The future of covid vaccines: Four big questions for the FDA as it considers a move to annual shots

Jonathan Lambert

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The Food and Drug Administration is considering a plan that would shift covid vaccines to annual shots, much like flu shots — and Thursday, the agency’s expert outside advisers will weigh in.

As the pandemic heads into its fourth year, these epidemiologists, vaccine researchers, immunologists and physicians will cast a consequential vote on the future of covid vaccines and vaccination in the United States. The panel will evaluate the FDA’s proposal for a once-a-year shot updated to match current circulating strains of the virus, drawing on new data from vaccine manufacturers and government officials.

The committee will end its daylong meeting with a vote on whether the FDA should simplify current vaccine recommendations. The vote is nonbinding, but the FDA usually follows suit.

Significant questions remain about the bivalent booster strategy the agency adopted last year, which only about 15 percent of people have received, and whether it’s the best way forward. Some committee members have also criticized the FDA for not sharing more data on the bivalent boosters during vaccine-advisory meetings last year.

Here are the big questions, both on and off the FDA panel’s agenda, that will determine vaccine policy moving forward.

Should the vaccine be simplified to a once-a-year shot for most people?

Right now, there’s no regular covid vaccine schedule. When vaccines first arrived in late 2020, people got them in waves as the government expanded eligibility. Uptake of the first batch of boosters, and the new bivalent ones, was also spread out over months. Guidance around what counts as “fully vaccinated” has been in flux during this period, as scientists have learned more about waning immunity from the shots themselves and how well new variants evade that immunity.

“I think right now, people are really confused about whether they’re eligible for a new shot,” said Jenna Guthmiller, an immunologist at the University of Colorado. “Uptake has been surprisingly low.”

Simplifying the guidance to a yearly shot would fit nicely into vaccination routines that many Americans are already used to for the flu. “We mobilize every fall to get ready for influenza vaccines. Special clinics are opened, and the same could be put to use for covid vaccines,” said Mark Sawyer, a pediatric infectious disease specialist at the University of California, San Diego, and FDA committee member. But those logistical advantages might not square with what’s best for overall health.

“From a program implementation perspective, it would be a lot easier if we have a single, annual booster,” said Walter Orenstein, a vaccine researcher at Emory University. “But that may not be the best thing from a public health perspective, and that’s where the discussion on the science will be very important.”

Could there be exceptions to a once-a-year plan?

By and large, the vaccines have held up when it comes to preventing severe disease, though that protection does wane over time and may wane more quickly in more vulnerable groups, especially with more immune-evasive variants. After three years of the pandemic, most Americans have both gotten the vaccine and been infected with the virus, conferring what scientists call hybrid immunity, which offers robust protection against severe disease for at least a year, according to a recent meta-analysis in the Lancet.

“The data suggest that after the primary series, or after infection and a dose, there’s longevity of the response against severe outcomes,” said Saad Omer, director of Yale University’s Institute for Global Health. “But there is waning immunity,” he said, especially against infection. Given that, simplifying to a yearly dose makes sense for most groups, he said, “and if you time it right before winter, you could get a transient reduction in infection.”

For those at highest risk of severe disease, including the elderly and immunocompromised people, “we need to do more research,” said Omer. More frequent boosting might be warranted, he said, “but the big question becomes, is our system able to handle a shot every six months?” And there’s some evidence that getting boosters too close together gives you less bang for your buck, immunologically speaking.

Some experts argue that only high-risk groups should be getting boosted at this point. “I think by saying everyone over six months of age should get a bivalent vaccine, they weaken the recommendation,” said Paul Offit, an infectious disease physician and the director of the Vaccine Education Center at Children’s Hospital of Philadelphia. “The goal of this vaccine is to keep people out of the hospital, not to prevent cases,” he said, and that existing evidence suggests those under 65 are well protected from severe disease without the booster, as long as they’ve had an initial vaccination.

Others disagree. “At this point, I’m concerned about whether boosters are needed more often, not less often, given waning immunity and immune evasion,” said Orenstein. “That’s why I’d like to see the data they present [at the meeting].”

Should covid vaccines be updated to match circulating strains? Is it better to include old and new strains, as with the latest boosters, or focus on one strain?

Last year, covid vaccines got their first update in an effort to adapt to the virus’ evolution. Regulators decided to pursue a “bivalent” strategy for designing the new shots, with half the dose still targeting the original coronavirus strain from 2020 and the other half targeting versions of omicron (BA.4 and BA.5 in the U.S.).

Federal officials hoped the bivalent shots would broaden immunity by reinforcing existing immune responses while cuing the immune system into newer variants. Laboratory studies suggested the bivalent boosters coaxed a bigger antibody response in people who received them compared with the old shots, but scientists didn’t have data on how the updated shots performed in the real world.

Those data now exist, but the picture is mixed.

“We know that the bivalent booster was beneficial for symptomatic disease, and especially for severe outcomes,” said Omer. Recent studies show that bivalent boosters offer modestly more protection against symptomatic disease compared with the original vaccine and can lower hospitalization rates. “What we don’t have is a [real-world] comparison between monovalent boosters and bivalent boosters, because it’s not available,” said Omer.

Given that, some experts argue the apparent benefits of the bivalent booster seen in real-world studies stem from boosting generally, not the specific impact of the bivalent booster. Two recent laboratory studies support this view, finding little difference in the immune response between people who got bivalent or monovalent shots.

One explanation for this non-difference is that our immune systems are too hung up on the first version of the coronavirus we encountered, a common immunological phenomenon known as imprinting. Scientists are still figuring out precisely how this phenomenon plays out for SARS-CoV-2, but some worry that continuing to include older strains of the virus in the shots could blunt our ability to adapt to newer strains.

“I don’t understand the need to keep the original strain in there. I’d like to hear why people think we still need to include it,” said Orenstein. “I’d much rather double the amount of the new strain.”

Other experts agree. “I think in the future, it’s reasonable to chase what variants are currently circulating because so many people already have preexisting immunity against that original SARS-CoV-2 virus,” said Guthmiller. That immunological memory can help retain a broad response that can protect against serious illness, even if the coronavirus throws another curveball.

How would the FDA and vaccine makers choose which strains to target?

If the committee recommends updating the vaccine annually, it will also have to weigh in on how to pick what’s proved to be a fast-moving target. Last June, the FDA vaccine panel was weighing whether to move forward with bivalent boosters based on laboratory studies of BA.1, an omicron variant that had largely disappeared in the U.S. by then. The group opted to go with a BA.4/BA.5 formulation, given the currently dominant strains at the time. But those strains were largely replaced by new omicron offshoots by the time the shots were rolled out.

Getting the formulation exactly right may not be as important for covid vaccines as it is for flu, where “if you’re wrong, a miss is a mile and you have no protection, even against severe disease,” said Offit. “That’s not true with coronaviruses,” he said, and there’s evidence that the BA.4/BA.5 vaccine confers some protection against other versions of omicron.

But there’s no system yet for covid shots the way there is for flu. And the way flu shots are formulated each year draws on established seasonal patterns in how flu strikes — in the fall and winter. Strains for flu shots in the Northern Hemisphere, including the U.S., are based in large part on which strains predominated in the Southern Hemisphere winter. But covid outbreaks, while egged on by cooler weather, don’t yet fit into such a neat pattern.

Choosing and producing a monovalent vaccine may also speed up the timeline, increasing the chance of a better match. “There may be some agility that comes with that,” said Omer. Such a system could allow regulators to decide on the formulation “in September, or late July or August.”

Given it’s still only January, committee members and federal officials still have months to fill in the details of whatever plan gets outlined Thursday.

Thanks to Lillian Barkley for copy editing this article.