Repeated Omicron exposures redirect SARS-CoV-2-specific memory B cell evolution toward the latest variants

Area of Science:

• Immunology
• Virology
• Vaccinology

Background:

• Immunological imprinting from ancestral SARS-CoV-2 strains may limit Omicron-specific responses from Omicron-based boosters.
• Understanding memory B cell responses is crucial for effective vaccine strategies against evolving viral variants.

Purpose of the Study:

• To investigate the specificity and neutralization activity of memory B cells after repeated BA.5 exposure in individuals primed with ancestral strain mRNA vaccines.
• To determine if pre-existing memory B cells can adapt to new SARS-CoV-2 variants.

Main Methods:

• Analysis of memory B (Bmem) cell specificity and neutralization activity post-BA.5 exposure.
• Clonal lineage analysis to track Bmem cell evolution and specificity redirection.
• Comparison of redirected Bmem cell development with de novo Bmem cells.

Main Results:

• A second BA.5 exposure elicited prompt BA.5 spike protein-skewed Bmem cell reactivity, correlating with existing antibody titers.
• Clonal lineage analysis revealed BA.5-skewed Bmem cells redirected specificity from ancestral strains via somatic hypermutation.
• Redirected BA.5-specific Bmem cells developed faster than de novo Bmem cells and showed resilience to viral mutations, adapting to variants HK.3 and JN.1.

Conclusions:

• Existing memory B cells primed by older vaccines can redirect their specificity towards emerging SARS-CoV-2 variants.
• This specificity redirection enhances B cell responses and resilience against viral evolution, offering a potential mechanism for broader vaccine effectiveness.