Emergence of Lambda Variant with Reduced Antibody Response; are We Facing another Worst Wave?

The variants, variants of concern (VOCs), and variants of interest (VOIs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pose a threat due to higher transmission rates, increased virulence, weakened vaccine protection, and reduced neutralizing antibody-based therapeutics. This poses a new challenge, particularly in low- and middle-income countries where vaccination is not widely available. Multiple variants of SARS-CoV-2, including B.1.351 (Beta), B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), B.1.526 (Iota), and B.1.1.248 (Gamma) express L452R, E484K, and E484Q mutations in the spike protein binding receptor, enabling neutralization of antibodies in vaccinated individuals and reduced efficacy [1],[2],[3],[4],[5].

The recent emergence of the lambda variant (C.37) in Peru and South America raises the risk of another wave of SARS-CoV-2 spreading around the world. While hundreds of lineages circulated simultaneously, SARS-CoV-2 C.37 spread quickly throughout South America, implying higher transmissibility for that lineage [5],[6]. On June 14, 2021, the World Health Organization designated the lambda variant as a variant of interest (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). Whole-genome sequencing and GISAID entry revealed that the lambda variant C.37 contains a unique deletion in the spike protein of SARS-CoV-2 at positions 247- 253 in the N-terminal domain (NTD), as well as six novel nonsynonymous mutations named T76I, L452Q, G75V, F490S, D614G, and T859N in the spike gene of SARS-CoV-2 that are highly (more than 90%) conserved. SARS-CoV-2 C.37 also has a unique deletion in the ORF1a gene at locations 3675-3677, which is similarly seen in Alpha, Beta, and Gamma variants of the virus [7],[8].

The L452Q substitution mutation is unique to this form, and the F490S and L452Q mutations occur in the spike protein’s RBD (receptor-binding domain). The delta variant (B.1.617.2) has the VOC mutation, the Epsilon variant (B.1.429/B.1.427) has the VOI mutation, and the kappa variant (B.1.617.1) has the VOI mutation, which is responsible for their greater infectivity. The L452Q and T76I substitution mutations cause increased binding affinity of the spike protein for the ACE2 receptor, which increases lineage transmissibility, whereas the L452Q and F490S mutations cause susceptibility to re-infection as well as decreased neutralizing antibody efficiency in vaccinated and unvaccinated individuals. The lambda variant (C.37) of SARS-CoV-2 is capable of evading vaccine-induced neutralizing antibodies due to the presence of a large, unique, and extremely conserved 7-amino-acid deletion in the NTD of the lambda spike protein called RSYLTPGD246-253N [5],[7],[8] (https://www.tbsnews.net/tags/lambda-variant).