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.
Background
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.
Conclusions
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.
