SARS-CoV-2 Viral Variants—Tackling a Moving Target

Abstract

In this issue of JAMA, Zhang and colleagues 1 report the emergence of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant in Southern California that accounted for 44% (37 of 85) of samples collected and studied in January 2021. The terminology of viral variation can be confusing because the media and even scientific communications often use the terms variant, strain, and lineage interchangeably. The terminology reflects the basic replication biology of RNA viruses that results in the introduction of mutations throughout the viral genome. When specific mutations, or sets of mutations, are selected through numerous rounds of viral replication, a new variant can emerge. If the sequence variation produces a virus with distinctly different phenotypic characteristics, the variant is co-termed a strain. When through genetic sequencing and phylogenetic analysis a new variant is detected as a distinct branch on a phylogenetic tree, a new lineage is born. New variants become predominant through a process of evolutionary selection that is not well understood. Once identified, several questions arise regarding the potential clinical consequences of a new variant: Is it more readily transmitted; is it more virulent or pathogenic; and can it evade immunity induced by vaccination or prior infection? For these reasons, new viral variants are studied, leading to the terms variant under investigation or variant of concern. To communicate effectively about new SARS-CoV-2 variants, a common nomenclature is needed, which like the virus, is evolving. Fortunately, the World Health Organization (WHO) is working on a systematic nomenclature that does not require a geographic reference, since viral variants can spread rapidly and globally. Currently, the terminology is overlapping, as reflected in the report by Zhang et al. 1 This new variant (CAL.20C) is termed lineage 20C/S:452R in Nextstrain nomenclature, 2 referring to the parent clade 20C and spike alteration 452R. Similarly, using a distinct PANGO nomenclature, 3 this variant derives from lineage B (B.1.429 and B.1.427). While alterations in any viral genes can have implications for pathogenesis, those arising in the spike protein that mediates viral entry into host cells and is a key target of vaccines and monoclonal antibodies are of particular interest. The new variant, identified in California and termed 20C/S:452R, has 3 amino acid changes in the spike protein, represented using the single-letter amino acid nomenclature: S13I, W152C, and L452R. To interpret this new set of alterations, it is useful to review what is known about recent variants that have become predominant in other regions of the world.

Acquisition of the L452R mutation in the ACE2-binding interface of Spike protein triggers recent massive expansion of SARS-Cov-2 variants

“…The recent emergence of mutational variants of SARS-CoV-2 (nCoV) around the globe suggests adaptive evolution of the virus, potentially affecting its transmissibility, infectivity, virulence and/or immune escape [1–4]. The primary target of current vaccines and monoclonal antibodies is the Spike protein which mediates viral attachment to and entry into host cells [5, 6].…”

“…Because of the important functional and antigenic properties of RBD, structural changes in this domain deserve special attention and have already been highlighted by such notorious RBD mutations as E484K (e.g. found in the ‘Brazil’ variant B.1.1.28) or N501Y (found in the ‘British’ B.1.1.7 variant and ‘South African’ B.1.351 variant) [1].…”

Quantitative detection of SARS-CoV-2 B.1.1.7 variant in wastewater by allele-specific RT-qPCR

“…Recent rollout of vaccines across a number of countries has been an important milestone in fighting the pandemic. However, the emergence of new variants of concern (VOCs) such as B.1.1.7 and B.1.351 suggests that continued vigilance is required to control the COVID-19 pandemic (Mascola, Graham, & Fauci, 2021). For example, the B.1.1.7 variant contains spike protein mutations D614G and N501Y that have been reported to increase transmission and to subsequently cause a more severe COVID-19 manifestation with increased hospitalization and mortality rates (Davies et al, 2021;Hou et al, 2020;Korber et al, 2020;Rambaut et al, 2020).…”

Convalescent Plasma for the Prevention and Treatment of COVID-19: A Systematic Review and Quantitative Analysis

“…Despite this incredible progress on COVID-19, many challenges remain post vaccine development including ongoing vaccine deployment, large-scale production and distribution of billions of vaccine doses [21], and uncertainty over the effectiveness of current vaccines against more transmissible new variants [22]. These factors, combined with public hesitation around vaccination, have casted doubt on the likelihood of achieving worldwide herd immunity in the near future [23].…”