Over the Labor Day weekend, pharmacies across the country began receiving shipments of new Omicron-specific mRNA booster vaccines against COVID-19, after Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) signed off on their use last week.

The updated formulas, which will become the standard booster for almost everyone in the US, were developed by Pfizer/BioNtech and Moderna in the 10 months since Omicron first appeared. Although the boosters are almost identical to the original vaccines, they are bivalent, meaning they can elicit an immune response to both the original SARS-CoV-2 strain and the BA.4/BA.5 Omicron strains that currently cause about 90 percent of the country’s COVID cases.

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Moderna’s bivalent booster will be available to anyone 18 years of age or older who has completed their primary vaccination series and has not been vaccinated for at least two months. Pfizer will be available to anyone aged 12 and over who meets the same time requirements. However, the CDC recommends waiting at least three months after a COVID infection before getting a boost.

“Hopefully this is the start of the movement.” [COVID boosters] to a more common type of vaccine recommendation and process,” Melinda Wharton, the CDC’s associate director for vaccine policy, said at a meeting last week about the updated photos. “I’m sure there will be some bumps in the road, but this is an important step toward simpler recommendations as well as an updated vaccine that we expect will provide broader protection.”

What is a bivalent vaccine?

Let’s start with a refresher: mRNA vaccines for COVID work by injecting the body with small sequences of rapidly degrading genetic material based on SARS-CoV-2. Your cells read this mRNA as an instruction manual and build the virus’s signature spike protein. After seeing these homegrown spikes, your body develops antibodies and other immune responses to target the pathogen’s primary weapon during future infections.

The original Pfizer/BioNtech and Moderna vaccines contained instructions for the spike protein of the first strain of SARS-CoV-2 and have remained highly effective in preventing severe disease and death from evolving variants and subvariants. But one of the reasons Omicron has been able to infect vaccinated people is that it carries a highly modified spike—roughly 30 mutations from the original—that resists the antibodies elicited by earlier injections. Thus, bivalent vaccines contain a 50/50 mix of mRNAs that reproduce the original spike protein and the identical spikes of BA.4 and BA.5.

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In principle, this is also how vaccines are made for other rapidly mutating viruses. Most importantly, the annual flu shot is a quadrivalent formula designed to train the immune system to recognize four strains of flu that are most likely to circulate in the coming year.

How well does it work?

The ability to quickly update snapshots of mRNA is one aspect of the new technology that has vaccine researchers excited. But the data used to review the clinical trial results and approve the updated photos is different from any previously used for COVID.

The CDC and FDA said they recommend the bivalent boosters based on the “body of evidence.” In other words, the decision was made using a combination of safety and efficacy data from slightly different trials Omicron bivalent vaccines and mouse trials including recently authorized updates.

Part of this is because the Omicron variant mutates rapidly. Just weeks after the variant became available last November, Pfizer, Moderna and other vaccine makers began to developg strain-specific pictures. But by the time the companies began submitting data to federal regulators for approval, Omicron had changed shape. When an independent panel of FDA advisors met in April, it largely agreed that the updated boosters should target the latest BA.4 and BA.5 strains. This forced pharmaceutical companies to start working on a secondly Omicron formulation of which person trials still going on.

BA.4/BA.5 firing results are based on several years of variant-specific firing data.

Pei-Yong Shi, an expert in vaccine development

On Sept. 1, the CDC presented its case for releasing the photos with the safety and efficacy data collected so far. First, Pfizer and Moderna officials presented results from human clinical trials on the original bivalent booster, which showed that it caused recipients to produce significantly higher levels of antibodies against the Omicron variant — and that those antibodies appeared to last longer and are better suited to respond everything COVID variants. They then explained that the new BA.4/BA.5 shot produced similar immune response patterns in mice that had been genetically engineered to make human cell receptors.

These results are based on data from several years of variant-specific photos, he points out Pei-Yong Shee, an expert in vaccine development and virology at the University of Texas Medical Branch. “Companies have tried multiple modified sequences before,” he says. Moderna and Pfizer took pictures of both the Beta and Delta variants that went through human trials.

“I fully support this recommendation for bivalent boosters,” Shi adds. “I think we can always say we want more clinical data, but if that’s the case, we’re always playing catch-up.”

Govind Persad, a bioethicist at the University of Denver’s Sturm College of Law, says it’s important not to confuse uncertainty about efficacy with uncertainty about safety. “I think there’s reason to be unsure if there’s going to be a big bump in efficacy from these BA.5 boosters,” he explains. “But I don’t think there’s much, if any, reason to worry that there will be any new scary side effects.”

Data presented by Moderna showing antibody response to its original bivalent Omicron booster against Omicron sublines. Courtesy of the CDC
Efficacy of the bivalent COVID vaccine booster in mice on different color line graphs
Data presented by Moderna showing antibody responses in mice following vaccination with the updated bivalent BA.4/BA.5 booster. Courtesy of the CDC
Efficacy of Pfizer's COVID vaccine boosters in blue and green bar graphs
Data presented by Pfizer/BioNTech showing anti-Omicron antibody responses following vaccination with an original bivalent Omicron booster. Courtesy of the CDC
Efficacy of bivalent COVID vaccine boosters on mice in four color line graphs
Data presented by Pfizer/BioNTech showing antibody responses in mice against various Omicron lines following vaccination with the updated BA.4/BA.5 booster. Courtesy of the CDC

The CDC’s Wharton told the panel that similar data is used to market flu vaccines. “Every year we approve new flu vaccines with new strains without clinical data,” she said. The CDC also warned that delaying a variant-specific booster would result in human casualties. Agency scientists presented models of COVID transmission that estimate 37,000 additional hospitalizations and 9,000 more deaths from the virus in the U.S. if bivalent boosters are not made available for another two months.

Despite widespread reservations about the lack of updated clinical data, the independent advisory panel voted 13-1 to recommend the vaccines. Sarah Long, a pediatric infectious disease expert at Drexel University College of Medicine, said she was ultimately swayed by the fact that both the BA.1 and BA.4/BA.5 vaccines target relatively similar strains of Omicron. “It’s the same scaffolding, the same roof,” she explained. “We’re just putting in new skylights and windows.”

What does this mean for future boosters?

At last week’s hearing, CDC and FDA officials they said they hope so the updated vaccine will simplify the confusing process for approval and eligibility of COVID boosters. Going forward, it doesn’t matter how many shots a person has had in the past or what risk group they are in: almost all boosters will be bivalent, and almost anyone two months since their last shot will be eligible.

The exceptions are children between the ages of 6 months and 5 years who are not yet eligible for any booster, and those aged 5 to 11 years. Last week, Pfizer told CDC advisers it would apply for FDA approval of a bivalent booster for this second age group in early October.

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According to a presentation by the CDC’s internal COVID vaccine task force, one effective strategy moving forward could be to follow the flu vaccine’s lead and issue annual booster updates.

“I think there’s a lot to learn from the flu,” Shi says. “But of course we have to be cautious. It’s not the flu.” States will need to monitor for new mutations every week or every month and track real-world outcomes in COVID patients, he notes, to understand how future variants interact with the bivalent vaccine.

Persad adds two other items he’d like to see from future booster updates. “People keep insisting that you have to do this based on mouse data, because a human trial would take too long. I really challenge whether it should take that long,” he says. He wonders if federal incentives for human trials or accelerated screening for vaccines with safety data are possible. He also stressed that the CDC and FDA need to “really understand what the barriers are among people who got the initial vaccine but didn’t get a booster.” only half of eligible Americans are boostedand getting the new picture to the people who need it will be a constant challenge.

Omicron boosters are the future of COVID vaccines in the US

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