumulating all
over now, and if we can reduce the total amount of harm, I think it’s worth
doing,” Plotkin says. “Extraordinary circumstances require extraordinary solutions.”

Human challenge trials could
help scientists answer important unknowns about the virus more quickly than
animal studies can, Plotkin says. “A human challenge trial could tell us
whether prior infection is protective or not, as well as what sort of immune
responses are protective,” Plotkin says. “Both of those have very large
implications in terms of whether people with prior infection could take care of
the sick,” as well as our ability to evaluate the efficacy of vaccine candidates
outside of challenge trials.

Plotkin acknowledges the
potential risks to participants. “Giving someone an infection can cause serious
harm,” he says, “but the usual way of doing things also means that many people
will become ill and possibly die.” To minimize risk, Plotkin says such trials
should only be carried out on young, healthy people who understand the risks
and give their full consent. “There are thousands of people willing to be
volunteers for such studies on moral grounds, with knowledge of the risks.”

A vaccine shown to work in a
challenge trial on young people may not work in older people, or may be less
effective, Plotkin says. “But a challenge trial could allow us to more easily
determine whether the immune responses we see in younger people are also seen
in older people,” who get the experimental vaccine but aren’t subjected to a
challenge virus. Even if the vaccine only worked in younger folks, “that could
still protect older people simply because they wouldn’t be getting infected by
younger [vaccinated] people,” he says.

While some have argued that challenge trials could replace Phase III
clinical trials
, Plotkin doesn’t see
human challenge trials as a full substitute for normal safety trials. He also doesn’t
expect them to result in regulators licensing a vaccine for widespread use.
“But it could allow for emergency use among high-risk people or health care
workers,” he says. “It could also help us determine which vaccine candidates
show signs of working,” which could allow manufacturers to get a potentially
lifesaving head start on mass production.

“This is not an exclusive
pathway,” he says, “it’s a supplementary pathway to try to speed things up.” If
normal vaccine trials revealed a candidate, or we learn more about the risks to
volunteers, Plotkin says challenge trials should be stopped. “But if we don’t
start planning human challenges now, they won’t be available if we decide
months from now that it would’ve been a good idea.”

Human challenge trials are too risky, and may not end up being that helpful.

“I still haven’t been
persuaded that a human challenge trial would be informative enough to make a
final decision about which vaccine is the right vaccine to roll out at scale,”
says Angela Rasmussen, a virologist at Columbia University.

The hallmark of any human
challenge trial is fully informed consent from participants. But Rasmussen
questions whether that’s possible at this stage. “I don’t know that we can
actually inform them of all the risks because there’s still so much that’s just
unknown about this virus,” she says.

Angela Rasmussen
Angela Rasmussen, a virologist at Columbia University, says that there’s still too much we don’t know about the coronavirus behind COVID-19 to purposefully infect the virus into humans to speed along research.A. Rasmussen

Evidence suggests that
young, healthy people are least likely to suffer severely from COVID-19
infection, but “we’re still learning about different types of disease that it
may cause,” Rasmussen says. Reports of young people suffering strokes, and
taking damage to the kidneys, heart and other organs have emerged in recent
months, making it difficult to quantify the actual risks. “I just don’t see how
a subject could provide their fully informed consent.”

Accepting those risks may result
in more harm than good, Rasmussen says. By design, any COVID-19 challenge trial
would be done on a small, homogenous group. That could limit its broader
applicability, she says, and “could miss issues with the vaccine that can only
be caught in a larger, more diverse study population.”

She points to previous
examples, like the mid-2000s HIV vaccine candidate that actually increased risk of HIV infection in those who got the vaccine, or a “SARS classic”
study in which older vaccinated mice experienced
more severe disease
after being
infected.

“My concern is that you
could have a major safety issue like that if you are doing only human challenge
trials in young, healthy volunteers,” Rasmussen says. A robust response in
young people could mask harmful effects that emerge in older people or a
different population, she says.

While a challenge trial
could identify promising vaccine candidates more quickly, it might also prop up
the wrong one based on limited results. If serious issues come up for other
populations, the consequences could be dire, Rasmussen says. “And we’d have wasted
resources that could have been devoted to standard Phase II and III trials.”

Other unknowns limit a
challenge trial’s potential utility, too, Rasmussen says. “We don’t know the
infectious dose for COVID-19,” she says, meaning the amount of virus that someone
must get to kick-start an infection. If a challenge trial got the dose or route
of infection wrong, it might not be comparable to pathogenic SARS-CoV-2, the
virus that causes COVID-19. “A vaccine would appear to work under those
conditions, but it might not be applicable to how people actually need to be
protected in the real world.”

Rasmussen doesn’t rule out
that challenge trials could be helpful. “It’s important to keep an open mind
about anything that can speed our way to a vaccine, but we need to be cautious
and be humble,” Rasmussen says. “There’s a lot more we don’t know about this
virus than what we do know. If a human challenge trial goes wrong, it could go
catastrophically wrong, which could ultimately be harmful for all vaccine
development efforts.”

Who decides?

Exactly who gives the green light for a COVID-19
challenge trial remains unclear. Normally the decision to proceed with such a trial
lies with the funder of the research (the U.S. National Institutes of Health,
for example) and ethics boards at the research institutions or regions where
the study will be done.

But given the extraordinary nature of the current
situation, the World Health Organization, as well as leaders of the NIH, have called for an additional layer of review for any
COVID-19 challenge trials, which could include an independent panel of
ethicists, clinical trial researchers and vaccine development experts.

In the United States, the Food and Drug
Administration would license a vaccine for widespread use, and they would have
to decide whether results of a human challenge study would weigh on their
ultimate decision. It’s not a given that the agency would take those results
into consideration.

Meanwhile, people are already volunteering to take part in COVID-19 human challenge trials, were they to happen. Already, over 20,000 people around the world have expressed interest in participating in COVID-19 challenge trials through “1 Day Sooner,” a campaign to collect volunteers.

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