The End of the Pandemic Is Now
in Sight
A year of scientific uncertainty is over. Two vaccines
look like they will work, and more should follow.
NOVEMBER 18, 2020
HERB
SNITZER / GETTY
Editor’s Note: The Atlantic is making vital coverage of the
coronavirus available to all readers. Find the collection here.
For all that scientists have done
to tame the biological world, there are still things that lie outside the realm
of human knowledge. The coronavirus was one such alarming reminder, when it
emerged with murky origins in late 2019 and found naive, unwitting hosts in the
human body. Even as science began to unravel many of the virus’s mysteries—how
it spreads, how it tricks its way into cells, how it kills—a fundamental
unknown about vaccines hung over the pandemic and our collective human fate: Vaccines
can stop many, but not all, viruses. Could they stop this one?
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The answer, we now know,
is yes. A resounding yes. Pfizer and Moderna have separately released
preliminary data that suggest their vaccines are both more than 90 percent
effective, far more than many scientists expected. Neither company has publicly
shared the full scope of their data, but independent clinical-trial monitoring boards have
reviewed the results, and the FDA will soon scrutinize the vaccines for
emergency use authorization. Unless the data take an unexpected turn, initial
doses should be available in December.
The tasks that lie ahead—manufacturing vaccines at
scale, distributing them via a cold or even ultracold chain, and persuading
wary Americans to take them—are not trivial, but they are all within the realm
of human knowledge. The most tenuous moment is over: The scientific uncertainty
at the heart of COVID-19 vaccines is resolved. Vaccines work. And for that, we
can breathe a collective sigh of relief. “It makes it now clear that vaccines
will be our way out of this pandemic,” says Kanta Subbarao, a virologist at the
Doherty Institute, who has studied emerging viruses.
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The invention of
vaccines against a virus identified only 10 months ago is an extraordinary
scientific achievement. They are the fastest vaccines ever developed, by a
margin of years. From virtually the day Chinese scientists shared the genetic
sequence of a new coronavirus in January, researchers began designing vaccines
that might train the immune system to recognize the still-unnamed virus. They
needed to identify a suitable piece of the virus to turn into a vaccine, and
one promising target was the spike-shaped proteins that decorate the new
virus’s outer shell. Pfizer and Moderna’s vaccines both rely on the spike
protein, as do many vaccine candidates still in development. These initial
successes suggest this strategy works; several more COVID-19 vaccines may soon
cross the finish line. To vaccinate billions of people across the globe and
bring the pandemic to a timely end, we will need all the vaccines we can get.
But it is no accident or
surprise that Moderna and Pfizer are first out of the gate. They both bet on a
new and hitherto unproven idea of using mRNA, which has the long-promised
advantage of speed. This idea has now survived a trial by pandemic and emerged
likely triumphant. If mRNA vaccines help end the pandemic and restore normal
life, they may also usher in a new era for vaccine development.
The human immune system is awesome
in its power, but an untrained one does not know how to aim its fire. That’s
where vaccines come in. They present a harmless snapshot of a pathogen, a
“wanted” poster, if you will, that primes the immune system to recognize the
real virus when it comes along. Traditionally, this snapshot could be in the
form of a weakened virus or an inactivated virus or a particularly distinctive
viral molecule. But those approaches require vaccine makers to manufacture
viruses and their molecules, which takes time and expertise. Both are lacking
during a pandemic caused by a novel virus.
mRNA vaccines offer a
clever shortcut. We humans don’t need to intellectually work out how to make
viruses; our bodies are already very, very good at incubating them. When the
coronavirus infects us, it hijacks our cellular machinery, turning our cells
into miniature factories that churn out infectious viruses. The mRNA vaccine
makes this vulnerability into a strength. What if we can trick our own cells
into making just one individually harmless, though very recognizable, viral
protein? The coronavirus’s spike protein fits this description, and the instructions
for making it can be encoded into genetic material called mRNA.
Both vaccines, from Moderna and from
Pfizer’s collaboration with the smaller German company BioNTech, package
slightly modified spike-protein mRNA inside a tiny protective bubble of fat.
Human cells take up this bubble and simply follow the directions to make spike
protein. The cells then display these spike proteins, presenting them as
strange baubles to the immune system. Recognizing these viral proteins as
foreign, the immune system begins building an arsenal to prepare for the moment
a virus bearing this spike protein appears.
This overall process
mimics the steps of infection better than some traditional vaccines, which
suggests that mRNA vaccines may provoke a better immune response for certain
diseases. When you inject vaccines made of inactivated viruses or viral pieces,
they can’t get inside the cell, and the cell can’t present those viral pieces
to the immune system. Those vaccines can still elicit proteins called
antibodies, which neutralize the virus, but they have a harder time stimulating
T cells, which make up another important part of the immune response. (Weakened
viruses used in vaccines can get inside cells, but risk causing an actual
infection if something goes awry. mRNA vaccines cannot cause infection because
they do not contain the whole virus.) Moreover, inactivated viruses or viral
pieces tend to disappear from the body within a day, but mRNA vaccines can
continue to produce spike protein for two weeks, says Drew Weissman, an
immunologist at the University of Pennsylvania, whose mRNA vaccine research has
been licensed by both BioNTech and Moderna. The longer the spike protein is around,
the better for an immune response.
All of this is how mRNA
vaccines should work in theory. But no one on Earth, until last week, knew
whether mRNA vaccines actually do work in humans for COVID-19.
Although scientists had prototyped other mRNA vaccines before the pandemic, the
technology was still new. None had been put through the paces of a large
clinical trial. And the human immune system is notoriously complicated and
unpredictable. Immunology is, as my colleague Ed Yong has written, where intuition goes to die. Vaccines can even
make diseases more severe, rather than less. The data from
these large clinical trials from Pfizer/BioNTech and Moderna are the first,
real-world proof that mRNA vaccines protect against disease as expected. The
hope, in the many years when mRNA vaccine research flew under the radar, was
that the technology would deliver results quickly in a pandemic. And now it
has.
“What a relief,” says Barney Graham, a
virologist at the National Institutes of Health, who helped design the spike protein
for the Moderna vaccine. “You can make thousands of decisions, and thousands of
things have to go right for this to actually come out and work. You’re just
worried that you have made some wrong turns along the way.” For Graham, this
vaccine is a culmination of years of such decisions, long predating the
discovery of the coronavirus that causes COVID-19. He and his collaborators had
homed in on the importance of spike protein in another virus, called
respiratory syncytial virus, and figured out how to make the protein more
stable and thus suitable for vaccines. This modification appears in both
Pfizer/BioNTech’s and Moderna’s vaccines, as well as other leading vaccine
candidates.
The spectacular efficacy
of these vaccines, should the preliminary data hold, likely also has to do with
the choice of spike protein as vaccine target. On one hand, scientists were
prepared for the spike protein, thanks to research like Graham’s. On the other
hand, the coronavirus’s spike protein offered an opening. Three separate
components of the immune system—antibodies, helper cells, and killer T
cells—all respond to the spike protein, which isn’t the case with most viruses.
In this, we were lucky.
“It’s the three punches,” says Alessandro Sette. Working with Shane Crotty, his
fellow immunologist at the La Jolla Institute, Sette found that COVID-19
patients whose immune systems can marshal all three responses against the spike
protein tend to fare the best. The fact that most people can recover from
COVID-19 was always encouraging news; it meant a vaccine simply needed to
jump-start the immune system, which could then take on the virus itself. But no
definitive piece of evidence existed that proved COVID-19 vaccines would be a
slam dunk. “There’s nothing like a Phase 3 clinical trial,” Crotty says. “You
don’t know what’s gonna happen with a vaccine until it happens, because the
virus is complicated and the immune system is complicated.”
Experts anticipate that
the ongoing trials will clarify still-unanswered questions about the COVID-19
vaccines. For example, Ruth Karron, the director of the Center for Immunization
Research at Johns Hopkins University, asks, does the vaccine prevent only a
patient’s symptoms? Or does it keep them from spreading the virus? How long
will immunity last? How well does it protect the elderly, many of whom have a
weaker response to the flu vaccine? So far, Pfizer has noted that its vaccine
seems to protect the elderly just as well, which is good news because they are
especially vulnerable to COVID-19.
Several more vaccines
using the spike protein are in clinical trials too. They rely on a suite of
different vaccine technologies, including weakened viruses, inactivated
viruses, viral proteins, and another fairly new concept called DNA vaccines. Never before have companies tested
so many different types of vaccines against the same virus, which might end up
revealing something new about vaccines in general. You now have the same spike
protein delivered in many different ways, Sette points out. How will the
vaccines behave differently? Will they each stimulate different parts of the
immune system? And which parts are best for protecting against the coronavirus?
The pandemic is an opportunity to compare different types of vaccines head-on.
If the two mRNA vaccines continue to be as
good as they initially seem, their success will likely crack open a whole new
world of mRNA vaccines. Scientists are already testing them against currently
un-vaccinable viruses such as Zika and cytomegalovirus and trying to make
improved versions of existing vaccines, such as for
the flu. Another possibility lies in personalized mRNA vaccines that
can stimulate the immune system to fight cancer.
But the next few months
will be a test of one potential downside of mRNA vaccines: their extreme
fragility. mRNA is an inherently unstable molecule, which is why it needs that
protective bubble of fat, called a lipid nanoparticle. But the lipid
nanoparticle itself is exquisitely sensitive to temperature. For longer-term
storage, Pfizer/BioNTech’s vaccine has to be stored at –70 degrees Celsius and
Moderna’s at –20 Celsius, though they can be kept at higher temperatures for a
shorter amount of time. Pfizer/BioNTech and Moderna have said they can
collectively supply enough doses for 22.5 million people in the United States by
the end of the year.
Distributing the limited
vaccines fairly and smoothly will be a massive political and logistical
challenge, especially as it begins during a bitter transition of power in Washington.
The vaccine is a scientific triumph, but the past eight months have made clear
how much pandemic preparedness is not only about scientific research. Ensuring
adequate supplies of tests and personal protective equipment, providing
economic relief, and communicating the known risks of COVID-19 transmission are
all well within the realm of human knowledge, yet the U.S. government has failed at all of that.
The vaccine by itself cannot slow the dangerous trajectory of COVID-19
hospitalizations this fall or save the many people who may die by Christmas.
But it can give us hope that the pandemic will end. Every infection we prevent
now—through masking and social distancing—is an infection that can, eventually,
be prevented forever through vaccines.
SARAH ZHANG is
a staff writer at The Atlantic.
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