Spike-specific memory B cells develop resilience to SARS-CoV-2

In a recent study posted to the bioRxiv* preprint server, researchers explored the cross-reactivity, avidity, and kinetics of memory B-cells and serum antibodies in vaccinated and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected individuals.

Study: Maturation of SARS-CoV-2 Spike-specific memory B cells drives resilience to viral escape. Image Credit: Kateryna Kon / Shutterstock

Background

With the emergence of SARS-CoV-2 Omicron subvariants, the incidence of coronavirus disease 2019 (COVID-19) among vaccinated and previously SARS-CoV-2 infected individuals has increased. Studies have shown that mutations in regions encoding the receptor binding domain of the SARS-CoV-2 spike (S) protein have given the emergent variants an enhanced ability to evade humoral immunity.

Memory B cells circulate in the body after infection or immunization and can rapidly produce neutralizing antibody responses when they re-encounter the antigen. While many studies have reported the immune evasion abilities of the emergent variants and a decline in neutralizing antibody titers in vaccinated and previously infected individuals, the avidity and efficacy of neutralizing antibodies produced by SARS-CoV-2-specific memory B cells in response to reinfections need to be investigated.

About the study

In the present study, the researchers from Australia, Switzerland and the United States used longitudinal samples of individuals with and without previous SARS-CoV-2 infections who had received three doses of the Pfizer/BioNTech BNT162b2 messenger ribonucleic acid (mRNA) vaccine to perform a single-memory B cell repertoire analysis.

Peripheral blood mononuclear cells and plasma were isolated from blood samples for the antigen-specific memory B cell repertoire analysis. Toll-like receptor 7/8-agonist R848 and Interleukin- 2 (IL-2) were used to selectively proliferate and differentiate the memory B cells into antibody-secreting cells.

Multiple enzyme-linked immunosorbent assays (ELISA) were performed to detect antibodies specific to the spike protein, S1 domain, S2 domain, receptor-binding domain (RBD), N-terminal domain (NTD), and nucleoprotein(N) of a wide range of viruses including SARS-CoV-2, human coronavirus Hong Kong university 1 (HCoV-HKU1), human coronavirus organ culture 43 (HCoV-OC43), and Middle East respiratory syndrome coronavirus (MERS-CoV).

The frequencies and specificity of memory B cells in healthy individuals vaccinated with the BNT162b2 mRNA vaccine were also analyzed after each of the three doses.

Cross-reactivity of memory B cells elicited as a response to the infection with Wuhan-Hu-1 and Alpha strains was tested using Beta, Delta, and Omicron variants, and Omicron sub-lineages BA.1, BA.2, BA.3, and BA.4/BA.5.

Results

The results indicated that although serum antibodies specific to SARS-CoV-2 decreased with time after infection or vaccination, memory B cells progressively increased and were stable at steady-state levels up to 16 months after infection or vaccination.

Longitudinal analysis of the samples showed a progressive increase and plateau of SARS-CoV-2 S-, RBD-, N-, S2-, and NTD- specific memory B cells. In comparison, the memory B cells specific to the S and N proteins of HCoV-HKU1 and HCoV-OC43 remained mostly constant.

Although the immunoglobulin G (IgG) antibodies specific to SARS-CoV-2 RBD, S, and N proteins decreased over time, no correlation was noted between the decrease of IgG antibodies and the increase of memory B cells. A slight increase was recorded in the levels of IgG antibodies against HCoV-HKU1 and HCoV-OC43 immediately after SARS-CoV-2 infection, but the levels dropped rapidly.

Vaccine-induced memory B cells targeted only pre-fusion S, but the memory B cells from individuals with previous infections with the Wuhan-Hu-1 and Alpha strains bound to both pre-and post-fusion S. Furthermore, the memory B cells that recognized post-fusion S showed cross-reactivity with human betacoronaviruses.

Two vaccine doses resulted in high RBD-specific memory B cells in both uninfected and previously infected individuals, with S2- and NTD-specific memory B cells present in lower frequencies. In uninfected individuals, subsequent doses of the vaccine elicited highly varied antibody levels. In contrast, in infected individuals, serum antibody titers reached the maximum levels after the first dose and did not increase with subsequent doses.

The avidity of the serum antibodies and the memory B cell-derived antibodies increased with time against all the tested SARS-CoV-2 variants. However, the resilience against the BA.4 and BA.5 sub-lineages was partial.

Conclusions

Overall, the study indicated that the although the serum antibodies generated in response to SARS-CoV-2 infection or COVID-19 vaccinations declined with time, the repertoire of memory B cells increased and reached stable frequencies in the months following infection or vaccination. Furthermore, the increase in frequency is followed by maturation and expansion, allowing the body to mount a potent secondary immune response to subsequent infections.

Hybrid immunity from a combination of previous SARS-CoV-2 infections and vaccinations can result in high-avidity memory B cells with the ability to target a broad range of SARS-CoV-2 variants and other sarbecoviruses. However, the lowered resilience of even these high-avidity antibodies to Omicron sub-lineages BA.4 and BA.5 is cause for concern.

*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.