What’s next for COVID-19 vaccines? Scientists and regulators chart a course amid uncertainty | Science


Just over 2 years ago, the first COVID-19 vaccines arrived—and a roller coaster ride of hope and science began. It soon became clear that although the vaccines protected against severe disease, their ability to fend off infection was limited and faded fast. Meanwhile, SARS-CoV-2 began to evolve rapidly to elude immunity. By now, many people have had four or five vaccine doses, including an updated booster tailored to Omicron strains that was introduced last fall.

Now, regulators and scientists are debating the near-term future. How often will we need booster doses and who should receive them? Should vaccines continue to be updated as new Omicron subvariants—or entirely new variants—emerge? Are people who have had COVID-19 along with multiple vaccine doses better protected, and for how long?

On Thursday, an advisory committee to the U.S. Food and Drug Administration (FDA) will consider some of these questions and provide guidance for the agency’s vaccine strategy this year. One focus of discussion will be whether to transition to a simpler strategy also used for influenza: a once-yearly shot of an updated vaccine offered in the fall. In advance of the meeting, Science spoke to scientists about where we stand and how to move forward.

The latest vaccines are designed to offer protection against Omicron. Should future doses be tailored to the latest variants as well?

The new shots are “bivalent,” evenly split between vaccine targeting the ancestral strain of SARS-CoV-2 from Wuhan, China, and Omicron strains BA.4 and BA.5, which were circulating when the shots were introduced in late summer 2022. (Omicron has continued to evolve.) The decision to include the original strain was something of a hedge: Although the Wuhan variant was long gone, FDA advisers worried that an Omicron-only vaccine would be less effective against an entirely new SARS-CoV-2 variant that might emerge.

Some wondered whether the bivalent strategy made sense. There were no human studies of the BA.4/BA.5 bivalent vaccine at the time; instead, FDA relied on limited human data on vaccines containing an earlier version of Omicron, BA.1, and mouse data on a BA.4/BA.5 bivalent. There were “theoretical reasons why it was a good reason to switch the variant, without a lot of solid science, in my view,” says Philip Krause, who recently stepped down as FDA’s deputy chief of vaccines. The “bivalent was authorized awfully quickly,” says Columbia University virologist David Ho.

By now, some groups have shown the bivalent vaccine generates somewhat higher antibody levels against various Omicron strains than the original shot, whereas others report no difference. Earlier this month, The New England Journal of Medicine published a study led by Ho and another by Harvard University immunologist Dan Barouch that both had disheartening results. Ho and others speculate that including the ancestral strain in the vaccine makes it more difficult for the immune system to ramp up against Omicron.

The bivalent vaccine is unquestionably effective at staving off severe illness and death, just as the monovalent vaccine was, stresses Mark Slifka, an immunologist at Oregon Health and Science University. But, “The only reason to modify a successful vaccine is to make it more successful,” he says.

Many scientists agree it’s reasonable to update the strain in the vaccines periodically—but based on better data. Ho points out that his study, which included fewer than 80 people, could easily have been done prior to greenlighting the new bivalent shot. We ought to be “a bit more systematic, methodical, in making these decisions,” Ho says.

By now, most people have had COVID-19 at least once, in addition to one or more vaccine doses. Does this offer superior protection?

By February 2022, almost 60% of the U.S. population, including 75% of children, had had COVID-19, the Centers for Disease Control and Prevention (CDC) has reported. By October 2022, the rate in children was more than 90%. (More recent data on adults are unavailable.) Meanwhile, in the United States, 92% of those 18 and older have received at least one dose of vaccine, and more than 40% of adults have gotten at least one booster.

The result is what scientists call “hybrid immunity,” melding protection from vaccines and infections. Multiple studies suggest it is a sturdier shield against infection, and especially against severe disease, than infection or vaccination alone.

In December 2022, a meta-analysis of 26 studies, published in The Lancet Infectious Diseases, found that 1 year after vaccination, hybrid immunity conferred about 42% protection from infection in adult populations and a whopping 97% protection from hospital admission or severe illness, compared with 25% and 75%, respectively, 1 year after infection alone. People with hybrid immunity, the authors wrote, “might be able to extend the period before booster vaccinations are needed compared to individuals who have never been infected.”

But how hybrid immunity should play into vaccine recommendations remains uncertain and may vary for different age groups.

Rushing to set policy is likely to result in revisions later, which would lead to confusion for the public.

  • David Ho
  • Columbia University

Should we move to a once-a-year booster strategy?

On Thursday, FDA advisers will discuss whether COVID-19 vaccination should shift to a new strategy akin to that for influenza, which consists of an annual vaccine dose tailored to flu strains expected to circulate the next winter. In a briefing document released on Monday, FDA said it anticipates assessing coronavirus strains “at least annually” and conferring with advisers “in early June of each year regarding strain selection for the fall season.” A new vaccine for all would be rolled out every September at the latest.

Many researchers agree that a once-a-year shot would be less cumbersome and confusing than more frequent boosters, and it’s logical to “vaccinate with the circulating variants,” just like we do for flu, says immunologist Rafi Ahmed, director of the Emory Vaccine Center. But there’s a crucial difference between flu and COVID-19: Flu is seasonal, whereas the coronavirus runs year-round. People who contract COVID-19 in August—which is vanishingly rare for flu—would have to decide whether to also take a shot in the fall, when immunity from their illness may still be robust.

It’s also unclear whether an annual booster offers everyone enough protection for a whole year; that may vary by age. The durability question “is a big one,” says Jennifer Gommerman at the University of Toronto, who is the immunology co-lead of CoVaRR-Net, a Canadian effort to track and respond to SARS-CoV-2 variants.

Many studies have looked at COVID-19 antibodies in people’s blood, but we don’t know how high a level is needed to protect. A strategy used to assess influenza shots might help gauge the durability and effectiveness of COVID-19 boosters as well, Slifka says. Called a test-negative design, it entails testing all patients coming to a hospital with flulike symptoms for the virus; researchers then compare how many of the people who test positive were and weren’t vaccinated.

Many scientists worry policy decisions will outpace the research. “There is a great need to simplify our boosting recommendations,” Ho says. “However, such policies should be guided by data, which are still lacking. Rushing to set policy is likely to result in revisions later, which would lead to confusion for the public.”

Will people even take more boosters?

Maybe, maybe not. Vaccine uptake has slid with each successive booster offering. Currently, only 15% of the U.S. population—and 40% of those 65 and older—has received the bivalent shot. By comparison, about half the population gets a flu vaccine annually, including about three-quarters of those 65 and up, who receive a higher dose for extra protection. 

This isn’t just “the antivaxxers, it’s a whole portion of the population,” most of whom willingly got the primary vaccine series, Slifka says. The immediate side effects of the Moderna and Pfizer vaccines—which cause flulike illness for a day or two in many people—may play a role, he says. Slifka would love to see efforts to reduce side effects in existing vaccines or develop new ones that are better tolerated.

Confusion over how well boosters work may also keep people from rolling up their sleeves. One of the most common reasons for those 40 years and older to decline the bivalent vaccine is that “they believed they were protected against infection or severe disease because of previous vaccination or infection,” CDC reported in a survey of U.S. adults last week.

Krause thinks too much attention has been paid to vaccinating healthy young adults and children, for whom the virus is generally less risky, and not enough to vaccinating older and more vulnerable people. “The guidance has all been so oversimplified,” he laments. “This then causes some people to discount it.”

 Some people are wary of messenger RNA (mRNA) vaccines. Might other types of vaccines improve uptake?

An alternative to the mRNA vaccines developed by Pfizer and Moderna might appeal to some people—especially if it had fewer side effects. One classic strategy, used in vaccines against hepatitis B, shingles, and human papillomavirus, among others, relies on a combination of proteins and an adjuvant; this design has, in the past, yielded durable protection. Novavax has developed such a vaccine for COVID-19, but real-world studies have been limited, and in Germany and some other European countries, uptake of the vaccine has been disappointing. In the United States, the Novavax vaccine is only approved for the unvaccinated and those who haven’t gotten any boosters, and a bivalent version has not been authorized yet. Bali Pulendran, an immunologist at Stanford University, says its limited availability is unfortunate. “I would have liked to have had that choice myself.”

It’s the infections right now that are important. That’s what causes the virus to mutate.

  • Charlotte Thålin,
  • Karolinska Institute

COVID-19 vaccines offer limited protection against becoming infected. Could nasal vaccines be a solution?

The protection against severe disease that current vaccines provide is crucial. But even mild COVID-19 still carries a risk of Long Covid, and rampant transmission risks creating new and more hazardous variants. “It’s the infections right now that are important,” says Charlotte Thålin, a physician and immunology researcher at the Karolinska Institute. “That’s what causes the virus to mutate.” Gommerman agrees. “With Omicron we got lucky,” she says, but “we have to force ourselves to think worst-case scenario.”

Some researchers believe nasal vaccines, which aim to induce mucosal immunity, might guard against infection. Thålin has found some intriguing clues in a study that has carefully documented vaccinations and infections in 2000 health care workers in Sweden since April 2020. In September 2022, she and her colleagues reported that people who were infected early in the pandemic, before they were vaccinated, had detectable levels of SARS-CoV-2–specific antibodies of a type named IgA in their noses. The antibodies were not seen in a vaccine-only group. Thålin thinks nasal vaccines would be more effective than current shots at stimulating such antibodies, which might block COVID-19 infections right where they start, in the respiratory tract.

Gommerman is intrigued by the potential for IgA antibodies in the nose and saliva as well. Right now, which level of IgA is an effective shield against infection is still unclear, she says, but “scientists are coming together to figure this out.”

Testing new COVID-19 vaccines in clinical trials is risky for companies, however, because the mRNA shots are now standard. Peter Marks, who directs the FDA center that reviews vaccines, wrote a December editorial in JAMA suggesting a new generation of vaccines may require randomized clinical trials enrolling tens of thousands of participants, like the ones used to obtain regulatory approval for first-generation vaccines. That “shocked me,” Krause says, because it seems unattainable. Regulators “need to be creative,” perhaps assessing vaccine safety in several thousand people and immune responses in a smaller number.

“If you can show a new vaccine is as good as the existing vaccines,” Krause says, “surely you’ve already met a standard showing it can be on the market.”

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