Typically, if you get a COVID-19 vaccine that requires two doses, you should get two of the same vaccine. Two Pfizer shots, or two Moderna shots. Not one and then the other.

But in the future, that could change, either by necessity or by design.

This idea of using two types of vaccines isn't a new concept. It's known as heterologous vaccination, although there's a more colloquial term.

"In the U.K. at the moment, we're sort of calling it 'mix and match,' " says Helen Fletcher, a professor of immunology at the London School of Hygiene & Tropical Medicine. She says shortages of a vaccine or concerns about side effects may induce health officials to adopt a mix-and-match strategy.

Health agencies in France and Germany are already encouraging people who've gotten the AstraZeneca vaccine to consider getting one of the mRNA vaccines for their second shot.

"So there's a practical reason why you would want to mix two different types of vaccine. But there is also a scientific reason as well," Fletcher says.

Basically, all vaccines work by showing people's immune systems something that looks like an invading virus but really isn't. If the real virus ever comes along, their immune systems will recognize it and be prepared to fight it off.

Using two different vaccines is a bit like giving the immune system two pictures of the virus, maybe one face-on and one in profile.

"If you give two different types of vaccine, then you tend to get a better immune response than if you give the same vaccine twice," Fletcher says.

Some vaccine manufacturers have embraced this approach and are making vaccines of two different types by design.

One is a company called Gritstone bio, based in Emeryville, Calif.

"The natural human response to a virus is to mobilize two distinct arms of the immune system," says Gritstone CEO Andrew Allen. One utilizes antibodies; the other relies on something called CD8 T cells. Unlike antibodies, CD8 T cells don't recognize a virus directly, but they do recognize a cell that has been infected by a virus and they can destroy the infected cell.

Gritstone has developed two different vaccines to activate each arm: a viral vector vaccine and an mRNA vaccine. The viral vector vaccine is very good at stimulating the production of CD8 T cells.

"The mRNA [vaccine] makes a really good antibody response. And so potentially by combining these, you kind of get the best of both worlds," Allen says.

Gritstone's approach is already being tested in human volunteers.

This mix-and-match approach has been tried with vaccines for a variety of diseases.

"Diseases such as HIV, malaria, TB, even influenza," says Bali Pulendran, Violetta L. Horton professor and professor of immunology and microbiology at Stanford University. "So there's ample evidence for the benefits of such strategies."

If it's such a good idea, why isn't it used routinely?

Pulendran speculates there are two main reasons. One has to do with the way new vaccines are approved.

"Regulatory authorities love simplicity," Pulendran says. "The simpler the vaccine regimen, the more palatable they find this to be."

The other reason is that while mix and match may make scientific sense, it doesn't always make business sense.

"For example, if Company A makes one vaccine and Company B makes another vaccine, unless there's some overarching incentive for the two companies to enter into some sort of a marriage, I think either company would in general prefer to go along with their own," Pulendran says.

Of course, if a small company like Gritstone shows that a mix-and-match strategy really leads to a dramatically better vaccine, you can bet other pharmaceutical companies will find a way to solve the business problem.

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