The evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causal agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, has reduced the efficacy of available vaccines. These vaccines were developed based on the spike protein of the ancestral SARS-CoV-2, which emerged in Wuhan, China, in 2019.
Scientists have classified the newly emerged SARS-CoV-2 variants as variants of concern (VOC), variants of interest (VOI), and variants being monitored (VBM). Researchers stated that for a virus, which is equipped with nsp14, i.e., proofreading machinery, the rapid rate of mutations is surprising.
Research has revealed that SARS-CoV-2 VOCs are highly contagious, virulent, and capable of evading immune protection induced via COVID-19 vaccination or natural infection. To date, five VOCs have been identified, namely, Alpha, Beta, Gamma, Delta, and Omicron.
In most countries around the world, the Omicron variant has replaced the Delta variant and has become the dominantly circulating strain. The World Health Organization has classified the Omicron variant into lineage B.1.1.529 and sublineages BA.1, BA.1.1, BA.2, and BA.3. At present, the BA.2 sublineage of Omicron is dominantly circulating in many parts of the world. Previous studies have revealed that this strain is more infectious than BA.1. Hence, it is imperative to understand why this strain is more transmissible than the other Omicron sublineages.
Recently, scientists have studied the mutation profile of BA.2 and analyzed its outcome based on the interaction with receptor and/or monoclonal antibodies. This study is available in the International Journal of Molecular Sciences.
To study the mutation profile of BA.2, scientists analyzed a large number of available sequences. This helped them to determine BA.2 signature mutations. Additionally, to assess the outcome of these mutations, the authors analyzed the structures of the spike receptor-binding domain (S-RBD) of Wuhan (ancestral strain) and Omicron strain in complex with monoclonal antibodies (mAbs).
In this study, researchers identified the mutations in BA.1 and BA.2 from sequences obtained from the GISAID repository. These sequences were aligned using different sequence alignment programs, such as MEGA X, MAFFT, and JalView, to identify BA.2 signature mutations. Amino acid changes were determined using Nextclade and, thereby, BA.2 mutations were identified. In this study, scientists considered any mutation that was prevalent greater than 50% to be a signature mutation.
In the current study, researchers analyzed the mutation profile of BA.2 and compared it with BA.1 (original Omicron strain). They reported a considerable difference in the number and distribution of mutations between the BA.2 and BA.1 Omicron strains. The structural data demonstrated that BA.2 maintained critical contact with ACE2 of the host, which is the primary mode of entry of the virus. Additionally, this variant showed evasion or reduced binding with neutralizing mAbs. Scientists stated that the combination of these two factors makes BA.2 an alarming variant that can impact the existing and future COVID-19 vaccination strategies.
Researchers reported that BA.2 retained the majority of mutations of BA.1 and has additionally acquired mutations, such as the G142D of the Delta variant, which is responsible for evasion of mAbs or reduction in their binding capacity, compared to the original strain. The current study revealed that the BA.2 variant has evolved and contains specific mutations that are linked with S-protein and antibodies.
Determination of the functions associated with BA.2 mutations in ORFs, other than the S-protein encoding region, had been challenging. This is because the frequency of reported S-protein structures is significantly more than nsp structures. Additionally, researchers faced difficulties in structurally predicting the role of mutations in proteins (e.g., nsp3, nsp5, nsp12, and nsp13) that possess a high number of enzymatic functions, unless mutation occurred at a highly conserved active site.
The authors highlighted one of the limitations of this study to be that all the sequences were obtained from the GISAID repository to analyze mutations in BA.1 and BA.2. Although these sequences were of high coverage and quality, some of the sequences contained gaps in different genes. This limited the identification of some mutations in certain genes.
Scientists believe that new Omicron lineages have emerged from unvaccinated or immunocompromised individuals. In this study, the authors pointed out that the BA.2 strain contained vital mutations that reduced the efficacy of neutralizing mAbs as well as retained receptor-mediated entry activity similar to that of the SARS-CoV-2 ancestral strain.