6 2 FO R T U N E F E B R UA RY/ M A R C H 2 0 2 2

BEHIND As Omicron rages, scientists

THE COVID inside Moderna are racing
to develop new vaccines
BATTLE that might someday outflank
LINES the virus.

CLEAN ROOM
Inside a
laboratory at
Moderna’s facility
in Norwood,
Mass., outside
Boston, where
researchers
are working on
adapting its
SpikeVax for
new variants.
 FO R T U N E F E B R UA RY/ M A R C H 2 0 2 2 6 3

Stéphane Bancel almost relaxed for a moment. The

By
ON THE AFTERNOON BEFORE THANKSGIVING,
CEO of Moderna, the biotech based in Cambridge, Mass., is a quintessential startup leader—
a hard-charging, around-the-clock-emailing whirlwind of energy. But as America turned its
focus to a long break full of turkey, traffic, and football, Bancel was in his home office getting Erika
ready to sign off a few hours early for the day. After all, he and his team had been working
flat-out for the better part of two years. They had raced to develop and manufacture their re-
Fry
markably effective COVID vaccine, known as SpikeVax, while simultaneously scaling up every
aspect of the organization to do so. A few extra hours of downtime before a holiday weekend
seemed in order.
 of the most likely “point mutations” to
the virus’s spike protein and analyzed
the ways those mutations might com-
bine to form new variants and impact
SpikeVax’s effectiveness. (The spike
protein is the critical part of the virus
that helps it infect cells, as well as the
target of vaccine-induced antibodies.)
The Moderna team’s working the-
ory was that there was a natural limit
to how much the spike protein could
change before it started to stumble—
they didn’t think it was possible for
the virus to thrive with more than 10
mutations. But these new sequences,
which contained every one of their
top 10 most likely mutations plus over
a dozen more, “blew that hypothesis
out of the water,” says Hoge.
The big question for Bancel and
RED ALERT Hoge was: Would the immune
Moderna CEO system of a Moderna vaccine recipi-
Stéphane Bancel and ent recognize what it was looking at
his team sprang into
action within hours of
when exposed to the highly mutated
identifying Omicron. new version of the virus? In other
words, would SpikeVax hold up?

FAST-FORWARD TO TODAY, and Omicron

Then Bancel received an urgent text message from Stephen Hoge, Mod- has radically altered the nature of
erna’s president and head of R&D: “Tracking a new variant. (B.1.1.529). the pandemic and the debate among
Doesn’t look good.” Hoge, an ER doctor turned McKinsey consultant who health officials, politicians, and the
joined Moderna in 2012, suggested they jump on a video call right away. public about the best COVID battle
Over the past two years, throughout the ticktock of the global pandemic, plan. The ultra-infectious strain of
Bancel, 47, has found himself playing a lead role in more than his share of the virus has swept across the globe
disaster-movie moments. There was the fateful day in early January 2020 at lightning speed—outmaneuvering
when he commanded his team to sequence a mysterious, little-known respi- other variants, smashing COVID case
ratory virus that was spreading in China and begin working on a vaccine, records in dozens of countries, filling
just in case. Or a few weeks later, when he found himself and a handful of hospitals, and adding to the ranks
other global health care leaders huddled around a napkin at Davos, in the of those lost forever. And almost as
Swiss Alps, scribbling out the pathogen’s expected rate of infection. Now, quickly as Omicron spiked, it has
here he was again, being briefed on the latest twist in the COVID saga—a begun to plummet again in the com-
scary new strain of the virus that would soon be dubbed Omicron. munities where it first took hold.
Suddenly, there was a potentially scary new plot twist. As Hoge and others feared,
A couple of days earlier, Hoge and his team of researchers had noticed Omicron has proved much better
some alarming data being reported out of South Africa and Botswana, and than previous versions of the virus at
then Hong Kong. Like many around the world, Moderna closely tracks evading our immune defenses, both
the real-time evolution of SARS-CoV-2, the virus that causes COVID-19, in people previously infected and
by monitoring the global database where scientists around the world post those fully vaccinated. But Omicron
newly collected genetic sequences of the virus. The hope is to quickly spot also appears less likely to cause
mutations that meaningfully change the nature of the virus, or the ability severe disease than previous variants,
of vaccines to protect against it. in part because it lurks more in our
Moderna had been preparing for such a scenario for months, using sophis- upper airways around the nose and
ticated machine-learning tools to game out the most gnarly twists SARS- throat than in our lungs. People who
CoV-2 might take in the future. They’d developed a hit list of more than 30 are fully vaccinated—especially those
 FO R T U N E F E B R UA RY/ M A R C H 2 0 2 2 6 5

TAKING AIM AT A MOVING TARGET

CORONAVIRUS VARIANTS IN THE U.S. SHARE OF ANALYZED SEQUENCES CORRESPONDING TO EACH VARIANT GROUP
OMICRON
100% 95.7%
BETA
GAMMA
EPSILON
80%
IOTA

60%

DELTA

40% OTHERS/NOT DOCUMENTED ALPHA

20%

OMICRON
0% MU

MAY 11, 2020 NOV. 16, 2020 FEB. 24, 2021 JUNE 4, 2021 JAN. 17, 2022

COVID-19 VACCINE DOSES ADMINISTERED IN THE U.S.

500 MILLION JOHNSON & JOHNSON

400

300
PFIZER/BIONTECH
200

100
MODERNA
0

JAN. 12, 2021 APRIL JUNE AUGUST OCTOBER JAN. 18, 2022
SOURCES: CDC; GISAID, VIA COVARIANTS.ORG AND OUR WORLD IN DATA
OPENING SPRE AD: C OURTESY OF MODERNA ; BANCEL: FR ANCE K E YSER /M YOP

who are boosted—are at much less to give us the weapons we need to continue the fight against future strains?
risk of serious illness. By the most For those like Bancel and Hoge who have spent the past two years on the
important measures, vaccines like front lines, Omicron has been a humbling reminder that this virus moves
Moderna’s do still work. faster than our science and more unpredictably than our most sophisti-
This dizzying new chapter in the cated tools can anticipate. The answer to a great number of things is: We
fight against COVID has prompted don’t know. And indeed, two months after Omicron’s emergence, much
both gloom and hope in almost equal about the new variant remains uncertain, including how long it will stick
measure, and a sparked a number around and whether Omicron-updated vaccines, such as one that Moderna
of weighty questions: Is Omicron a is currently developing, will be used, or even necessary.
major step toward COVID’s end- To better understand what lies ahead, we asked Moderna to give us a
game, with the virus losing some of rare inside look at how the company is grappling with Omicron and how
its virulence and the population’s it’s thinking strategically about the different scenarios that could play out
increased exposure and immunity? Or in the months and years ahead.
is it merely a distraction before some
doomsday variant to come? And can IT’S HARD TO OVERSTATE SpikeVax’s
importance to Moderna. Before the
vaccine makers adapt quickly enough pandemic, the company was a promising startup with a much-hyped
6 6 FO R T U N E F E B R UA RY/ M A R C H 2 0 2 2

FOUR SHOTS AT
FIGHTING COVID
As the world grapples with the Omicron
surge, health officials and vaccine
makers such as Moderna are weigh-
ORIGINAL COVID STRAIN DELTA
ing the best approach for the ongoing
fight against SARS-CoV-2. Here are
four vaccination strategies under
consideration:

Booster doses of the current vaccines

Data shows that a third mRNA dose is

highly effective at preventing Omicron-
related hospitalizations or urgent care
visits, and that it offers more robust
protection against infection. Studies are
underway to understand how long that
protection lasts, and what effect another
booster dose would have. (Israel has al-
ready adopted this approach for people
age 60 and above.)

Omicron-specific boosters

Because the variant is so dramatically

VARIATIONS ON A VIRAL THEME
mutated, some suspect an Omicron- These computer simulations, produced with data from a cryo-electron
specific vaccine—one that makes more microscope, show top and side views of the spike protein of the original strain
durable antibodies against the strain— of SARS-CoV-2, the Delta variant, and Omicron. The red, white, and blue circles
may be a better strategy. While John all denote mutations. Omicron’s large number of mutations is what makes it so
Moore, a virologist at Weill Cornell Medi- effective at eluding our immune defenses.
cal College, says the need is not yet clear,
it’s reasonable to stockpile them for a
worst-case scenario, like Omicron taking
a more virulent form, he says.
technology, lots of ideas about how to apply it, and very little in the way of
sales. The vaccine changed all of that. SpikeVax was the source of virtually
Hybrid, or multivalent, boosters all of Moderna’s estimated $17.5 billion in revenue in 2021, the first year
To many tracking the virus, Omicron
the company cracked a billion in sales. The company’s stock chart tells the
came out of left field. It didn’t evolve story of its wild ride. In January 2020, Moderna’s shares were trading at
from Delta, the previously dominant roughly $20. They rocketed up to nearly $485 per share in August 2021
strain. And the next variant may not before tumbling late in the year. As of late January, the stock was trading
spring from Omicron. For that reason,
around $157. Along the way, the SpikeVax windfall has allowed Moderna to
some, including Moderna CEO Bancel,
think it may be better to make a booster make more ambitious investments in advancing other applications for its
that offers broader protection, targeting mRNA platform. For instance, the startup recently started Phase III clini-
both Omicron and the original strain. cal trials for a vaccine to prevent CMV, a latent virus that can be passed by
pregnant women to their babies and is a common cause of birth defects.
Variant-proof vaccines Moderna says it expects to produce as many as 3 billion doses of its vac-
cines in 2022, up from 800 million last year. As of late January, some 62%
Why chase variants if we can beat them all
of the world’s population had received at least one shot of vaccine. But that
with a single variant-proof or pan-coro-
navirus shot? It won’t happen in 2022. means there are hundreds of millions of people who are either not yet vac-
But the Coalition for Epidemic Prepared- cinated or candidates for booster shots. Even as they continue to ramp up
ness Innovations (CEPI) has committed SpikeVax production, however, Bancel and Hoge are hustling to develop
$200 million into such efforts. Says CEPI Omicron-targeting versions of their jab.
director of vaccine R&D Melanie Saville:
“We’d like to get to a situation that rather
Moderna can’t just roll out an updated vaccine on its own, of course.
than the virus being one step ahead of It needs the green light from regulators like the FDA, which requires the
us, we will be ahead of the virus.” company conduct a small clinical trial to demonstrate the benefit of a
 Top view

FO R T U N E F E B R UA RY/ M A R C H 2 0 2 2 6 7

among a group in the medical community who believe vaccination efforts

have become wrongly focused on trying to prevent all infection, rather
than severe disease. Put another way, rather than boosting the vaccinated,
we should be vaccinating the unvaccinated. Says Offit, “We can’t boost our
way out of this pandemic.”
OMICRON Vaccine makers, meanwhile, have been discussing plans for doing just
that: Pfizer CEO Albert Bourla said recently that his company had initi-
ated manufacturing so that an Omicron-specific product could be available
as early as March. In late January, Pfizer said that it had begun testing its
Omicron-specific booster in adults.
Bancel tells Fortune that he expects the best strategy may be to offer a
multivalent booster shot that targets both Omicron and the original SARS-
CoV-2 strain in the fall—assuming, that is, that the trial data supports it,
regulators approve it, and the pandemic doesn’t veer violently in a new
direction again.
As Anthony Fauci, director of the National Institute of Allergy and
Infectious Diseases, put it at a World Economic Forum event in January:
“We really don’t want to get into the Whac-a-Mole approach towards every
new variant.”

THEY CERTAINLY NEVER INTENDED IT, but Whac-a-Mole is more or less the game
Side view
Moderna’s researchers have been playing since the first COVID variants of
concern, Alpha and Beta, emerged in late 2020. Alpha, a travel ban–induc-
ing, Christmas spoiler in the U.K., got a lot of attention. But Hoge’s team
was more concerned about Beta. There were worrying reports coming
strain change and future need for it. from South Africa, where the variant was first identified, suggesting the
Moderna began its trial in January. strain caused more severe disease. Moderna’s experience with Beta created
And the company expects to submit the template for how it is now tackling Omicron.
data on safety and the compara- When tested in the lab, Alpha didn’t make a dent in the vaccine’s protec-
tive antibody levels of participants, tion. But Beta, despite having only a couple of mutations, did. It reduced
before and after they received an the level of neutralizing antibodies sixfold. Moderna’s team thought
Omicron-targeting booster, in March SpikeVax still offered sufficient protection against Beta, though they
or April. “I expect the neutralizing feared it could wane over time, explains Andrea Carfi, the company’s chief
antibodies will be very high,” Bancel scientific officer of infectious disease. Should they make a vaccine targeting
says. As with other COVID vaccines Beta specifically? Or one that would offer combined protection against the
and drugs, if the FDA authorizes original strain and this new, more virulent one?
the product the CDC will then make Government officials and scientists were ambivalent. “Nobody wanted to
C O U R T E S Y O F F I O N A K E A R N S & M I A R O S E N F E L D /A M A R O L A B , U C S A N D I E G O

recommendations on its use. say for sure that it’d be necessary,” says Hoge. There was an ongoing debate
But the very concept of updated as to whether the virus was likely to mutate more. Regulators had also re-
boosters is a subject of intense media cently made it clear that the bar for an approval of an updated vaccine was
interest and some controversy. De- set high: Manufacturers had to prove need, a case that many at Moderna
spite the CDC’s recommendation that thought they’d only be able to make persuasively when it was too late.
all people 12 and above get a booster, Beyond that, after a yearlong sprint to get SpikeVax authorized and into
some in the public health commu- people’s arms, everyone at Moderna was exhausted. Even with Moderna’s
nity argue it’s misguided policy. For cutting-edge mRNA technology platform, scrambling to develop new ver-
healthy young people, “a booster sions of the vaccine just as they were ramping up production of the original
buys you three to four months of would be a huge lift. “There were definitely voices inside saying, ‘This isn’t
additional protection against mild going to be worth it,’ ” says Hoge, who manages to exude a Ted Lasso–like
illness. That’s not a public health positivity even when discussing the grimmest scenarios. “We should focus
strategy,” says Paul Offit, director on the prototype. Don’t go chasing variants.”
of the Vaccine Education Center at In the end, Moderna’s executives decided the risk of not chasing variants
Children’s Hospital of Philadelphia. was greater than the risk of wasted work. Says Hoge: “The prudent thing
(He does recommend them for the to do was to plan for the worst-case scenario even while you’re hoping for
old and immunocompromised.) He’s the best.”
6 8 FO R T U N E F E B R UA RY/ M A R C H 2 0 2 2

The team drew up a three-pronged strategy, the same one they’ve used for
variants of concern, including Omicron, ever since. They’d explore a triple
“There’s nothing
play of options against the strain: They would start by testing a booster dose about the virus
of the original vaccine, and at the same time they’d develop two new vac-
cines and quickly put them into clinical trials—a Beta-specific version, and
that says it’s done
another mRNA vaccine that combined the original with the Beta. mutating,” says
It turned out the Beta-targeting vaccines weren’t necessary. Neither
were the Delta-specific versions Hoge’s team developed a few months later
Hoge, Moderna’s
when that variant took off. In both cases, clinical studies showed Mod- president and
erna’s original vaccine worked just as well as a variant-specific booster. head of R&D.
There’s a chance that Moderna will reach the same conclusion with
Omicron. But even if this iteration doesn’t yield a new version of SpikeVax, “It’s gonna keep
the process has yielded insights about the virus and their vaccine. evolving. It’s gonna
That this type of real-time experimentation is even possible is a testa-
ment to the leap forward that the mRNA technology has afforded. The op- keep poking holes
portunity for “prudence” is practically unheard-of in the long-underfunded in the wall.”
worlds of pandemic preparedness and American public health. “I really
applaud Moderna and Pfizer,” says Rick Bright, CEO of the Rockefeller
Foundation’s Pandemic Prevention Institute and former director of the
Biomedical Advanced Research and Development Authority, or BARDA. variant began to arrive in early De-
(The agency invested in Moderna during his tenure.) “They’re thinking cember. His first thought? “We’re go-
about the power [of the technology] they have in their hands now and how ing to get through the current wave,”
to harness it to think smarter and have a smarter vaccine.” says Hoge. Two doses of SpikeVax
Still, it troubles him that a variant-specific COVID vaccine hasn’t yet didn’t offer a robust defense against
been run through the regulatory process. “If we wait until we really, really Omicron. But three shots did. In a
need that strain change to figure this out, there’s going to be much more study from the U.K. the vaccine ap-
pressure, much more chaos. It’s going to be much harder to do the right peared to be more than 70% effective
thing fast enough.” in preventing symptomatic COVID
Bright argues regulators and public health officials need to shed older in boosted participants. And 90% of
ideology and embrace more creative strategies. “We’re watching [the those individuals were protected from
vaccine’s] power diminish as the virus continues to change, but we’re still hospitalization.
placating ourselves that it’s good enough, that it’s still working to prevent Now, as Moderna plunges into clini-
serious illness and hospitalization. But we have data that shows it’s strug- cal trials for its Omicron-specific and
gling more and more to do so.” multivalent vaccines, the company is
Others in the public health community worry that the conversation simultaneously working to develop a
around vaccine updates so far appears to be manufacturer-driven. With pan-respiratory vaccine that would
influenza vaccines, the WHO recommends strains, regulators such as the take aim at flu, COVID, and other
FDA select them, and manufacturers deliver them. But with COVID, it’s respiratory viruses such as RSV. Mod-
the manufacturers, at least publicly, who have been out in front. A growing erna is also in the very initial stages of
chorus of stakeholders are in favor of adapting the model used for devel- work on a vaccine that would target
oping annual influenza vaccines to SARS-CoV-2. That system involves a all coronaviruses, not to mention,
global surveillance network and regular multinational committee meetings all SARS-CoV-2 variants—a jab that
over vaccine strain selection. would theoretically be variant-proof.
That kind of Hail Mary innova-
ON THE SAME NOVEMBER AFTERNOON that Hoge texted Bancel about Omicron, tion—whether it emerges from
a scientist at Moderna cut and pasted the new variant’s genetic sequence Moderna or another vaccine maker—
into the company’s Drug Design Studio, a computer interface that looks could be our best chance for actually
a bit like an online shopping platform but is actually an A.I.-powered, getting ahead of COVID. “There’s
mRNA-optimizing tool. The scientist clicked “order,” and within minutes, nothing about the history of the virus
the company’s robots were beginning to fill pipettes with plasmids in its that says it’s done mutating,” says
Norwood, Mass., factory, the first step in a three- to four-week process Hoge. “It’s gonna keep evolving. It’s
to manufacture a new mRNA vaccine—one that would train the body’s gonna keep poking holes in the wall.”
defenses precisely against Omicron. The key is being there to patch up the
Hoge breathed a huge sigh of relief when real-world data on the new defenses.
MARCH 3-6
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