Implications of the Novel Mutations in the SARS-CoV-2 Genome for Transmission, Disease Severity, and the Vaccine Development

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of the coronavirus disease 2019 (COVID-19), has been identified in China in late December 2019. SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA betacoronavirus of the Coronaviridae family. Coronaviruses have genetic proofreading mechanism that corrects copying mistakes and thus SARS-CoV-2 genetic diversity is extremely low. Despite lower mutation rate of the virus, researchers have detected a total of 12,706 mutations in the SARS-CoV-2 genome, the majority of which were single nucleotide polymorphisms. Sequencing data revealed that the SARS-CoV-2 accumulates two-single nucleotide mutations per month in its genome. Recently, an amino acid aspartate (D) to glycine (G) (D614G) mutation due to an adenine to guanine nucleotide change at position 23,403 at the 614th amino-acid position of the spike protein in the original reference genotype has been identified. The SARS-CoV-2 viruses that carry the spike protein D614G mutation have become dominant variant around the world. The D614G mutation has been found to be associated with 3 other mutations in the spike protein. Clinical and pseudovirus experimental studies have demonstrated that the spike protein D614G mutation alters the virus phenotype. However, the impact of the mutation on the rate of transmission between people, disease severity and the vaccine and therapeutic development remains unclear. Three variants of SARS-CoV-2 have recently been identified. They are B.1.1.7 (UK) variant, B.1.351 (N501Y.V2, South African) variant and B.1.1.28 (Brazilian) variant. Epidemiological data suggest that they have a higher transmissibility than the original variant. There are reports that some vaccines are less efficacious against the B.1.351 variant. This review article discusses the effects of novel mutations in the SARS-CoV-2 genome on transmission, clinical outcomes and vaccine development.

Keywords: COVID-19; SARS-CoV-2; mutation; new UK variant; vaccine.

Figure 1

Genomic Landscape of SARS-CoV-2 Virus. (A) The receptor binding domain (RBD) in the spike protein is the most varibale part of the genome. Six amino acids have been shown to be pivotal for binding to ACE2 receptors. Key residues in the spike protein that make contact to ACE2 receptor are shown with blue boxes. (B) Polybasic cleavage site (PRAR) at the junction of S1 and S2 subunit is a relevant feature of the viral genome. This allows effective cleavage by furin and other proteases and has a role in determining viral infectivity (3).

Figure 2

Life Cycle of the Coronaviruses. Coronaviruses particles bind to ACE2 receptor. TMPRSS2 promote viral uptake and fusion at the cellular or endosomal membrane. Following entry, the release and uncoating of the genomic RNA subject it to the immediate translation of the two large open reading frames, ORF1a, and ORF1b. During the cellular life cycle, coronaviruses express and replicate their genomic RNA to produce full-length copies that are incorporated into newly produced viral particles (8).