U.S. scientists are expanding efforts to evaluate when fully vaccinated people will need booster shots – and, if so, whether people can switch brands – in the latest chapter of the global quest to stop the pandemic.

For people eager to put the health crisis behind them, the relief of being vaccinated is being replaced by a new worry. Is immunity a ticking clock? Should they plan a family wedding this fall? Will everyone need booster shots? When? Are people locked into the same brand or vaccine technology for their next shot?

“As we know, COVID is not going to go away anytime soon, and we know that the antibodies decrease over time, so that a boost will be needed at some juncture. I can’t predict when,” said John Beigel, associate director for clinical research in the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases.

Beigel is working on a U.S. trial, set to launch this week, that will provide one piece of the answer, testing whether people can mix and match shots when the need arises. Can a person fully vaccinated with Pfizer-BioNTech’s vaccine in February take a third shot of Moderna? Is there an advantage – or a risk – in switching from one brand or vaccine technology to another?

The U.S. efforts come as health experts in China are already recommending a third coronavirus shot to some at-risk individuals.

Scientists know that vaccine-induced immunity against most diseases wanes, but the answers to those questions about the coronavirus will begin to coalesce only in the coming weeks and months.

First, scientists need to identify a threshold – what level of immunity is too low to protect people? Then, they need to learn how long it typically takes for immunity to decay to that level. And then they need to figure out how to best boost people’s immunity.

Progress is being made on all three fronts:

AN IMMUNITY BASELINE

In the next month, Beigel expects results from studies of people who got sick despite being vaccinated in clinical trials, findings that could help establish an immunity baseline – what scientists call a “correlate of protection.” Those studies could help researchers establish a threshold – such as a minimum antibody level – that signals whether someone is immune or whether that person has become vulnerable to infection.

Scientists are analyzing blood samples from the first people who were vaccinated a year ago in trials, hoping to determine whether antibodies continue to stick around or if they vanish. Earlier research found that the disease fighters remain at robust levels for at least six months following Moderna vaccination, although variants can complicate that, with antibody protection that fades faster. A recent Nature study found that antibodies do decline after people recover from infection, but they don’t keep plummeting – they plateau and persist nearly a year later.

CAN YOU MIX AND MATCH?

The clinical trial being launched by NIAID this week will systematically test whether people who received one brand of vaccine in January – a single shot of Johnson & Johnson, two shots of the Moderna vaccine or two shots of Pfizer-BioNTech – need to get the same brand of vaccine, or whether there might be benefits to mixing and matching.

“People just have to recognize the limitations of the data we have right now, and the critical need to generate the data to inform the decisions that matter,” said Beigel, who is leading the mix-and-match booster trial. “We assume that it would be okay to give a boost with any other vaccine, but we want to make sure.”

For people such as Martin Silberberg, 76, a semiretired biochemist and textbook author who lives in Pelham, Mass., the questions have moved to the forefront. Silberberg and his wife would like to travel to Scotland in September for a family wedding but are nervous – both about the potential their immunity will wane and the confusing questions swirling around vaccine passports.

On shorter trips, they hope to attend museums and chamber music concerts and go out to restaurants, even when the weather gets cold. Silberberg would be happy to get a booster or even an antibody test to check if he’s still protected but keeps finding himself at the frontier of the unknown. The Food and Drug Administration has advised against antibody tests, in part because it isn’t clear how to interpret whether a particular test result indicates immunity.

“My friends are my age, and we’ve been throwing back and forth – what are we going to do and when should we start being concerned?” Silberberg said.

LOOKING FOR WARNING SIGNS

Scientists are watching several streams of data for indicators of concern.

They will be closely monitoring what happens among vaccinated people in the trials and in the real world, in part because declining antibodies won’t necessarily mean that people get sick, because other parts of their immune response can step up.

If scientists encounter unexpectedly high numbers of “breakthrough infections” that overcome immunity in vaccinated people, particularly infections that result in severe disease, it would be a warning sign that people need boosters.

A recent study of the Moderna vaccine found that antibodies capable of neutralizing the variant B.1.351 decayed in nearly half of people below a laboratory test’s level of detection over six months. But such lab tests can’t predict what will happen if those vaccine recipients encounter that variant.

One possibility is that those people would get sick, but another is that even if protection wanes, the immune system “is going to recognize the virus quickly upon infection and still protect,” said John Mascola, director of NIAID’s Vaccine Research Center.

But Mascola cautioned “we don’t know that for sure.”

“And if you take a less-than-optimal scenario, someone who didn’t respond optimally to the vaccine for whatever reason, and we add on top of that they get exposed to a variant of concern,” Mascola said, it could prove problematic.

Companies have already been testing boosters, including an additional shot of their own vaccines and revamped boosters designed against the variant. A test of the Moderna boosters showed that a third shot and a variant-specific version both increased antibody levels – an encouraging sign. A study of yet another booster option that would offer protection against the original strain and the variant-specific virus is ongoing.

The mix-and-match trial should help answer practical questions about how to best use vaccines, and will consider public health questions – such as whether there are advantages or risks to switching brands or technologies. The trial is designed to yield results by midsummer, in hopes it could inform decisions as soon as this fall if necessary, Beigel said.

The trial will test which combinations work best and may simply show that any vaccine can be used – which could ease logistics so that people were not bound to one brand or technology platform. Most people, for example, have no idea which company made the flu vaccine they receive each year.

The trial will take groups of 50 people who are fully vaccinated with an authorized vaccine and try one combination in each group. Tracking antibody levels after vaccination will show whether the boosters have the intended effect of topping off immunity and could reveal if certain combinations are better than others. In HIV vaccine research, many trials combine different technologies.

“We’re entering a data-poor zone here – we don’t have the data,” Barton Haynes, a professor of immunology at Duke University School of Medicine, said about the questions he has been getting about boosters. Haynes is developing a next-generation coronavirus vaccine and testing it as a booster to a messenger RNA vaccine, the technology used in the Moderna and Pfizer-BioNTech shots.

He said his experience with messenger RNA vaccines tested in monkeys against HIV and Zika found that while antibodies do drift downward, they then plateau and remain stable for nearly a year. If that happens with the coronavirus, it might mean boosters aren’t needed as soon as some people think. But many factors are in play. Haynes said researchers will need to consider the level of antibodies required to thwart variants and the extent of protection people get from other parts of the immune response.

In the United States, chief executives of companies that make vaccines have predicted booster shots will be needed before the end of the year. Pfizer chief executive Albert Bourla recently told Axios that boosters could be needed as soon as September or October.

John Moore, an immunologist at Weill Cornell Medicine, said public health officials and scientists will decide if and when boosts are necessary – not drug companies.

He cautioned that the notion of declining immunity may be less scary than it sounds. The shield of protection from vaccines won’t suddenly vanish, and while trials have shown vaccines are slightly less effective against infections caused by some variants, they still strongly protect against severe disease and death.

Because shots have been rolled out over several months, there won’t be a day when the world is suddenly unprotected at once, even as immunity wanes.

“Antibody (levels) don’t fall off a cliff,” Moore said. “We don’t see something where one week the vaccines are working and another week they’re not – this is going to be a gradual process.”