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Astra’s Covid-19
Vaccine Won Approval, But How Good Is It?
A shot developed by the drugmaker and the University of
Oxford just gained clearance in the U.K. Here’s what you need to know.
By Bloomberg Opinion
December 30, 2020, 4:55 PM GMT
Sam Fazeli, a
Bloomberg Opinion contributor who covers the pharmaceutical industry for
Bloomberg Intelligence, answered
questions about the approval in the U.K. Wednesday of a Covid-19 vaccine
developed by AstraZeneca Plc and the University of Oxford. It follows the shot
developed by Pfizer Inc. and BioNTech SE, which was cleared earlier this month
and has already been rolled out in the U.K., U.S. and Europe. Moderna Inc.’s
vaccine also gained emergency authorization in the U.S. The conversation has
been edited and condensed.
The Astra vaccine is the third to be approved by either the
U.K., U.S. or EU, but it’s different
from the first two. How so?
All vaccines aim to deliver pieces of a live virus or a whole inactive (killed) virus to the
body so that the immune system has an opportunity to raise a response to it and
form a memory. That way, when the actual pathogen arrives, it is ready to
rapidly deploy antibodies and immune cells (T-cells) to kill the virus and
infected cells, respectively. The Pfizer-BioNTech
and Moderna vaccines deliver the genetic material in the form of “messenger RNA,” which instructs cells to create a modified version
of a key coronavirus protein. This, in turn, prompts an immune response that
can fend off the real virus. AstraZeneca-Oxford’s
vaccine, AZD1222, uses a “viral vector”
– a tool for delivering the same genetic material – which it derived from an engineered
chimp adenovirus, similar to the virus that causes the common cold. (Johnson & Johnson uses a similar approach, but its
vaccine uses a human adenovirus to deliver the genetic
material.) One of the other key differences between the Astra vaccine and those
of Pfizer-BioNTech and Moderna is that it doesn’t
require super-cold storage and can be transported and kept at normal
refrigerator temperatures. This makes it much easier to use and distribute,
especially in more rural areas and countries where cold-chain logistics are
problematic.
How well does the
Astra vaccine work compared with those other two?
In preclinical tests and early trials in humans, the vaccine
did O.K. It was not as protective against viral infection in the nose and
throat of nonhuman primates, though it did prevent severe disease. In the early
stages of human trials, the vaccine did not induce as strong an immune
response, measured by looking at antibody
levels, as that seen with Pfizer-BioNTech and Moderna’s shots. This
may explain the lower efficacy seen so far in its later-stage U.K. and Brazil
trials and may have to do with the way the vaccine delivers its genetic
material. There are also subtle
differences in the actual protein structure Astra uses in its vaccine
compared with the other two shots. While all of the shots target what’s called
the “spike” protein — the rod-like structures that protrude from the virus and
help in binding to cells and infecting them — Astra’s is the only one to use an original form of that protein, which has been shown to be less immunogenic in some experimental
settings.
Wasn’t there a problem
with the Astra trials? The dosage was given out incorrectly, and the data
was confusing?
Yes. The Astra-Oxford team reported late-stage preliminary
results from its U.K. and Brazil trials that contained data from about 12,000
subjects vaccinated with AZD1222 and a similar number on placebo. Not only were
the trials smaller than the Pfizer-BioNtech and Moderna trials, the efficacy of the vaccine was also lower at 70%, compared with the more
than 90% seen with the other two vaccines. And the Astra data was complicated
by the fact that 1,367
subjects in the U.K. trial, out of a total of 3,744 who received the vaccine,
got only half of the required dose on their first jab because of a
manufacturing issue. If you ignore those subjects, the efficacy was about 62%
when combining the U.K. and Brazil data. The other issue is that there were only 718 participants 55 or
older, who are at higher risk of hospitalization and death, and that’s
not enough to judge the potential of the vaccine for that important cohort.
There was also a problem with the time interval between the first and the
second dose as the trials started looking at the vaccine as a single dose, only later converting to a two-dose regime.
All of this raised questions and caused some confusion, which is unfortunate
given the generally positive results.
Are you comfortable with the data now? Did the U.K. make the right decision?
The vaccine clearly
works. We just don’t know how well. In a normal world, the Astra data we’ve seen so far would
be the kind that would generate hypotheses requiring further trials to prove
things like efficacy, the required dose level, the best dosing interval and its
effect in the older population. The U.K.’s Medicines & Healthcare
products Regulatory Agency, which cleared the shot, has for sure seen more data
than has been published; that data, whenever it is revealed, will be crucial in
helping us understand what the approval was based on. The MHRA's analysis
suggests that the vaccine’s efficacy was 73% up to 12 weeks after one dose of the
vaccine. But this is what is called an exploratory analysis and was not based
on predefined criteria, again making it hypothesis-generating and needing a
future trial. It’s also possible that the trial has some data on the new
variant of the virus that has been discovered in the U.K., and how sensitive it
is to the vaccine.
Speaking of that variant, it appears to be more
transmissible than the original forms of the virus . Despite the lockdowns and
restrictions it triggered in the U.K., it has since spread elsewhere including
the U.S. The good news is that vaccines may work just as well against this
variant, but given that viruses are always mutating, there’s a risk of other
variations cropping up that could be more resistant to shots. How adaptable is the
Astra vaccine?
The Astra, J&J, Pfizer-BioNTech and Moderna shots
are all amenable to rapid reengineering with any new variant. All four vaccine developers can make new
candidates within a few weeks. That is one of their strengths compared with
other technologies.
The U.K. has approved a dose schedule that seems different
from other vaccines. What was this based on?
The approval is for a first dose, followed by a second dose
up to 12 weeks later. This is much longer than that for Pfizer-BioNTech's vaccine
(21 days) and Moderna (28 days). In the published data on Astra’s trials, there
was a reference to the fact that the median time interval for subjects who
received two standard doses of the vaccine in the U.K. trial was 69 days, with
a range of 50 days to 86 days. So the 12-week interval is at the very top end
of that range. I don't believe there is likely to be enough data to judge which
dose interval is best until the MHRA publishes its approval letter and shows
the data that was used to back its decision. What I am worried about is that if the first shot does not provide a strong
enough immunity to suppress viral replication in people, it may lead to the
virus amassing even more mutations and
developing the ability to evade the vaccine. This could affect the efficacy
of other shots, too. We just don't know.
What about U.S.
approval? Is that close to happening?
U.S. approval will need data from the much larger and
simpler trial that Astra is conducting there. That data should come out in
the first quarter. Astra
is testing two standard doses of the vaccine four weeks apart in as many as
20,000 individuals. The question is what happens if the efficacy comes out at
the same 60% to 64% level seen in the U.K. and Brazil trials. Even though this
meets regulatory guidelines for approval, which require efficacy of 50% or
more, will the U.S. approve it given the much higher efficacy of the
Pfizer-BioNTech and Moderna vaccines? And if it does not, what will that
mean for the U.K. approval? Will U.K. subjects, and those of other countries
that approve Astra’s vaccine, be deemed
as vaccinated when it comes to U.S. travel? This remains to be seen.
This column does not necessarily reflect the opinion of the
editorial board or Bloomberg LP and its owners.
To contact the author of this story:
Bloomberg Opinion at davidshipley@bloomberg.net
To contact the editor responsible for this story:
Beth Williams at bewilliams@bloomberg.net
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