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Omicron booster shots are coming—with lots of questions

For the first time since the start of the pandemic, COVID-19 vaccines look set to receive an update. Boosters reformulated to protect against the Omicron variant, which has dominated globally since early this year, may get deployed on both sides of the Atlantic Ocean as early as this month.

The United Kingdom has already authorized a shot produced by vaccinemaker Moderna against the Omicron subvariant BA.1 and may start using it soon. This week, after Science went to press, the European Medicines Agency (EMA) was set to review applications for Moderna’s BA.1 vaccine and another from the Pfizer-BioNTech collaboration.

But BA.1 is no longer circulating; the BA.4 and BA.5 subvariants eclipsed it in the spring. In June, the U.S. Food and Drug Administration (FDA) asked manufacturers to develop a booster specifically targeting those two subvariants, and last week, both Moderna and the Pfizer-BioNTech collaboration said they have submitted data about their BA.4/BA.5 vaccines to FDA. President Joe Biden’s administration has already placed an order for 170 million doses of such vaccines. (Pfizer and BioNTech have also submitted the data to EMA; the European Union could first approve a BA.1-based booster and switch to BA.4/BA.5 vaccines later.)

The data on the updated boosters are limited, however, and the impact they will have if greenlit is unclear. Here are some of the questions surrounding this new generation of vaccines.

What do the new boosters contain?

A bit of the old and a bit of the new. Both the Pfizer-BioNTech collaboration and Moderna make their vaccines from messenger RNA (mRNA) coding for the spike protein of SARS-CoV-2. The new vaccines are bivalent. Half of the mRNA codes for the spike protein of the ancestral virus strain that emerged in Wuhan, China, in late 2019, which is also in the original shots; the other half codes for the spike protein in BA.1 or the one in BA.4 and BA.5, which have identical spikes. Because they contain a lower dose of mRNA, the shots are meant to be used as boosters only, and not in people who were never vaccinated.

What sort of data have the companies collected?

Human data are only available for the companies’ boosters targeted to BA.1. At a June meeting of FDA’s vaccine advisory committee, both the Pfizer-BioNTech collaboration and Moderna presented data showing that the shots had side effects similar to those of the original vaccines—including soreness at the injection site and fatigue—and induced strong antibody responses to both the original strain and Omicron BA.1. The companies also showed that the BA.1 vaccines prompted significant antibody responses to BA.4 and BA.5, although lower than that to BA.1.

For the BA.4/BA.5 boosters, the companies have submitted animal data. They have not released those data publicly, although at the June FDA meeting, Pfizer presented preliminary findings in eight mice given BA.4/BA.5 vaccines as their third dose. Compared with the mice that received the original vaccine as a booster, the animals showed an increased response to all Omicron variants tested: BA.1, BA.2, BA.2.12.1, BA.4, and BA.5.

The companies say clinical trials for the BA.4/BA.5 vaccines will begin next month; they need clinical data both for full approval of the vaccines—their recent submissions are only for emergency use authorization—and to help develop future updates. Presumably they will measure recipients’ antibody levels, but not the vaccine’s efficacy against infection or severe disease. Such trials are very expensive and were not done for the BA.1 shot either.

How can authorities consider authorizing vaccines without data from human trials?

Influenza vaccines are updated each spring to try to match the strain most likely to circulate in the fall and winter. The reformulated shots don’t have to undergo new clinical trials unless the manufacturers significantly change the way they make the vaccine. A similar approach for new COVID-19 variants makes sense, says Leif Erik Sander, an infectious disease expert at the Charité University Hospital in Berlin. The changes to the mRNA are minor and providing updated vaccines as quickly as possible is “an ethical issue,” Sander says. “We need to allow people to protect themselves from a virus that we can’t fully control.”

But there is a potential downside: Authorizing updated vaccines without clinical data could lower public acceptance. “If a variant booster is going to reduce overall uptake, that’s a potential problem” that could offset the gains in protection from the new vaccine, says Deborah Cromer, a mathematical modeler at the Kirby Institute of the University of New South Wales.

Why do the new vaccines still contain mRNA targeting the ancestral strain, which is long gone?

It isn’t entirely clear. Hana El Sahly, a vaccine development expert at Baylor College of Medicine, says she can’t see a biological reason to include both versions of spike. In Pfizer’s mouse experiments, an Omicron-only vaccine triggered slightly higher antibody responses against Omicron viruses than a bivalent vaccine did. But the limited human data available show no significant difference between the two formulations. However, Angela Branche of the University of Rochester Medical Center, who leads a study comparing multiple strain-specific vaccines, notes that the next variant to emerge might be more closely related to the ancestral strain than to Omicron, so the bivalent formula could be a useful hedge.

Will the strain-specific mRNA lead to better protection?

That’s hard to predict. It depends in part on how much BA.4 and BA.5 are still circulating by the time the shots are delivered and how closely the next dominant strain matches them. It also depends on how many people have immunity from a recent infection.

In a preprint posted on medRxiv on 26 August, Cromer and colleagues attempt to calculate the possible impact of strain-specific vaccines. They combined data from eight clinical trial reports that compared vaccines based on the original spike protein with formulations targeted to the Beta, Delta, and Omicron BA.1 strains. The studies all measured the ability of recipients’ serum to neutralize virus variants in the lab.

They found that the biggest effect came from administering any booster: On average, an additional dose of a vaccine coding for the ancestral virus’ spike protein resulted in an 11-fold increase in neutralizing antibodies against all variants. But strain-specific vaccines improved things slightly. Recipients of updated vaccines had, on average, antibody levels 1.5 times higher than those who received an ancestral strain vaccine. Even if the vaccine didn’t exactly match the viral strain, there was still some benefit.

“A variant-modified booster will give you a better booster than an ancestral-based booster even if it’s not matched, but the most important thing is getting boosted at all,” Cromer says. “Don’t throw out all those ancestral-based boosters! They can do a good chunk of the work for you.”

Strain-adapted boosters had some benefit at the population level as well, according to Cromer’s models, although much depends on the existing levels of immunity in a population. If, for example, a population already has 86% protection against severe disease, ancestral-strain boosters could increase that to 98%, and updated boosters to 98.8%. That might not sound like much, Cromer admits, “but if you have a large population and limited hospital beds it can make a difference.”

If the benefits are limited, do we really need the new boosters?

Some scientists don’t think we do. Paul Offit, a vaccine researcher at the Children’s Hospital of Philadelphia, was one of two members of FDA’s committee who voted against asking companies to make Omicron-specific boosters. Offit doesn’t dispute that the new vaccines will have some benefit but doubts it’s worth the additional resources. Current COVID-19 vaccines still prevent the most severe outcomes, Offit says, and if the goal is to stop infections, even updated vaccines will have little impact.

That’s because the incubation period for COVID-19—the time between getting infected and becoming infectious to others—is too short, he says. Unless levels of neutralizing antibodies are already high, the immune system doesn’t have time to recognize and fight off the virus in the few days between exposure and when someone sheds enough virus to infect others. Diseases such as measles or rubella have a 2-week incubation period, which means a vaccinated person’s immune memory cells can ramp up production of enough antibodies in time to prevent them from passing it on. That’s why measles and rubella vaccines can halt the spread of those diseases, Offit says, whereas in the case of COVID-19, “even if 100% of the population were vaccinated and the virus hadn’t evolved at all, vaccines would do very little to stop transmission.”

Even so, Branche says, the broadened immunity that updated vaccines may confer would pay off if new variants emerge. “We need to cover as much of the map as possible,” she says.

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