Get Published | Subscribe | About | Write for Our Blog    

Posted on September 15, 2020 at 10:39 AM

To
those who’ve never thought about volunteering to be intentionally infected to
test a vaccine, the idea may at first seem a bit bonkers. But such “challenge”
studies not only have a rich history, but nearly 40,000 people have already
checked the box “I
am interested in being exposed to the coronavirus to speed up vaccine
development”
 at 
1daysooner, a website and non-profit organization that launched in
April.

Challenge studies go
by other names: “controlled human infection models,” “human viral challenge,”
and “purposeful infection.” Dripping virus-tainted saltwater into a volunteer’s
nostrils enables researchers to track infection, and the immune system’s
response to it, right from the start. The approach complements phase 3 clinical
“field” trials of efficacy that await natural infection in the community.

A
bioethical quandary

A challenge study can
speed discovery of whether or not a vaccine works. That’s important because a
vaccine hastens the herd immunity that builds from natural infection. But the
risk of possible harm to a recipient of an experimental vaccine may be greater
with intentional infection than with community exposure, simply because it’s
more likely to happen.

Use of a placebo group is another matter.

A placebo is the gold standard in a conventional clinical trial
collecting initial data. But it isn’t necessarily needed for a challenge trial
when phase 3 results are forthcoming, as is the case for COVID-19.

Exposure
to SARS-CoV-2 after taking an experimental vaccine is scary enough — it’s
riskier if the “vaccine” is really a placebo. Philosopher Kent A. Peacock and
psychologist John R. Vokey, both of the University of Lethbridge, argued
against placebos in COVID challenge trials in STAT News.

Seema Shah, JD, professor of Medical Ethics at the Northwestern
University Feinberg School of Medicine, explained the nuances of using
placebos:
“If you
are testing whether vaccines or treatments work, a placebo is usually
necessary. Challenge studies can create a reliable model of infection where
researchers learn what dose is needed to infect all volunteers but not make them
too sick, and then you wouldn’t use a placebo. Models are also used to
investigate transmission and learn about the early stages of infection, and
those don’t require placebo.”

Several prominent bioethicists who’ve given the matter of COVID
challenge trials much thought support the idea.

Bioethicists
Stanley A. Plotkin from the University of Pennsylvania and Arthur Caplan from
New York University call developing and distributing an efficacious COVID-19
vaccine a “moral imperative for the world
in the journal Vaccine, calling for immediate
discussion of beginning challenge studies. Those conversations are now well
underway.

 

A challenge study isn’t a new idea 

Considering
the design of COVID challenge trials might benefit from a look back at the
history of protection of research subjects that led to the founding of the field of
bioethics
 in 1970 .

The
National Research Act of 1974 inspired the Belmont Report of
1979 that established three requirements for people who volunteer for
experiments, including clinical trials: respect for autonomy (ability to make
decisions); beneficence (benefit); and justice (anyone who meets criteria can
volunteer).

 

More
recent renditions of participant protection expanded the definition of ethical research to
embrace non-maleficence (“do
no harm”
) and, vital for vaccine testing, utilitarianism, which
justifies actions if they benefit a majority. Even more on target, in 2014
an international group of
ethicists
 interpreted utilitarianism to include “maximization
of public health.”

Should we potentially harm a few to possibly save many? That’s
the risk of challenge trials. With thousands still dying of COVID-19 every
week, demonstrating efficacy another way, to complement the phase 3 trials,
would save lives. Overlapping phases and early production of vaccine candidates
will surely speed the conventional trajectory, but it isn’t enough.

Even
challenge trials with coronaviruses aren’t novel. In 1967 researchers reported in the British Medical Journal experiments that dripped a
new respiratory virus “surrounded by a fringe of club-shaped projections”
collected from six students with colds into the noses of 26 healthy volunteers.
Would they come down with the sniffles? Counting the number of handkerchiefs
soiled daily revealed that half of them did. The culprit? Seasonal coronavirus
229-E.

Challenge
studies sped development of an improved cholera vaccine in Baltimore from 1977
through 1995, using volunteers and strict quarantine protocols in a hospital to
manage symptoms. Most participants who became ill suffered only mild, brief
fever and diarrhea.

Over
the years challenge studies have been deployed against a list of horrors:
dengue, shigella, typhoid fever, giardia, tuberculosis, rhinovirus, norovirus,
and most commonly, malaria and influenza. It was considered for Zika virus
infection but never done because the epidemic abated, and led to approval of an
Ebola vaccine in 2019 in a mere 10 months.

 

In
December 2019, Ricardo Palacios from the University of São Paulo in Brazil and
Shah wrote a prescient commentary in
the journal Trials: “When could human challenge
trials be deployed to combat emerging infectious diseases? Lessons from the
case of a Zika virus human challenge trial.”
 

They couldn’t have known a novel virus was about to unfurl on
the world.

Volunteering, not coercion
Challenge
studies have a checkered past. 
Doctors in Nazi Germany did
it, but without consent.

So did
Werner Henle, a virologist at the University of Pennsylvania, who tested
an influenza vaccine on
prisoners and intellectually disabled children in a state facility. Jonas Salk,
of polio vaccine fame, tested flu vaccines on
mental patients and prisoners in Michigan.

The huge difference between then and now is the word “forced.”
Participants in challenge studies for COVID-19 vaccines will follow an informed
consent process that ensures that they understand and accept the risks —
including the unknown and the possibility of receiving a placebo, if that’s
part of a particular plan.

It’s
especially important for potential participants to read the consent forms
carefully, because regulations have loosened a bit, in a way that may maximize
the information gleaned from a challenge trial. Health and Human Services (HHS)
updated the “Common Rule” from
1981 that stated that benefits to the participant and to society must outweigh
risks to the subject. The amendment in 2018 stated that risks to the subject
might be “reasonable,” not zero.

 

That
regulatory flexibility is appreciated now. Jerry Menikoff, MD, JD, Director of
the Office for Human Research Protections at HHS, points out that
unlike challenge studies for malaria, cholera, and influenza, COVID-19 is
riskier because we know less about it. Plus, there’s no “rescue” treatment if
an experimental treatment harms someone.

 

The
flip side of potential risk is
potential benefit. In a
challenge study, investigators can track the nuances of the immune response and
degree of viral shedding from the precise start of infection, something not
possible in the community, where conventional vaccines are tested. What we can
learn from challenge studies may outweigh the concerns. Protocols can be
designed to compare vaccines using the fewest volunteers possible, such as by
using one placebo group for multiple vaccine candidates.

 

Bioethicist
Nir Eyal, PhD, and epidemiologists Marc Lipsitch, PhD, and Peter G. Smith, DSc,
added perspective in an article in The Journal of Infectious Diseases.
They compare the sacrifice of a challenge study participant to those of
volunteer firefighters, participants in drug trials, members of the military,
and living organ donors.

 

How
challenge studies will unfold

 In June, the Advisory
Group on Human Challenge Studies from the World Health Organization (WHO)
released a draft of an 81-page “technically valid roadmap
to guide discussion among bioethicists, public health experts, epidemiologists,
and physicians. It’s currently open for public comment. The report is more
specific than a similar guide published
in 2001 from NIH researchers

The WHO document
begins with “factors that warrant special caution” when conducting a challenge
study for COVID-19: severity, high transmissibility, deaths of young healthy
individuals, activity of the virus on surfaces for hours, lack of rescue
treatment, and the surprises that the evolving pandemic brings. These are the
factors that give pause to thoughts of including placebo arms. Then the
document lists steps.

First is creation of
“challenge strains” of the virus for the volunteers. Four strains are being
considered because they represent the distribution of SARS-CoV-2 around the
world.

Genetic modification
of the challenge strains can insert telltale DNA “tags” that enable tracking of
distinct viruses, and other tweaks can render the viruses milder than the
predominant natural strains. If a vaccine fails to protect, a person wouldn’t
get too sick.

The WHO group decided
that participants should be between ages 18 and 25, who are less likely to
develop severe symptoms, if any.

Next, the test virus,
or placebo, is placed in the nostrils using a pipette, rather than a nasal
spray that can shoot virus deep into the lungs. Experiments have shown that
three doses are needed to infect most, if not all, participants.

The volunteers then
will spend up to 3 weeks in single rooms on isolation units in facilities that
have constant monitoring from a nursing station and presence of an expert
physician, availability of ICU equipment, and existing treatments like
remdesivir and steroids, until PCR tests are negative. The protocol also
includes mental health screening for ability to tolerate the isolation. Some of
these places were developed for influenza studies.

Researchers can
analyze mounting viral load as well as the unfolding immune response in real
time in participants who’ve been infected, categorizing T cells, identifying
the viral antigens that different antibodies attack, and charting inflammatory
markers in blood. They’ll also be on the lookout for “disease enhancement,”
which is when a vaccine worsens an infection.

No challenge trial for
a COVID-19 vaccine has yet to begin, and details are still being worked out.
The 19 members of the Advisory Group agreed on using young people, four viral
strains, and existing treatments, but were split on three other issues: whether
studies should proceed even if no better rescue treatments come along; whether
a vaccine that protects young people will work on older people or those with
pre-existing conditions; and whether the study should or will accelerate
regulatory approval, including emergency use authorization. Perhaps comments
from the public will help to flesh out these issues.

Where
are we now?
Interest in challenge
trials for COVID-19 has been building.

Seema
Shah and her colleagues published a framework and analysis in Science in May that included “developing a
challenge strain, drafting consensus protocols that address ethical concerns,
and engaging stakeholders to enhance their social value, minimize risks, and
build public trust.”

By
midsummer, Adrian Hill, MD, PhD, director of Oxford University’s Jenner
Institute, made the media rounds to
discuss their candidate vaccine, the adenovirus-based ChAdOx1 nCoV-19, noting:We’re hoping to be doing challenge
trials by the end of the year. This might be in parallel or might be after
the phase three trial is completed. They’re not competing options, they’re
complementary.

Phase 3 trials of the
vaccine are ongoing or about to begin in the UK, Brazil, South Africa, Japan,
Russia, and the US, but were temporarily paused on September 
8 due to
a participant becoming ill.

Even
if challenge trials start soon, making sense of findings will take time. Cautioned
Meagan E. Deming
, MD, PhD, of the Center for Vaccine Development and
Global Health, University of Maryland and colleagues in the September 3 New
England Journal of Medicine
, developing “a robust challenge model
for testing SARS-CoV-2 vaccines” may take a year or two. “Investigators at
potential sites should begin soon to engage stakeholders in the scientific,
regulatory, public health, and local communities.”

Bioethicists
Plotkin and Caplan eloquently sum up the challenge of challenge studies: “Deliberately
causing disease in humans is normally abhorrent, but asking volunteers to take
risks without pressure or coercion is not exploitation but benefitting from
altruism. As Shakespeare put it, ‘Desperate diseases by desperate measures are
relieved.”

Those who
volunteer to receive an experimental vaccine and 
then be infected with a potentially lethal viral
pathogen exemplify selflessness. They are the polar opposite of the people who
flagrantly ignore public health recommendations to prevent spread of COVID-19. *Post was originally published at the Genetic Literacy Project at: 
https://geneticliteracyproject.org/2020/09/15/challenge-studies-should-we-be-testing-covid-

Comments are closed.