Effect of SARS-CoV-2 Omicron subvariant breakthrough infection on memory response

In a recent study published in Bio Rxiv*In a preprint server, researchers investigated antibodies produced by memory B cells (MBC) after 3 and 4 SARS-CoV-2 exposures by infection with SARS-CoV-2 Delta and Omicron BA.1 variants ( Abs), respectively.

A study reported enhanced immune protection against SARS-CoV-2 among people who received three doses of the 2019 coronavirus disease (COVID-19) messenger ribonucleic acid (mRNA) vaccine. However, data on the impact of breakthrough SARS-CoV-2 infection on MBC responses are lacking.

About research

In this study, researchers reported the occurrence of MBC Abs in vaccinated individuals (n=67) with Delta or Omicron breakthrough infection (BT).

Vaccinated individuals who developed Delta infection (n=24) or Omicron infection (n=29) between 13 August 2021 and 3 February 2022 Registered from date to February 3, 2022. (n = 33), Moderna her mRNA-1273 (n = 12), or a combination of both vaccines (n = 8).

Sera were obtained from Delta BT and BA.1 BT patients with a median duration of 27 and 24 days, respectively, after SARS-CoV-2 detection. Sample collection periods corresponded to a median of 6 months after the second vaccination and 2.4 months after the third vaccination, respectively. In addition, paired serum samples were obtained from her two patients immediately after the third vaccination and her BA.1 breakthrough infection.

Serum immunoglobulin G (IgG) levels against the SARS-CoV-2 Wuhan-Hu-1 strain (wild-type, WT), delta receptor binding domain (RBD) protein, and Omicron BA.1 spike (S) protein was rated by Linked Immunosorbent Assay (ELISA). Plasma neutralizing activity was measured using human immunodeficiency virus 1 (HIV-1) pseudotyped with SARS-CoV-2 WT S among 49 patient samples.

Pseudotyped viruses were used to assess serum neutralizing activity against Delta, Omicron BA.1, BA.2, and BA.4/5 subvariants. In addition, S RBD-specific MBCs were analyzed by flow cytometry (FC) analysis. Antibody genes of WT S RBD-specific MBC from 10 delta BT or BA.1 BT patients after the second and third vaccinations, respectively, were sequenced to assess the neutralizing activity and specificity of MBC Abs .

Binding affinities of anti-RBD monoclonal antibodies (mAb, n=338) were evaluated using ELISA. This included Abs induced after Delta breakthrough infection (Delta BT, n=115), Abs from samples after the third vaccination, followed by those infected (Vax3, n=40) , Abs from 6 individuals after BA.1 BT (n=183), and Abs bound to WT RBD at half-maximal effective concentration (EC₅₀) values ​​<1000 ng/mL (n=288).

A pseudotyped neutralization assay was used to assess the neutralization potential of all 288 MBCs. Additionally, 105 randomly selected Abs from all four groups were tested against Omicron BA.4/5. pseudovirusBiolayer interferometry (BLI) analysis was performed to compare epitopes detected by anti-RBD MBC Abs induced after BT and mRNA vaccination.

result

The median ages of Delta BT and Omicron BT patients were 30 and 22.5 years, respectively, and most study participants were male. Her third SARS-CoV-2 exposure with Delta BT increased the number of MBC producing Abs with breadth and potency comparable to triple mRNA vaccination. However, BA.1 BT did not increase the overall frequency, breadth or potency of MBC compared with his 3 doses of COVID-19 mRNA.

Anti-WT-RBD IgG titers significantly elevated post-delta BT in double-mRNA-vaccinated individuals over vaccinated individuals who did not develop SARS-COV-2 infection (5m -Vax2). BA.1 BT patients showed higher anti-Delta-RBD IgG and anti-BA.1-S IgG titers than Delta BT patients or triple-vaccinated individuals. The neutralization assay showed that Delta BT had an 11-fold mean half-maximal neutralization titer (NT₅₀) than those who received two doses.

Resulting NT₅₀ Antibody titers were lower than those who had been vaccinated three times. NT₅₀ Antibody titers after Omicron BA.1 BT vaccination were not significantly different from those in those who received 3 doses of Omicron BA.1 BT. In contrast, Delta BT enhanced neutralization titers by 15-fold over double-vaccine recipients with no history of COVID-19. Delta BT enhanced neutralization of Omicron BA.1, Omicron BA.2, and Omicron BA4/5. However, titers were not significantly different from those in those who received 3 doses.

In contrast, Omicron BT post triple mRNA vaccination increased titers to Omicron BA.1 and Omicron BA.2 by 4-fold and 3-fold, respectively, over those in triple vaccinated individuals . BA.4/5 were the most resistant to neutralization (NT₅₀=72) after the second vaccination. The numbers of WT RBD-specific MBCs after delta BT were significantly higher than those after 2 and 3 vaccinations. MBC induced by BA.1 BT was 1.7-fold higher than that observed in those who received 3 doses.

RBD-specific MBC are delta or Vax3 or delta or BA. 1. BT showed a higher frequency of IgG compared to IgA and IgM expression. Ab epitopes were not significantly different between those obtained after BT and after mRNA vaccination. Ab sequencing showed that in Delta BT patients he overexpressed VH1-24, VH3-49, and VH4-38 genes, and in BA.1 BT patients he showed VH1-58, VH1-69, VH4-38, and showed overexpression of the VH4-61 gene. Specific MBC Ab responses induced by Delta BT and BA.1 BT.

Overall, the study results show that the third SARS-CoV-2 exposure (Delta BT) induced variant-specific MBC responses and increased overall MBC breadth and potency, while the fourth SARS-CoV-2 2 showed a slight improvement with exposure (BA.1 BT).

*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 .