Why mixing vaccines could help boost immunity

A dozen covid-19 vaccines are now being used around the world. Most require two doses, and health officials have warned against mixing and matching: the vaccines, they argue, should be administered the way they were tested in trials. But after emerging concerns about the very rare risk of blood clots linked to the Oxford-AstraZeneca vaccine, that advice may soon change.

Guidance on this issue varies from country to country. Germany and France, for example, have advised younger citizens who received the first shot to switch vaccines for their second dose. Canada, where millions of people have received their first dose of Oxford-AstraZeneca, is still deciding how to proceed.

David Masopust, an immunologist at the University of Minnesota Medical School, points out that most of the vaccines target the same protein. So switching vaccines should work, at least in theory.

We should soon have a better idea. A handful of trials are now under way to test the power of vaccine combinations, with the first results due in later this month. If these mixed regimens prove safe and effective, countries will be able to keep the vaccine rollout moving even if supplies of one vaccine dwindle because of manufacturing delays, unforeseen shortages, or safety concerns.

But there's another, more exciting prospect that could be a vital part of our strategy in the future: mixing vaccines might lead to broader immunity and hamper the virus's attempts to evade our immune systems. Eventually, a mix-and-match approach might be the best way to protect ourselves.

Mixing on trial

The covid-19 vaccines currently in use protect against the virus in slightly different ways. Most target the coronavirus's spike protein, which it uses to gain entry to our cells. But some deliver the instructions for making the protein in the form of messenger RNA (Pfizer, Moderna). Some deliver the spike protein itself (Novavax). Some use another harmless virus to ferry in the instructions for making it, like a Trojan horse (Johnson & Johnson, Oxford-AstraZeneca, Sputnik V). Some offer up whole inactivated virus (Sinopharm, Sinovac).

In a study published in March, researchers from the National Institutes for Food and Drug Control in China tested combinations of four different covid-19 vaccines in mice, and found that some did improve immune response. When they first gave the rodents a vaccine that relies on a harmless cold virus to smuggle in the instructions and then a second dose of a different type of vaccine, they saw higher antibody levels and a better T-cell response. But when they reversed the order, giving the viral vaccine second, they did not see an improvement.

Why combining shots might improve efficacy is a bit of a mystery, says Shan Lu, a physician and vaccine researcher at the University of Massachusetts Medical School who pioneered this mixing strategy. The mechanism we can explain partially, but we don't fully understand." Different vaccines present the same information in slightly different ways. Those differences might awaken different parts of the immune system or sharpen the immune response. This strategy might also make immunity last longer.

Whether those results translate to humans remains to be seen. Researchers at Oxford University have launched a human trial to test just how mixing might work. The study, called Com-CoV, offers participants a first shot of Pfizer or Oxford-AstraZeneca. For their second dose, they will either get the same vaccine or a shot of Moderna or Novavax. The first results should be available in the coming weeks.

Other studies are under way as well. In Spain, where Oxford-AstraZeneca is now being given only to people over 60, researchers plan to recruit 600 people to test whether a first dose of the shot can be paired with a second dose from Pfizer. According to reporting in El Pais, about a million people received the first dose of the vaccine but aren't old enough to receive the second dose. Health officials are waiting for the results of this study before issuing recommendations for this group, but it's not clear whether any participants have yet been recruited.

Late last year Oxford-AstraZeneca announced that it would partner with Russia's Gamaleya Institute, which developed Sputnik V vaccine, to test how the two shots work in combination. The trial was supposed to launch in March and provide interim results in May, but it's not clear whether it has actually begun. And Chinese officials have hinted that they'll explore mixing vaccines to boost the efficacy of their shots.

The biggest gains might come from mixing vaccines that have lower efficacies. The mRNA vaccines from Pfizer and Moderna provide excellent protection. I don't think there's reason to mess with that," says Donna Farber, an immunologist at Columbia University. But mixing might improve protection for some of the vaccines that have reported lower levels of protection, like Oxford-AstraZeneca and Johnson & Johnson, as well as some of the Chinese vaccines. Many of these vaccines work quite well, but mixing might help them work even better.

Johnson & Johnson, Sputnik V, Oxford-AstraZeneca, and China's CanSino, all contain adenoviruses, a class of viruses that includes cold viruses. The manufacturers tweak these viruses to ferry DNA blueprints for the coronavirus spike protein into cells. With these vaccines, the body develops an immune response to the spike, but also to the adenovirus carrying the spike. That poses a risk: a second shot might prompt an immune response against the adenovirus and make the booster less effective.

To get around this issue, Johnson & Johnson and CanSino offer only one dose. Sputnik V requires two doses, but the first and second incorporate different adenoviruses. The two-dose Oxford-AstraZeneca shot relies on a chimpanzee adenovirus. That allows the vaccine to avoid any preexisting immunity-the virus doesn't typically infect humans. And perhaps because the first dose is relatively low, there doesn't seem to be a problem offering a second shot.

In fact, some researchers speculate that may be why one Oxford-AstraZeneca trial, which mistakenly offered participants a lower first dose, showed better efficacy. The body does not generate a strong immune response against the adenovirus, but still generates an immune response against the spike, Lu says. But he cautions that a third booster shot might not work as well.

That could pose a problem. With an increasing number of variants, we may get in a situation where we're going to need a yearly booster shot," Masopust says. That's easy to do with the Pfizer and Moderna vaccines, but the vaccines that rely on adenoviruses may run up against the body's pre-existing immunity.

More mix-and-match

Combining vaccines that are already in use is just one way to mix and match. Another option is to mix up the vaccine targets.

With the surge in new variants, some experts fear that the virus may eventually be able to evade the body's antibody response by changing its spike protein, the target of most existing vaccines. Luckily the immune system has another line of defense: T cells.

After vaccination, your immune system generates antibodies that can bind to particular portions of the spike protein. If you come in contact with the virus , these antibodies will bind to the spike and only the spike. T cells see the world differently," Masopust says. They can recognize protein fragments from inside the virus too, and more of them. A vaccine that contains the spike and another protein might broaden the vaccine's coverage and decrease the probability of escape. T-cells don't block infection, but they can help clear the virus.

And a strong T-cell response is much harder to evade. Many of the proteins that T-cells recognize don't mutate as quickly as the spike protein. And T-cells in one person might recognize different protein fragments than T-cells in another. So even if the virus slips past T-cells in one individual, it's unlikely to evade the immune response at the population level. If you have broad T-cell immunity you're much less vulnerable to viral mutations," Masopust says.

Adding another vaccine target to boost the T-cell response is an interesting idea," says Marc Jenkins, director of the Center for Immunology at the University of Minnesota Medical School. Nucleoprotein, which is found inside the virus, could be a good candidate. Eliciting an immune response against both nucleoprotein and the spike could boost the number of T cells and antibodies, he says. And more is better when it comes to wiping out the virus."

Farber envisions another kind of mixing that might provide benefits: pairing an injectable vaccine with a vaccine delivered into the nose. Putting the second dose in the nose would bring the immune response into the lungs, priming T cells that live there. These tissue-resident T cells provide protection against severe lung disease. So offering this type of mixed vaccine to older adults, who are more susceptible to developing lung problems like pneumonia if they do become infected, might be a worthwhile strategy, she says.

Despite evidence that mixing vaccines can boost immunity, the idea hasn't really caught on-yet. Vaccine development is expensive. Companies don't necessarily have an incentive to develop two different vaccines if one will do the trick, Lu says. Nor are they likely to partner with another drug company to create this kind of combination approach. But the pandemic has changed the vaccine development landscape, and the idea may be gaining traction. It's a very ripe time," Farber says.