What to Know About a Fourth COVID-19 Vaccine Dose

Most people ages 12 and older are considered “up to date” with their COVID-19 vaccines if they received either three doses of the mRNA shots from Pfizer-BioNTech or Moderna, or two doses of Johnson & Johnson’s Janssen vaccine. But for people over age 50, and for adults with weakened immune systems, being up to date now means they need another dose.

On March 29, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for a fourth dose of Pfizer-BioNTech’s and Moderna’s mRNA vaccines for people 50 and older, or for those with immunocompromised conditions, who received their first booster at least four months ago. The U.S. Centers for Disease Control and Prevention (CDC), which makes vaccination recommendations based on FDA’s authorizations, updated its COVID-19 immunization guidance to include a second booster dose for these groups, as well as for people who received a primary dose and first booster of Johnson & Johnson’s vaccine.

“The FDA believes this option will help to save lives and prevent severe outcomes among the highest risk patients,” said Dr. Peter Marks, director of the FDA Center for Biologics Evaluation and Research, in a briefing on March 29.

As for healthy adults younger than 50, the FDA’s vaccine advisory committee will most likely discuss the available data on April 6 and come up with a more focused plan about COVID-19 boosters. The independent experts will review the emerging data to determine whether continuing to boost with the existing vaccines, or boosting with modified vaccines targeting variants, would provide the best protection against disease. They will also discuss options for boosting schedules, which will be guided by what studies show about how long protection from booster doses seems to last.

“I don’t want to shock anyone, but there may be a need for people to get an additional booster in the fall,” Marks said. “It may be that the decision is made that rather than [using] vaccines we currently have against the [original] virus, we will move to a vaccine that is either against one of the variants—whether that’s Omicron, Beta, or Delta—or that is a mix.”

What we know about the efficacy of a fourth shot

In authorizing a fourth shot, the FDA considered still-emerging data, from both the U.S. and Israel, that don’t paint a definitive picture about whether an additional dose is necessary for most people. On one hand, there are troubling signs that the immunity provided by the vaccines is starting to wane, which could make people more vulnerable to COVID-19’s more severe effects. Recent data published by the CDC, for example show that protection against hospitalization for COVID-19 waned even after a booster dose of either the Pfizer-BioNTech or Moderna vaccines. From Aug. 2021 to Jan. 2022—a time span that includes waves of both Delta and Omicron variants—the booster was 91% effective at protecting against hospitalization in the first two months after people received it, but dropped to 78% four months after the shot. The vaccine efficacy against emergency room and urgent care visits for COVID-19 symptoms followed a similar decline, from 87% up to two months after the booster to 66% four to five months after the booster.

Marks also cited data from Israel, where people over 60 years have been receiving second booster doses, to support the FDA’s authorization, noting that health officials there saw reductions in hospitalizations and deaths among older people who received a second booster beginning four months after their first. He said the FDA decided to authorize the booster for everyone 50 years and older since about half of this group have conditions such as chronic diseases like diabetes or heart disease that can increase the risk of severe outcomes if they get sick with COVID-19.

Dr. Anthony Fauci, the White House’s chief medical advisor on COVID-19 and director of the National Institute of Allergy and Infectious Diseases, hinted a few weeks ago that the U.S. was leaning toward authorizing the additional dose for older people and with weaker immune responses. “We don’t know when you get to six months, seven months, or eight months after the third dose whether that 78% [protection] is going to go down to 60%, 50%, or 40%,” he told TIME. “For that reason, you are going to hear serious consideration for giving a fourth boost to the elderly and those with certain underlying health conditions. What we might be seeing in the reasonable future is that individuals, merely on the basis of age, and perhaps some underlying health conditions yet to be determined, would get an immediate boost.”

Will everyone need a fourth shot?

Whether the same holds true for the rest of the population who are otherwise healthy isn’t so clear, which is why the FDA and CDC limited its recommendation for now. A small study published in the New England Journal of Medicine among younger health care workers in Israel, for instance, showed that adding a fourth dose for people vaccinated and boosted with the Pfizer-BioNTech shot may only have “marginal benefits,” according to the researchers. While the additional dose raised levels of antibodies that can neutralize the virus, including Omicron, slightly, those levels were relatively similar to peak amounts of antibodies people generated after the first booster, or third dose. The study did not focus on elderly people or those with compromised immune systems.

Read More: Researchers Are Getting Closer to Understanding Long COVID. But Treatments Are Likely Still a Ways Off

The U.S. CDC already recommends a fourth mRNA vaccine dose for people with weakened immune systems, including transplant patients and those undergoing chemotherapy for cancer, and other countries have similar guidelines. For them, the new recommendation would mean a fifth dose of the Pfizer-BioNTech or Moderna vaccines, since their primary vaccination consists of three doses. Israeli health officials have gone one step further; on Jan. 22, as cases and hospitalizations crept upward, the country authorized a fourth dose of the Pfizer-BioNTech mRNA vaccine for all health care workers and people over 60 years old. The decision was based on early data from Israel’s Ministry of Health and researchers at several Israeli universities showing that among nearly a million vaccinated people over age 60, a fourth dose of the vaccine offered up to twice the protection against getting infected, and up to three times the protection against severe illness, compared to those who received three doses.

There is also growing evidence that all types of vaccine-induced protection continue to wane. Scientists have long known that the antibodies people make immediately after getting vaccinated are relatively short-lived, but the vaccine triggers the body to also produce other immune defenses, including T cells, which tend to be more durable. Even those responses, however, start to taper after several months, says Dr. Otto Yang, professor of medicine, infectious diseases, microbiology, immunology, and molecular genetics at the University of California, Los Angeles. That means existing vaccine regimens may need to be supplemented with yet another booster dose to keep both antibody and T cell numbers high enough to protect people from severe disease, he says.

Whether everyone needs an additional vaccine dose, and whether or not we can anticipate getting one every year or every few years, depends on what we want the vaccines to accomplish. The vaccines were not designed to prevent people from getting infected by the virus, but to protect them from getting extremely sick with COVID-19, and to keep them from needing hospitalization and intensive care. Remembering that goal, says Dr. Paul Offit, director of the Vaccine Education Center and professor of pediatrics at Children’s Hospital of Philadelphia, is useful when thinking about whether a fourth dose is necessary for most people.

“We got hung up using the word ‘breakthrough’ in describing mild illness,” he says, referring to the term for any infection occurring among vaccinated and boosted people (most of which were mild or even asymptomatic). “But that’s a win—it meant the vaccine was working for you and protected you from serious illness. We have developed a zero tolerance strategy that we are going to have to get over: the idea that it’s not okay to have mild illness after you’ve been vaccinated.”

If the goal of a COVID-19 vaccine is to protect people from severe disease, Offit says that there is still insufficient data supporting the need for a booster for most healthy adults. “I think we have to accept the notion that this is a three-dose vaccine in certain groups and a two-dose vaccine in others,” Offit says.

Read More: A New Report Shows the True COVID-19 Death Toll May Be Three Times Higher Than We Thought

Offit, who serves on the FDA vaccine advisory committee of independent experts that reviews data and makes recommendations to the FDA about whether or not a vaccine is safe and effective, says that trying to protect the world’s population from mild disease with continued booster doses isn’t a realistic or practical public health goal. The question becomes one of balancing any marginal benefit in protecting against mild illness against potential side effects, which for the mRNA vaccines include the risk of inflammation of heart tissue. “Everything has costs, including boosting,” he says. “If it doesn’t benefit you in terms of protection against serious illness, then you have to consider the side effects.”

Fauci says health officials will be watching the hospitalization rate among vaccinated and boosted people closely in coming weeks and months; if it creeps upward, then it would signal a concerning waning of protection even against severe disease, which could warrant another booster dose. “We don’t know now if we are going to need it, but as long as this virus hangs around, I would not be surprised if we are going to need one more shot than we have had,” he says.

Will we eventually need even more boosters?

He and others also don’t anticipate continuing to boost as new variants crop up. Up to this point, that strategy came out of the urgent need to tamp down the virus as quickly as possible in as many people as possible. But it’s not a durable or practical game plan over the long term. “We’ve been chasing our tails with every variant, and we will perpetually be behind [the virus],” says Dr. Kirsten Lyke, professor of medicine at University of Maryland, who spearheaded studies about mixing and matching different types of COVID-19 vaccines.

But now that a good portion of the U.S. population has some degree of immunity through infection, vaccination, or both, the National Institutes of Health is launching new studies in search of a more targeted approach to potential booster shots. Rather than responding to new variants as they emerge and hoping the existing vaccines continue to protect against severe disease, scientists there are mapping out SARS-CoV-2’s mutations and trying to design vaccines against broad collections of changes that would ideally quell a number of different, but related strains that the virus may generate in the future. The study will involve up to 1,500 people at 25 sites. “By mid-summer, we would like to put all the data together so we can make a more scientific assessment as to whether additional boosters will work, whether we will need them, and which one we might need to use,” says Lyke.

In the meantime, Fauci says scientists at the National Institute of Allergy and Infectious Diseases’ Vaccine Research Center are also investigating whether that additional dose should come from the same vaccine people have been receiving, or whether that additional dose should be with a new vaccine that targets a specific variant, such as Omicron. So far, the original booster produces similar immune responses to those generated by a variant-specific boosters in non-human primates. “Given the fact we have waning immunity, we may need a regular boost at intervals yet to be determined,” Fauci says.

Whether a fourth dose will be recommended for most Americans, and what that dose will be, depends heavily on future hospitalization rates among vaccinated and boosted people; if they continue to increase, that might push health officials to consider recommending another booster dose for most people around the fall, said Marks.