Over the course of the pandemic, the coronavirus has evolved multiple times, generating new variants and subvariants. However, a process called "immune imprinting" may have limited people's immune systems from keeping up with newer variants over time, as well as the effectiveness of updated COVID-19 vaccines.

How your first experience with the coronavirus affects your immunity

According to The Atlantic, something that may be impacting people's immune response to the coronavirus over time is a phenomenon called "original antigenic sin," or "immune imprinting."

Through imprinting, the body may latch on to the first version of a virus that it encounters, whether that is through infection or vaccination. This "imprint" of a virus allows the immune system to quickly recognize and respond to the virus if it infects again, which is generally why repeat infections tend to be milder.

According to Katelyn Gostic, an immunologist and infectious disease modeler, imprinting is "a fundamental part of being able to create immunological memory."

Similarly, Gabriel Victora, an immunologist at Rockefeller University, said that "[h]aving a good [immune] memory and being able to boost it very quickly is sometimes a very good thing."

However, while immune imprinting can help quickly boost a response to a familiar pathogen, it may also make it more difficult for the body defend against newer pathogens. Because so many immune cells may be primed towards an older version of a virus, it may be less likely to recognize a newer version, which can then leave "people more vulnerable, perhaps, than they might have been otherwise," The Atlantic writes.

Did immune imprinting reduce the effectiveness of updated boosters?

Currently, researchers are studying the potential impact of immune imprinting on the updated bivalent boosters released last fall. Because most of the COVID-19 vaccines people have received were targeted against the original coronavirus strain, their immune systems may generate antibodies based on that instead of newer variants targeted by the updated boosters.

According to two new studies published in the New England Journal of Medicine (NEJM), the updated boosters, which were designed to target the original coronavirus strain, as well as BA.4 and BA.5, did not produce significantly greater antibody responses than an additional dose of the original mRNA vaccines.

In the first study of 40 patients, the researchers found that the bivalent boosters "did not elicit a discernibly superior virus-neutralizing peak antibody response as compared with boosting with the original monovalent vaccines" across all coronavirus strains tested.

Similarly, the second study, which included 33 participants, found "that median BA.5 neutralizing antibody titer was similar after monovalent and bivalent mRNA boosting, with a modest trend favoring the bivalent booster by a factor of 1.3."

"The immune systems of people immunized with the bivalent vaccine, all of whom had previously been vaccinated, were primed to respond to the ancestral strain of SARS-CoV-2," wrote Paul Offit, a vaccine expert from the Children's Hospital of Philadelphia, in an accompanying editorial. "They therefore probably responded to epitopes shared by BA.4 and BA.5 and the ancestral strain, rather than to new epitopes on BA.4 and BA.5."

However, not all health experts agree that the updated boosters are less effective than expected. In fact, Eric Topol, a professor of molecular medicine at Scripps Research, argues that extensive data suggests that bivalent boosters have performed better than expected.

For example, four preprint studies that assessed neutralizing antibody responses using live viruses found that the updated vaccine had between a two and eight-fold increase in neutralizing antibodies against BA.5 and between a two and six-fold increase against XBB compared to the original vaccine.

Several real-world studies have also shown the effectiveness of the updated boosters against severe outcomes, Topol writes. In Israel, a study of over 700,000 participants ages 65 and older found that those who received an updated booster had an 81% lower risk of hospitalization and 86% lower risk of death from COVID-19.

Similarly, a CDC study published last month found that individuals 65 and older who received an updated booster reduced their risk of hospitalization by 73% to 84%. A second report that included all adults found that the updated booster was between 38% to 57% effective against hospitalization.

"While the clinical benefit of reduced hospitalizations and deaths [from the updated boosters] is best seen in the high risk population of age 65 and older, there is certainly evidence for benefit across all adults," Topol wrote.

What will happen with future COVID-19 vaccination strategies?

So far, it is still unclear exactly how imprinting affects the immune system and how it specifically affects people's responses to both updated vaccines and newer COVID-19 variants. However, going forward, it may be necessary to adjust future vaccination strategies to account for the potential impact of imprinting.

According to Rafi Ahmed, an immunologist at Emory University, people may want to get multiple doses of an updated vaccine to increase their exposure to a new version of a virus. These new exposures "could help break an old habit, and nudge the immune system to move on," The Atlantic writes.

For example, data from the United Kingdom suggests that people who were previously infected by an early omicron subvariant had better immune responses to a bivalent vaccine that targeted BA.1. Currently, U.S. researchers are also testing to see if Americans who were infected by an omicron subvariant before getting the updated BA.4/BA.5 booster will experience a similar response.

Separately, Deepta Bhattacharya, an immunologist from the University of Arizona, said spacing out COVID-19 vaccine shots to an annual basis, much like flu shots, could also help with any imprinting issues.

According to Bhattacharya's recent studies, which have not yet been published, there is a possibility the immune system might "forget" older coronavirus variants if enough time has passed. The vaccine ingredients that remain in the body over time may also give the immune system more time to mount a more effective response against newer variants.

"In an ideal world, researchers might someday know enough about imprinting to account for its finickiness whenever they select and roll out new shots," The Atlantic writes. But, "after three years of an ever-changing coronavirus and a fluctuating approach to public health, it's clear that there won't be a single vaccine recipe that's ideal for everyone at once." (Wu, The Atlantic, 1/11; Hein, MedPage Today, 1/12; Topol, Ground Truths, 1/11)