Does It Matter Which COVID-19 Booster Shot You Get?

Now that it’s fall, it’s time to get updated on your COVID-19 vaccines if you want to stay protected throughout the winter, when infectious diseases flourish. But does it matter which shot you get?

For now, there are only two options—both mRNA-based vaccines, made by Moderna and Pfizer-BioNTech. The U.S. Food and Drug Administration (FDA) is still reviewing data from Novavax, which makes a different type of vaccine based on recombinant viral proteins. Both Moderna’s and Pfizer-BioNTech’s vaccines are approved for people 12 years and older, and have an emergency use authorization for children under 12.

Practically speaking, if you’re eager to get your shot soon, you’ll get an mRNA vaccine, since these are the only ones approved so far. And the sooner you get boosted, the sooner you’ll be protected against getting infected and also from getting really sick, so most health officials will probably advise you not to wait for Novavax’s shot, if and when it is authorized. While the updated mRNA shots target XBB.1.5, a different virus variant than the ones that are circulating now, studies that the manufacturers presented to health officials show that the shots still produce a strong antibody response against the newer variants like EG.5 and BA.2.86.

But if and when Novavax’s vaccine becomes available, does it make sense to switch if you’ve received mostly mRNA shots so far? Does the type of vaccine matter when it comes to how well you’ll be protected, both against infection and against serious disease?

Dr. Kirsten Lyke, professor of medicine at the University of Maryland School of Medicine, who conducted some of the earlier mix-and-match studies on previous combinations of vaccines, says she didn’t see much difference when people who were vaccinated with earlier mRNA vaccines received boosters of earlier Novavax shots. “It doesn’t look like Novavax following mRNA is any better than mRNA-mRNA,” she says. Those data, however, were based on studies that only looked at antibody levels people generated up to six months after a booster shot.

Looking more specifically at how the mRNA and recombinant protein vaccines work, Dr. Otto Yang, professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles, says there may be a difference between the two technologies in how the immune system sees SARS-CoV-2. Vaccines using the mRNA technology contain the genetic code for the virus’ spike protein, and this code instructs certain cells in the human body to make this viral protein and then present it to the immune system. Recombinant protein vaccines, like Novavax’s, skip that step and directly provide the viral protein. In theory, Yang says, that would mean that the levels of viral protein that the immune system initially sees might be higher with Novavax than with mRNA vaccines, since the amount produced by the mRNA vaccines depends on how many immune cells get the code and start producing the protein. But it’s not clear whether those potentially higher levels of protein translate into stronger immune responses in the form of antibodies.

The genetic approach of the mRNA vaccines, however, also has an advantage because it may produce a more robust T cell response. T cells and antibodies make up two of the major parts of an immune response; antibodies are the front-line defenses designed to prevent viruses from infecting cells in the first place, and T cells are then recruited to recognize and destroy infected cells, and provide protection against serious disease. But in order for the body to generate killer T cells, viral proteins need to make their way into a specific part of the immune cell, and mRNA vaccines ensure that happens. “[Viral] proteins have to be in that area of the cell to generate the killer T cell response, which has evolved to deal with problems like infected cells by killing the cells,” says Yang. “Recombinant protein vaccines are not going to access this part of the cell.”

Studies have shown that it’s likely the T cell response, which could be slightly more durable than the antibody response, that may be largely responsible for protecting vaccinated people from severe disease, since antibodies produced by any vaccine tend to wane after a few months. “Antibodies seem to be the upfront gatekeepers, and T cells seem to be the palace guard that clears out invaders once they get in,” says Yang. That may explain why, as new variants emerge, some people who are vaccinated still get infected, but they don’t end up in the hospital or die from their infections as many people did in the early days of the pandemic before vaccines were available.

Another advantage of a stronger T cell response is that T cells can also target parts of the virus that are less exposed to immune system attacks, and therefore, less prone to mutating. Experts believe T cells  may be recognizing the virus’ nucleocapsid protein, which forms the core structure of the virus, and which remains relatively similar among the various variants that have appeared so far.

Novavax says that its original vaccine also produces a good T cell response, because the vaccine is fortified with an adjuvant, or additive, that is designed to rev up the immune response and amplify it. “That adjuvant can induce the types of T cell responses that we think are more important in fighting viruses,” says Bob Walker, chief medical officer for Novavax. He says the company is currently testing its updated vaccine in people to get more specific data on the antibody and T cell responses the shot can produce.

“Personally, I think there is probably not a lot of difference between the [two types of vaccines,” says Lyke. “You get good responses with all of them. That’s why anyone who is vaccinated probably has good protection even this far out from getting severe disease.” Which means that it’s not that important which vaccine you get—but that you get one of the updated shots.