For the first time since the start of the pandemic, the vaccines against COVID-19 appear to be getting an update. Boosters reformulated to defend against the Omicron variant that has dominated the world since early this year could be deployed on both sides of the Atlantic as early as this month.
The UK has already authorized a vaccination made by vaccine maker Moderna against Omicron’s BA.1 sub-variant and may soon start using it. This week, after Science went to press, the European Medicines Agency (EMA) had to review applications for Moderna’s BA.1 vaccine and another from the Pfizer-BioNTech collaboration.
But BA.1 no longer circulates; the BA.4 and BA.5 sub-variants eclipsed it in the spring. In June, the US Food and Drug Administration (FDA) asked manufacturers to develop a booster specifically targeting these two subvariants, and last week both Moderna and the Pfizer-BioNTech collaboration said they had submitted data for their BA.4 /BA.5 FDA vaccines. President Joe Biden’s administration has already placed an order for 170 million doses of such vaccines. (Pfizer and BioNTech have also provided the data to the EMA; the European Union may approve a BA.1-based booster first and move to BA.4/BA.5 vaccines later.)
However, data on the updated boosters is limited 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 little of the old and a little of the new. Both the Pfizer-BioNTech collaboration and Moderna make their vaccines from messenger RNA (mRNA) encoding the SARS-CoV-2 spike protein. The new vaccines are bivalent. Half of the mRNA encodes the spike protein of the ancestral virus strain that emerged in Wuhan, China, in late 2019, which is also in the original photos; the other half encodes the spike protein in BA.1 or that in BA.4 and BA.5, which have identical spikes. Because they contain a lower dose of mRNA, the vaccines are intended to be used only as boosters and not in people who have never been vaccinated.
What kind of data have the companies collected?
People data is only available for company boosters targeting BA.1. At a June meeting of the FDA’s vaccine advisory committee, both the Pfizer-BioNTech collaboration and Moderna presented data showing that the injections had side effects similar to those of the original vaccines — including injection site soreness and fatigue — and elicit strong antibody responses to both the original strain and Omicron BA.1. The companies also showed that the BA.1 vaccines elicited significant antibody responses to BA.4 and BA.5, although lower than those to BA.1.
For the BA.4/BA.5 boosters, the companies provided animal data. They have not released these data publicly, although at the FDA meeting in June, Pfizer presented preliminary findings in eight mice given BA.4/BA.5 vaccines as a third dose. Compared to mice that received the original vaccine as a booster, the animals showed an increased response to all tested Omicron variants: 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 the full approval of vaccines — their latest submissions are for emergency use only — and to help develop future updates. They are supposed to measure the recipients’ antibody levels, but not the vaccine’s effectiveness against infection or severe disease. Such attempts are very expensive and were not made for the BA.1 shot either.
How can authorities consider authorizing vaccines without human trial data?
Flu vaccines are updated each spring to try to match the strain most likely to circulate in the fall and winter. Reformulated vaccines do not have to undergo new clinical trials unless the manufacturers significantly change the way they make the vaccine. Such an approach for new variants of COVID-19 makes sense, says Leif Erik Sander, an infectious disease expert at the Scharrite University Hospital in Berlin. The changes in mRNA are minor, and making updated vaccines available as quickly as possible is an “ethical issue,” Sander says. “We need to allow people to protect themselves from a virus that we cannot fully control.”
But there is a potential downside: Allowing updated vaccines without clinical data could reduce public acceptance. “If a variant booster is going to reduce overall uptake, that’s a potential problem” that could offset gains in protection from the new vaccine, says Deborah Cromer, a mathematical modeler at the Kirby Institute at the University of New South Wales.
Why do new vaccines still contain mRNA targeting the ancestral strain that is long gone?
It’s not entirely clear. Hannah El Sali, an expert in vaccine development at Baylor College of Medicine, says she sees no biological reason to include both versions of the peak. In Pfizer’s mouse experiments, an Omicron-only vaccine elicited slightly higher antibody responses to Omicron viruses than a bivalent vaccine. But the limited human data available show no significant difference between the two formulations. However, Angela Branch of the University of Rochester Medical Center, who led a study comparing multiple strain-specific vaccines, notes that the next variant to emerge may be more closely related to the ancestral strain than to Omicron, so that the bivalent formula can be a useful hedge.
Will strain-specific mRNA lead to better protection?
This is difficult 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 well the next dominant strain matches them. It also depends on how many people have immunity from a recent infection.
In a preprint published on medRxiv on August 26, Cromer and colleagues attempt to quantify 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 targeting the Beta, Delta and Omicron BA.1 strains. All studies measured the ability of recipient serum to neutralize viral variants in the laboratory.
They found that the biggest effect came from the administration of any booster: On average, an additional dose of vaccine encoding the spike protein of the virus’s predecessor led to 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 the wild-type vaccine. Even if the vaccine didn’t exactly match the virus strain, it still had some benefit.
“A modded booster will give you a better booster than an ancestor-based booster, even if it’s not a match, but the most important thing is to be a booster at all,” Cromer says. “Don’t throw away all those ancestor-based boosters! They can do a lot of the work for you.”
Strain-adapted boosters also had some benefit at the population level, according to Cromer’s models, although much depended on existing levels of immunity in the population. If, for example, a population already has 86% protection against a severe disease, ancestral strain boosters can increase this 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 think we don’t. Paul Offitt, a vaccine researcher at the Children’s Hospital of Philadelphia, was one of two FDA panel members who voted against requiring the companies to produce Omicron-specific boosters. Offit doesn’t dispute that the new vaccines will have some benefit, but he doubts it’s worth the extra resources. Current COVID-19 vaccines still prevent the worst 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 being infected and infecting others — is too short, he says. Unless neutralizing antibody levels are already high, the immune system does not have time to recognize and fight the virus in the few days between exposure and when someone sheds enough virus to infect others. Diseases like measles or rubella have a 2-week incubation period, which means that a vaccinated person’s immune memory cells can ramp up production of enough antibodies in time to prevent them from passing them on. That’s why measles and rubella vaccines can stop the spread of those diseases, Offit says, while in the case of COVID-19, “even if 100 percent of the population was vaccinated and the virus didn’t evolve at all, the vaccines would do very little to stop the show.”
However, Branch says, the extended immunity that updated vaccines can provide will pay off if new variants emerge. “We need to cover as much of the map as possible,” she says.