New study suggests Omicron BA.1 breakthrough infection drives long-term remodeling of memory B cell repertoire in vaccinated populations

By Dr. Priyom Bose, Ph.D.Reviewed by Aimee MolineuxFeb 1 2023

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causal agent of the current coronavirus disease 2019 (COVID-19) pandemic, is a highly infectious virus and has claimed more than 6.8 million lives worldwide. The continual emergence of new SARS-CoV-2 variants has reduced the efficacy of the available COVID-19 vaccines. 

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

The emergence of the Omicron variant (BA.1) has led to a prominent antigenic shift in SARS-CoV-2 evolution. The spike region of this variant harbors thirty-two mutations, with reference to the original SARS-CoV-2 (Hu-1) strain. These mutations decrease the neutralizing capacity of antibodies induced via natural infection or vaccination, as a result, a large number of vaccinated individuals reported breakthrough infection in the early weeks of 2022.

Even though several SARS-CoV-2 variants were able to escape immune responses, the diverse memory B cell (MBC) repertoire generated by mRNA vaccines (after two or three vaccine doses) revealed high-affinity neutralizing clones against all variants up to BA.1. MBCs produced in response to ancestral Hu1 pre-fusion spike encoded by the original mRNA vaccines, offered an additional layer of immune protection which prevented severe SARS-CoV-2 infections.

Scientists hypothesized that after breakthrough infections, the MBCs repertoire will get narrow and select broadly reactive B cell receptors (BCR). This will lead to a limited diverse immune response, which will be ineffective in preventing infection by future variants. Another hypothesis entails that exposure to new antigens (in variants) engages a de novo naive B cell response with slow maturation that ensures continual diversity.

Several studies have indicated that early immune response against Omicron BA.1 breakthrough infection or Hu-1 mRNA vaccination equips cross-reactive clones against conserved Spike glycoprotein epitopes, instead of employing naive B cells specific to mutated BA.1 residue.

About the study

A recent study posted on the bioRxiv* preprint server has longitudinally characterized the MBC repertoire and humoral response after Omicron BA.1 breakthrough infection in individuals vaccinated with the COVID-19 mRNA vaccine. The immune responses were assessed for up to six months after the breakthrough infection.

The current longitudinal study analyzed a cohort consisting of fifteen individuals with no previous history of COVID-19. All the participants were infected with Omicron BA.1 between the latter half of December 2021 and the end of January 2022, shortly (32 days) after receiving the third booster vaccine dose (BNT162b2 mRNA vaccine). 

To determine the affinity and neutralizing potency evolution of the MBC repertoire, functional analysis of many naturally expressed antibodies from receptor binding domain (RBD)-specific MBCs were combined with single-cell multi-omics. The authors performed multiparameter flow cytometry analysis, a single-cell culture of spike and RBD-specific B cells, and single-cell RNA sequencing (scRNA-seq), for complete characterization of B cell responses from the early extra-follicular reaction to the late settlement of long-term memory. These analyses were conducted at three-time points, i.e., 1, 2, and 6 months, after BA.1 breakthrough infection

Findings

Characterization of B cell responses revealed that imprinting was not limited to the early extrafollicular response, but continued over time. A very small number of BA.1-restricted naive B cell clones were found to be recruited in de novo germinal centers. Even though all participants received the third booster vaccine dose, they developed a breakthrough infection by Omicron BA.1 strain. 

The prevalence of breakthrough infection in vaccinated individuals could be due to the absence of sufficient viral antigen levels to activate naive B cells, as it is rapidly removed by broadly neutralizing antibodies generated by newly recruited cross-reactive MBC. The absence of de novo recruitment of BA.1-restricted naive B cells and simultaneous focus on cross-reactive MBC clones could lead to a decrease in overall diversity.

After BA.1 infection, changes in the B cell repertoires (up to 6 months) were not found to be particularly restricted to expansion and contraction of a cross-reactive MBC response through the extra-germinal center response. Notably, the longitudinal tracking of RBD-specific clones clearly indicated an overall improvement in affinity and neutralization breadth. The increased mutational load in newly-expanded clones suggested the important contribution of these cells in the remodeling of the MBC repertoire. More research is required to elucidate whether low-frequency clones reenter germinal centers (GCs).

Conclusions

It is important to understand how the memory B cell repertoire induced after vaccination gets re-shaped by BA.1 breakthrough infection. The current study revealed that the reorganization of clonal hierarchy, combined with novel GC reactions enabled the maintenance of antibody diversity. Furthermore, induction of progressive maturation of the MBC repertoire against the ancestral strain as well as the BA.1 variant was also observed. In terms of vaccination, more research on expanding the immune response beyond the conserved RBD epitopes is required. This will favor diversity and help cope with future SARS-CoV-2 variants.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.