At the end of March, the Food and Drug Administration authorized a second COVID-19 booster, or fourth dose, of the Pfizer/BioNTech and Moderna vaccines for people 50 years of age and older.
The idea is to shore up any flagging immunity among the most vulnerable, particularly as the omicron subvariant BA.2 sweeps across the country and could potentially lead to a surge in cases.
But there isn’t a lot of data showing a strong benefit, especially for the youngest eligible people.
“A lot of us have been a little surprised by this,” E. John Wherry, an immunologist at the University of Pennsylvania, told us.
Even the FDA has called the evidence-base “emerging.” The Centers for Disease Control and Prevention declined to make a blanket recommendation that everyone eligible receive the booster. Instead, the agency said people 65 and older and people 50 and older with medical conditions that put them at higher risk for severe COVID-19 would be the “most likely” to benefit.
Still, multiple experts told us that giving doctors the flexibility to offer second boosters is reasonable, even if it’s not clear that the extra doses are needed.
Here, we break down the available evidence and share what scientists recommend.
What did the FDA authorize, and what has the CDC said?
On March 29, the FDA announced it was authorizing a second booster of either mRNA COVID-19 vaccine for adults 50 years of age and older, four months or more after a previous shot.
The agency also began allowing immunocompromised people 12 years of age and older to receive a second booster. Because those individuals received three doses for their initial vaccination series, instead of the standard two doses, a second booster would be a fifth dose of the mRNA vaccines.
The authorizations are based on the FDA’s determination that the “known and potential benefits” of the additional dose “outweigh their known and potential risks” for those groups. The agency cited “emerging” data, much of it from Israel, that an additional dose “improves protection against severe COVID-19 and is not associated with new safety concerns.” Israel began giving fourth doses to medical workers and people ages 60 and over in early January.
Also on March 29, the CDC endorsed the FDA’s authorization by updating its recommendations to allow second boosters for those populations. The CDC, however, did not say that everyone who is eligible should get a second booster — only that they can.
CDC Director Dr. Rochelle P. Walensky said in a statement that second boosters are “especially important for those 65 and older and those 50 and older with underlying medical conditions that increase their risk for severe disease from COVID-19 as they are the most likely to benefit from receiving an additional booster dose at this time.”
In an April 5 press briefing, Walensky echoed that advice, saying the agency “really would encourage people who are over 50 who have underlying medical conditions, those over the age of 65, to go ahead and get that next shot.” She also told NBC News that for people 50 to 65 who are healthy, whether to get a second booster is “a personal judgement call” and that getting it now or waiting until the fall were both “very reasonable.”
At the time of the announcement, the CDC also said that anyone over the age of 18 who had received the Johnson & Johnson vaccine for both their primary and booster doses could now receive a second booster of an mRNA vaccine, as long as their last shot was at least four months ago. That was based on the results of a study that found poorer protection against hospitalization among those who were vaccinated and boosted with the J&J vaccine, compared with those who had received an mRNA booster or only mRNA vaccines.
In making their decisions on a second booster, neither agency relied on its outside vaccine advisory group, which normally reviews and discusses the evidence in a public forum and then makes a recommendation to the parent agency.
Dr. Paul A. Offit, a vaccine expert at the Children’s Hospital of Philadelphia and member of the FDA’s advisory committee, was critical of that move, saying in an interview with FactCheck.org that advisory review should always occur — and that in this case, “the recommendation proceeds compelling science.”
In a press briefing, Dr. Peter Marks, the director of the FDA’s Center for Biologics Evaluation and Research, defended forgoing the advisory meeting, saying that it was a “relatively straightforward decision made based on data that was analyzed.” The FDA’s advisory committee met on April 6 to discuss how to best plan for future COVID-19 vaccines, including possible variant-specific shots and how much to space apart boosters. Nothing was decided at that meeting, but Marks said the agency planned to hold another meeting by early summer about possible boosters in the fall or winter.
Most other countries have not yet permitted second boosters, but there are some exceptions. Israel, which has been the source of much of the real-world data on the extra doses’ safety and effectiveness in older people, expanded second booster eligibility in late January to all adults who are at higher risk because of their jobs or underlying health conditions, along with caregivers.
On April 6, the European Centre for Disease Prevention and Control and the European Medicines Agency said that it was “too early” to give second boosters to the general population, but did recommend them for people 80 years of age and older.
Dr. Andrea Ammon, the director of the ECDC, said in a video statement that there is “no clear evidence at the moment that vaccine protection against severe disease is waning substantially in adults between 60 and 79 years of age with a normal immune system to support the need of a fourth dose.” She said, however, that this could change, and emphasized the need for people to get their initial vaccinations and first boosters.
What studies have been done on fourth doses?
As of early April, FactCheck.org identified four studies of second boosters, all of which have been done in Israel.
The first, published in the New England Journal of Medicine on March 16, investigated the safety and effectiveness of fourth doses in health care workers during the omicron wave. The study included 154 people who got a Pfizer/BioNTech vaccine as a second booster and 120 people who got a Moderna vaccine as a second booster, and compared them with age-matched controls who had not received a second booster.
While the extra shots were safe and increased neutralizing antibodies against the virus by around 10-fold, the boosters were not particularly good at preventing infection and only moderately good at preventing illness.
The study was too small to make accurate estimates of booster effectiveness, but pegged the Pfizer/BioNTech and Moderna vaccines as 30% and 11% effective against any infection and 43% and 31% effective against symptomatic disease, respectively. The authors concluded that second boosters “may have only marginal benefits” for a healthy, young population.
The second paper, posted as a preprint on Feb. 1 and published in the New England Journal of Medicine on April 5, used an Israeli Ministry of Health database to look back at the outcomes of more than 1.2 million people 60 years of age and older who were eligible for a fourth Pfizer/BioNTech dose while the omicron variant was “overwhelmingly dominant.” About half of the people opted for the shot.
The study found that in the fourth week after the booster, those who got the shot were about two times less likely to have a confirmed infection and around three times less likely to have severe COVID-19 than those who did not get the extra vaccine. Protection against infection was estimated to last only about eight weeks, but protection against severe illness had not decreased by the study’s end, after six weeks.
The results, the authors said, provide “evidence for the effectiveness of a fourth vaccine dose against severe illness caused by the omicron variant,” but that for infection, the extra dose “appeared to provide only short-term protection and a modest absolute benefit.”
The third study, an unpublished paper under review at a Nature journal, looked back at the outcomes of more than half a million booster-eligible members of Clalit Health Services, the largest of Israel’s four health service organizations, during the omicron surge. The study found that compared with people who had received three Pfizer/BioNTech shots, those who got four were 78% less likely to die during a 40-day follow-up period.
A fourth study, unpublished and not yet peer-reviewed, also looked back at data from a different Israeli health service organization, Maccabi Healthcare Services, which included just under 100,000 eligible seniors 60 years of age and older who had taken a PCR test during a 10-week period when omicron was dominant. The authors again identified a large and durable reduction in risk against severe disease following a Pfizer/BioNTech second booster, but weaker and waning protection against infection.
Compared with those who had three doses of the vaccine, those who had four were 64% less likely to be infected during the third week, which declined to a 29% reduction in risk by 10 weeks. In contrast, people who received second boosters remained at least 73% less likely to develop severe COVID-19 than their single-booster peers throughout the nine-week period.
What do experts think of the decision to permit second boosters?
Expert opinion is mixed, with some scientists critical of the FDA’s decision, while others are supportive.
Offit, for example, does not think the Israeli data are “strong enough to say that you clearly benefit from a fourth dose.” There could be a benefit against serious illness for people over 65, he said, but the studies were not randomized, meaning the reductions in severe disease among people who were boosted a second time might not necessarily be due to the vaccine.
“Someone who chooses to get a fourth dose may be more attentive to their health, may be more likely to mask or social distance, may be more likely to exercise, less likely to smoke. So you may be selecting for a healthier group,” he said. “And that’s the biggest weakness of those kinds of data.”
All of the studies showing a benefit were done in people 60 years and older, so there are “no data” to suggest a clear benefit in people who are younger, Offit said. “I don’t understand that recommendation,” he said.
Other scientists were more accepting of the FDA’s decision, although they acknowledge that the evidence base is small. Johns Hopkins epidemiologist David Dowdy told us that he thinks the benefits of a fourth shot, “especially for people who are older, probably do outweigh the risks, as these vaccines are very safe and are very effective.” But, he said, the data are “limited,” and the U.S. trajectory may not mirror Israel’s experience.
“Their waves have not always shown the same pattern as others, and the representativeness of those data may not be representative of the U.S. population,” he cautioned. “That being said, it does look like a fourth dose does provide additional protection, at least in the short term against infection, which I think is to be expected.”
Dowdy also questioned the timing of the FDA’s announcement. While he said it’s “reasonable” for the FDA to provide flexibility for people to get a fourth shot if they want it, it would be better for the public to get a second booster when facing a new surge.
“I personally would prefer to see more of the push happen as we’re starting to see a new wave, as opposed to right now in the midst of … a relative lull,” he said.
Some have worried that the more contagious omicron subvariant BA.2 could be the source of another surge. But while BA.2 has wreaked havoc elsewhere in the world, including parts of Europe and China, it hasn’t done so everywhere, and there is little sign of a rise in cases in the U.S., except in some areas, notably in the Northeast. That’s despite the subvariant accounting for more than 70% of identified infections, according to the CDC.
“There’s not much more room for BA.2 to go in terms of creating a wave,” Dowdy said.
“From the perspective of the FDA authorizing it, I don’t think it’s inappropriate for them to do so,” he said of second boosters. “But I just hope that the messaging isn’t that now everyone needs to run out and get a fourth dose right now.”
Wherry, the University of Pennsylvania immunologist, took a similar view. “I think having more options on the table for people is good. It gives physicians a little more choice and ease of recommending a fourth shot if they think it’s necessary,” he said, adding that some people were getting extra doses even before the authorization.
But, he said, there is little to suggest that second boosters are needed for some of the eligible population. “There’s no data that I can find that really suggests that healthy people between 50 and 64 are ending up in the hospital more, having severe outcomes more, after the third shot with waning antibodies,” he said.
The FDA, for its part, has said that its decision to include people 50 years and older was based on the fact that many people in that group had underlying medical conditions.
“We know people in the age range from about 60 to 65, about a third of them have significant medical comorbidities,” Marks said in a press briefing. “So by choosing age 50 and up — which is often something we use for other respiratory viruses like influenza, to consider those at high risk or higher risk — we felt like we would capture the population that might most benefit from this fourth booster dose.”
How are scientists advising those who are eligible about whether and when to get a second booster?
Short of strong recommendations from the government, many people 50 and older are confused about whether they should get a booster, and if they do, when to get it.
Since the additional dose was announced, health officials have been more direct in pushing boosters for those who are immunocompromised, 65 and older, and those 50 and older with underlying health conditions — essentially leaving out healthy people below the age of 65.
The scientists we spoke with generally agreed with that advice, but also told us that the decision shouldn’t only be based on age or a person’s health status, and will of course depend on a person’s risk tolerance.
“It’s not only what your individual risk is for severe outcomes, it’s also how much infection is going on in your community,” Wherry said.
In the U.S., infection rates are quite low now, and so it could make more sense to wait until the risk of exposure increases, particularly because protection against infection is likely to be short-lived.
If you got a fourth shot now, Wherry said, you’d have a heightened level of antibodies for one to three months, which could mean you’d be susceptible to infection again by summer.
“If we see another spike in let’s say, July, you will have had your fourth shot, that antibody level is going to be waning by then, and now you might wish that you had waited until June to get the fourth shot,” he said.
Deepta Bhattacharya, an immunologist at the University of Arizona College of Medicine, agreed. “If indeed vaccine effectiveness does wane relatively quickly against Omicron for older and otherwise vulnerable populations, there isn’t much sense in getting a shot during a period of relative calm—you’d rather time it just as cases start to rise so that your protection can last out the wave,” he told us in an email.
It could also make sense to time the second booster for when a person’s individual risk goes up because of a choice to participate in higher-risk activities. Dowdy gave the example of his 69-year-old mother, who is traveling to Italy — where cases are 10 times higher.
“You should think about the timing of when you are going to be exposed to an increased risk of COVID-19, and you should try to take this vaccine 2 to 3 weeks before that time,” Dowdy said.
On the other hand, there is risk in trying to time a booster, because there’s a chance you won’t get the timing right.
Dr. Sean X. Leng, a geriatrician at Johns Hopkins University, said he was wary of such approaches, and would generally recommend that all older people get the booster, and anyone at higher risk get it with “some urgency.”
“The case rate of COVID is low, but you don’t know when it’s going to get back up again,” he said, citing past experiences with the delta and omicron variants. “Once you know the cases [are] rampant here, it’s probably too late.”
He called the booster a “luxury” that “other places don’t have.”
Still, Dowdy said that it was important to remember that three doses remain highly protective against severe disease.
“If you’ve already gotten 3 doses, you already have very strong protection against getting seriously ill, so you don’t need to feel like your protection is somehow incomplete,” he said. “But if you want to prevent yourself from getting infected, the best time to take that fourth dose is as best as you can tell, a few weeks before your own individual risk is going to go up.”
What are the risks of the second booster, and should you wait for a variant-specific vaccine?
Data from Israel show the vaccine is safe, and there don’t appear to be any new safety concerns, according to the FDA.
Offit, however, said it’s important not to be in the habit of just assuming that there can’t be any downsides to boosting. In his case, he doesn’t plan to get the second booster, even though he’s over 65, because he’s otherwise healthy and it’s not worth the expected side effects, such as fever, headache, muscle pain and tiredness. Such side effects aren’t dangerous but can be unpleasant.
“I think I’m very likely to be protected against severe disease, and I don’t want to have to go through the side effects of this vaccine … for what I think is minimal benefit,” he said.
Bhattacharya, too, said that as a younger and healthier person, he is waiting for now, although he would recommend vulnerable people get the booster if they’re many months out from their last dose and a surge begins. “I don’t intend to get a 4th shot unless I see some much more compelling data or they come up with an updated vaccine,” adding that he “felt pretty awful after my 2nd and 3rd shots.”
Offit also raised the possibility that boosting now with a vaccine designed against the original virus could ultimately be detrimental for protection against future coronavirus variants because it could “lock [people] into that original exposure,” narrowing the range of antibodies that are made. Such issues have occurred with other vaccines.
However, as we’ve explained before, there isn’t any sign that that is a problem now. Wherry, whose lab has been researching immune responses following vaccination, said the data from his lab and others are showing that the original vaccine continues to give “very good breadth.”
“A booster with the original vaccine seems to still give you a good boost of antibodies against omicron, even though the omicron spike is not in the original vaccine,” he said, referring to the instructions for the specific coronavirus spike protein used in the vaccines to generate an immune response. And some data in animal models suggest boosting with an omicron-specific spike, Wherry added, “doesn’t do any better than boosting with the original vaccine.”
“There’s also new data out that suggests that if the only exposure you have is to omicron — through infection in that case — that does actually narrow your response and you’re less able to neutralize delta,” he said. “So I think right now that there’s no evidence that getting a boost with the original wildtype vaccine is detrimental in any way in terms of narrowing the response.”
Bhattacharya said that a study in mice did find a large increase in omicron-specific antibodies after an omicron booster. It’s possible, he said, that the other studies are underestimating the benefit of an updated vaccine because they are evaluating the responses too soon, and it could take some time for the new antibodies to show up.
Still, he said it would be unwise to wait for a variant-specific vaccine because it’s unclear when one might be available. “So as always, the decisions need to be made based upon the reality on the ground, community transmission, and on what options are available. If we see another bad wave and there is no updated vaccine to be had,” Bhattacharya said, then another dose of the original vaccine will do.
The National Institutes of Health announced on March 31 that it would begin a clinical trial testing different versions of second boosters in adults, which would provide more information about how best to protect against variants in the future.
Do you need a second booster if you’ve been recently infected?
Experts say you can delay a second booster if you’ve had a recent confirmed infection. Wherry said he thinks of an infection as similar to any exposure, and recommended waiting four to six months for your immune response to mature before getting an extra dose.
CDC officials have also said that those individuals can wait. “If you’ve had COVID since Christmas, you’ve likely had omicron, and in those cases you might be able to wait. That omicron exposure was probably your boost,” Walensky told NJ Advance Media.
Will you eventually need a third booster?
Yes, it’s possible that more vulnerable people could need an additional booster, even as early as the fall.
CDC’s Walensky cautioned that that could be a possibility in an April 5 press briefing, and FDA’s Marks also mentioned it in a press conference.
“It would not be surprising if there is a potential need,” he said. “I don’t want to shock anyone, but there may be a need for people to get an additional booster in the fall, along with a more general booster campaign, if that takes place. Because we may need to shift over to a different variant coverage.”
Marks said that people who get the second booster now wouldn’t necessarily be prevented from getting an additional booster in the fall, if evidence shows it would be beneficial.
Wherry said that he didn’t think that the fall booster, if there is one, would necessarily be an omicron-specific vaccine, but the situation remains challenging to predict.
Several experts we spoke with said it was too soon to say whether COVID-19 vaccination might become an annual event, but that it was a possibility.
“I think it is likely that we will come to some schedule where doses are made available annually, just like for flu. But whether that is too often, too infrequent, or just right depends on a lot of things such as viral evolution that are very difficult to predict,” Bhattacharya said. “What I do hope is that we broaden out the coverage on the vaccines to cover more possibilities and hopefully buy ourselves some more time between doses. Asking people to get doses every few months is not sustainable—people just won’t do it.”
Dowdy said it was also possible that vaccines might not even be needed every year, but it would take a year in which there is no spring, summer or fall wave “before we can start to say things like that.”
“The more people are able to start thinking of both vaccines and immunity as less of a dichotomy of either you’re vaccinated or not, you’re immune or not,” he added, “and to start think about when cases go up, that’s when we want to boost our immunity a little bit more, I think that would be a positive development.”
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