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Immune imprinting after XBB.1.5 COVID mRNA booster vaccination

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped, positive-sense, single-stranded RNA virus. Its genome encodes four structural proteins, namely the spike (S), envelope (E), nucleocapsid (N), and membrane (M) protein. In messenger RNA (mRNA)-based vaccines, an mRNA sequence determines the structure and assembly of the immunogen, the SARS-CoV-2 S glycoprotein. The authors from the United States investigated the humoral immunity elicited after administration of the XBB.1.5 S mRNA booster vaccine in individuals who had previously received multiple doses, regardless of whether or not they had a known infection with SARS-CoV-2. The results showed persistent immune imprinting after XBB.1.5 S mRNA COVID-19 booster vaccination.

Immunological memory is crucial in the long-term protection against pathogens. It can be beneficial and harmful. A memory response primed by a viral strain leads to a certain level of pre-existing cross-reactive immunity. Under certain conditions, the development of B cells in response to the subsequent infection of a novel, but the related virus can be blocked by the memory B cells with high affinity and specificity, which are induced by a primary viral infection. If the humoral immunity elicited by the second antigen not only cross-reacts but also reacts better with the first antigen presented to the immune system, this phenomenon is called immune imprinting or “original antigenic sin”.

The manifestation of immune imprinting during viral infection is that the immune response to successive viral variants is shaped by the ancestral virus to which the immune system was previously exposed, and is skewed toward the ancestral immunogen. 




Neutralizing antibodies are a correlate of protection against SARS-CoV-2, and most plasma-neutralizing activity is directed to the receptor-binding domain (RBD) of the S protein. The memory B cells are a powerful defense against emerging variants of concern (VOCs) as they provide long-lived “antibody memory” with the capacity to adapt to the diversification of viral antigens. However, pre-existing and cross-reactive memory B cell pools may complicate the B cell response induced by vaccination through immune imprinting.

Different platforms are used to develop anti-COVID-19 vaccines, including mRNA, viral vectors that express full-length spike proteins, inactivated whole virus, or purified spike proteins. These vaccines are based on the ancestral SARS-CoV-2 genomic sequence, Wuhan Hu-1, from 2020. The emergence of immune evasive SARS-CoV-2 variants led to the development of two updated vaccine boosters, a bivalent Wuhan-Hu1/BA.5 (or BA.1 for a few countries) S mRNA booster vaccine, and a monovalent XBB.1.5 S mRNA booster vaccine.

Previous studies have shown that Omicron breakthrough infections and bivalent COVID-19 vaccines primarily recall cross-reactive memory B cells and antibodies induced by prior mRNA vaccination with the Wuhan-Hu-1 S, rather than priming naïve B cells that recognize Omicron-specific epitopes. This indicates a strong immune imprinting. However, it was reported that repeated Omicron infections in people who received inactivated Wuhan-Hu-1 vaccine could overcome immune imprinting, leading to the elicitation of de novo antibody responses specific to these variants. It is unknown whether a similar outcome could be achieved through repeated administration of updated vaccine boosters to individuals previously imprinted via multiple Wuhan-Hu-1 S exposure.

The same research group has shown before that Omicron infection of Wuhan-Hu-1 mRNA vaccinees recalls cross-reactive memory B cells specific for epitopes shared by multiple SARS-CoV-2 variants rather than priming naïve B cells that bind Omicron RBD-specific epitopes.

They have also demonstrated that immune imprinting persists in individuals vaccinated with Wuhan-Hu-1 mRNA vaccines who had the Omicron infection and got the bivalent Wu/BA.5 updated mRNA vaccine booster.

A recent review article from Chinese and American authors, published in Vaccines, also discussed the impact of immune imprinting on anti-COVID-19 vaccination. Zhou Z, Barrett J, He X. Immune Imprinting and Implications for COVID-19. Vaccines (Basel). 2023 Apr; 11(4): 875.


About the study

To evaluate humoral immunity elicited upon receipt of an XBB.1.5 S mRNA vaccine booster, researchers collected plasma from individuals who had previously received multiple vaccine doses, regardless of whether or not they had a known infection. The results showed that the XBB.1.5 S booster elicited higher neutralization potency against Wu/G614 S (vaccine-mismatched) relative to XBB.1.5 S (vaccine-matched) pseudovirus, a serological indication of immune imprinting.

To investigate this further, researchers depleted polyclonal plasma antibodies recognizing Wu S and found that this entirely abrogated binding to XBB.1.5 S except in 2 individuals. This suggests that virtually all plasma antibodies binding to XBB.1.5 S were Wu S-reactive. Accordingly, no neutralizing antibodies against Wu/G614 and XBB.1.5 S pseudoviruses were detected after depletion, indicating that there are no XBB.1.5 S-specific plasma neutralizing antibodies (i.e. that were not cross-reactive with Wu S). The authors concluded that XBB.1.5 S-specific antibodies were absent in the plasma of these subjects. They also stated that XBB.1.5 S vaccination increased titers of cross-reactive antibodies previously elicited by exposure to Wu S that also bind to and neutralize XBB.1.5 and other variants rather than inducing de novo antibody response against XBB.1.5 S.

Researchers then used flow cytometry to analyze memory B cell populations in the peripheral blood after XBB.1.5 S vaccination and assess the frequency of XBB.1.5 RBD-reactive memory B cells that also bind to the Wuhan-Hu-1 RBD. Memory B cells that recognized the XBB.1.5 RBD, but not the Wuhan-Hu-1 RBD, were detected in 5 of 12 individuals. These memory B cells were rare (0.4-13.3%). This means that virtually all XBB.1.5 RBD-binding memory B cells were cross-reactive with the Wuhan-Hu-1 RBD. The authors concluded that de novo elicitation of memory B cells by variant-specific mRNA booster is possible, but difficult to induce due to the immune imprinting and preferential recall of pre-existing Wu-reactive memory B cells.



This study has shown that XBB.1.5 S booster vaccine elicits neutralizing antibody responses against the current variants, dominated by recall of pre-existing memory B cells previously induced by the Wuhan-Hu-1 S, instead of inducing de novo responses against these new variants. These results demonstrate that Wuhan-Hu-1 immune imprinting persists even after multiple exposures to Omicron S through vaccination and infection, including the XBB.1.5 S mRNA booster vaccine. This should be considered in the development of future vaccine boosters.


The results of the study have been published on a preprint server and are currently being peer-reviewed.

Journal Reference

Tortorici MA, Addetia A, Seo AJ et al. Persistent immune imprinting after XBB.1.5 COVID vaccination in humans. bioRxiv preprint.




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