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 Researchers are trying to determine just what level of COVID-19
antibodies a vaccine must produce to provide protection against the
illness. Regulators already use such benchmarks - known as
correlates of protection - to evaluate flu vaccines without
requiring large, lengthy clinical trials.
"You could use it to predict efficacy from a vaccine, which will be
more important as we are less able to conduct placebo-controlled
trials," said Stanley Plotkin, inventor of the Rubella vaccine and
an expert on correlates of protection.
"The information is flowing in," he said. "By the end of this year,
I think there will be enough data to convince everyone."An
established benchmark for COVID-19 would allow drugmakers to conduct
vaccine trials in just a few thousand people, about one-tenth the
size of the studies conducted to gain authorization for currently
widely-used coronavirus shots, researchers and drugmakers told
Reuters. Those studies, involving tens of thousands of volunteers,
compared the rate of COVID-19 infections in people who received the
shot with the rate in participants who got a placebo. Such
randomized, controlled trials may no longer be considered ethical in
some countries, as researchers cannot give a dummy shot to people
where an effective vaccine is widely available. In addition, many of
the new shots are being developed by small companies that may not be
able to conduct very large trials without government funding or a
partner with deep pockets. With an established correlate, drugmakers
could test blood samples from a smaller number of trial participants
who receive an experimental vaccine to see whether they produced
that benchmark level of protective antibodies.
Such a benchmark is “urgently needed” to help overcome challenges
faced by vaccine developers and boost availability of shots, Dr.
Florian Krammer, a virologist at the Icahn School of Medicine at
Mount Sinai in New York wrote this month in the journal Nature.
Researchers at Oxford University late last month proposed a
potential correlate of protection based on antibodies found in
people who had received the AstraZeneca vaccine. The work awaits
peer reviewed by other scientists. Results from a U.S.-backed study
of Moderna’s vaccine are expected to be published in a medical
journal later this summer. "We're writing the paper right now," said
Dr. Peter Gilbert, a biostatistician from the Fred Hutchinson Cancer
Research Center. Some vaccine experts question whether antibody
levels will be a strong enough indicator of protection. Other
components of the immune system, such as T-cells and B-cells, are
thought to provide important defenses against COVID-19, but are more
difficult to measure.
That has been the contention of some top vaccine experts at Pfizer,
maker along with BioNTech of one of the most effective COVID-19
vaccines, produced in the largest quantities globally. It is also
possible that each different type of coronavirus vaccine will
require its own correlate, some experts said. Drugmakers working on
a new type of vaccine likely would not be able to rely on the
correlates based on Moderna’s messenger RNA shot, they say.
BRIDGING THE GAP Meanwhile, vaccine developers are trying to devise
acceptable substitutes to huge, placebo-controlled trials. Some aim
to show their shot provokes antibody responses at least as good as
those seen with currently authorized shots. European and UK health
regulators are working with companies to set standards for these
so-called “immunobridging” studies. The U.S. Food and Drug
Administration declined to say whether it would accept such trials
for next-generation vaccines.
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“It doesn't have to be an established correlate of protection, but
we have to ... arrive at the right pre-specified criteria, because
we cannot risk that a second-generation vaccine ... is of low or
modest vaccine efficacy," FDA vaccine official Dr. Marion Gruber
told fellow regulators at a World Health Organization Meeting in
May. "That would undermine confidence in the vaccine enterprise."
Italy's ReiThera Srl is developing a vaccine using technology
similar to AstraZeneca's and will try to demonstrate that its shot
is at least as effective.
The company has an agreement in principle on trial design with
European and British regulators, ReiThera's senior director Stefano
Colloca told Reuters. Massive clinical trials are "no longer ethical
and feasible in most countries worldwide," he said. French biotech
Valneva and Taiwan's Medigen Vaccine Biologics Corp plan to test
their vaccines against the AstraZeneca shot, even though both use a
different technology. Valneva's trial design was approved by UK
regulators. Medigen has a green light from Taiwan.
Sanofi, with partner GlaxoSmithKline, and Canada’s Medicago are
still opting for placebo-controlled trials involving thousands of
participants, including in countries with high infection rates and
fewer authorized vaccines available.
NEED FOR BOOSTERS? The hunt for a correlate is underway from the UK
to the United States and Australia. Scientists are comparing
antibody levels in vaccinated people who became infected with
COVID-19 to those who did not, to find a threshold of protection
that made the difference. Oxford University researchers said work is
needed to address correlates for emerging virus variants, such as
the highly transmissible Delta that has quickly become dominant
globally. Their proposed antibody model is based on trial volunteers
who had mainly contracted the earlier Alpha variant, first
identified in the UK. U.S. government-backed
scientists are studying infections in people who received the
Moderna vaccine. Moderna spokesman Ray Jordan said the company is
also working on the analysis and will publish updates when
available. The correlate benchmark might also indicate when and
whether people need vaccine boosters.
Pfizer has sought authorization for a third booster dose of its
vaccine, citing evidence of waning neutralizing antibody levels. But
the company has pushed back against the idea that those same
antibodies could be used to predict vaccine efficacy.
"No formal timeline is in place to have correlates of protection
established," a Pfizer spokesperson said. "We will continue to work
with the scientific community to better understand what immune
responses, whether neutralizing antibodies or otherwise, might
contribute to protection.”
(Reporting by Julie Steenhuysen in Chicago and Ludwig Burger in
Frankfurt; Additional reporting by Emilio Parodi in Milan, Matthias
Blamont in Paris, Michael Erman in Maplewood, New Jersey, Allison
Martell in Toronto and Ben Blanchard in Taipei; Editing by Michele
Gershberg and Bill Berkrot)
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