The crux of waning COVID-19 booster effectiveness against new variants

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In a recent study published in the journal Dr Nature MicrobiologyResearchers conducted a systematic review to understand the phenomenon of immune imprinting in host antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its impact on the efficacy of coronavirus disease 2019 (COVID-19). Booster immunization program.

Study: Immune imprinting and next-generation coronavirus vaccines.  Image credit: Corona Borealis Studio / ShutterstockStudy: Immune imprinting and next-generation coronavirus vaccines. Image credit: Corona Borealis Studio / Shutterstock


The efficacy of COVID-19 booster vaccines against emerging SARS-CoV-2 variants declined in a pattern similar to that observed for seasonal influenza vaccines. The World Health Organization (WHO) reformulates influenza vaccines each year to provide protection against the strains that are likely to circulate each flu season. These vaccines are live attenuated influenza vaccine or inactivated influenza vaccine. The immunodominant antigens of these vaccines consist of surface glycoproteins such as hemagglutinin and neuraminidase, and anti-hemagglutinin immune responses consist primarily of strain-specific antibodies raised against the hypervariable head region of hemagglutinin.

The large variation in antigenic regions significantly reduces antibody titers, thereby necessitating a seasonal update of influenza vaccines. Furthermore, despite the effects of frequent booster vaccines and seasonal exposure to influenza virus, influenza vaccine efficacy has been limited. Two proposed explanations for this decline in vaccine uptake are due to mutations in viral epitopes and immune imprinting in the host due to lifelong exposure to the virus.

Immune imprinting and SARS-CoV-2

As observed for the hemagglutinin antigen in influenza virus, preferential targeting was observed for the receptor binding domain of the spike protein of SARS-CoV-2. SARS-CoV-2 variants emerged at a remarkable rate after the virus entered humans, and differences between later lineages of SARS-CoV-2, such as delta and omicron, are comparable at a level. Antigenic changes are observed in influenza A virus. Moreover, despite the development of bivalent messenger ribonucleic acid (mRNA) vaccines that comprise the currently circulating Omicron sub-lineage antigens, the lack of an optimal immune response even after booster doses suggests possible immune imprinting at play.

Immune imprinting occurs when immunity to different forms of the original antigen due to vaccination or repeated viral infections is limited after re-exposure. An antigenic seniority model suggests that an earlier strain of virus has a higher seniority and that exposure to this strain leads to a pattern of stronger antibody responses against this strain after reexposure than to later strains.

Pre-existing immunity against severe acute respiratory syndrome virus (SARS-CoV-1), the common cold coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV) and its interaction with multiple SARS-CoV-2 variants of concern results in a complex immune imprinting landscape. which affects the antibody response to SARS-CoV-2. The results discussed findings from various studies that provided evidence of immune imprinting against SARS-CoV-2, such as antibody binding activity against the spike protein of the common cold coronavirus and SARS-CoV-2 seen in individuals who were SARS-CoV-2 seronegative. . Another study reported higher immunoglobulin G (IgG) responses against wild-type strains than Omicron, beta, or delta strains, even in individuals vaccinated with mRNA Bnt162B2 vaccine or mRNA vaccine beta encoding SARS-CoV-2. Variant

Immune imprinting and immunization

A better understanding of immune imprinting can help inform decisions on various aspects of vaccine development, such as design and expression of immunogens, administration regimens, and improvement of delivery platforms to achieve sustained, optimal, and broad immune responses.

Given the importance of first viral exposure in the development of immune imprinting, primary vaccines given to naïve infants need to be designed for controlled first exposures that result in the generation of a pool of B cells that can be broadly reactive and expanded upon subsequent viral exposures. Adults should be vaccinated sequentially with immunologically distinct strains.

New technologies such as subunit or chimeric immunogens, immunogens designed in silico containing specific epitopes, and multivalent nanoparticle immunogens must be used to provide next-generation solutions to generate optimal immune responses.


Overall, the review presented a comprehensive understanding of the role of immune imprinting in the development of suboptimal antibody responses after exposure to emerging SARS-CoV-2 variants despite booster vaccination. The researchers also present a detailed discussion of different ways in which next-generation vaccines can be improved, as well as immunization strategies to elicit sustained, broad and optimal antibody responses to emerging variants of SARS-CoV-2.

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