Pre-existing memory B cell dynamics during SARS-CoV-2 Omicron breakthrough infection

A recent study posted to the bioRxiv* preprint server analyzed the recall of pre-existent cross-reactive memory B cells upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron breakthrough infections.

Study: Recall of pre-existing cross-reactive B cell memory following Omicron breakthrough infection. Image Credit: Fit Ztudio/Shutterstock


In clinical trials, messenger ribonucleic acid (mRNA)-based SARS-CoV-2 vaccines displayed a considerably high level of protection against the SARS-CoV-2 Wuhan-1 variant. Nonetheless, the subsequent emergence of mutated SARS-CoV-2 variants of concern (VOC), like Omicron and Delta, and decreased vaccine-elicited immunity have substantially hampered the coronavirus disease 2019 (COVID-19) vaccine efficacy.

Prior reports indicated that Omicron or Delta breakthrough infection enhances the serum neutralizing capacity against the infecting variant and the SARS-CoV-2 Wuhan-1 vaccine isolate, implying that cross-reactive vaccine-induced memory B cells (MBCs) may be recalled.

The specificities, roles, and genetic aspects of the antibodies that mediate this response, on the other hand, are unknown. Of note, a better comprehension of immune responses following breakthrough SARS-CoV-2 infections will aid the development of next-generation COVID-19 vaccines.

About the study

In the present study, the researchers assessed the SARS-CoV-2 spike (S)-targeted peripheral and serological B cell responses following the SARS-CoV-2 Omicron (BA.1) infection in COVID-19 mRNA-based vaccinated individuals.

The study included seven SARS-CoV-2 BNT162b2 or mRNA-1273 vaccinated people from the Northeastern area of the United States (US) with COVID-19 breakthrough history between December 30, 2021, and January 19, 2022. All study volunteers tested SARS-CoV-2-positive by reverse transcription-polymerase chain reaction (RT-PCR) and had mild or asymptomatic COVID-19. Although the authors failed to conduct genomic sequencing of the samples, SARS-CoV-2 variant monitoring data showed that the Omicron variant was responsible for most COVID-19 cases in the Northeast US during the study period.

Peripheral blood mononuclear cell (PBMC) and serum samples were procured two to three weeks following PCR-confirmed SARS-CoV-2 infection to analyze the acute B cell response after breakthrough COVID-19. The authors assessed serum immunoglobulin A (IgA) and IgG responses to recombinant perfusion stabilized SARS-CoV-2 BA.1 and wild type (WT) receptor-binding domain (RBD) and S protein subunits after breakthrough Omicron infection.

The team also tested serum antibody responses in a different group of previously uninfected people who were recipients of the second dose of an mRNA-based COVID vaccination one to six months before sampling or a third mRNA vaccine dose one month before sampling. The serum neutralizing capacity of SARS-CoV-2 D614G mutant strain, and Beta, Omicron, and Delta VOCS employing a murine leukemia virus (MLV)-based pseudovirus assay was determined.

Findings and discussions

The study results showed that the serum WT and BA.2 RBD and S protein binding IgG titers of volunteers with Omicron breakthrough infection were similar. By contrast, mRNA vaccinated/uninfected donors exhibited two to four times higher serum IgG binding titers to WT S protein than BA.1 and four to nine times greater binding to WT RBD than BA.1.

In addition, donors with breakthrough COVID-19 displayed dramatically higher serum IgA antibody titers to both BA.1 and WT RBDs than vaccinated/uninfected subjects. These data imply that Omicron breakthrough infection triggers serum IgA and IgG binding responses to both BA.1 and WT S antigens in people with prior COVID-19 vaccination status.

Congruent to prior reports, vaccinated/uninfected donors demonstrated 3.4 to 11-times and seven to 22-times decreased neutralizing capacity against the SARS-CoV-2 Beta and Omicron VOCs, respectively, compared to the D614G mutant strain. On the contrary, people with Omicron breakthrough infections exhibited equivalent neutralizing titers against all the tested SARS-CoV-2 variants, indicating BA.1 breakthrough infections widen serum neutralizing capacities.

Interestingly, vaccinated/uninfected and Omicron breakthrough infected cohorts had comparable SARS-CoV neutralizing responses, implying that the breadth of serum reactivity elicited by Omicron breakthrough infections does not significantly neutralize more antigenically distinct sarbecoviruses.

The BA.1 breakthrough infections and vaccinated/uninfected groups displayed comparable frequencies of IgG B cells reactive towards Omicron and WT RBDs. Nevertheless, the frequencies of IgA B cells reactive towards Omicron RBDs were higher in the BA.1 breakthrough infection group than in the vaccinated/uninfected cohort.

The authors found that Omicron breakthrough infections selectively demonstrate cross-reactivity with the original SARS-COV-2 Wuhan-1 strain and the BA.1 VOC. Omicron breakthrough infections redirected the B cell immunodominance hierarchy from the SARS-CoV-2 S2 subunit to the viral RBD.

Index sorting experiments depicted that the WT-directed antibodies observed during Omicron breakthrough infections probably stemmed from resting MBCs induced by vaccination. The significantly mutated clones with BA.1 and WT RBD cross-reactivity dominate the early B cell response to SARS-CoV-2 Omicron breakthrough infections.

The Omicron neutralizing antibodies utilizing the heavy-chain-variable (VH) germline gene, IGHV3-53/66, recognized an antigenic site that was overlapping yet different from the previously reported IGHV3-53/66 antibodies elicited by SARS-CoV-2 vaccination and infection. Lastly, the Omicron breakthrough infections elicited various recurrent classes of broad reactive anti-SARS-CoV-2 RBD antibodies.


The study findings demonstrated that reactivated vaccine-elicited MBCs exhibiting extensive cross-reactivity against SARS-CoV-2 VOCs characterized the acute antibody response that occurred during Omicron breakthrough infections. The SARS-CoV-2 BA.1 VOC breakthrough infections shifted the immunodominance hierarchy of B cells from the more conserved viral S2 subunit to the more diverse RBD.

Considerable quantities of RBD-specific neutralizing antibodies extracted from individuals with BA.1 breakthrough infections exhibited convergent sequence characteristics and widely recognized SARS-CoV-2 VOCs. 

On the whole, the present work sheds light on how BA.1 breakthrough infections influence pre-existing immunity in the broader B cell response to different SARS-CoV-2 variants. These findings illustrate that a COVID-19 booster vaccination by heterologous SARS-CoV-2 S protein could be a potential tactic for inducing extensive neutralizing activities against the SARS-CoV-2 VOCs, which might emerge in the future. Moreover, the antibodies discovered in this study were possible options for COVID-19 vaccines with broader neutralizing capacities.

*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.

Journal reference:
  • Chengzi I Kaku, Alan J Bergeron, Clas Ahlm, Johan Normark, Mrunal Sakharkar, Mattias NE Forsell, Laura M Walker. (2022). bioRxiv. Recall of pre-existing cross-reactive B cell memory following Omicron breakthrough infection. doi:

Posted in: Medical Science News | Disease/Infection News | Healthcare News

Tags: Antibodies, Antibody, Assay, B Cell, Blood, Cell, Coronavirus, Coronavirus Disease COVID-19, covid-19, Efficacy, Gene, Genetic, Genomic, Genomic Sequencing, Germline, immunity, Immunoglobulin, Leukemia, Omicron, Polymerase, Polymerase Chain Reaction, Protein, Pseudovirus, Receptor, Respiratory, Ribonucleic Acid, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Transcription, Vaccine, Virus

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Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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