From all the mutations identified in this new variant (Fig. 1), mutation E484K, located in the receptor-binding domain of the spike protein, has been related to ACE2 and antibody binding being considered a variant of concern. This mutation was first identified in viral sequences from Brazil and South Africa being related to reinfection cases, an increase in ACE2 binding and, most importantly, it was shown to confer resistance to neutralizing antibodies in vaccinated people (9)(10)
Bioinformatic analyses showed that the B.1.526 lineage, first detected in New York (11), presents 17 amino acid substitutions compared to the initial SARS-CoV-2 reference genome (Wuhan-Hu-1), which are the following: S: A701V, D253G, D614G, E484K, L5F and T95I; N: M234I and P199L; NSP3: P42L and Q57H; NSP8: T11I; NSP2: T85I; NSP4: L438P: NSP6: F108del, G107del and S106del; NSP12: P323L and NSP13: Q88H (Fig. 1). Mutation C14408T (P323L) on the NSP12 (RNA-dependent RNA polymerases, RdRp) protein is detected in 94% of substitutions detected in 5996 complete genomes reported in South America (Fig. S1). Although the proline to leucine substitution was proposed to not have functional consequences on RdRp (12), it is required to establish whether the loss of steric restriction imposed by the proline residue alters the functionality of RdRp (13).
The L5F mutation in the spilke protein was found in 0,6% of viral genome sequences (36 sequences) reported in South America and only 6 genomes include the pattern L5F and E484K, suggesting a low positive selection pressure. L5F is located in the signal peptide domain of the spike protein (14). Recent data using prediction algorithms indicate that this mutation could be unsuccessful because it increases the affinity of different HLA alleles and enhances CD8 T cells killing of SARS-CoV-2 infected cells (15). However, the emergence of the L5F mutation in combination with E485K should be kept under surveillance. Spike replacement of T95I does not have relevant characteristics to the virus and humans. Nevertheless, more studies are required to determine its effect.
The D253G mutation in the N-terminal domain (NTD) of Spike protein only has been found in four complete genomes sequenced in South America of the 1.432 genomes that register the mutation worldwide. Recently, D253G mutation was described as important for recognition of mAb and it may be related with scape mutation of NTD (16). E484K substitution was also reported in South Africa B.1.351 lineage (2) and Brazil P.1 lineage (17).This mutant has been reported in 13.6% of complete genomes registered in South America of the 2,683 genomes that include E484K mutation worldwide. with the biological background of this substitution, a more exhaustive genomic surveillance in South America is necessary.
D614G substitution is a dominant mutation around the world and may improve viral fitness (18) but clinical effect is yet not to be fully determined (14).
The A701V mutation has been identified in three genome sequences from South America, one from Brazil and two reported in this study (Fig. 1) according to GISAID (https://www.gisaid.org/). The A701V mutation was found in the South African lineage (B.1.351) along with the D614G mutation in mid-October. This substitution is located near to protease cleavage sites S2 subunit of Spike protein (19).
Phylogenetic analysis of 2,122 genomes presenting the E484K substitution showed that the two B.1.526 samples from South America are grouped in the cluster conformed mainly by viral sequences obtained in the US in green (Fig. 2, Table S1). The origin of this variant would not be from Brazil or South Africa, although they share point mutations with the P.1 and B.1.351 variants. It is important to determine whether the B.1.526 variant is being distributed continuously in South America. For instance, on August 11th, 2020, a sample of clade B.1.1.74 (ID: EPI_ISL_671989) was identified in the same city where B.1.526 is being reported (Fig. 2).
The introduction of a variant carrying the immune escape-associated mutation E484K mutation such as the B.1.526 in South America, and especially in Ecuador, is of utmost concern since massive access to vaccines is not equally guaranteed across countries. The rapid emergence of new variants of biological interest such as that reported in this study highlights the need to increase mobility restrictions and accelerate vaccination processes in South America, specifically in countries where vaccination is limited. Further, genomic and immune surveillance are critical to determining the impact of this new variant in SARS-CoV-2 transmission and immunity dynamics.