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Evaluating Memory B Cell Cross-Reactivity Between Ancestral and Future SARS-CoV-2 Variants-Evidence for Original
Lingling Yao1, Zoltán Megyesi2, Paul V Lehmann1
1Research and Development, Cellular Technology Ltd. (CTL), Shaker Heights, OH 44122, USA.
Vaccines
|July 27, 2026
Summary
Original antigenic sin impacts immune memory after COVID-19 infection or vaccination, favoring cross-reactive memory B cells over variant-specific responses. A new assay helps distinguish these SARS-CoV-2 specific B cell responses.
Area of Science:
- Immunology
- Virology
- Vaccinology
Background:
- Pre-COVID era individuals lacked pre-existing immunity to SARS-CoV-2 Spike (S) protein from related cold-causing coronaviruses (CCCs).
- Initial SARS-CoV-2 infection or mRNA vaccination primed robust memory B cell (Bmem) responses against the ancestral Wuhan-Hu-1 strain (WH1-S).
- This priming generated cross-reactivity for Omicron variants but raised questions about "original antigenic sin" constraining future responses.
Purpose of the Study:
- To investigate the extent of immunological imprinting on Bmem responses towards WH1-S.
- To determine if original antigenic sin detrimentally constrains variant-specific antibody responses after booster vaccinations or breakthrough infections (BTIs).
- To develop and validate a novel assay for distinguishing strain-specific and cross-reactive B cell responses.
Main Methods:
- Evaluated peripheral blood mononuclear cells (PBMCs) for IgG+ antibody-secreting cell (ASC) reactivity against CCC and SARS-CoV-2 Spike proteins using ImmunoSpot®.
- Developed a novel dual-label inverted FluoroSpot assay to differentiate strain-specific and cross-reactive IgG+ ASCs targeting the Omicron variant receptor binding domain (RBD).
- Analyzed PBMCs from defined human cohorts, including samples collected in 2025.
Main Results:
- No significant back-boosting of IgG+ Bmem recognizing conserved epitopes shared between CCCs and SARS-CoV-2 was observed.
- Evidence of immunological imprinting and preferential expansion of Bmem recognizing cross-reactive RBD epitopes was found following BTIs.
- Omicron strain-specific Bmem were detected in PBMC donors from 2025, indicating potential for variant-specific responses over time.
Conclusions:
- The novel inverted dual-label FluoroSpot assay confirmed preferential expansion of cross-reactive Bmem post-BTI, supporting original antigenic sin's influence on recall responses.
- The assay effectively distinguishes strain-specific from cross-reactive B cell responses, offering a flexible tool for translational vaccine research.
- Findings have broad applications for developing vaccines against pathogens with antigenic drift, like SARS-CoV-2.
Related Concept Videos
00:42Cross-reactivity
Overview
01:23Cells of the Adaptive Immune Response
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00:57Viral Recombination
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01:23Immunological Memory
Immunological memory, a pivotal pillar of the adaptive immune system, is responsible for the body's ability to remember and respond more swiftly and effectively to previously encountered pathogens. This remarkable feature is what makes vaccines so effective in preventing diseases.
What is Immunological Memory?
Immunological memory is an integral function of the immune system that allows it to recognize and react more rapidly and effectively to pathogens previously encountered. This feature is...
What is Immunological Memory?
Immunological memory is an integral function of the immune system that allows it to recognize and react more rapidly and effectively to pathogens previously encountered. This feature is...
01:28Diversity of Antigen Receptors
Antigen receptors are essential components of the immune system crucial in defending the body against foreign invaders. These receptors are present on the surface of B and T cells, enabling them to recognize antigens and mount an appropriate immune response.
Before encountering any antigen, lymphocytes express these receptors. On B cells, the antigen receptor is a membrane-bound antibody molecule called BCR; on T cells, it is a T cell receptor or TCR. B and T cell receptors are composed of two...
Before encountering any antigen, lymphocytes express these receptors. On B cells, the antigen receptor is a membrane-bound antibody molecule called BCR; on T cells, it is a T cell receptor or TCR. B and T cell receptors are composed of two...
00:36Viral Mutations
A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material for adaptive...