For the first time since the start of the pandemic, the COVID-19 vaccines appear to be getting an update. Boosters redesigned to protect against the Omicron variant, which has dominated globally since the beginning of this year, could be deployed on both sides of the Atlantic Ocean as early as this month.
The UK has already authorized a vaccine made by vaccine maker Moderna against the Omicron BA.1 subvariant 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 running; subvariants BA.4 and BA.5 eclipsed it in the spring. In June, the US Food and Drug Administration (FDA) asked the manufacturers to develop an enhancer that specifically targets these two subvariants, and last week, both Moderna and the Pfizer-BioNTech collaboration said they had submitted data for BA.4/BA .5 of their vaccines to the FDA. President Joe Biden’s administration has already placed an order for 170 million doses of such vaccines. (Pfizer and BioNTech have also submitted 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 updated boosters is limited and the impact they will have if given the green light is unclear. Here are some of the questions about 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) that codes for the spike protein of SARS-CoV-2. 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 a booster, and not in people who have never been vaccinated.
What kind of data have the companies collected?
Human data is only available for boosters of target companies for BA.1. At a June meeting of the FDA’s vaccine advisory committee, both the Pfizer-BioNTech collaboration and Moderna presented data showing the injections had side effects similar to those of the original vaccines — including pain at the injection site and fatigue – and elicited strong antibody responses to both the original strain and Omicron BA.1. The companies also showed that the BA.1 vaccines induced significant antibody responses to BA.4 and BA.5, although lower than that to BA.1.
For BA.4/BA.5 boosters, companies have submitted animal data. They have not released those data publicly, although at the FDA meeting in June, Pfizer presented preliminary findings in eight mice given the BA.4/BA.5 vaccines as their third dose. Compared to mice that received the original vaccine as a booster, the animals showed an increased response to all the 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 vaccine approval — their latest submissions are for emergency use authorization only — and to help develop future updates. Apparently they will measure the antibody levels of the recipients, but not the effectiveness of the vaccine against infection or serious disease. Such tests are very expensive and were not even made for BA.1 shooting.
How can authorities consider authorizing vaccines without data from human trials?
Flu vaccines are updated each spring to try to match the strain most likely to circulate in the fall and winter. Reformulated injections should not undergo new clinical trials unless the manufacturers significantly change the way the vaccine is made. A similar approach to new variants of COVID-19 makes sense, says Leif Erik Sander, an infectious disease expert at the Charité University Hospital in Berlin. The changes in mRNA are small, and providing updated vaccines as soon as possible is “an ethical issue,” says Sander. “We have to let people protect themselves from a virus that we can’t fully control.”
But there is a potential downside: Authorizing 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 the gains in protection from the new vaccine, says Deborah Cromer, a mathematical modeler at the University of New South Wales’ Kirby Institute.
Why do new vaccines still contain mRNA targeting the long-extinct ancestral strain?
It is not 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 the spike. In Pfizer’s mouse experiments, an Omicron-only vaccine elicited slightly higher antibody responses against Omicron viruses than a bivalent vaccine. 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 is leading a study comparing multiple specific vaccines, notes that the next variant to emerge may be more closely related to the ancestral type than to Omicron, so the bivalent formula it can be a useful defense.
Will strain-specific mRNA lead to better protection?
It is difficult to predict. This depends in part on the amount of BA.4 and BA.5 still circulating at the time of the hits and how well the other dominant type matches them. It also depends on how many people have immunity from a recent infection.
In a preprint posted on medRxiv on Aug. 26, Cromer and colleagues attempt to quantify the potential 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. All studies measured the ability of recipient serum to neutralize virus variants in the laboratory.
They found that the biggest effect came from the administration of any booster: On average, an additional dose of a vaccine encoding the spike protein of the ancestral virus resulted in an 11-fold increase in neutralizing antibodies against all variants. But strain-specific vaccines improved things slightly. Recipients of the updated vaccines had antibody levels on average 1.5 times higher than those who received an ancestral vaccine. Even if the vaccine didn’t exactly match the viral strain, it still had some benefits.
“A variant-modified booster will give you a better booster than an ancestral-based booster, even if it doesn’t match, but the most important thing is to breed at all,” says Cromer. “Don’t throw out all those ancestral-based boosters! They can do a good deal of the work for you.”
Strain-adapted enhancers also had some benefit at the population level, 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, boosters of the ancestral strain can 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 FDA committee members who voted against the companies’ request to make Omicron’s 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 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 being infected and infecting others — is very short, he says. Unless neutralizing antibody levels are already high, the immune system doesn’t 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 raise enough antibody production in time to prevent it from passing 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% of the population had been vaccinated and the virus hadn’t evolved at all, the vaccines would to do a lot. little to stop streaming.”
Even so, Branche says, the enhanced immunity that updated vaccines can provide would pay off if new variants emerge. “We need to cover as much of the map as possible,” she says.