Inside Moderna’s plan to battle Omicron and develop a booster that works against any future variants

Then Bancel received an urgent text message from Stephen Hoge, Moderna’s president and head of R&D: “Tracking a new variant. (B.1.1.529). Doesn’t look good.” Hoge, an ER doctor turned McKinsey consultant who joined Moderna in 2012, suggested they jump on a video call right away.

Over the past two years, throughout the ticktock of the global pandemic, Bancel, 47, has found himself playing a lead role in more than his share of disaster-movie moments. There was the fateful day in early January 2020 when he commanded his team to sequence a mysterious, little-known respiratory virus that was spreading in China and begin working on a vaccine, just in case. Or a few weeks later, when he found himself and a handful of other global health care leaders huddled around a napkin at Davos, in the Swiss Alps, scribbling out the pathogen’s expected rate of infection. Now, here he was again, being briefed on the latest twist in the COVID saga—a scary new strain of the virus that would soon be dubbed Omicron.

Suddenly, there was a potentially scary new plot twist.

A couple of days earlier, Hoge and his team of researchers had noticed some alarming data being reported out of South Africa and Botswana, and then Hong Kong. Like many around the world, Moderna closely tracks the real-time evolution of SARS-CoV-2, the virus that causes COVID-19, by monitoring the global database where scientists around the world post newly collected genetic sequences of the virus. The hope is to quickly spot mutations that meaningfully change the nature of the virus, or the ability of vaccines to protect against it.

Moderna had been preparing for such a scenario for months, using sophisticated machine-learning tools to game out the most gnarly twists SARS-CoV-2 might take in the future. They’d developed a hit list of more than 30 of the most likely “point mutations” to the virus’s spike protein and analyzed the ways those mutations might combine 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 theory 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 Hoge was: Would the immune system of a Moderna vaccine recipient recognize what it was looking at when exposed to the highly mutated new version of the virus? In other words, would SpikeVax hold up?

Fast-forward to today, and Omicron has radically altered the nature of the pandemic and the debate among health officials, politicians, and the public about the best COVID battle plan. The ultra-infectious strain of the virus has swept across the globe at lightning speed—outmaneuvering other variants, smashing COVID case records in dozens of countries, filling hospitals, and adding to the ranks of those lost forever. And almost as quickly as Omicron spiked, it has begun to plummet again in the communities where it first took hold.

As Hoge and others feared, Omicron has proved much better than previous versions of the virus at evading our immune defenses, both in people previously infected and those fully vaccinated. But Omicron also appears less likely to cause severe disease than previous variants, in part because it lurks more in our upper airways around the nose and throat than in our lungs. People who are fully vaccinated—especially those who are boosted—are at much less risk of serious illness. By the most important measures, vaccines like Moderna’s do still work. 

This dizzying new chapter in the fight against COVID has prompted both gloom and hope in almost equal measure, and a sparked a number of weighty questions: Is Omicron a major step toward COVID’s endgame, with the virus losing some of its virulence and the population’s increased exposure and immunity? Or is it merely a distraction before some doomsday variant to come? And can vaccine makers adapt quickly enough to give us the weapons we need to continue the fight against future strains?

For those like Bancel and Hoge who have spent the past two years on the front lines, Omicron has been a humbling reminder that this virus moves faster than our science and more unpredictably than our most sophisticated tools can anticipate. The answer to a great number of things is: We don’t know. And indeed, two months after Omicron’s emergence, much about the new variant remains uncertain, including how long it will stick around and whether Omicron-updated vaccines, such as one that Moderna is currently developing, will be used, or even necessary.

To better understand what lies ahead, we asked Moderna to give us a rare inside look at how the company is grappling with Omicron and how it’s thinking strategically about the different scenarios that could play out in the months and years ahead. 

It’s hard to overstate SpikeVax’s importance to Moderna. Before the pandemic, the company was a promising startup with a much-hyped 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 all of Moderna’s estimated $17.5 billion in revenue in 2021, the first year the company cracked a billion in sales. The company’s stock chart tells the story of its wild ride. In January 2020, Moderna’s shares were trading at roughly $20. They rocketed up to nearly $485 per share in August 2021 before tumbling late in the year. As of late January, the stock was trading around $157. Along the way, the SpikeVax windfall has allowed Moderna to make more ambitious investments in advancing other applications for its mRNA platform. For instance, the startup recently started Phase III clinical 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.  

Moderna says it expects to produce as many as 3 billion doses of its vaccines in 2022, up from 800 million last year. As of late January, some 62% of the world’s population had received at least one shot of vaccine. But that means there are hundreds of millions of people who are either not yet vaccinated or candidates for booster shots. Even as they continue to ramp up SpikeVax production, however, Bancel and Hoge are hustling to develop Omicron-targeting versions of their jab.

Moderna can’t just roll out an updated vaccine on its own, of course. It needs the green light from regulators like the FDA, which requires the company conduct a small clinical trial to demonstrate the benefit of a strain change and future need for it. Moderna began its trial in January. And the company expects to submit data on safety and the comparative antibody levels of participants, before and after they received an Omicron-targeting booster, in March or April. “I expect the neutralizing antibodies will be very high,” Bancel says. As with other COVID vaccines and drugs, if the FDA authorizes the product the CDC will then make recommendations on its use.

But the very concept of updated boosters is a subject of intense media interest and some controversy. Despite the CDC’s recommendation that all people 12 and above get a booster, some in the public health community argue it’s misguided policy. For healthy young people, “a booster buys you three to four months of additional protection against mild illness. That’s not a public health strategy,” says Paul Offit, a professor of pediatrics and director of the Vaccine Education Center at Children’s Hospital of Philadelphia. (He does recommend them for the old and immunocompromised.) He’s 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.”

Vaccine makers, meanwhile, have been discussing plans for doing just that: Pfizer CEO Albert Bourla said recently that his company had initiated 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 Moderna’s researchers have been playing since the first COVID variants of concern, Alpha and Beta, emerged in late 2020. Alpha, a travel ban–inducing, 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 from South Africa, where the variant was first identified, suggesting the strain caused more severe disease. Moderna’s experience with Beta created the template for how it is now tackling Omicron.

When tested in the lab, Alpha didn’t make a dent in the vaccine’s protection. But Beta, despite having only a couple of mutations, did. It reduced the level of neutralizing antibodies sixfold. Moderna’s team thought SpikeVax still offered sufficient protection against Beta, though they feared it could wane over time, explains Andrea Carfi, the company’s chief scientific officer of infectious disease. Should they make a vaccine targeting Beta specifically? Or one that would offer combined protection against the original strain and this new, more virulent one?

Government officials and scientists were ambivalent. “Nobody wanted to say for sure that it’d be necessary,” says Hoge. There was an ongoing debate as to whether the virus was likely to mutate more. Regulators had also recently made it clear that the bar for an approval of an updated vaccine was set high: Manufacturers had to prove need, a case that many at Moderna thought they’d only be able to make persuasively when it was too late. 

Beyond that, after a yearlong sprint to get SpikeVax authorized and into people’s arms, everyone at Moderna was exhausted. Even with Moderna’s cutting-edge mRNA technology platform, scrambling to develop new versions of the vaccine just as they were ramping up production of the original would be a huge lift. “There were definitely voices inside saying, ‘This isn’t going to be worth it,’ ” says Hoge, who manages to exude a Ted Lasso–like positivity even when discussing the grimmest scenarios. “We should focus on the prototype. Don’t go chasing variants.”

In the end, Moderna’s executives decided the risk of not chasing variants was greater than the risk of wasted work. Says Hoge: “The prudent thing to do was to plan for the worst-case scenario even while you’re hoping for the best.”

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 play of options against the strain: They would start by testing a booster dose of the original vaccine, and at the same time they’d develop two new vaccines and quickly put them into clinical trials—a Beta-specific version, and another mRNA vaccine that combined the original with the Beta.

It turned out the Beta-targeting vaccines weren’t necessary. Neither were the Delta-specific versions Hoge’s team developed a few months later when that variant took off. In both cases, clinical studies showed Moderna’s original vaccine worked just as well as a variant-specific booster.

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, the process has yielded insights about the virus and their vaccine.

There’s nothing about the virus that says it’s done mutating. It’s gonna keep evolving. It’s gonna keep poking holes in the wall.

Stephen Hoge, Moderna’s president and head of R&D

That this type of real-time experimentation is even possible is a testament to the leap forward that the mRNA technology has afforded. The opportunity for “prudence” is practically unheard-of in the long-underfunded 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. (The agency invested in Moderna during his tenure.) “They’re thinking about the power [of the technology] they have in their hands now and how to harness it to think smarter and have a smarter vaccine.”

Still, it troubles him that a variant-specific COVID vaccine hasn’t yet been run through the regulatory process. “If we wait until we really, really need that strain change to figure this out, there’s going to be much more pressure, much more chaos. It’s going to be much harder to do the right thing fast enough.”

Bright argues regulators and public health officials need to shed older ideology and embrace more creative strategies. “We’re watching [the vaccine’s] power diminish as the virus continues to change, but we’re still placating ourselves that it’s good enough, that it’s still working to prevent serious illness and hospitalization. But we have data that shows it’s struggling more and more to do so.”

Others in the public health community worry that the conversation around vaccine updates so far appears to be manufacturer-driven. With influenza vaccines, the WHO recommends strains, regulators such as the FDA select them, and manufacturers deliver them. But with COVID, it’s the manufacturers, at least publicly, who have been out in front. A growing chorus of stakeholders are in favor of adapting the model used for developing annual influenza vaccines to SARS-CoV-2. That system involves a global surveillance network and regular multinational committee meetings over vaccine strain selection.

On the same November afternoon that Hoge texted Bancel about Omicron, a scientist at Moderna cut and pasted the new variant’s genetic sequence into the company’s Drug Design Studio, a computer interface that looks a bit like an online shopping platform but is actually an A.I.-powered, mRNA-optimizing tool. The scientist clicked “order,” and within minutes, the company’s robots were beginning to fill pipettes with plasmids in its Norwood, Mass., factory, the first step in a three- to four-week process to manufacture a new mRNA vaccine—one that would train the body’s defenses precisely against Omicron.

Hoge breathed a huge sigh of relief when real-world data on the new variant began to arrive in early December. His first thought? “We’re going to get through the current wave,” says Hoge. Two doses of SpikeVax didn’t offer a robust defense against Omicron. But three shots did. In a study from the U.K. the vaccine appeared to be more than 70% effective in preventing symptomatic COVID in boosted participants. And 90% of those individuals were protected from hospitalization.

Now, as Moderna plunges into clinical trials for its Omicron-specific and multivalent vaccines, the company is simultaneously working to develop a pan-respiratory vaccine that would take aim at flu, COVID, and other respiratory viruses such as RSV. Moderna is also in the very initial stages of work on a vaccine that would target all coronaviruses, not to mention, all SARS-CoV-2 variants—a jab that would theoretically be variant-proof.

That kind of Hail Mary innovation—whether it emerges from Moderna or another vaccine maker—could be our best chance for actually getting ahead of COVID. “There’s nothing about the history of the virus that says it’s done mutating,” says Hoge. “It’s gonna keep evolving. It’s gonna keep poking holes in the wall.” The key is being there to patch up the defenses. 

4 shots at fighting COVID

As the world grapples with the Omicron surge, health officials and vaccine makers such as Moderna are weighing 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 already adopted this approach for people age 60 and above.) 

Omicron-specific boosters 

Because the variant is so dramatically mutated, some suspect an Omicron-specific vaccine—one that makes more durable antibodies against the strain—may be a better strategy. While John Moore, a virologist at Weill Cornell Medical 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. 

Hybrid, or multivalent, boosters 

To many tracking the virus, Omicron came out of left field. It didn’t evolve from Delta, the previously dominant strain. And the next variant may not spring from Omicron. For that reason, some, including Moderna CEO Bancel, think it may be better to make a booster that offers broader protection, targeting both Omicron and the original strain. 

Variant-proof vaccines 

Why chase variants if we can beat them all with a single variant-proof or pan-coronavirus shot? It won’t happen in 2022. But the Coalition for Epidemic Preparedness Innovations (CEPI) has committed $200 million into such efforts. Says CEPI director of vaccine R&D Melanie Saville: “We’d like to get to a situation that rather than the virus being one step ahead of us, we will be ahead of the virus.” 

This article appears in the February/March issue of Fortune with the headline, “Behind the COVID battle lines.”