To boost again or not to boost again. That is the question—for some, at least.

A second COVID booster currently isn’t an option for most Americans. When asked by Fortune on May 13 why guidance has not yet been released for second boosters for a majority of people, or when it would be, the U.S. Centers for Disease Control failed to answer specifically.

It did, however, point to updated guidance for those who are eligible—the elderly and immunocompromised, mainly—urging them to consider how likely they are to get “very sick” from the virus based on preexisting health issues and community exposure. The federal agency’s revised message: Think twice before scheduling a fourth jab. It comes amid concerns that the U.S. government may be rationing a dwindling supply of vaccines as potential new COVID funding stalls in Congress.

For those who are eligible, is a second booster worth it? And are those who are ineligible missing out—especially during a fifth COVID wave, with yet another predicted by the White House this fall and winter?

“A second booster is sort of on the bubble,” said Arijit Chakravarty, a COVID researcher and CEO of Fractal Therapeutics. “The effects seem small and short lived. But if you’re implementing your own ‘swiss cheese’ strategy, it’s one more layer. In that respect, it’s worthwhile.”

“Somewhat efficacious”

The question of whether to recommend a second booster for most Americans is complicated, said Keri Althoff, an epidemiologist at the Johns Hopkins Bloomberg School of Public Health.

“We don’t want to recommend anything that isn’t going to confer more benefit than potential harm,” she told Fortune on May 13. “Although mRNA vaccines have an incredible safety profile, we still want to make sure that these vaccines are working effectively to keep people out of the hospital or protect people from death.”

“Even better, we need to make sure these vaccines are still doing it as the virus changes.”

Those who had been vaccinated made up nearly half of COVID fatalities in January and February of this year during the initial Omicron surge—up from 23% during the Delta wave last fall, The Washington Post recently reported.

Althoff wouldn’t comment on The Post’s reporting without seeing the data behind it. But there is growing awareness that immunity—whether from vaccination or previous infection—wanes with time.

“We know immunity starts to wane after four months or so, and we have a variant circulating that is more capable of breaking through our immunity,” Dr. Marcus Pereira, an infectious disease expert and assistant professor of medicine at Columbia University Vagelos College of Physicians and Surgeons, said in an April blog post.

“A fourth booster does not seem to create much of a benefit when it comes to more severe outcomes for those who are younger,” he said, citing an April study out of Israel published in The New England Journal of Medicine. It found that among health care workers who received a second booster, antibodies were restored to levels around those typically seen after a first booster. Among health care workers who weren’t boosted a second time, antibody levels continue to wane.

A second booster, however, didn’t significantly reduce the percentage of those who eventually developed Omicron—around 20% of those who received a second booster, as compared to 25% of those who had been boosted only once. All participants who developed COVID, regardless of how many boosters they’d received, experienced minimal symptoms but saw high viral loads, meaning they were likely infectious.

The study called a second booster “immunogenic” and “safe” but only “somewhat efficacious, primarily against symptomatic disease.” It failed to make a strong case for a fourth vaccine in the young and healthy.

The trouble with placing individuals in two categories—immunocompromised and not—is that there is “a lot of person to person heterogeneity in the strength of immune response,” Chakravarty said, adding that his research team would soon be publishing a paper on the topic.

“It lives on a very wide bell curve. Some people have a very, very short half life for neutralizing antibodies; some have very long half lives. They don’t neatly break down into two buckets.”

“Transient” benefit

While boosters restore protection against severe disease, “the duration is quite a bit shorter,” said Chakravarty, citing a study published to JAMA Network Open on May 13. It found a decline in vaccine efficacy against Omicron just weeks after a third dose, versus months after the initial two-dose regime, calling the antibody response after a booster “transient.”

But there’s more at play than one’s ability to mount a response to repeated vaccinations.

“Your body is responding differently to each new dose, but the virus is also reacting,” he said.

Omicron subvariants have become increasingly adept at evading immunity from both prior infection and vaccination. A recent study found that those who had been previously infected with Omicron BA.1 but not vaccinated suffered a nearly eightfold drop in neutralizing antibodies when exposed to BA.4 and B.5, the new Omicron variants sweeping South Africa. Those who had been vaccinated and previously infected saw a milder threefold decrease, according to the study.

The initial hope was that antibodies against the Wuhan strain of COVID would hold up against future variants and subvaraints, “but the virus is working night and day to solve that problem,” Chakravarty said.

Those who’ve yet to receive a first booster shot should do so, Chakravarty advised, and boost again if they’re eventually able.

“Me, personally? I’ll get a second booster,” he said. “Is it going to be amazing? No. I think most people missed the memo that the vaccines are, in fact, fading—have almost completely faded—in the ability to protect against infection. They may also be losing the ability to protect against severe disease as well.”

“Get the second booster or don’t—but either way, six months down the road, we’re all in the same bucket again, more or less.”

Far from a quick fix, vaccines are a tool in an arsenal of weapons against COVID, Chakravarty said. Those who wish to decrease their chances of contracting the sometimes deadly virus—and of developing a potentially disabling case of Long COVID—can also wear a quality mask like an N95.

“Right now the single most effective intervention is to wear a mask,” he said. “That's unfortunate, because two years in, we should have been past this point.”

His message to those eligible for a second booster: “You need to figure out, if you’ve only got a few weeks of added protection, or a few months, when is the right time for you?” he said.

“That’s what you’re going to get as of now. Your mileage may vary, because the next variant may be able to evade that as well.”