Emerging Variants of SARS-CoV-2 And Novel Therapeutics Against Coronavirus (COVID-19)

Link to article at PubMed

2022 Jan 5. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–.


Coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a devastating effect on the world’s population resulting in more than 5.4 million deaths worldwide and emerging as the most significant global health crisis since the influenza pandemic of 1918. Since being declared a global pandemic by the World Health Organization (WHO) on March 11, 2020, the virus continues to cause devastation, with many countries continuing to endure multiple waves of outbreaks of this viral illness.

Adaptive mutations in the viral genome can alter the virus's pathogenic potential. Even a single amino acid exchange can drastically affect a virus's ability to evade the immune system and complicate the vaccine development progress against the virus. SARS-CoV-2, like other RNA viruses, is prone to genetic evolution while adapting to their new human hosts with the development of mutations over time, resulting in the emergence of multiple variants that may have different characteristics compared to its ancestral strains. Periodic genomic sequencing of viral samples helps detect any new genetic variants of SARS-CoV-2 circulating in communities, especially in a global pandemic setting. The genetic evolution of SARS-CoV-2 was minimal during the early phase of the pandemic with the emergence of a globally dominant variant called D614G, which was associated with higher transmissibility but without increased disease severity of its ancestral strain. Another variant was identified in humans, attributed to transmission from infected farmed mink in Denmark, which was not associated with increased transmissibility. Since then, multiple variants of SARS-CoV-2 have been described, of which a few are considered variants of concern (VOCs), given their impact on public health. VOCs are associated with enhanced transmissibility or virulence, reduction in neutralization by antibodies obtained through natural infection or vaccination, the ability to evade detection, or a decrease in therapeutics or vaccination effectiveness. Based on the recent epidemiological update by the WHO, as of December 11, 2021, five SARS-CoV-2 VOCs have been identified since the beginning of the pandemic:

  1. Alpha (B.1.1.7): first variant of concern described in the United Kingdom (UK) in late December 2020

  2. Beta (B.1.351): first reported in South Africa in December 2020

  3. Gamma(P.1): first reported in Brazil in early January 2021

  4. Delta (B.1.617.2): first reported in India in December 2020

  5. Omicron (B.1.1.529): first reported in South Africa in November 2021

All five reported VOCs -Alpha(B.1.1.7); Beta(B.1.351); Gamma (P.1); Delta(B.1.617.2); and Omicron (B.1.1.529) have mutations in the RBD and the NTD, of which N501Y mutation located on the RBD is common to all variants except the Delta variant which results in increased affinity of the spike protein to ACE 2 receptors enhancing the viral attachment and its subsequent entry into the host cells. Along with NBD, RBD serves as the dominant neutralization target and facilitates antibody production in response to antisera or vaccines. Two recent preprints reported that a single mutation of N501Y alone increases the affinity between RBD and ACE2 approximately ten times more than the ancestral strain (N501-RBD). Interestingly the binding affinity of Beta (B.1.351) variant and Gamma (P.1) variant with mutations N417/K848/Y501-RBD and ACE2 was much lower than that of N501Y-RBD and ACE2. The mutations seen in Omicron are described below.

Despite the extraordinary speed of vaccine development against COVID-19 and continued mass vaccination efforts including guidelines recommending vaccine boosters, the continued emergence of new variant strains of SARS-CoV-2 threaten to overturn the significant progress made so far in halting the spread of SARS-CoV-2. This review article aims to comprehensively describe these new variants of concern, the latest therapeutics available in managing COVID-19 in adults, and the efficacy of different available vaccines against this virus and its new variants.

SARS-CoV-2 Variants of Concern (VOCs)

With the emergence of multiple variants, the CDC and the WHO have independently established a classification system for distinguishing the emerging variants of SARS-CoV-2 into variants of concern(VOCs) and variants of interest(VOIs).

  1. Alpha (B.1.1.7 lineage)

    1. In late December 2020, a new SARS-CoV-2 variant of concern, B.1.1.7 lineage, also referred to as Alpha variant or GRY(formerly GR/501Y.V1), was reported in the UK based on whole-genome sequencing of samples from patients who tested positive for SARS-CoV-2.

    2. In addition to being detected by genomic sequencing, the B.1.1.7 variant was identified in a frequently used commercial assay characterized by the absence of the S gene (S-gene target failure, SGTF) PCR samples. The B.1.1.7 variant includes 17 mutations in the viral genome. Of these, eight mutations (Δ69-70 deletion, Δ144 deletion, N501Y, A570D, P681H, T716I, S982A, D1118H) are in the spike (S) protein. N501Y shows an increased affinity of the spike protein to ACE 2 receptors, enhancing the viral attachment and subsequent entry into host cells.

    3. This variant of concern was circulating in the UK as early as September 2020 and was based on various model projections. It was reported to be 43% to 82% more transmissible, surpassing preexisting variants of SARS-CoV-2 to emerge as the dominant SARS-CoV-2 variant in the UK. The B.1.1.7 variant was reported in the United States (US) at the end of December 2020. An initial matched case-control study reported no significant difference in the risk of hospitalization or associated mortality with the B.1.1.7 lineage variant compared to other existing variants. However, subsequent studies have since reported that people infected with B.1.1.7 lineage variant had increased severity of disease compared to people infected with other circulating forms of virus variants. A large matched cohort study performed in the UK reported that the mortality hazard ratio of patients infected with B.1.1.7 lineage variant was 1.64 (95% confidence interval 1.32 to 2.04, P<0.0001) patients with previously circulating strains. Another study reported that the B 1.1.7 variant was associated with increased mortality compared to other SARS-CoV-2 variants (HR= 1.61, 95% CI 1.42-1.82). The risk of death was reportedly greater (adjusted hazard ratio 1.67, 95% CI 1.34-2.09) among individuals with confirmed B.1.1.7 variant of concern compared with individuals with non-1.1.7 SARS-CoV-2.

  1. Beta (B.1.351 lineage)

    1. Tegally et al. reported a new variant of SARS-CoV-2 lineage B.1.351 also referred to as Beta variant or GH501Y.V2 with multiple spike mutations, which resulted in the second wave of COVID-19 infections in Nelson Mandela Bay in South Africa in October 2020.

    2. The B.1.351 variant includes nine mutations (L18F, D80A, D215G, R246I, K417N, E484K, N501Y, D614G, and A701V) in the spike protein, of which three mutations (K417N, E484K, and N501Y) are located in the RBD and increase the binding affinity for the ACE receptors. SARS-CoV-2 501Y.V2(B.1.351 lineage) was reported in the US at the end of January 2021.

    3. This variant is reported to have an increased risk of transmission and reduced neutralization by monoclonal antibody therapy, convalescent sera, and post-vaccination sera.

  1. Gamma (P.1 lineage)

    1. The third variant of concern, the P.1 variant also known as Gamma variant or GR/501Y.V3, was identified in December 2020 in Brazil and was first detected in the US in January 2021.

    2. The B.1.1.28 variant harbors ten mutations in the spike protein (L18F, T20N, P26S, D138Y, R190S, H655Y, T1027I V1176, K417T, E484K, and N501Y). Three mutations (L18F, K417N, E484K) are located in the RBD, similar to the B.1.351 variant. Based on the WHO epidemiological update on March 30, 2021, this variant has spread to 45 countries. Importantly, this variant may have reduced neutralization by monoclonal antibody therapies, convalescent sera, and post-vaccination sera.

  1. Delta (B.1.617.2 lineage)

    1. The fourth variant of concern, B.1.617.2 also referred to as the Delta variant was initially identified in December 2020 in India and was responsible for the deadly second wave of COVID-19 infections in April 2021 in India. In the United States, this variant was first detected in March 2021 and is currently the most dominant SARS-CoV-2 strain in the US.

    2. The Delta variant was initially considered a variant of interest. However, this variant rapidly spread around the world prompting the WHO to classify it as a VOC in May 2021

    3. The B.1.617.2 variant harbors ten mutations ( T19R, (G142D*), 156del, 157del, R158G, L452R, T478K, D614G, P681R, D950N) in the spike protein

  1. Omicron (B.1.1.529 lineage)

    1. The fifth variant of concern B.1.1.529, also designated as the Omicron variant by the WHO was first identified in South Africa on 23 November 2021 after an uptick in the number of cases of COVID-19.

    2. Omicron was quickly recognized as a VOC due to more than 30 changes to the spike protein of the virus along with the sharp rise in thenumber of cases observed in South Africa. The reported mutations include T91 in the envelope, P13L, E31del, R32del, S33del, R203K, G204R in the nucleocapsid protein, D3G, Q19E, A63T in the matrix, N211del/L212I, Y145del, Y144del, Y143del, G142D, T95I, V70del, H69del, A67V in the N-terminal domain of the spike, Y505H, N501Y, Q498R, G496S, Q493R, E484A, T478K, S477N, G446S, N440K, K417N, S375F, S373P, S371L, G339D in the receptor-binding domain of the spike, D796Y in the fusion peptide of the spike, L981F, N969K, Q954H in the heptad repeat 1 of the spike as well as multiple other mutations in the non-structural proteins and spike protein.

    3. Initial modeling suggests that Omicron shows a 13-fold increase in viral infectivity, and is 2.8 times more infectious than the Delta variant. Early reports also suggest that monoclonal antibodies including Bamlanivimab and the Rockefeller University antibody C144 are likely to have reduced efficacy against the Omicron variant, however, REGN-COV2 (Casirivimab and Imdevimab), as well as the Rockefeller University antibody C135 are predicted to still be effective against Omicron based on early modeling studies.

    4. The Spike mutation K417N (also seen in the Beta variant) along with E484A is predicted to have an overwhelmingly disruptive effect, making Omicron more likely to have vaccine breakthroughs.

SARS-CoV-2 Variants of Interest (VOIs)

VOIs are defined as variants with specific genetic markers that have been associated with changes that may cause enhanced transmissibility or virulence, reduction in neutralization by antibodies obtained through natural infection or vaccination, the ability to evade detection, or a decrease in the effectiveness of therapeutics or vaccination. So far since the beginning of the pandemic, the WHO has described eight variants of interest (VOIs), namely Epsilon (B.1.427 and B.1.429); Zeta (P.2); Eta( B.1.525); Theta (P.3); Iota (B.1.526); Kappa(B.1.617.1); Lambda(C.37)and Mu (B.1.621).

  1. Epsilon (B.1.427 and B.1.429) variants, also called CAL.20C/L452R, emerged in the US around June 2020 and increased from 0% to >50% of sequenced cases from September 1, 2020, to January 29, 2021, exhibiting an 18.6-24% increase in transmissibility relative to wild-type circulating strains. These variants harbor specific mutations (B.1.427: L452R, D614G; B.1.429: S13I, W152C, L452R, D614G). Due to its increased transmissibility, the CDC classified this strain as a variant of concern in the US.

  1. Zeta (P.2) has key spike mutations (L18F; T20N; P26S; F157L; E484K; D614G; S929I; and V1176F) and was first detected in Brazil in April 2020.This variant classified as a VOI by the WHO and the CDC due to its potential reduction in neutralization by antibody treatments and vaccine sera.

  1. Eta (B.1.525) and Iota (B.1.526) variants harbor key spike mutations (B.1.525: A67V, Δ69/70, Δ144, E484K, D614G, Q677H, F888L; B.1.526: (L5F*), T95I, D253G, (S477N*), (E484K*), D614G, (A701V*)) and were first detected in New York in November 2020 and classified as a variant of interest by CDC and the WHO due to their potential reduction in neutralization by antibody treatments and vaccine sera.

  1. Theta (P.3) variant, also called GR/1092K.V1 carries key spike mutations (141-143 deletion E484K; N501Y; and P681H) and was first detected in the Philippines and Japan in February 2021 and is classified as a variant of interest by the WHO.

  1. Kappa(B.1.617.1) variant harbor key mutations ((T95I), G142D, E154K, L452R, E484Q, D614G, P681R, and Q1071H) and was first detected in India in December 2021 and is classified as a variant of interest by the WHO and the CDC.

  1. Lambda(C.37) variant was first detected in Peru and has been designated as a VOI by the WHO in June 2021 due to a heightened presence of this variant in the South American region.

  1. Mu(B.1.621) variant was identified in Columbia and was designated as a VOI by the WHO in August 2021.

The CDC has designated the Epsilon (B.1.427 and B.1.429) variants as a VOC and Eta(B.1.525); Iota (B.1.526); Kappa(B.1.617.1); Zeta (P.2); Mu(B.1.621,B.1.621.1) and B.1.617.3 as VOIs.

PMID:34033342 | Bookshelf:NBK570580

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