Emerging SARS‐CoV‐2 variants can potentially break set epidemiological barriers in COVID‐19

Abstract

Young age, female sex, absence of comorbidities, and prior infection or vaccination are known epidemiological barriers for contracting the new infection and/or increased disease severity. Demographic trends from the recent coronavirus disease 2019 waves, which are believed to be driven by newer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, indicate that the aforementioned epidemiological barriers are being breached and a larger number of younger and healthy individuals are developing severe disease. The new SARS-CoV-2 variants have key mutations that can induce significant changes in the virus-host interactions. Recent studies report that, some of these mutations, singly or in a group, enhance key mechanisms, such as binding of the receptor-binding domain (RBD) of the viral spike protein with the angiotensin-converting enzyme 2 (ACE2) receptor in the hostcells, increase the glycosylation of spike protein at the antigenic sites, and enhance the proteolytic cleavage of the spike protein, thus leading to improved host-cell entry and the replication of the virus. The putative changes in the virus-host interactions imparted by the mutations in the RBD sequence can potentially be the reason behind the breach of the observed epidemiological barriers. Susceptibility for contracting SARS-CoV-2 infection and the disease outcomes are known to be influenced by host-cell expressions of ACE2 and other proteases. The new variants can act more efficiently, and even with the lesser availability of the viral entryreceptor and the associated proteases, can have more efficient host-cell entry and greater replication resulting in high viral loads and prolonged viral shedding, widespread tissue-injury, and severe inflammation leading to increased transmissibility and lethality. Furthermore, the accumulating evidence shows that multiple new variants have reduced neutralization by both, natural and vaccine-acquired antibodies, indicating that repeated and vaccine breakthrough infections may arise as serious health concerns in the ongoing pandemic.

An in silico analysis of early SARS-CoV-2 variant B.1.1.529 (Omicron) genomic sequences and their epidemiological correlates

“…Notably, it has many of the mutations common with the earlier variants of concern (Fig. 3), many of which have been shown to enhance RBD:ACE2 binding in comparison to the WT strain 28 , as has also been reflected in our analysis (Table 1-2). The selective mutations which are either present at or in the vicinity of the RBM (N440K , S477N, T478K, and N501Y) in majority of the Omicron sequences are believed to stabilize binding with ACE2 (Table 2).…”

“…The emerging preliminary evidence from in situ studies indicate potential immune escape by Omicron against convalescent sera, vaccine acquired antibodies, and therapeutically used monoclonal antibodies 23,35,36 . Interestingly, Omicron contains K417N and E484A, which are present in multiple existing variants, and are believed to contribute to immune escape 28 . Of note, K417 locus is a known epitope for CB26—a therapeutically used monoclonal antibody in COVID-19 28 .…”

“…The selective mutations which are either present at or in the vicinity of the RBM (N440K , S477N, T478K, and N501Y) in majority of the Omicron sequences are believed to stabilize binding with ACE2 (Table 2). D614G, a key mutation characteristically present in all B.1 descendents 28 , is known to stabilize the trimeric structure and create a more open conformation of the RBD allowing a stronger binding with ACE2 28 .…”

“…Interestingly, Omicron contains K417N and E484A, which are present in multiple existing variants, and are believed to contribute to immune escape 28 . Of note, K417 locus is a known epitope for CB26-a therapeutically used monoclonal antibody in COVID-19 28 . A larger number of mutations in Omicron spike protein, more specifically in RBD may be an evolutionary gain in this variant providing it higher immune escape.…”

“…The data records show that a significant proportion of the local population in SA has been fully vaccinated by now (25.2%) 45 . Notably, the high number of immune escape mutations in Delta has contributed to lowered efficacy of the vaccines, immunity from the natural infections, and therapeutically used antibodies 28 . As Omicron contains much higher number of immune escape related mutations, including many shared with Delta (Fig.…”