Medical News & Perspectives
COVID-19 and mRNA Vaccines—First Large Test for a NewApproach
Jennifer Abbasi
On January 10, Chinese researchers
posted thenovel coronavirus’RNA
sequence on a preprint server. Immediately,
scientistswhostudy genetic vaccines
turned their efforts to the emerging
pathogen that causes coronavirus disease
2019 (COVID-19). They knew that rapid response
genetic platforms could shave precious
weeks to months off development,
crucial during a pandemic.
Theywereright.WhenthefirstUSclinical
trial for a vaccine against severe acute
respiratory syndrome coronavirus 2 (SARSCoV-
2) began just 66 days later, volunteers
received mRNA-1273, a messenger RNA
(mRNA) candidate codeveloped by biotechnology
company Moderna, Inc and the
National Institute of Allergy and Infectious
Diseases (NIAID).
On July 27, based on encouraging
early results, mRNA-1273 and another
mRNA vaccine candidate, BNT162b2 from
BioNTech and Pfizer, both entered phase
3 trials, which together
will enrollan
estimated 60000
volunteers. The milestone came “at a
remarkably rapid pace compared to the
usual pace for vaccine preparation,”
National Institutes of Health (NIH) Director
Francis Collins, MD, PhD, said at a press
briefing that day. Results could be available
as early as this fall, NIH officials said.
Despite the unprecedented speed,
mRNA vaccines are clinically unproven. No
commercially available vaccines use the platform
and, until now, it hasn’t been tested in
large-scale human trials. With COVID-19,
that’s all set to change. Experts said in interviews
that if the technology pans out, the
pandemic could help to usher in anewplugand-
play approach to vaccinology.
The Genetic Advantage
Current antiviral vaccine designs can
be described as falling into 2 camps: protein
based or gene based. Protein-based
vaccines deliver the immune system–
stimulating antigen to the body. This category
includes whole-inactivated (killed)
vaccines, as in the polio and flu shots, and
subunit vaccines and virus-like particles,
like in the hepatitis B and human papillomavirus
vaccines.
Gene-based vaccines take a different
tack. They carry the genetic instructions for
the host’s cells to make the antigen, which
more closely mimics a natural infection.
In the case of coronaviruses, the antigen of
interest is the surface spike protein the
virus uses to bind and fuse with human
cells. “You’re not giving them the protein—
you’re giving them the genetic material that
then instructs them how to make that spike
protein, to which they make an antibody
response that hopefully is protective,”
University of Pennsylvania vaccinology professor
Paul Offit, MD, explained in a JAMA
livestream in June.
The approach isn’t entirely unfamiliar. In
live-attenuated vaccines, like the measles,
mumps, and rubella shot, weakened viruses
incorporate their genetic instructions
into host cells, causing thebodyto churn out
viral copies that elicit antibody and T-cell responses.
In newer gene-based designs—
viral vector, DNA, and mRNA vaccines—
scientists synthesize and insert genetic
instructionsfromthe pathogen of interest to
induce immune responses.
The viral vector technique transports
genetic information in a less harmful virus—
often acommoncold–causing adenovirus—
that’ssometimes engineered so it can’t replicate
in the host. DNA and mRNA vaccine
designs deliver naked nucleic acids or, more
recently, encapsulate them in a carrier
nanoparticle. Within each of these versatile
platforms, the same production and purification
methods and manufacturing facilities
can be used to make vaccines for different
diseases.
Thesehighly adaptable techniqueswere
waitinginthewingswhenCOVID-19 hit. “The
people who jumped on this right away are
the people who had vaccine platforms that
were conducive for this thatwere simply sitting
there,” said Louis Picker,MD, associate
director of theOregonHealth&Science University’s
Vaccine and Gene Therapy Institute.
“All theyhadtodois basically figure out
what part of [the virus] they were going to
put in the vaccine and then run with it.”
Thanks to research beginning in 2002
on the severe acute respiratory syndrome
coronavirus and then the Middle East respiratory
syndrome coronavirus, which
emerged a decade later, scientists knew to
focus their initial attention on the novel
Audio and Video
News & Analysis
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coronavirus’ spike protein. They also already
knew which genetic modifications
would stabilize the spike in its “prefusion”
configuration—important for a robust and
safe antibody response—and those that
would make the mRNA less inflammatory
and therefore safer. They had also learned
how to purify mRNA to rid it of contaminants
and howto protect it from degrading
too quickly in the body by encasing it in lipid
carrier molecules.Thesedeliveryvehicles, already
in use with therapeutic small interfering
RNAs, also help mRNA cross the cell
membrane andmay even have an immunestimulating
adjuvant effect.
Many of these innovations weren’t
possible until recently, according to Barney
Graham, MD, PhD, deputy director of the
NIAID Vaccine Research Center. “Over the
last 10 years, vaccinology has just changed
radically,” he said. “I’ve been doing this kind
of work for a long time and the kinds of
things that can be done now, the technologies
available, the way we can understand
things in a very detailed level is really stunning
tome.”
Unlike conventional vaccines, mRNA
vaccines aren’t grownin eggs or cells, a timeconsuming
and costly process. At their essence,
these vaccines are simply chemicals
catalyzed in test tube or a tank. This makes
them easier to develop quickly and—at least
theoretically—at scale, although they’ve
never been mass-produced before.
“Wewere makingRNAwithin aweek or
so” of the SARS-CoV-2 sequence being published,
said DrewWeissman,MD, PhD, who
researches mRNA vaccines at the University
of Pennsylvania Perelman School of
Medicine. That speed propelled development:
according toWeissman, both groups
currently testing nucleic acid-based vaccines
in phase 3 trials licensed his team’s
mRNA formulation from the university.
Why mRNA?
As of August 20, thirty potential vaccines
against COVID-19were in clinical trials, with
another 139 in preclinical development, including
both gene- and protein-based candidates.
But genetic approaches have a potential
immunologicaladvantage. Inaddition
to eliciting antibodies and CD4+ helper
T cells, they recruit CD8+ cytotoxic T cells,
also known as killer T cells, through the major
histocompatibility class I pathway.
According to Otto Yang, MD, an infectious
disease researcher and clinician at the
University of California, Los Angeles, David
Geffen School of Medicine, the body’s cells
only display viral proteins on their surface
through this pathway if those cells themselves
have produced the proteins. “If you
just inject a protein or inject a dead virus, it
doesn’t get into that pathway and doesn’t
get displayed that way, and so the T cells
don’t get stimulated,” he said.
Even among the gene-based platforms,
distinct advantages exist. In cutting
out the viral vector, both DNA and mRNA
vaccines eliminate the risk of preexisting immunity
against it, which can limit effectiveness.
“If your immune system clears a vector
before it will actually get into the cells,
that’s a big problem,”Yang said. Such immunity
could also be more common in some
geographic areas than others, rendering a
vectored vaccine more or less effective depending
on the region.
Preexisting immunity could explain
why a non–replicating viral vector COVID-19
candidate from CanSino Biologics Inc and
several Chinese institutions elicited lessthan-
impressive neutralizing antibody levels
in a phase 1 trial. Preexisting neutralizing
antibodies to the vector, the human adenovirus
5, known as Ad5, ranges from up to
69% in the US to 80% in Africa. Of additional
concern, Offit said in an August
livestream, more than a decade ago, men
with preexisting Ad5 immunity had an
increased risk of acquiring HIV infection
after receiving an experimental Ad5-
vectored HIV vaccine.
To get around these issues, ChAdOx1
nCoV-19, a non–replicating viral vector candidate
inphase3trialsfromAstraZenecaand
the University of Oxford, uses an adenovirus
that infects chimpanzees instead of humans.
But, it’s possible that cross-reacting
preexisting immunity to human adenoviruses
could still diminish the response.
According to Weissman, mRNA vaccines
also have a leg up on DNA vaccines. In
a DNA vaccine, the genetic material must
first enter the host cell’s nucleus. From
there, messenger RNA is created, which
travels out of the nucleus into the cytoplasm,
where protein is formed from it.
However, genetic information can only
enter the nucleus when the cell is dividing,
making the process inefficient.
Researchers are trying to solve this
problem using electric pulses to increase
DNA uptake into cells at the time of vaccination.
But the mRNA platform simply bypasses
that step. “Ninety-fivepercent of cells
that meet the RNA take it up and make protein,
so it’s an incredibly efficient process,”
Weissman said.
Proof Is in the Pudding
The first 4 COVID-19 vaccine developers
with published clinical trial data all used
either a non–replicating adenovirus or
mRNA platform. The US government is betting
on some of these new technologies.
Under the auspices of its Operation Warp
Speed vaccine development initiative, it
has already purchased hundreds of millions
of doses of ChAdOx1 nCoV-19, mRNA-1273,
BNT162b2, and an investigational non–
replicating viral vector vaccine in early trials
from Johnson & Johnson–owned Janssen
Pharmaceutical Companies, aswell as other
candidates. Doses should be standing by if
or when any of these are approved.
All eyes arenowonsafetyandeffectiveness.
Non–replicating viral vector vaccines,
whilearelatively recent approach,havebeen
studied extensively in HIV and other disease
trials. Janssen’snewEbola vaccine regimen,
which uses 2 different non–replicating
viral vectors, received European
authorization in July.
mRNA vaccines haven’t been clinically
tested to thesameextent, though.Researchers
have studied investigational mRNAbased
therapeutic antibodies and therapeutic
cancervaccines.ButGermanfirmCureVac
andacademic collaboratorspublished phase
1 results from the first prophylactic mRNA
vaccineclinicaltrial,foracandidateagainstrabies,
less than 3 years ago.
Since then, potential mRNA vaccines
against rabies, influenza, Zika, and a few
other viruses have been studied in small,
early-phase trials,many of which are still underway.
In both rabies and influenza trials,
the candidates stimulated promising but
lower-than-expected neutralizing antibodies.
Somemoderate andsevere injection site
or systemic reactions were reported, although
severe events were rare.
So far, in early COVID-19 trials, mRNA
platforms have turned up encouraging
results. “Certainly, these vaccines look like
they’re generating the immune response
that we need, and the reaction profiles
have not been associated with severe reactions,”
said Kathryn Edwards, MD, scientific
director of the Vanderbilt Vaccine Research
Program. But, she continued, “the real
proof of the pudding will be the phase 3
News & Analysis
1126 JAMA September 22/29, 2020 Volume 324, Number 12 (Reprinted) jama.com
© 2020 American Medical Association. All rights reserved.
trials where we see if the vaccine actually
prevents disease.” The US Food and Drug
Administration has said that a COVID-19
vaccine will need at least 50% efficacy to
be approved.
Tolerability could be another issue.
“People will have to know that they may
have some local reactions or feel like
they’re a little under the weather for a day
or so after the vaccine,” said Edwards, who
is among the independent experts monitoring
investigational COVID-19 vaccine safety.
She and others said that, as with any new
pharmaceutical product, phase 3 studies
could also reveal more serious safety concerns
and unexpected adverse effects
could emerge later.
Speaking at the July 27 media briefing,
Collins addressed concerns: “Yes, we’re
going fast. But, no, we are not going to
compromise safety or efficacy.” Experts say
several factors argue for mRNA vaccines’
safety. For one, mRNA can’t cause an infection.
It also doesn’t enter the cell’s nucleus,
so the chance of its integration into human
DNA is believed to be very low. In addition,
the body breaks down mRNA and its lipid
carrier within a matter of hours, assuaging
some concerns about long-term risks.
However, this rapid degradation raises
questions about mRNA vaccines’ protective
duration. Of added concern for vaccine
durability, researchers in Hong Kong recently
confirmed that a man with SARSCoV-
2was later reinfected, although his second
case was asymptomatic. Yang and
colleagues found that antibodies rapidly
wane among patients with mild COVID-19.
The current candidates’ 2-dose regimens
could help toovercomethis,Yangnoted,and
their cell-mediated immunity should provide
additional oomph.
Offit, who is a member of an NIH Accelerating
COVID-19 Therapeutic Interventions
and Vaccines working group, said that how
long protection from any COVID-19 vaccine
lasts likelywon’tbe knownuntil after a productisapprovedandputintouse.
But,asPicker
put it, a vaccine that’s safe and effective for
evena finiteamountof time couldbeenough
to “break the back of the pandemic.”
Beyond COVID-19
If an mRNA vaccineworks, the implications
could stretch far beyond COVID-19. Success
could pave the way for the platform’s
widespread use for both emerging and established
pathogens.
“We are really making great strides in
vaccine development, which will hopefully
change theway vaccines are approached in
the future,” saidAmesh Adalja,MD, a senior
scholar at the Johns Hopkins University Center
for Health Security.
One such advance might be thermostable
vaccines that don’t have to be frozen
or refrigerated, something scientists say
mRNA might enable. Chinese researchers
recently showed that a potential mRNAbased
SARS-CoV-2 vaccine could be stored
at room temperature for at least a week.
Weissman is trying to develop a more
potent second-generation mRNA vaccine
that protects with a single shot.He’s also set
his sights on a universal coronavirus vaccine
using the genetic platform. “We’ve had
3 coronavirus epidemics in the past 20
years,” he said. “The next time this happens,
we’ll have a vaccine already made,
ready to be shipped out and used very
quickly to prevent the pandemic from taking
over.”
Before COVID-19, his team was working
on mRNA flu vaccines, as well as candidates
for genital herpes and HIV. Influenza
viruses acquire variations from season to
season, making them excellent candidates
for a rapid “vaccine on demand” platform.
In Weissman’s view, mRNA has the
potential to be truly transformative. In a
soon-to-be-published study, he said he
combined mRNA for 20 antigens for different
diseases in the same vaccine. All 20
elicited good responses in mice. In theory,
he said, it might one day be possible for
children to get 2 shots that cover their
more than 50 vaccinations.
He’s not alone in that belief. The
authors of a recent review article wrote
that mRNA vaccines that “can simultaneously
target multiple antigens, and pathogens
will have broad utility for a range of
diseases, reduce the number and frequency
of vaccinations, and alleviate
healthcare worker burden.”
Much of this could rest on the success
or failure of an mRNA COVID-19 vaccine—
and hopes are high. “I think this is an opportunity
for that technology to shine,”
Yang said.
Additional Reporting: Elena Guobyte.
Note: Source references are available through
embedded hyperlinks in the article text online.
Accompanying this article is the JAMA Medical
News Summary, an audio review of news content
appearing in this month’s issues of JAMA. To listen
to this episode and more, visit the JAMA Medical
News Podcast.
News & Analysis
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