By Peter Loftus
As more Covid-19 vaccines become available in the U.S., it is
getting tougher to run large clinical trials to test a new
vaccine's ability to prevent disease because people are less
willing to take a placebo -- forcing drugmakers and researchers to
look for workarounds as they vet the next generation of shots and
test new uses for authorized ones.
One potential workaround would be to determine what level of
immune response a vaccine has to trigger to protect people from the
coronavirus, as measured in blood samples, and to use that
information to create smaller, faster and less-expensive clinical
trials.
Instead of requiring tens of thousands of volunteers and costing
several hundred million dollars, such trials could involve only
hundreds of people at a fraction of the cost. They could be used to
speed the availability of new vaccines targeting emerging
variants.
Moderna Inc., Pfizer and its partner BioNTech SE, and a
federally funded network of researchers are conducting analyses to
learn what immune response is necessary for protection with current
vaccines, known as an immune correlate of protection. They say it
could come in handy for new studies of already-authorized vaccines
-- such as testing the shots in children or whether reduced doses
are effective -- as well as for trials of the next generation of
shots, including those targeting new coronavirus strains. Over
time, such knowledge could also help determine how long protection
from the vaccines lasts.
Another workaround is to run future large efficacy trials
outside the U.S., in places where viral transmission is high and
vaccine availability is more limited. Arcturus Therapeutics
Holdings Inc., whose Covid-19 vaccine is in mid-stage testing, may
run a large Phase 3 trial of its experimental shot outside the U.S.
because of the diminishing feasibility of running it in the U.S.,
Chief Executive Joseph Payne said in an interview. The company
hasn't disclosed which country or countries.
Large studies involving tens of thousands of people have been
launched in the U.S. for five Covid-19 vaccines, including the two
authorized for use from Moderna and Pfizer and a vaccine from
Johnson & Johnson, for which J&J is seeking U.S.
authorization. In these studies, researchers randomly assign the
volunteers to receive either the vaccine or a placebo and then
compare how many get sick with Covid-19 in each group.
Vaccine vs. Placebo
But it is becoming more difficult to run these
placebo-controlled efficacy trials because prospective recruits
increasingly want one of the highly effective authorized shots
rather than an experimental shot or a placebo, researchers say. The
challenge is heightened among groups that now have access to the
vaccines, like health-care workers and the elderly.
In a large study of Novavax Inc.'s vaccine, about 1.5% of the
volunteers who were assigned to receive a placebo subsequently
decided to get one of the authorized vaccines, Gregory Glenn, the
company's head of research, said in an online scientific forum this
week. More than half of those making that choice were over the age
of 65.
"People in the U.S. don't want a placebo anymore if they're in a
group that can get the authorized vaccines," said Dr. Kathleen
Neuzil, a vaccine researcher at the University of Maryland who
helps lead the federally funded Covid-19 Prevention Network, made
up of research sites running large clinical trials of Covid-19
shots.
Covid-19 vaccines are designed to work by inducing a person's
immune system to produce antibody proteins that can neutralize the
coronavirus. The immune correlate of protection is the
concentration of those antibodies at a level that prevents Covid-19
disease; antibodies below that level aren't protective, while at or
above that level are protective.
The immune correlate of protection wouldn't be definitive proof
that a vaccine is effective at protecting people from disease, but
it could be sufficient to guide regulatory authorization of new
vaccines or new uses for existing vaccines, said Peter Gilbert, a
biostatistician at the Fred Hutchinson Cancer Research Center in
Seattle and part of the Covid-19 Prevention Network. Regulators
would still require reports of any side effects to determine safety
and might require further studies to confirm efficacy.
A Predictive Blueprint
Such correlates of protection have been used for past vaccine
development. The Food and Drug Administration has approved certain
meningitis vaccines based on their ability to induce an immune
response that correlates with protection, rather than requiring
large placebo-controlled efficacy trials.
"It saves time, it saves money and it may be the only thing
that's logistically feasible going forward," Dr. Neuzil said.
Covid-19 vaccines researchers expect to determine the immune
correlate of protection by comparing antibody levels in blood
samples taken from vaccinated people who stayed healthy with
antibody levels in the relatively small number of vaccinated people
in the studies who still got sick from Covid-19.
Researchers from the Covid-19 Prevention Network are running
analyses to try to determine the immune correlate of protection for
Moderna's vaccine within the next couple of months. They are
examining some of the blood samples taken from all subjects about
one month after the second dose in the large clinical study of the
Moderna vaccine.
They plan to conduct similar analyses for other Covid-19
vaccines from J&J, AstraZeneca PLC and Novavax, which are being
tested in trials run by the researchers' network.
Pfizer and BioNTech are conducting their own analysis to
determine the correlate of protection for their Covid-19 vaccine. A
Pfizer spokeswoman said the company would explore the use of immune
responses in additional studies of its vaccine, such as in pregnant
women, children and people with compromised immune systems.
Leaders of the Covid-19 Prevention Network expect that future
vaccines could be approved based on trials of only several hundred
people, if results show that they had an immune response believed
to be protective.
Moderna is exploring the use of an immune correlate of
protection to test whether a half-dose of its vaccine could offer
sufficient protection against Covid-19 disease, Chief Medical
Officer Tal Zaks said at a recent investor conference.
Expanding Vaccine Uses
An FDA spokeswoman said that when immune correlates of
protection are established for these vaccines, they will be useful
for a variety of studies including the evaluation of vaccines in
children and assessing the response to new variants.
There are challenges for determining protective immune
responses. There were relatively few cases of symptomatic Covid-19
in people who received the Moderna and Pfizer vaccines in the large
studies at the time they were authorized, making statistically
significant comparisons difficult. But researchers continue to
follow study subjects and expect to see higher numbers.
Write to Peter Loftus at peter.loftus@wsj.com
(END) Dow Jones Newswires
February 11, 2021 19:27 ET (00:27 GMT)
Copyright (c) 2021 Dow Jones & Company, Inc.
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