Rapidly evolving COVID variants complicate vaccine updates – go.nature.com

Vaccines may be more effective if they target new types of SARS-CoV-2, not just the original virus.Credit: Joseph Prezioso/AFP/Getty

As countries prepare for another Omicron wave driven by variants BA.4 and BA.5, calls are growing to update COVID-19 vaccines.

Current vaccines based on the version of the SARS-CoV-2 virus that emerged in Wuhan, China, in late 2019 are a poor match for current Omicron strains. As a result, vaccines now offer only short-lived protection from infection — even though they seem to hold up against severe disease.

This week, an advisory panel to the U.S. Food and Drug Administration (FDA) will meet to discuss whether COVID-19 vaccines should be updated — and what upgraded vaccines should look like.

Many scientists agree – though by no means all – that the COVID-19 vaccines are too late to change. But constantly emerging variables and hard-to-predict immune responses mean it’s not clear what the new punches should look like.

“I think it’s time,” says Megan Deming, a virologist and vaccinologist at the University of Maryland School of Medicine in Baltimore. “The virus is changing, and what worked two years ago may not work with future variables.” But she and other scientists cautioned that updating COVID-19 vaccines wouldn’t be as simple as switching genetic material based on the Wuhan strain for that identical to Omicron.

moving sands

Omicron changed the course of the epidemic and produced a series of subsidiaries, the most recent of which are BA.4 and BA.5. Each has eroded immunity acquired from vaccination and infection with previous strains, including earlier versions of Omicron.

So if the upcoming vaccines are based on the original Omicron, called BA.1, there’s a real possibility that by the time they come out later this year, the Omicron strains in circulation will be different. “BA.1 is yesterday’s news,” says John Beagle, MD, a physician and scientist at the US National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, who is leading a trial of potential vaccine updates.

It’s also possible — and some scientists say it’s likely — that an entirely new variant will emerge from a remote part of the SARS-CoV-2 family tree. “My concern is that there is too much focus on Omicron, and the assumption that Omicron is what we are going to deal with in the future,” says Benny Moore, a virologist at the University of the Witwatersrand in Johannesburg, South Africa. “We have a track record of understanding that error.”

As a result of such uncertainty, scientists say the next COVID-19 vaccines need to cast a wide net, ideally triggering an immune response that can recognize variables in the past, present and future. “A broader response is definitely what I want,” Deming says.

mix and pray

How to achieve this breadth is the million dollar question. Moderna, a biotech company in Cambridge, Massachusetts, which co-developed a successful mRNA-based vaccine with NIAID, is trialling an updated vaccine that encodes two versions of the SARS-CoV-2 spike protein: the original formula and a BS1-based version.

On June 25, the company published the results of the experiment1, which gives a booster dose of this “bivalent” vaccine to people who received three doses of the original Moderna vaccine, and compares their immune responses to those seen in people who received a fourth dose of the original vaccine. But data announced this month indicates that the updated vaccine elicited antibody responses that were 75% stronger against BA.1 and 24% stronger against a copy of SARS-CoV-2 from the early months of the pandemic, compared to an extra dose of the original vaccine. . “This is clearly a superior booster,” said the company’s president, Stephen Hogg, in a call to investors on June 8.

And last week, Moderna added that the bivalent vaccine generates antibodies that still block BA.4 and BA.5, although their levels were three times lower than those against BA.1. However, the company did not provide a comparison with the responses resulting from the additional dose of the original vaccine.

Other vaccine manufacturers, including Pfizer in New York City and its collaborator BioNTech in Mainz, Germany, as well as Novavax of Gaithersburg, Maryland, are testing their Omicron-based vaccines. In a June 25 press release, Pfizer-BioNTech reported that only the Omicron BA.1 vaccine produced neutralizing antibody responses against BA.1 that were approximately 2-3 times more effective than an additional dose of the original vaccine. And their bivalent vaccine, similar to Moderna’s, BA.1 responses were about 1.5 to 2 times stronger. BA.4 and BA.5 deplete these responses similarly to the Moderna vaccine.

Beigel says Moderna’s experience shows why now is the time to update COVID-19 vaccines. “We have to move away from the prototype because Omicron looks so much better,” he says.

But John Moore, a vaccinologist at Weill Cornell Medicine in New York City, questions whether the improvements offered by updated vaccines are worth it. “The question for FDA advisors to decide is whether this modest increase is sufficient to justify the cost and complexity of switching configuration,” Moore says. “I haven’t seen anything in the Pfizer and Moderna data that clearly justifies switching the configuration to Omicron.”

Beigel and colleagues will soon report the first results of an NIAID-funded trial testing formulations of vaccines based on a range of variants, including Omicron, Beta, Delta and the original strain. This trial, called COVAIL, includes mRNA vaccines manufactured by Moderna and Pfizer-BioNTech, as well as an experimental protein-based booster developed by Sanofi in Paris and GSK in London.

surprise participant

Beigel says we shouldn’t assume that the original vaccine is the best way to stimulate a response against earlier strains other than Omicron. He hopes his study will shed light on ideal combinations. Another experiment found that the Sanofi-GSK enhancer, which is based on a Beta variant, elicited robust neutralizing antibody responses against all variants, including BA.1 and Delta2. Scientists say this hints that beta should not be ruled out as a component of future updates.

The search for an updated formula is also complicated by the possibility that vaccines based on a particular strain, such as Omicron, may not always elicit a strong immune response against that strain. Some recent studies3 He found that omicron infections after vaccination recall the same antibodies that vaccines against previous strains had, rather than eliciting all new omicron responses. But it is not yet clear whether the updated vaccines will behave in the same way. John Moore says that preclinical studies of omicron-based vaccines in animals show little difference between omicron and the original strain boosters suggest this might occur.

A similar phenomenon, known as fingerprinting, affects how people respond to influenza vaccination and infection, causing levels of protection to vary between people and from year to year. However, health officials are trying to match the composition of seasonal vaccines to potentially circulating strains.

This strategy makes sense with SARS-CoV-2, says Jesse Bloom, an evolutionary biologist at the Fred Hutchinson Cancer Center in Seattle, Washington. “We can safely assume that getting the vaccine as close as possible to the virus circulating would be better overall.”

But decisions about composition of flu vaccines are based on a solid understanding of how those viruses evolve, Beagle says, something researchers can’t yet claim with regard to SARS-CoV-2. “We know the rules of flu and we can predict that very well. For COVID, we don’t.”

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