The Emergence of SARS-CoV-2 Variant Lambda (C.37)

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The evolution of SARS-CoV-2 variants with potentially increased transmissibility, virulence, and resistance to antibody neutralization poses new challenges for the control of COVID-19 (1), particularly in low and middle-income countries (LMICs) where transmission remains high and vaccination progress is still incipient.

Peru has been severely hit by the COVID-19 pandemic: As of May 31, 2021, it had the highest rate of COVID-19 deaths globally relative to its population (180764 out of 33.38 million: ∼0.54% of the country’s population) (2). By June 2021, 1424 genome sequences from Peru were available on GISAID, comprising 64 circulating PANGO lineages (3). Routine genomic surveillance in early 2021 revealed a deep-branching sublineage of B.1.1.1, now classified as C.37 (Figure 1).

It was first reported in Lima in December 2020 (1 of 192 genomes, 0.5%), expanding to 20.5%, 36.4%, 79.2%, and 96.6% in January, February, March, and April 2021, respectively (Figure 2). In contrast, Variants of Concern were detected less frequently over these four months in Peru: Alpha, n=7, 0.5%; Gamma, n=17, 1.2% (Figure 1).

Maximum likelihood tree from 1424 SARS-CoV-2 genomes reported in Peru as of June 2021, highlighting variants Alpha (n=5), Gamma (n=26) and Lambda (n=239).

Relative frequencies of predominant SARS-CoV-2 lineages in Argentina, Chile, and Peru from November 2020 to May 2021.

C.37 contains a novel deletion (S:Δ247-253, located at the N-terminal domain) and six nonsynonymous mutations in the Spike gene (G75V, T76I, D614G, L452Q, F490S, T859N) (Table 1). Mutations L452Q and F490S both map to the Spike protein’s receptor-binding domain (RBD). While L452Q is almost exclusive to C.37, L452R is present in VOC Delta (B.1.617.2) and Variants of Interest (VOI) Epsilon (B.1.427/B.1.429) and Kappa (B.1.617.1) and is associated with increased affinity for the ACE2 receptor (4). F490S has been associated with reduced in vitro susceptibility to antibody neutralization (5,6). C.37 also displays the ORF1a:Δ3675–3677 deletion, found in VOCs Alpha, Beta, and Gamma (7).

Table 1.

The earliest record of C.37 on GISAID is from Argentina in November 2020. By June 19, 2021, there were 1771 C.37 sequences from 25 countries, including Chile (n=670), USA (n=510), Peru (n=222), Argentina (n=86), Germany (n=79), Mexico (n=55), Spain (n=40), and Ecuador (n=39). Beyond Peru, C.37 has expanded rapidly in Chile and Argentina, reaching 33% and 12% of all sequenced genomes on GISAID by April 2021, respectively (Figure 2). The emergence of this lineage in Peru and its export to other countries is a current hypothesis, given its earlier detection and rise to nearly 100% of public sequences by April. We are sequencing additional Peruvian samples from October to December 2020 to confirm and date the origin of C.37.

Expansion of C.37 has occurred in South America in the presence of hundreds of circulating lineages and VOCs Alpha and Gamma (Figure 1B), suggesting increased transmissibility of this lineage. However, additional epidemiological data and analyses are needed to assess its transmission, virulence, and immune escape properties.

On June 15, 2021, the World Health Organization designated C.37 as VOI Lambda (8).


Figure

Highlights

  • Lambda S is highly infectious and T76I and L452Q are responsible for this property
  • Lambda S is more susceptible to an infection-enhancing antibody
  • RSYLTPGD246-253N, L452Q and F490S confer resistance to antiviral immunity

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During the pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has been diversified. As of July 2021, there are four variants of concerns (VOCs), Alpha [B.1.1.7 lineage; the lineage classification is based on Phylogenetic Assignment of Named Global Outbreak (PANGO): https://cov-lineages.org/resources/pangolin.html], Beta (B.1.351 lineage), Gamma (P.1 lineage) and Delta (B.1.617.2 lineage), and four variants of interests (VOIs), Eta (B.1.525 lineage), Iota (B.1.526 lineage), Kappa (B.1.617.1 lineage) and Lambda (C.37 lineage) (WHO, 2021a). These variants are considered to be the potential threats to the human society.

VOCs and VOIs harbor multiple mutations in their spike (S) protein and are relatively resistant to the neutralizing antibodies (NAbs) that are elicited in convalescent and vaccinated individuals (Chen et al., 2021; Collier et al., 2021; Garcia-Beltran et al., 2021; Hoffmann et al., 2021; Liu et al., 2021a; Liu et al., 2021b; Planas et al., 2021; Wall et al., 2021a; Wang et al., 2021a; Wang et al., 2021b). Because the receptor binding domain (RBD) of the SARS-CoV-2 S protein is immunodominant, mutations in this domain can lead to the immune evasion (Piccoli et al., 2020). Additionally, the mutations in the N-terminal domain (NTD) of the SARS-CoV-2 S protein are associated with the escape neutralization (McCallum et al., 2021). Moreover, the antibodies that enhance viral infectivity [enhancing antibodies (EAbs)] were detected in severe COVID-19 patients, and these EAbs target NTD (Li et al., 2021; Liu et al., 2021c). Because natural mutations in the S NTD crucially influence the sensitivity to antibodies (Gobeil et al., 2021), the accumulation of mutations in this domain is closely associated with the infection spread of VOCs and VOIs.

The Lambda variant (also known as the C.37 lineage) is the newest VOI (designated on June 14, 2021) (WHO, 2021a) and is currently spreading in South American countries such as Peru, Chile, Argentina, and Ecuador (WHO, 2021a). Based on the information data from the Global Initiative on Sharing All Influenza Data (GISAID) database (https://www.gisaid.org; as of June 29, 2021), the Lambda variant has been isolated in 26 countries. Notably, the vaccination rate in Chile is relatively high; the percentage of the people who received at least one dose of COVID-19 vaccine was ~60% on June 1, 2021 (https://ourworldindata.org/covid-vaccinations). A recent paper also suggested that the vaccines have effectively prevented COVID-19 in Chile (Jara et al., 2021). Nevertheless, a big COVID-19 surge has occurred in Chile in Spring 2021 (WHO, 2021b), suggesting that the Lambda variant is proficient in escaping from the antiviral immunity elicited by vaccination. In this study, we reveal the evolutionary trait of the Lambda variant by molecular phylogenetic analysis. We further demonstrate that the RSYLTPGD246-253N mutation, a unique mutation in the NTD of the Lambda S protein, is responsible for the virological phenotype of the Lambda variant that can associate with the massive infection spread mainly in South American countries.

reference link: https://www.biorxiv.org/content/10.1101/2021.07.28.454085v1.full


reference link :https://www.medrxiv.org/content/10.1101/2021.06.26.21259487v1.full-text

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