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CureVac, a pioneer in the effort to use messenger RNA as a vaccine platform, and its partner, pharmaceutical giant GSK, saw the writing on the wall last fall.

When CureVac’s Covid-19 mRNA vaccine candidate underwhelmed in a Phase 2b/3 trial, the pair shifted plans. Too many other vaccines had already proven superior and been cleared by regulators. Rather than spend months tweaking a candidate that would end up battling for a rapidly shrinking share of the Covid vaccine market, they would focus instead on a second-generation product.

Soon, experts tell STAT, other would-be Covid vaccine manufacturers are set to confront the same kinds of hard reality. With two new players — Novavax and a Sanofi-GSK partnership — making or about to make their way into the already crowded global Covid vaccine market, the prospects for those still struggling to prove their vaccines are protective are becoming ever slimmer.

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It doesn’t help that demand is contracting.

“We think there’s likely going to be long-term ongoing demand for Covid vaccines, for boosters at least,” said Matt Linley, analytics director for Airfinity, a London-based health analytics company that has been closely tracking Covid vaccine development, regulation, sales, and usage. “But it will be a lot smaller than it is. We believe it’s kind of peaked.”

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The world can now produce more Covid vaccine than it needs or can administer — more than 12 billion doses a year. For a number of existing manufacturers, purchases have plateaued; some players are already scaling back production. A company hoping to enter the market with yet another vaccine that targets the original SARS-CoV-2 strain or that offers no advantages over existing products will be hard-pressed to find buyers, experts warned.

Demand for newer vaccines — products that aren’t as difficult to use as the mRNA vaccines — is either modest or stagnant, experts said. Even in countries where the mRNA vaccines are impractical to use, they are seen as the gold standard. Can the recombinant protein vaccines made by Novavax and Sanofi-GSK break through? Unclear, Linley suggested. “I think there’s been a lot of hype around Novavax, but really, only time will tell.”

Meanwhile, the virus is raising the bar that late-comers have to hurdle to show their vaccines are protective.

The earliest market entrants — Pfizer/BioNTech, Moderna, AstraZeneca, Johnson & Johnson, Russia’s Sputnik V, and multiple Chinese vaccines — conducted their clinical trials when the only way to get vaccinated was to volunteer for a study. Finding unicorns might be easier than locating people now who are both unvaccinated and willing to enter a Covid vaccine trial.

The companies that developed the early vaccines also conducted their trials before the arrival of a string of variants with mutations that have helped them evade the immunity induced by Covid inoculations and by prior infection. The Pfizer vaccine, with its initial, jaw-dropping 95% efficacy, would have looked much less impressive had its clinical trial been conducted in the era of Omicron. Testing a first-generation Covid vaccine now, one that was designed to protect against the original genetic sequence of the virus shared in January 2020, is like issuing a wanted poster not of a suspect but of his great-grandfather.

Furthermore, the urgency to speed vaccines into use that permeated the regulatory and political landscape in the fall of 2020 is no longer the state of play. The Food and Drug Administration and other regulatory agencies are processing emergency authorizations with a much-less-rapid turnaround these days. There is ample supply of other options.

All of this adds up to substantial challenges for companies still working on Covid vaccines, and diminishing opportunities to score the sales they all seek.

That’s not to say there’s no opportunity at all. Experts agree there is still a market for better vaccines.

“I would have to say none of the vaccines I’ve seen are the vaccines we need for the future,” said Michael Osterholm, director of the Center for Infectious Diseases Research and Policy at the University of Minnesota. “They’re very important stopgap measures right now, but what we need for the future is going to be a substantially improved version of what we have so far.”

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Courtesy Airfinity

Those would include vaccines that reduce transmission of the SARS-CoV-2 virus by protecting against even mild infections, perhaps via intranasal delivery. The market would also have room for vaccines that are longer lasting, or can protect more broadly against the various shapes SARS-2 viruses can come in — in other words, vaccines that aren’t as vulnerable to the emergence of variants. It would also have room for vaccines that could protect against multiple coronaviruses, thereby cutting the risk of future coronavirus pandemics.

“Finding a way to future-proof them is, I think, the next big challenge for the world,” said Phil Krause, who was deputy director of the FDA’s office of vaccines until he abruptly quit last year. Krause is now a consultant, working frequently with the World Health Organization. (He does not consult on Covid vaccines with industry clients.)

Norman Baylor, a former director of the FDA’s office of vaccines, agreed there is a need for better vaccines, but he warned getting new products into this crowded field isn’t going to be easy. And the regulatory fast-track in the United States — the FDA’s emergency use authorization — isn’t likely to be an option for much longer, he said.

“I think that door is closing,” said Baylor, who now runs Biologics Consulting and serves on scientific advisory boards for CureVac and Valneva, a French company that has produced an inactivated Covid vaccine. “I mean if you just look at the regulations, it should be closing because now we have plenty of vaccines.”

According to the WHO’s Covid vaccine tracker, there are 149 candidate vaccines in clinical development — being tested in people — and another 195 in earlier stages of testing. In addition, at least 21 vaccines have been approved or authorized for use around the world — some by multiple countries, others serving a sole domestic market.

This kind of level of research isn’t sustainable, Baylor said. Countries like the United States, which plowed billions of dollars into vaccine development through Operation Warp Speed, are tightening purse strings.

“Remember, the big players, they were subsidized by the government. That subsidy is going to dry up,” Baylor said. “And so now they’re going to have to go to the venture capitalists and the venture capitalists are gonna say ‘Huh, another Covid vaccine? Why?’”

Why indeed.

For most of the existing manufacturers, sales have flattened and production is dropping, Airfinity’s Linley said in an interview.

”We’ve peaked at around 1.4 billion doses [per month] being produced,” he said. “That was in around November time. And then now we’re around 0.8 billion doses being produced per month.”

The exception to the trend is the mRNA vaccines produced by Pfizer and Moderna, which continue to outperform the market even though their efficacy appears to wane more quickly than that of some other competitors.

“They are the only vaccines to continue making, consistently, new deals and new agreements to sell their vaccines. Only Pfizer and Moderna,” Linley said.

Airfinity modeling suggests that even in the most optimistic scenario — countries vaccinating 80% of their people, then boosting once or twice a year thereafter — the Covid vaccine market is going to contract.

Many countries will get nowhere close to that 80% figure. For context, in the United States, the percentage of people who are eligible to be vaccinated — in other words, the population aged 5 and older — who have completed a primary series has hovered just shy of 70% for quite some time. (And only 46% of people who are eligible for a booster have received one. Baylor, for one, doesn’t believe regular boosters are going to find eager recipients. “Even if it was mandated, people wouldn’t do it. People are tired,” he said.)

The WHO has set a target for 70% vaccination in all countries by June but Seth Berkley, CEO of Gavi, the Vaccine Alliance, said it will likely take longer for many countries to have all the components of vaccination programs in place — vaccine plus enough trained vaccinators plus ancillary supplies like cold chain for the mRNA vaccines and the right syringes — to hit that figure. Some won’t even try to reach 70%. A number of countries have set more modest targets for themselves, he said.

“I think we’re going to see a lot of countries miss those goals,” Berkley said, noting that could change if a new variant that triggers more severe disease emerges. If that happens, he said, the supply-demand equation could flip.

Future demand is likely to be determined by two factors: the path of future variants, as well as how long protection against serious disease holds up. If new variants emerge that evade the vaccines’ ability to protect against hospitalization and death, countries will move to purchase updated vaccines. Likewise, if immunity from vaccination or prior infection no longer prevents severe disease, governments will order boosters. If these scenarios emerge, some portion of people will again roll up their sleeves.

Manufacturers clearly hope to sell annual booster shots. Pfizer is already seeking approval for an additional booster for people 65 and older. And Moderna indicated last week it will ask the FDA for permission to offer a booster to all adults. But the jury is still out on the booster question.

“I would have to say it is unclear whether we will need boosters for all,” Berkley said. “We will have to follow the science.”

Krause agreed, noting the lack of clarity is tough on policymakers and industry.

“From a public health perspective I don’t think you can say, ‘We’re sure we won’t need to do that.’ And yet — and I think this, of course, creates a planning problem — it’s not obvious that we certainly will need to do that either,” Krause said.

Airfinity’s Linley said the company isn’t sure what the future holds over the long term — a decade from now, say. But a number of wealthy countries have purchased vaccine doses to use as boosters for the next couple of years. “If we look at the next two to three years … I still think that that’s a reasonable assumption,” he said. “Because it’s still fresh in people’s minds, the impact of Covid. It really has been quite devastating.”

The company estimates that 11.3 billion doses were produced and delivered in 2021, but predicts that the number this year will be in the 7 billion to 9.5 billion dose range — and could drop to 2.2 billion and 4.4 billion doses in 2023. Pfizer/BioNTech alone could supply a good portion of that.

Manufacturers are aware this contraction is coming.

Some are trying to hedge their bets by announcing they will make a vaccine that protects against both influenza and Covid — a product they would hope to sell annually. But flu shots aren’t used much outside of wealthy countries; even in those countries uptake doesn’t come close to replicating the sales bonanza Covid vaccines have been in the past year.

“If we’re not sure that everybody’s going to need a Covid vaccine every year and that the fall will be the best time to administer that, the question really is: Is that going to be a sustainable strategy or not?” Krause wondered.

Linley noted there is one niche smaller companies that are still developing first-generation Covid vaccines could still find — being a domestic producer in a market without other such options.

“People are very conscious of the fact that the major countries that produce vaccines were the ones that got access to those vaccines first,” he said, suggesting a number of countries that are not traditional vaccine production hubs may see value in purchasing from a company located within their borders as a hedge against the next pandemic.

“Certainly countries want to have their own domestic vaccine. There is potential for that.” Linley said.

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