Impact of SARS-CoV-2 Omicron subvariant breakthrough infections on memory responses

In a recent study posted on the bioRxiv* preprint server, researchers examined antibodies (Abs) generated by memory B cells (MBCs) after three and four SARS-CoV-2 exposures by infections with SARS-CoV-2 Delta and Omicron BA.1 variants, respectively.

Study: Memory B cell responses to Omicron subvariants after SARS-CoV-2 mRNA breakthrough infection. Image Credit: CROCOTHERY/Shutterstock
Study: Memory B cell responses to Omicron subvariants after SARS-CoV-2 mRNA breakthrough infection. Image Credit: CROCOTHERY/Shutterstock

Studies have reported enhanced immune protection against SARS-CoV-2 among persons who have received triple coronavirus disease 2019 (COVID-19) messenger ribonucleic acid (mRNA) vaccinations. However, data about the effects of breakthrough SARS-CoV-2 infections on MBC responses are lacking.

About the study

In the present study, researchers reported on the development of MBC Abs among vaccinated persons (n=67) with Delta or Omicron breakthrough infections (BT).

Vaccinated individuals who received double and triple mRNA vaccines and developed Delta infections (n=24) or Omicron infections (n=29) were enrolled for the study between 13 August 2021 and 3 February 2022. The study participants were vaccinated with Pfizer-BioNTech’s BNT162b2 (n=33), Moderna’s mRNA-1273 (n=12), or a combination of both vaccines (n=8).

Sera were obtained from Delta BT and BA.1 BT patients at median durations of 27 days and 24 days after SARS-CoV-2 detection, respectively. The sample collection periods corresponded to medians of six months post the second vaccine dose, and 2.4 months after the third vaccine dose, respectively. Additionally, paired serum samples were obtained from two patients shortly post-third vaccination and post-BA.1 breakthrough infection.

Serum immunoglobulin G (IgG) levels against SARS-CoV-2 Wuhan-Hu-1 strain (wildtype, WT), Delta receptor-binding domain (RBD) protein, and Omicron BA.1 spike (S) protein were assessed by enzyme-linked immunosorbent assays (ELISA). Plasma neutralizing activity was measured using human immunodeficiency virus 1 (HIV-1) pseudotyped with SARS-CoV-2 WT S among samples of 49 patients.

Serum neutralizing activity was assessed against Delta, Omicron BA.1, BA.2 and BA.4/5 subvariants using pseudotyped viruses. Further, S RBD-specific MBCs were analyzed by flow cytometry (FC) analysis. Antibody genes from WT S RBD-specific MBCs from 10 patients with Delta BT or BA.1 BT after the second and third vaccinations, respectively, were sequenced to evaluate the neutralizing activity and specificity of MBC Abs.

Binding affinities of anti-RBD monoclonal Abs (mAb, n=338) were assessed using ELISA, including Abs induced subsequent to Delta breakthrough infections (Delta BT, n=115), Abs from samples post third vaccination among persons that were infected that were subsequently (Vax3, n=40), Abs obtained from six persons post- BA.1 BT (n=183) and Abs bound to WT RBD with half maximal effective concentration (EC50) values below <1000 ng/mL (n=288).

The neutralization potential of all 288 MBCs was assessed using pseudotype neutralization assays. In addition, 105 randomly chosen Abs from all four groups were tested against an Omicron BA.4/5 pseudovirus. Biolayer interferometry (BLI) analyses were performed to compare epitopes detected by anti-RBD MBC Abs induced post-BT and mRNA vaccinations.

Results

The median ages of Delta BT and Omicron BT patients were 30 years and 22.5 years, respectively, and most of the study participants were men. The third SARS-CoV-2 exposure by Delta BT increased the count of MBCs that produced Abs with equivalent breadth and potency as triple mRNA vaccinations. However, BA.1 BT did not elevate the overall MBC frequency or their breadth or potency compared to triple COVID-19 mRNA vaccination.

Anti-WT-RBD IgG titers significantly elevated post-Delta BT among persons who had received double mRNA vaccinations than vaccinated persons who did not develop SARS-COV-2 infections (5m-Vax2). BA.1 BT patients demonstrated greater anti-Delta-RBD IgG and anti-BA.1-S IgG titers than Delta BT patients or triply vaccinated persons. The neutralizing assays showed that Delta BT led to 11-fold greater mean half-maximal neutralization titers (NT50) than doubly vaccinated persons.

The resultant NT50 titers were lesser than those among triply vaccinated persons. The NT50 titers post-Omicron BA.1 BT did not significantly differ from those among triply vaccinated persons. In contrast, Delta BT enhanced neutralizing titers by 15-fold more than in doubly vaccinated persons without prior COVID-19 history. Delta BT enhanced neutralization of Omicron BA.1, Omicron BA.2, and Omicron BA4/5; however, the titers did not significantly differ from the titers of triple-vaccinated persons.

Contrastingly, Omicron BT post triple mRNA vaccination increased titers by four-fold and three-fold against Omicron BA.1 and Omicron BA.2, respectively, than the titers of triply vaccinated persons. BA.4/5 was most resistant to neutralization (NT50=72) post-second vaccination. The count of WT RBD-specific MBCs after Delta BT was significantly greater than that post-double and triple vaccination. MBCs induced by BA.1 BT were 1.7-fold more than that observed among triply vaccinated persons.

The RBD-specific MBCs are induced by Delta or Vax3 or Delta or BA.1 BTs exhibited greater frequencies of IgG compared to IgA and IgM expression. Ab epitopes did not significantly differ among those obtained post-BTs and post-mRNA vaccinations. Ab sequencing showed overrepresentation of VH1-24, VH3-49, and VH4-38 genes in Delta BT patients and VH1-58, VH1-69, VH4-38 and VH4-61 genes in BA.1 BT patients, indicative of variant-specific MBC Ab responses induced by Delta BT and BA.1 BT.

Overall, the study findings showed that the third SARS-CoV-2 exposure (Delta BT) elicited variant-specific MBC responses and increased the overall MBC breadth and potency, that marginally improved by the fourth SARS-CoV-2 exposure (BA.1 BT).

*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:
Pooja Toshniwal Paharia

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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