New Insights into Hybrid Immunity Generated by mRNA Vaccine-induced Diverse Memory B Cells in Response to Omicron Breakthrough Infection- A Recent Study

Full article: Structural insights into broadly neutralizing antibodies elicited by hybrid immunity against SARS-CoV-2 (

The continuing emergence of SARS-CoV-2 variants far outpaces the development of new COVID-19 vaccines and antibodies. Since late 2021, we have seen several new waves of global infections with Omicron substrains, including BA.1, BA.2, BA.2.12.1, and BA.4/5. Apparently, each substrain is more resistant to vaccine-induced neutralizing antibodies and even causes antigenic changes. Understanding the hybrid immunity that occurs in vaccinees with breakthrough infections is critical for determining the magnitude, breadth, and potency of neutralizing antibody responses to SARS-CoV-2 Omicron variants.

In a recent study, the scientists investigated the types of memory B cell responses generated during hybrid immunization in a breakthrough post-infection mRNA vaccine with SARS-CoV-2 Omicron BA.1. Analysis of 104 mAbs derived from a single memory B cell showed that BA.1 infection effectively induced a variety of B cell clonotypes and activated Ig genes to produce WT and BA.1 specific NAbs.

They found that it works in parallel with and produces predominantly cross-reactive bNAbs (60%).  The majority of these neutralizing antibodies (24/35, 68.6%) were RBD-specific. Notably, the eight most potent NAbs consisted of both potent class I/II and class III bNAbs. These bNAbs, which contain different IgH and IgL sequences and binding epitopes, showed equally high potency against both WT and BA.1. This is probably due to specific and reciprocal antigens within the mRNA vaccine and the homogenous breakthrough strain BA.1.

Scientists then showed that these bNAbs exhibited different neutralizing activities against other VOCs and micron substrains due to their sequence and structural differences. Two class III bNAbs, P2D9 and P3E6, were able to neutralize all VOC and micron substrains tested, including the BA.4/5 ascending strain. Structural analyzes revealed that bNAbs have consistently different mechanisms of action due to different binding lanes of bNAbs to viral RBDs or spike proteins.

This study added new insights into hybrid immunity generated by mRNA vaccine-induced diverse memory B cells in response to Omicron breakthrough infection, which may have implications for implementing public measures of population protection and next-generation vaccine development.

NAB-Sure™ enables cell-free NAb (Neutralizing Antibody) testing of Omicron variants in addition to the original Wild-type. It can be used for longitudinal testing, sero-surveillance, or retrospective studies.