The omicron wave is finally on the decline in the U.S. Workers are returning to offices again, hospital wards are emptying, and states have lifted mask mandates. But a new strain, BA.2, has spread widely in Europe and is growing in prevalence in the U.S. And Pfizer Inc. and Moderna Inc. have now asked U.S. regulators to clear an additional Covid-19 booster as protection provided by the first three shots fades.
While the vaccines at first were remarkably good at preventing Covid infections, successive mutations and the passage of time have rendered the shots less effective. The boosters people received late last year did help ward off some Covid infections during the most recent surge, but those may not end up being the final shots for those who want to stay ahead of this virus. “It is clear that we are going to have to develop a strategy for fourth, and possibly continuing, shots,” says Arnold Monto, an epidemiologist and influenza expert at the University of Michigan who believed this during the spread of the delta variant. The emergence of omicron, he says, “only strengthens my view.”
That’s where the knowns end. Figuring out which variants future boosters should target, when the shots might be needed, and who should take them is a murky work in progress. Answers to basic questions such as how long protection from existing shots lasts and how many further variants of Covid will arise remain elusive. Future variants may not end up being better at evading the immune system, which could make additional shots unnecessary for most people. Or more harmful mutations may emerge, making the urgent development of variant-specific vaccines the better course of action.
“There is a lot of sentiment in the vaccine community that we can’t go on chasing variants, as we have been throughout the last couple of years,” says Stanley Plotkin, a renowned vaccinologist who discovered the rubella vaccine. Scientists like Plotkin are pushing for the development of a “universal coronavirus vaccine” that works against multiple coronaviruses and Covid variants, eliminating the need for a booster to address every new strain. But while early research into universal coronavirus vaccines offers promise, it may be years before this becomes a viable option because it’s such a scientifically complex task.
Existing mRNA shots, with a booster, appear to be working well at preventing severe cases, even vs. the existing omicron mutations. A study released on Friday by the Centers for Disease Control and Prevention found that two or three doses of the vaccines made by either Moderna Inc. or partners Pfizer Inc. and BioNTech SE reduced by 90% the risk of needing to be put on a ventilator or dying because of Covid-19. Another study in Qatar, published in March in the New England Journal of Medicine, found that three mRNA doses gave strong protection against severe omicron while providing about 50% additional protection against symptomatic cases. Since the study was submitted, however, efficacy against mild cases has waned, says lead author Laith Abu-Raddad, an infectious disease epidemiologist at Weill Cornell Medicine-Qatar. “It’s not a practical strategy” in the long run to keep giving repeat jabs, he says. More durable vaccines will be needed.
The financial stakes are enormous for Pfizer, BioNTech, and Moderna. Last year, Pfizer garnered $36.8 billion in sales of its Covid vaccine, making it the bestselling pharmaceutical product in the world. Sales of Moderna’s shot were $17.7 billion in 2021. In 2022, sales of both mRNA jabs could grow to $68.4 billion, according to London-based research firm Airfinity Ltd. Analysts generally expect sales to decline after that. How much of a market remains depends on whether the companies can show that fourth, fifth, and sixth shots will provide useful benefits.
Some countries such as Israel and Chile haven’t waited for further data—or for omicron boosters currently being tested—and have started rolling out fourth doses of the existing vaccines to older citizens. In the U.S., this approach is being recommended for the immunocompromised, but officials are closely measuring such things as hospitalization rates for signs of waning protection before suggesting anyone else get a fourth dose.
Early last week, Pfizer applied for authorization from U.S. regulators for a fourth dose for older Americans, forcing a debate on the question. Pfizer’s request was based on Israeli Ministry of Health real-world data showing lower rates of infection and severe illness in those 60 and older who got a fourth shot. Meanwhile, a separate Israeli study of Covid in younger health-care workers found quite modest benefits from a fourth shot. Showing just how unsettled the debate over additional Covid boosters remains, Moderna one-upped Pfizer two days later by asking for U.S. authorization of a fourth dose for all adults.On April 6th, Food and Drug Administration plans to hold an all-day meeting of its Vaccines and Related Biological Products Advisory Committee to hash out the issues involved with additional shots. Illustrating the broad, almost philosophical nature of the booster debate, the FDA says the external advisors won’t discuss specific company applications, but instead come up with a broad framework for determining who might need additional boosters, in what timeframe, and when the composition of vaccines should be updated to address new strains.
Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, says it’s a “moving target” as to whether Americans will need a fourth dose of Covid vaccine. “It is likely that a certain segment of the population, particularly the elderly, will need a fourth dose” eventually, he said in an interview on Feb. 14. Whether the general population will need additional shots will depend on whether efficacy against severe disease and hospitalization declines over time. "The bottom line is, we just don’t know," he says. "It would be difficult and also inappropriate to make any definitive statements now about any of this," including when an additional booster might be needed and what form it might take.
Like all things Covid, science won’t be the only determinant of how big the market is for additional shots. Sociology and politics will also play roles. Governments are still the buyers of Covid vaccines, and wealthy countries may err on the side of overpurchasing, knowing they can later give unneeded doses to poorer countries that are in short supply, says Matt Linley of Airfinity. This will support the market and give drugmakers incentive to make new shots.
Right now, with memories of Covid disruptions fresh in people’s minds, many Americans say they would be willing to get annual Covid boosters. An Axios-Ipsos poll released on Feb. 8 found that 70% of Americans would be somewhat or very likely to get an annual Covid shot if it turns into a seasonal virus. “There is still a higher sense of risk and threat” with Covid, compared with the flu, says Cliff Young, president of U.S. public affairs at Ipsos. “From that perspective, the market size here is large.”
Knowing that some form of future immunization may be warranted, Pfizer and Moderna are testing multiple strategies for new boosters. In January, both companies started clinical trials of omicron-specific shots, and the companies are also looking at what happens when people get a fourth shot of their original vaccines. Both companies are also testing so-called “bivalent” vaccines that contain both the original vaccine and an omicron-specific shot. Pfizer expects to release initial omicron-specific results by early April, while Moderna says it will get results in the second quarter.
While a strain-specific booster sounds like a logical next step, research has yet to demonstrate it will be necessary. A study preprint released by National Institute of Allergy and Infectious Diseases researchers on Feb. 4 found that Moderna’s omicron-specific booster provided no advantage over its existing booster in preventing omicron-related lung infections in monkeys. Moderna President Stephen Hoge says those results, which have yet to be peer-reviewed, don’t address whether an omicron-targeted booster will provide longer-lasting protection than the company’s original booster.
The corporate free-for-all in Covid booster development contrasts with the business of influenza vaccines, where a well-honed system has for decades monitored viral changes and come up with recommendations for vaccine strain changes. Every year, labs around the world collect influenza samples and send them to various World Health Organization-designated labs for analysis, including one at the Centers for Disease Control and Prevention in Atlanta and others in Melbourne, London, Beijing, and Tokyo. Then, twice a year—in February for the Northern Hemisphere and in September for the Southern Hemisphere—the WHO convenes a panel of experts who examine the data and make recommendations for what the next season’s flu shot should contain, doing their best to anticipate what strains will be circulating six to nine months later.
There’s no such system yet for Covid, though the WHO is working on it. “These are early days, and we are learning a lot about the virus and the process as we go,” says Kanta Subbarao, a virologist at the Peter Doherty Institute for Infection and Immunity in Melbourne who chairs a panel advising the WHO on vaccine composition. The problem is that for Covid-19, scientists don’t yet have any good models for predicting what will come next. Even for the flu, it’s hardly an exact science. This season’s shot was only 16% effective in preventing mild to moderate cases in the U.S., government researchers found.
Usually companies like to have a clear idea what their market is before developing a product. But governments and public-health experts haven’t reached any consensus on when vaccine strain changes may be needed, or what should be in them. The only thing in place are the orders: Moderna and Pfizer combined already have deals for more than $50 billion worth of vaccines for 2022—some governments have contracts to buy doses through 2023—which has reduced the research and development risk for drugmakers.
Even so, for drug companies that lack guidance from governments, it’s “much more of a slam-dunk to do a virus-specific, variant-specific vaccine,” says Eric Topol, director of the Scripps Research Translational Institute. That’s because it will take much longer to figure out if a universal coronavirus vaccine will work; its effectiveness would become clear only gradually, as new variants emerge over time. “We have a conflict between what we need vs. the practical aspects of what these manufacturers would be interested in.”
Pfizer and Moderna executives say they’re trying to plan for anything and everything. In a best-case scenario, Covid-19 will transition to become an endemic seasonal virus with flare-ups every winter, says Pfizer research head Mikael Dolsten. “That would fit with an annual vaccination” in the fall, he said. But he says Pfizer will be ready to roll out its omicron-specific shot much sooner, if needed. Moderna, meanwhile, is “looking to the fall” as the most likely time frame for introducing a new shot, Hoge says.
Given how long it takes to make a vaccine, companies like Moderna can’t “sit and wait” to see what variants might arise in the spring, or what recommendations the WHO panel comes up with in a few months. It needs to make decisions now. “It’s uncertain on all sides. People just don’t know what the future will bring,” Hoge says. “We are just trying to get ahead of the problem as best we can.” —With Riley Griffin and Madison MillsRead next: Maker of Covid Drug Sotrovimab Plots New Course as BA.2 Spreads
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