Insights into Immune Imprinting: Evaluating the Humoral Response to XBB.1.5 S mRNA Booster in Individuals with Prior Wuhan-Hu-1 Exposure


The emergence of immune-evading SARS-CoV-2 variants has posed challenges to the effectiveness of existing COVID-19 vaccines. To address this, two updated vaccine boosters were developed: a bivalent Wuhan-Hu1/BA.5 (or BA.1 for select countries) spike (S) mRNA booster approved in August 2022 and a monovalent XBB.1.5 S mRNA booster approved in September 2023.

This study investigates the humoral immune responses elicited by the XBB.1.5 S booster in individuals with prior Wuhan-Hu-1 exposure, exploring neutralizing antibody activity, immune imprinting, and the potential for de novo responses.

Introduction: The continual evolution of SARS-CoV-2 variants has prompted the development of updated COVID-19 vaccine boosters. The study focuses on the XBB.1.5 S mRNA booster, aiming to evaluate its efficacy in individuals previously exposed to the Wuhan-Hu-1 S spike. Understanding the humoral immune responses, including neutralizing antibody activity and memory B cell populations, provides critical insights into the long-term impact and effectiveness of these boosters.

Methods: Plasma samples were collected from individuals who had received multiple vaccine doses with or without known infection. Vesicular stomatitis virus (VSV) pseudotyped with various SARS-CoV-2 variants, including Wuhan-Hu-1/D614G, BQ.1.1, XBB.1.5, and BA.2.86, were utilized to assess the potency and breadth of neutralizing antibodies. Depletion experiments and ELISAs were employed to investigate immune imprinting, antibody specificity, and potential de novo responses. Flow cytometry was utilized to analyze memory B cell populations in response to XBB.1.5 S vaccination.

Results: Neutralizing antibody responses were evaluated against different SARS-CoV-2 variants following XBB.1.5 S vaccination. The XBB.1.5 S booster elicited potent neutralizing activity against current variants, with higher titers against Wuhan-Hu-1/D614G S VSV compared to XBB.1.5 S VSV, indicating immune imprinting. Depletion experiments revealed increased cross-reactive plasma antibody titers, suggesting that XBB.1.5 S vaccination augmented pre-existing Wuhan-Hu-1 S-specific responses.

Conclusion: In conclusion, the updated XBB.1.5 S mRNA vaccine booster demonstrates efficacy in eliciting neutralizing antibodies against circulating variants. However, the study highlights the dominance of immune imprinting, emphasizing the challenges in inducing de novo responses. These findings emphasize the importance of considering immune imprinting in the design of future COVID-19 vaccine boosters to ensure sustained and effective protection against evolving SARS-CoV-2 variants.

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