With COVID-19 vaccines now widely available in the U.S., Dr. Shan Lu’s friends and colleagues keep peppering him with the same question: Even though they are fully vaccinated, could they crank their immunity even higher by double-dipping with a dose of a different type?

Lu’s answer is an emphatic “no,” but not because he’s opposed to mixing and matching vaccines.

As a physician and vaccine researcher at the University of Massachusetts Medical School, he helped pioneer the approach. He just doesn’t think it makes sense for people who are already well protected to get another kind of shot at this point in the pandemic.

“You don’t need it,” he said.

Public health officials also discourage people from seeking extra doses or mixing brands.

But Lu and other experts say combining COVID-19 vaccines has many potential benefits and is likely to become more common in the future.

Being able to interchange vaccines would provide greater flexibility for countries and individuals and reduce the pinch from bottlenecks, like the glitches in manufacturing Johnson & Johnson’s vaccine or India’s recent suspension of exports to Africa and other parts of the developing world due to the country’s own devastating coronavirus surge. There are also hints that inoculating people with two different types of vaccine might actually trigger more powerful immunity.

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“This is a really open, exciting area of vaccine research,” said Lu, who started mixing and matching ­— scientists call it heterologous prime-boost — as part of the long and frustrating quest for an AIDS vaccine. He discovered that following one type of vaccine with a different type of booster could yield an immune response stronger than either vaccine on its own.

Pharma companies and researchers are already exploring COVID-19 vaccine combinations, with results just beginning to trickle in. A study of 600 people in Spain who initially got the AstraZeneca vaccine widely used in Europe showed a higher immune response among those who received a booster shot of the Pfizer vaccine. Results are preliminary, but antibody levels in the mixed group appear to be higher than in people who got two doses of the AstraZeneca vaccine.

Scientists at China’s National Institutes for Food and Drug Control experimented in mice with four types of vaccines in multiple combinations and also found some of the mixed regimens generated stronger immune responses than two identical doses.

“You can get a synergistic effect when you start to mix and match vaccines, because they are sometimes stimulating different types of responses or engaging different immune cells in the body,” said Deborah Fuller, a virologist and vaccine researcher at UW Medicine who also experimented with vaccine combinations against AIDS.

If vaccine mixtures do confer broader protection, that could be a key to combating new variants of the novel coronavirus, she said.

No one understands exactly how that synergy arises, but it seems to be related to the different approaches employed to stimulate immunity.

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The dozen or so COVID-19 vaccines in use around the world all work by delivering a snippet of the novel coronavirus to teach the body to recognize the invader and be ready to attack future infections. The mode of delivery and the package itself can differ.

Messenger RNA vaccines, like Pfizer’s and Moderna’s, use tiny lipid spheres to deliver genetic instructions for the spike protein that allows the virus to latch onto and infect human cells. The J&J and AstraZeneca vaccines use inactivated cold viruses to deliver the gene for the spike protein, a method called viral vector. Others deliver the spike protein itself.

Interactions between vaccines are highly complex, but one example illustrates why a combination might be better than the sum of its parts, Fuller said.

The COVID-19 viral vector vaccines appear to be good at inducing antibody responses, but even better at stimulating T cells, a branch of the immune system that destroys infected cells and revs up antibody production. In mRNA vaccines, the equation is flipped: They’re good at inducing T-cells, but even better at stimulating antibody production, she said.

“If you combine them, you’re getting the best of both worlds,” Fuller said.

Mixing can also overcome an inherent shortcoming of viral vector vaccines: The body can mount an immune response against the carrier virus itself, which makes subsequent shots less effective.

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J&J avoids that problem with a single-dose regimen. AstraZeneca uses a chimpanzee cold virus the human body is less likely to attack. Russia’s Sputnik V vaccine, which is 92% effective, employs different viral vectors in the first, or prime, dose and the booster.

The Russians and AstraZeneca recently started collaborating to see how their vaccines work in tandem.

The leading research project is in the U.K., where vaccine shortages and concerns about rare clotting problems linked to AstraZeneca, the country’s homegrown vaccine, led to a kind of accidental experiment. Regulators said people could get a different vaccine for their second dose — a recommendation later echoed in France and other countries.

The Com-Cov study at Oxford University was launched in February to figure out how mixing and matching between AstraZeneca and Pfizer would work. It was expanded in April to include Moderna and Novavax, a not-yet-approved vaccine that delivers spike proteins attached to nanoparticles.

Fuller and her colleagues are also studying a combined regimen with a couple of next-generation COVID-19 vaccines. One is an RNA vaccine from Seattle biotech firm HDT Bio. The other is a protein-based vaccine developed by Neil King and his team at the UW Institute for Protein Design. Both are in the early stages but could prove useful as the pandemic continues to rage in poorer countries, Fuller said.

Lu is taking the mix-and-match concept even further, combining two types of vaccine approaches in a single dose that worked well in monkeys.

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The first results from the Com-Cov study, published two weeks ago, focused on safety. Researchers found people who got a mixed AstraZeneca-Pfizer regimen, in either order, were more likely to experience mild side effects, like fever, chills, headache and body pain.

None of the symptoms were serious but the findings underscore the need for more research to determine the best combinations, the best order in which to administer them, and any safety concerns, said Fuller.

U.S. regulators have been cautious, urging people to stick to the regimens that were tested in large clinical trials and approved for emergency use by the Food and Drug Administration.

“They don’t want people to start running off and mixing and matching on their own,” Fuller said.

It’s also not clear what kind of evidence the FDA would require before any mixed-regimens are approved, and how — or if — they will make financial sense for the companies involved, Lu pointed out.

“I think this is going to be very dynamic.”

For those who still want to “top off” their own tank with an extra vaccine dose, there are really no regulatory barriers — just their own conscience to grapple with.

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Before administering the shots, providers ask people if they have already received a COVID-19 vaccine, a spokesperson for the Washington State Department of Health said in an email.

“We hope people are honest with their providers in order to ensure they get the best possible medical advice about risk and safety.”

The Pfizer and Moderna vaccines are both so highly effective an extra shot couldn’t make much difference, said Angela Rasmussen, a virologist at the University of Saskatchewan.

It’s still not clear how long immunity will last, but five months into the U.S. vaccination campaign, there are no signs of waning. Booster shots might eventually be needed, but Rasmussen advises people to wait until the evidence is in from mixing-and-matching studies about which vaccines are most effective for topping off the tank, and whether the “original recipe” still works or needs to be tweaked for new variants.

Rasmussen got the J&J jab, which is less effective than the mRNA vaccines. Friends have asked if she wants a Pfizer or Moderna booster, but she has no interest. J&J is almost as effective as the others against serious illness, which is the key metric, she noted.

“These are all great vaccines and they have all exceeded our expectations,” Rasmussen said. “Instead of looking for extra doses of vaccine, I think our supply can be best used by putting them into the arms of people who are unvaccinated — either in the U.S. or around the world.”