Omicron BA.1 breakthrough infection in vaccinated individuals invokes memory B cells to confer immunity

In a recent study posted on Bio Rxiv*Server, Team of Researchers Followed Individuals Vaccinated with the Messenger Ribonucleic Acid (mRNA) Platform-Based Coronavirus Disease 2019 (COVID-19) Vaccine Up to 6 Months After Omicron BA.1 Breakthrough Infection investigated and tracked its evolution. antibody immunity.Notably, they identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD)-specific Neutralizing antibody (nAb) The responses of these vaccinated individuals evolved over time.

Background

Currently available COVID-19 vaccines induce high levels of protection against pre-omicron variants (such as Delta). However, the omicron substrains, including BA.2, BA.2.12.1, BA.4/5, BA.2.75, BA.2.75.2, and BA.4.6, are antigenically distant and have broad immunity. Developing avoidance. More contagious subvariants continue to emerge, superseding previous subvariants.

Select Omicron Spike(S)-based booster mRNA vaccines have received Emergency Use Authorization (EUA) to combat the Omicron breakthrough infectious disease epidemic, supporting their immunogenicity data and Effectiveness still limited in humans. There is a need to understand whether secondary exposure to antigenically diverse variants such as Omicron BA.1 triggers SARS-CoV-2-specific B cell memory. If yes, how this immunity evolves with SARS-CoV-2 RBD-specific antibodies remains to be determined.

About research

In the current study, researchers generated a cohort of 7 donors vaccinated with mRNA-1273 vaccine and tested SARS-CoV-2-specific serology up to 6 months after Omicron BA.1 breakthrough infection. We profiled target and memory B responses. First, they characterized antibody responses from 14 to 27 days after BA.1 breakthrough infection. They then took blood samples from his six of her seven participants to examine the evolution of this response over four to six months after breakthrough infection.

In addition, the team tested among these plasma samples against multiple SARS-CoV-2 variants, including the D614G ancestral strain, beta, delta, and omicron BA.1, BA.2, BA.4/5, and BA.2.75. sum activity was tested. , using a murine leukemia virus (MLV)-based pseudovirus assay. Additionally, they screened for a more antigenically diverse SARS-CoV.

The researchers used flow cytometry (FC) to determine the magnitude and cross-reactivity of SARS-CoV-2-specific B-cell responses. B-cell staining included the use of differentially labeled RBD tetramers from Wuhan-Hu1 and BA.1. In addition, the team found 71 to 110 class-switched RBDs from his four vaccinated donors (IML4042, IML4043, IML4044, and IML4045) between 139 and 170 days post-BA.1 infection. Reactive B cells were sorted by single cells.

They randomly selected 1–2 antibodies belonging to each convergent germline from 363 natively paired full-length immunoglobulin G (IgG) for deep mutation scanning (DMS) analysis. ran. This screen included a library encoding all possible amino acid substitutions from BA.1. These analyzes helped the investigator compare the molecular properties of antibodies isolated at early and late time points after his BA. 1 infection.

Survey results

From the study cohort, three mRNA-vaccinated donors experienced a BA.1 breakthrough infection after two doses of mRNA-1273, while the remaining three developed this infection after a booster dose.

Sera from all vaccinated donors were detectable against all tested SARS-CoV-2 variants at 5–6 months, despite the decline in nAb titers over time showed neutralizing activity, with median titers ranging from 117 to 552. Notably, nAb titers remained. was within 3-fold of D614G for all SARS-CoV-2 variants except Omicron BA.4/5, which showed a 5.5-fold reduction compared to D614G. However, cross-neutralizing activity or serum neutralization breadth remained the same over time for all SARS-CoV-2 variants except SARS-CoV.

Total RBD-reactive B cells and WT/BA.1 cross-reactive B cells constituted median 0.44% and 0.37% class-switched IgG+ or IgA+ B cells, respectively, at 5–6 months . Thus, 86% of these B cells showed BA.1/WT cross-reactivity compared to 75% at 1 month post-infection. WT-specific B cells decreased from 25% to 11% at 1-5-6 months.

A decline phenomenon led to a moderate but marked reduction in the frequency of WT/BA.1 cross-reactive B cells at early and late time points in the study. At a later time point, the authors also noted the emergence of BA.1-specific B-cell populations in three of the six vaccinated donors, although the magnitude of this response was 1%. Omicron BA.1 breakthrough infection elicited a WT/BA.1 cross-reactive B cell response at early time points post-infection, and this response decreased slightly at 6 months. it just went down.

Similar to antibodies isolated at early time points, 73–97% of newly isolated antibodies primarily recognized both WT and BA.1 RBD. Moreover, they exhibited clonal diversity, favoring VH germline genes, IGHV1-46, 1-69, 3-13, 3-53, 3-66, 3-9 and 4-31. The magnitude of somatic hypermutation (SHM) of cross-reactive nAbs increased from a median of 9 VH nucleotide substitutions at 1 month to 11 VH nucleotide substitutions at 5–6 months, with secondary germinal centers (GC) shows affinity maturation.

These antibodies exhibited 1.7-fold improved binding to BA.1 and a 2-fold decreased binding affinity to WT RBD compared to earlier antibodies, compromising WT affinity for BA.1. It indicates that the affinity to 1 has matured. These late antibodies showed a more balanced affinity profile than the early antibodies (73% vs 24%). Notably, convergent nAb classes dominated the BA.1 breakthrough response at early and late time points.

The BA.2.75 and BA.4/5 RBDs have increased binding resistance to the IGHV3-53/66 antibody, suggesting greater antigenic convergence of recent Omicron subvariants and reduced immune evasion capacity compared to BA.1. It explains the increase molecularly. Therefore, engineering S-based immunogens to induce diverse nAbs targeting multiple co-dominant epitopes may help limit the convergence of immune pressure, thereby suppressing viral evolution. I have. It could also be key to a ‘variant-proof’ COVID-19 vaccine.

Conclusion

In summary, BA.1 breakthrough infection in mRNA-vaccinated individuals triggered nAbs with good neutralization breadth and mature B-cell (MBC) responses that persisted for a minimum of 6 months. Perhaps this explains how BA.1 breakthrough infections protect against infections from BA.1, BA.2 and BA.5 for at least 5-6 months. Cross-reactive vaccine-induced MBC and SHM recall mediate this MBC response after breakthrough infection, evolving to increase its spread and potency for at least 6 months. A second heterologous exposure further broadens the serological repertoire by activating these affinity-matured MBCs.

Overall, research data indicate that infection or vaccination with antigenically diverse SARS-CoV-2 variants such as Omicron BA.1 can confer protection by expanding pre-existing B-cell memory or MBC recall. showed.

*Important Notices

bioRxiv publishes non-peer-reviewed, preliminary scientific reports and should not be considered conclusive, to guide clinical practice/health-related actions, or to be treated as established information .