The neutralizing antibody escape of BA.2.75 in mRNA-vaccinated and BA.1-infected individuals

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
Study: Evasion of Neutralizing Antibody Response by the SARS-CoV-2 BA.2.75 Variant. Image Credit: Niphon Subsri/Shutterstock

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.

*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:
Shanet Susan Alex

Written by

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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Comments

  1. Thomas E A Thomas E A Denmark says:

    They did not analyze the neutralization escape of Omicron BA.2.75 or any other SARS-CoV-2 virus, but a completely different virus equipped with spike proteins similar to the BA.2.75. Perhaps this reflects the neutralization escape of Omicron BA.2.75, but unknown, especially for the convalescents who have other potentially neutralizing antibodies than spike antibodies.

  2. Elizabeth Vartabedian Elizabeth Vartabedian United States says:

    The paper cited has yet to go through peer review. When indeed an interesting study. It is dangerous to draw conclusions or take this as fact. This is a great example of double checking sources cited.

    Here is an excerpt for the bioRxiv:
    "bioRxiv posts many COVID19-related papers. A reminder: they have not been formally peer-reviewed and should not guide health-related behavior or be reported in the press as conclusive."

    If you click the link provided by the journalist you can see for yourself as well. Don't take my word for it make sure to do your own proper research too!

    Happy Researching! Smile

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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