Mix and Match mRNA Boosters? It May Be a Good Idea, Experts Say

The two mRNA vaccines authorized in the U.S. prompt different immune responses -- and that could suggest a benefit for mixing and matching booster shots, researchers said.

Galit Alter, PhD, of Harvard Medical School in Boston, and colleagues set out to investigate the immune responses driven by three doses of Pfizer or Moderna in a cohort of 73 healthcare workers. Both vaccines induced robust functional humoral immune responses, but there were clear differences, they reported in a paper in Science Translational Medicine.

Moderna appeared to have an advantage in mucosal immunity, as measured by immunoglobulin (Ig) A, while Pfizer had a "really functional IgG response," Alter told MedPage Today.

"The mRNA vaccines are inducing different flavors of immunity," Alter said. "That suggests the immune system is seeing them in slightly different ways. And we know that 'different' is incredibly important for training the immune system."

Clinicians on medtwitter quickly interpreted the findings as supporting mixing and matching mRNA boosters -- a strategy that may become even more relevant as certain groups are now eligible for second boosters.

While that wasn't the intention of the study, Alter said it was a "creative" response and agreed that heterologous boosting could be advantageous, based on these findings.

"By slightly changing the way that the immune system sees the COVID antigen, we could essentially not only improve the overall quality and levels of the antibodies we induce, like the amount of neutralizing antibodies, but it could give us better mucosal immunity, or better affinity maturation," Alter said.

In their study of healthcare workers -- 28 received Moderna and 45 had Pfizer -- Alter and colleagues found that those who received Moderna had higher concentrations of IgA binding titers targeting the receptor binding domain (RBD) and the N-terminal domain (NTD). They also had higher levels of antibodies that elicit neutrophil phagocytosis and natural killer cell activation.

When looking specifically at variants of concern, they again found similarly robust functional antibody responses, but vaccination with Pfizer was associated with an IgM- and IgG-biased profile, whereas Moderna prompted an IgA- and IgG-driven profile, they reported.

Alter and colleagues noted that there's an "emerging appreciation" of the importance of antibody functions aside from neutralization, especially with the rise of new variants. Mutations can affect specific regions on the spike protein targeted by neutralizing antibodies, but functional antibodies can target the whole surface of the spike protein, and thus aren't compromised in the same way.

Earlier data have suggested that mixing and matching vaccines was safe and induced robust immune responses, said Christine Johnston, MD, MPH, of the University of Washington School of Medicine in Seattle, who was involved in an NIH-funded study of various boosting strategies published in the New England Journal of Medicine. That study supported an FDA recommendation in October allowing for mixing and matching boosters.

"It makes sense ... that if you're stimulating slightly different parts of the immune system, you would get better overall coverage from the version of SARS-CoV-2 that's circulating, or from variants that are emerging," Johnston said of the interpretations of Alter's data.

While Moderna "looks a little bit better for IgA," or mucosal immunity, Johnston said, she warned that "we don't know the real correlate of immunity -- the overall profile of immune response that's going to give us the best protection against infection or severe disease."

Because that correlate is still unknown, Alter said, "I think the suggestion [of mixing and matching mRNA vaccines] is brilliant, to get the best of both."

"You can diversify your immune response as much as possible to get maximal protective immunity," Alter said. "And then one day when we have the mechanistic correlate of protection, we'll be able to design vaccines that specifically give you that response."

Johnston said studies are ongoing to determine whether mixing and matching various vaccines can lead to clinical benefit, though these will never be at the same scale as the initial vaccine trials. "It's going to be a hard question to answer," she said.

Robert Schooley, MD, of the University of California San Diego, noted that both mRNA vaccines are "highly efficacious" and that any difference in immune profile, "if real, is not sufficiently great to make a recommendation of one over the other."

"If someone is in line for a booster vaccination," Schooley said, "the vaccines are so similar in efficacy that it would be a mistake to delay being vaccinated with whichever of the two is available."

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