In a recent study posted to the bioRxiv* preprint server, investigators analyzed the neutralization escape of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2.75 variant.
Study: Evasion of Neutralizing Antibody Response by the SARS-CoV-2 BA.2.75 Variant. Image Credit: Niphon Subsri/Shutterstock
This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources
Background
The emergence of the SARS-CoV-2 Omicron variant by the end of 2021 led to an extraordinary surge of coronavirus disease 2019 (COVID-19) cases globally. Omicron exhibited significant escape from infection- and vaccine-induced immunity. Besides, the recent appearance of Omicron subvariants sparked more infection waves.
The Omicron BA.1 subvariant caused the first Omicron wave and was shortly substituted by BA.2, which showed marginally improved transmissibility and resistance to BA.1-induced antibodies. Subsequently, various progeny subvariants evolved from BA.2, such as the BA.2.12.1 variant, which later became predominant worldwide. Notably, the BA.5 and BA.4 variants, which possess similar spike (S) proteins and developed from BA.2, are presently dominating the world.
Another unique BA.2-stemmed subvariant, BA.2.75, has been found recently. Compared to the ancestor Omicron BA.2 variant, the newly discovered SARS-CoV-2 Omicron BA.2.75 variant displays an alarming nine extra mutations in its S protein. These mutations raised concerns regarding future immune evasion, especially the receptor binding domain (RBD) mutations.
About the study
In the current research, the scientists investigated the neutralizing antibody (nAb) escape of Omicron BA.2.75 variant in COVID-19 messenger ribonucleic acid (mRNA)-vaccinated and BA.1-infected individuals. They also analyzed the molecular underpinning of functional alterations across the BA.2.75 S protein.
The team aimed to assess the sensitivity of the BA.2.75 78 variant to SARS-CoV-2 vaccine-elicited immunity in 15 mRNA-vaccinated or boosted health care workers (HCWs) from Ohio State University Wexner Medical Center. The sera samples were taken three to four weeks following vaccination with a second dose of COVID-19 Pfizer/BioNTech BNT162b2 or Moderna mRNA-1273 vaccine and one to 12 weeks after immunization with a homologous booster shot. Patient sera were tested for nAb titers towards lentivirus pseudotyped with S from archaic SARS-CoV-2 S containing solely the D614G mutation and S from BA.2, BA.1, BA.4/5, BA.2.12.1, and BA.2.75.
The researchers also examined the nAb reactions in a group of 30 non-intensive care unit (ICU) SARS-CoV-2 patients admitted at the Ohio State University Wexner Medical Center during the Omicron BA.1-wave of the COVID-19 pandemic. Further, they evaluated all nine point mutations in the BA.2 backdrop and the nine comparable reversion mutations in the BA.2.75 background to understand the factors contributing to neutralization resistance in the BA.2.75 strain. In addition, the authors looked at the BA.2.75 fusogenicity, infectivity, and S processing.
Results
The study results demonstrated that the Omicron BA.2.75 subvariant displays an improved neutralization resistance relative to the ancestral BA.2 strain for triple-dose mRNA vaccinated HCWs and COVID-19 patients hospitalized during the Omicron wave. Yet, it had much less neutralization resistance than BA.5/BA.4.
Importantly, the authors showed that the BA.2.75 S protein's N460K and G446S mutations were responsible for its higher neutralization resistance. On the other hand, the R493Q mutation, a reversion mutation, makes BA.2.75 more sensitive to neutralization. These observations might indicate compensatory mutations that have emerged to enhance S function while preserving neutralization resistance.
Structural assessments imply that the side chain incorporation by G446S establishes a steric collision with the complementarity-determining regions (CDR) of class 3 nAbs, thereby potentially hindering their recognition. As a result, swapping these mutations might modify the vulnerability of BA.2.75 to class 3 and class 2 nAbs.
The scientists depicted that BA.2.75 displays improved S-triggered cell fusion relative to BA.2, although to a lesser degree than BA.4/5. They discovered that the augmented fusion phenotype depends on the N460K mutation in BA.2.75.
Conclusions
The study findings showed that the SARS-CoV-2 Omicron BA.2.75 variant possesses superior neutralization resistance than the Omicron BA.2 variant, whereas less than the BA.4/BA.5 variant. The N460K and G446S mutations of BA.2.75 were chiefly accountable for their heightened resistance to nAbs.
The team discovered that the BA.2.75 neutralization resistance was decreased by the R493Q mutation, representing a prototype sequence reversion. The mutational influence of these mutations was constant with their placements in frequent nAb epitopes.
Additionally, compared to BA.2, the BA.2.75 variant exhibits improved cell-to-cell fusion, likely attributable to the N460K mutation, which boosts S processing. Besides, structural modeling supported a pathway of upregulated receptor usage and syncytia generation by identifying a novel receptor interaction that N460K introduced.
Overall, the study data add to the knowledge of SARS-CoV-2 evolution and will help to combat the ongoing challenge posed by arising SARS-CoV-2 variants.
This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources
Journal references:
- Preliminary scientific report.
Qu, P. et al. (2022) "Evasion of Neutralizing Antibody Response by the SARS-CoV-2 BA.2.75 Variant". bioRxiv. doi: 10.1101/2022.08.14.503921. https://www.biorxiv.org/content/10.1101/2022.08.14.503921v1
- Peer reviewed and published scientific report.
Qu, Panke, John P. Evans, Yi-Min Zheng, Claire Carlin, Linda J. Saif, Eugene M. Oltz, Kai Xu, Richard J. Gumina, and Shan-Lu Liu. 2022. “Evasion of Neutralizing Antibody Responses by the SARS-CoV-2 BA.2.75 Variant.” Cell Host & Microbe 30 (11): 1518-1526.e4. https://doi.org/10.1016/j.chom.2022.09.015. https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(22)00471-1.
Article Revisions
- May 13 2023 - The preprint preliminary research paper that this article was based upon was accepted for publication in a peer-reviewed Scientific Journal. This article was edited accordingly to include a link to the final peer-reviewed paper, now shown in the sources section.
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