Our writer unpacks the data behind the new vaccines and wonders what happened to nuance in the CDC’s recommendations.
One month ago, health authorities in several nations approved and recommended updated booster shots against SARS-CoV-2, the virus that causes COVID-19. This includes the United States, where the U.S. Food and Drug Administration (FDA) granted two new booster formulations emergency use authorization, and the Centers for Disease Control and Prevention (CDC) recommended their use on September 1.
The CDC statement was extremely broad, recommending the new boosters for all Americans aged 12 and older who have received at least a primary vaccine series, consisting of two shots for most COVID-19 vaccines. The new, updated vaccines—one from Moderna for those aged 18 and older, the other from Pfizer-BioNTech for those aged 12 and older—are boosters only. At the same time, the U.S. Department of Health and Human Services, which oversees both the CDC and the FDA, rolled out a new public health campaign to encourage uptake of the new boosters. By last week, some 4.4 million Americans had taken them up on the offer, which is roughly 2 percent of the population turning out to receive the newly formulated shot.
Should everyone take one of the new boosters? Well the CDC sweepingly says yes. But the best answer may be more nuanced, as things in medicine usually are, and depends on your particular health situation. What’s warranted for a 75 year-old, immunocompromised woman is not necessarily warranted for a 12 year-old boy, or a 30 year-old woman with no health issues.
To avoid the kind of broad-brush answer that has unfortunately come from the CDC, I sat down earlier this week with Paul Offit, a noted expert on vaccines. He is a pediatrician, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, co-inventor of the rotavirus vaccine, and member of the FDA’s Vaccines and Related Biological Products Advisory Committee. Offit opposed discarding the old boosters and replacing them with new formulations when he voted on the issue back in June, based on a lack of demonstrated benefit.
To understand what we should expect of the new vaccines, it’s important to understand how they differ on a technical level. So let’s get technical for a moment.
How are the new boosters different?
In the United States, the major selling point is that both new boosters contain a sequence of mRNA that is tweaked to give your immune system added “target practice” against the major variants of the virus that are currently circulating—BA.4 and BA.5. These are the new omicron variants, derived from the original omicron variant, BA.1.
But the new boosters are fundamentally different in that they are also bivalent. They are basically two vaccines in one, containing not just a dose intended to strengthen protection against BA.4 and BA.5, but also a second dose of mRNA sequence, which corresponds to the original, ancestral Wuhan variant. The rationale is to give the immune system added shots on goal against the newest viral spike protein, which the BA.4 and BA.5 variants have in common, without dumping the ancestral sequence of the old boosters.
All that makes the updated booster sound wonderful on paper, except for the inclusion of the original sequence. If the point is to improve immunity against variants that currently circulate, why also include a sequence that aims the immune system against a variant that has since disappeared? There is a long history of bundling different vaccines together into one shot. Annual flu shots, for instance, protect against several strains of influenza, and the routine pediatric MMRV vaccine protects against four completely different viruses (measles, mumps, rubella, and varicella).
But we don’t vaccinate people against infectious agents that are gone. Flu shots are updated every year to target the specific strains in circulation. If the measles virus were to be eradicated, we’d remove that component and the tetravalent MMRV would become the trivalent “MRV.”
“Pfizer and Moderna did their studies the right way, comparing groups of a few hundred people getting the first three monovalent shots with the ancestral [Wuhan] strain sequence and the fourth shot either monovalent with the ancestral strain or a bivalent consisting of an ancestral and a BA.1 sequence,” Offit says. “Then they looked at neutralizing antibodies against BA.1, asking, ‘Did you have significantly greater antibodies against BA.1 if you received the bivalent booster as the fourth shot?’”
The answer was yes and no, he says. While the antibody effect of the new bivalent vaccine was greater, it wasn’t so much greater as to be clinically significant. In the case of Pfizer, the new bivalent vaccine made 1.57-fold more antibodies, while the Moderna vaccine induced 1.75 fold more, when the dose of the BA.1 sequence matched the dose of the old monovalent boosters (30 microgram for Pfizer, 50 micrograms for Moderna). When the Pfizer dose was doubled (to 60 micrograms), the neutralizing antibody levels rose to 1.97 fold versus the old booster.
However, there’s no reason to think that even such increased amounts of neutralizing antibody levels have any clinical significance. If you look back to December 2020, when Moderna and Pfizer both presented initial data on their original vaccines, those early studies showed that the neutralizing antibodies were about two-fold higher for Moderna compared with Pfizer. And yet in terms of saving people from infections and severe outcomes, that two-fold difference had no actual clinical significance. The real, measured protection between the two brands did not differ at all.
The old Pfizer monovalent booster provided 30 micrograms of a single, monovalent mRNA sequence, while the new bivalent booster provides 15 micrograms for each sequence.
In a comment to proto.life editor-in-chief Jane Metcalfe earlier this week, University of California, San Diego virologist Douglas Richman characterized the new bivalent vaccine as being only incrementally better. “The implications from the announcements are that it’s a significant improvement,” he said. “I’d say it’s marginal.”
We’re losing perspective. The purpose of creating vaccines with this beautiful new mRNA technology was to prevent the severe kind of COVID-19 that leads to overwhelmed intensive care units and deaths. Such immunity relates less to antibody titers (their levels in the bloodstream) than to other immune phenomena, notably T cells and memory B cells, which seem to persist in the long term, which explains why two or three shots of vaccine is enough to keep people out of the ICU, and out of the morgue —unless they are very old, or have some major health issue, in which case they benefit from additional boosters.
So to regain our perspective, we need to get even more technical for a moment and ask the real question: Are the new CDC-recommended bivalent vaccines actually better?
Two variants but half the dose?
On September 7, the clinical trial Offit reviewed in June was published in the New England Journal of Medicine. Some of the volunteers (health care workers) received (as their fourth dose) bivalent boosters formulated to match the ancestral variant as well as the older omicron BA.1 variant—and not the ever-so-slightly different BA.4 and BA.5 currently in circulation. Other volunteers in the trial received the BA.1 sequence without an accompanying ancestral sequence, and a control group received the old booster. Based on all that clinical evidence, Canada and the United Kingdom approved the BA.1 bivalent boosters.
Meanwhile, the United States went a different route. The FDA issued its emergency use authorizations (EUA) for Pfizer and Moderna boosters formulated for BA.4 and BA.5, the currently circulating omicron variants, and not the vaccines containing the sequence for BA.1, the original omicron variant, which Canada and the U.K. approved. What’s more, the FDA made its decision based on data that came only from mice. That’s not as bad or dangerous as it might sound, since the actual differences between BA.1 and BA.4/5 are minuscule. If there were problems with the BA.4/5 formulations, those dangers likely would have shown up in the mice. And at the end of the day, this is where things may be heading in the future. Proponents of the new boosters think that we ought to be able to tweak SARS-CoV-2 vaccines without human studies in the future, just as we do with annual influenza vaccines.
If that all sounds completely rational, why did Offit oppose reformulating from the old monovalent boosters and replacing them with the new bivalent formulation back in June? His reasoning becomes clear as day when you recall there’s no reason to assume that the higher neutralizing antibody levels in the mice and in humans mean that the bivalent boosters will provide any advantage over the old monovalent formulation.
If anything, there might be a reason to worry that protection might not be as good, and that reason involves the dosing. As noted earlier, in the trials of BA.1 sequences showing higher neutralizing antibody levels whose clinical significance isn’t even known, volunteers received doses either matched to the usual doses of the old monovalent vaccines, or double those doses. But in the new bivalent boosters, you’re getting half the previous dose for each sequence. The old Pfizer monovalent booster provided 30 micrograms of a single, monovalent mRNA sequence, while the new bivalent booster provides 15 micrograms for each sequence. Likewise, for Moderna, the old booster was a 50 microgram single dose, while the bivalent is half that dose—25 micrograms—for each of the two mRNA sequences.
“From a biological standpoint, you’re basically giving a pediatric dose.”
What this means, Offit says, is that the new bivalent vaccine might be akin to getting two vaccines, although each one at half the dose. It adds up in terms of arithmetic, he says, “But I would argue that from a biological standpoint, you’re basically giving a pediatric dose.” On top of that, he warns that the proteins produced by the two different low dose sequences could compete for the attention of the immune system in the germinal centers of lymph nodes where they go after being injected together into the same arm. “The BA.1 is new, so you’re trying to get those epitopes that are distinct from the ancestral strain epitopes and you’re making it harder when you’re competing in the same lymph node that’s already been primed for the other one,” he says. “When you give it alone you know you have a better chance.”
A limited amount of clinical data—from 16 cases of SARS-CoV-2 infections—actually suggests you’re better off getting the monovalent omicron BA.1 vaccine by itself, rather than the bivalent dose.
One last concern worth noting is that the bivalent vaccines come with a shortened minimum time interval that one must wait before receiving the booster. Now, after receiving either the primary vaccine series or the most recent monovalent booster, you are required to wait just two months before getting the new bivalent booster, as opposed to the five months recommended in the old emergency use authorization for the older, monovalent boosters. But there is not a shred of science to support this shortened timeframe. In fact, one notable thing that was learned last year was that long-term immunity improves when you increase the interval between doses.
The bottom line: We need better guidance
So where does this leave us after two-and-a-half years of a highly politicized pandemic that has already left all Americans confused, scared, angered, and hurt in so many ways? What is the bottom line? Am I saying people should avoid the new boosters? Absolutely not. They are completely safe, for one thing. People who would benefit anyway from another dose of the old booster—which could be a fourth or fifth shot for a high-risk person, or possibly a third shot for low-risk person who has delayed that booster—have no particular reason to fear the new boosters.
Even if there is no harm, is there still a benefit? Only the same very short-lived benefit that you get from any boost. For a few months, you have extra protection against mild COVID-19, but the added protection drops off and there are diminishing returns with each new booster. Hyper-focusing on antibody levels whose significance is unknown, possibly to the point of getting boosted after only two months, makes almost no sense. So if you are not high risk—for instance, you are a healthy 30-something who has received three doses already and has had a natural infection to boot—would holding off and awaiting data from the millions of people who have received the shots already be a reasonable course of action? The data may support that.
If you are looking for an easy answer, you won’t find it here. This is an opinion piece, and I am not dispensing medical advice. I cannot say, in a sweepingly general way, what you should or shouldn’t do, but maybe that’s the exact point. The best answer, the one you are looking for to guide your own health decisions, should be specific for you—and way more nuanced than the CDC guidelines suggest.
