Study finds immune imprinting response to COVID-19

Immune systems of vaccinated people responded to multiple exposures by prepping antibodies and memory cells for future fights.

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A study of the immune response to the initial surge of the SARS-CoV-2 virus and its early variants shows that repeated vaccine exposures shaped immune responses to subsequent infections.

Immune imprinting, a process in which the body creates antibodies and memory cells encoded with information about vaccines or viruses to which it has previously been exposed, is a recognized phenomenon. But researchers in the University of Washington School of Medicine lab of biochemist David Veesler have found an extraordinary occurrence of it in response to the COVID-19 pandemic: 

Essentially, the imprinting gives the body’s immune response a head start at the beginning of subsequent infections. 

“It is surprising because it is completely different from what we know from the influenza virus, where imprinting is overcome after exposures to antigenically distinct flu viruses,” said Veesler, a professor and chair in the Department of Biochemistry and investigator with the Howard Hughes Medical Institute.

The findings were published March 14 in Immunity. M. Alejandra Tortorici, a biochemist in Veesler’s lab, is lead author. Contributors from the Division of Allergy and Infectious Diseases, including Dr. Helen Chu, also participated in the research.

Veesler’s lab analyzed plasma samples obtained from humans who had been recently vaccinated with the XBB.1.5 mRNA booster, which was updated in September 2023.

“There are two leading hypotheses about what we are seeing,” Veesler said, “and I don’t know which of the two options explains it yet.”

One hypothesis for this is residents of Seattle, where most of the samples came from, were exposed to the virus so many times — mostly through vaccination, but also infection — that they began developing antibodies and memory cells created for the original virus. The first U.S. death of the COVID-19 pandemic happened in Seattle, where symptoms of the virus emerged in early 2020.

“People in Seattle, including myself, have been so compliant,” Veesler said. “We have been exposed many, many times over the past four years through vaccination and usually at least one infection. And that's very unusual to have so many exposures in such a short amount of time — up to seven vaccine doses in the cohort we analyzed.” 

A second possibility, which Veesler called a working hypothesis, is that the strong imprinting induced by mRNA vaccines and delay in updating the composition of vaccine boosters throughout the pandemic influenced the imprinting.

“MRNA vaccines may have been so good and elicited such strong immune responses that the imprinting may be stronger than what we have been used to seeing with vaccines for other viruses such as for influenza virus,” Veesler said. “Imprinting is not a new concept, but the situation we are looking at seems to be quite unique.

“Most of the antibodies recalled by the updated vaccine boosters are cross-reactive and help block new variants, which is a good thing. However, could we do an even better job? The answer is most likely yes.”

This study was supported by the National Institute of Allergy and Infectious Diseases (DP1AI158186, P01AI167966, and 75N93022C00036), a Pew Biomedical Scholars Award, an Investigators in the Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund, Fast Grants, the University of Washington Arnold and Mabel Beckman Cryo-EM Center, and the National Institutes of Health (S10OD032290).

The authors’ conflict-of-interest statements are in the published paper, which will be provided to journalists upon request.


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