Will Omicron BA.2 become the next dominant variant?

The rapid outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in the coronavirus disease 2019 (COVID-19) pandemic. Since its emergence in 2019, SARS-CoV-2 has evolved due to multiple genomic mutations.

The newly emerged SARS-CoV-2 variants have been classified as variants of concern (VOC) or variants of interest (VOI) in accordance with their virulence and transmissibility by the World Health Organization (WHO).

Study: Omicron BA.2 (B.1.1.529.2): high potential to becoming the next dominating variant. Image Credit: SergeyBitos / Shutterstock.com

Background

The SARS-CoV-2 Omicron variant (B.1.1.529) was first reported from South Africa and subsequently classified as a VOC by the WHO. An artificial intelligence (AI) model predicted the Omicron variant to be nearly 2.8 times more infectious than the Delta variant, which was the previously dominant circulating strain of SARS-CoV-2.

The model also predicted that the Omicron variant could most likely escape vaccine-induced immune protection, as well as severely compromise the efficacy of currently approved monoclonal antibodies (mAbs). More studies quickly supported these predictions and revealed that the Omicron variant is highly transmissible and is associated with a high vaccine breakthrough rate and enhanced antibody escape rate. As a result of these factors, the Omicron variant quickly replaced the Delta variant to become the dominant circulating strain in many countries around the world.

Scientists have revealed that the Omicron has three sub-lineages, of which include BA.1 (B.1.1.529.1), BA.2 (B.1.1.529.2), and BA.3 (B.1.1.529.3).

As compared to the original SARS-CoV-2 strain, Omicron BA.1 has a total of sixty mutations on the non-structural protein (NSP3) and structural proteins including the spike (S), envelope, membrane, and nucleocapsid proteins. Among the sixty mutations, thirty are located in the S region, which is the main antigenic target of antibodies generated through vaccination or natural infection.

Multiple mutations are also present in the receptor-binding domain (RBD) of the S protein, whose predominant function is to bind with the host angiotensin-converting enzyme 2 (ACE2) to allow entry of the virus into the host cell. BA.2 shares twenty-eight distinct mutations with BA.1, with four unique mutations at the RBD region. BA.3 shares most of its mutations with BA.1 and BA.2, except for one on NSP6 (A88V).

According to a recent Danish study, Omicron BA.2 is substantially more transmissible than BA.1 and capable of vaccine breakthrough. An Israeli study also revealed that few individuals infected with Omicron BA.1 strain were re-infected with BA.2 within a short period.

Although the BA.2 Omicron strain manifested symptoms similar to the original Omicron BA.1 strain, BA.2 can evade antibodies generated by BA.1 strain. Hence, it is important to determine whether BA.2 has the potential to become the next globally dominating strain.

About the study

A new study currently available on the Research Square* preprint server presents a comprehensive analysis of the potential of both Omicron BA.2 and BA.3 to become the next dominant circulating SARS-CoV-2 strain. This study focuses on the RBD of the S protein, as it is crucial for virus invasion into the host cell and is a determining factor of the COVID-19 vaccine and therapeutic efficacy.

In this study, the authors integrated thousands of mutational and deep mutational data, biophysics, and algebraic topology to construct an AI model. They systematically studied the binding free energy (BFE) changes of an RBD-ACE2 complex structure associated with the RBD mutations of Alpha, Beta, Gamma, Delta, Lambda, Mu, BA.1, BA.2, and BA.3 to analyze the altered infectivity, vaccine-escape potential, and antibody resistance.

Study findings

The scientists revealed that the larger the BFE change is, the higher infectivity will be. Generally, the most contagious variant is inclined to become the dominant circulating strain under the same competing conditions.

The SARS-CoV-2 Delta variant exhibited the highest BFE change and was reported to be most infectious before the emergence of the Omicron variant. Among the Omicron strains, the current study reports Omicron BA.2 is the most contagious variant, which is about 4.2 times as transmissible as the Delta variant.

3D structures of Omicron strains, their ACE2 complexes, and their mutation-induced BFE changes. a Spike protein (PDB: 7WK2 [3]) with Omicron mutations being marked yellow. b BA.1 and BA.2 RBD mutations at the RBD-ACE interface (PDB: 7T9L [21]). The shared 12 mutations are labeled in cyan, BA.1 mutations are marked with magenta, and distinct BA.2 mutations are plotted in yellow. b The structure of the RBD-ACE2 complex with mutations on cyan spots. e, f, and g BFE changes induced by mutations of Omicron BA.1, BA.2, BA.3, respectively. h Comparison of predicted mutation-induced BFE changes for a few SARS-CoV-2 variants.

The key finding of this study is in line with previous reports, which revealed that BA.2 is about 1.5 times as contagious as BA.1. This finding implies that Omicron BA.2 may eventually replace the original Omicron strain BA.1.

The researchers also analyzed the intrinsic vaccine-escape capability of SARS-CoV-2 variants in terms of BFE changes of ACE2-RBD. To this end, they observed that all Omicron sub-lineages exhibited more negative BFE changes than positive ones, which indicates that all three Omicron strains facilitate the breakthrough of current vaccines. However, among the three subvariants, the distribution of BA.2 showed a wider negative domain, and therefore, exhibited the strongest antibody resistance.

The authors performed a comprehensive analysis and revealed that the Omicron BA.2 variant is approximately 1.5 times as infectious as BA.1 and about 4.2 times as infectious as the Delta variant. The current study also reported that the Omicron BA.2 variant has a 30% higher potential than BA.1 to escape COVID-19 vaccine-induced immune responses.

Conclusions

The current study offers deep learning predictions of the potential of both BA.2 and BA.3 l to become the dominant circulating strain of SARS-CoV-2, with BA.2 demonstrating the greatest potential for dominance.

*Important notice

Research Square 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.

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.