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. 2021 Sep 17;224(6):989-994.
doi: 10.1093/infdis/jiab368.

SARS-CoV-2 B.1.617 Mutations L452R and E484Q Are Not Synergistic for Antibody Evasion

Isabella A T M Ferreira  1   2 , Steven A Kemp  1   2 , Rawlings Datir  1   2 , Akatsuki Saito  3 , Bo Meng  1   2 , Partha Rakshit  4 , Akifumi Takaori-Kondo  5 , Yusuke Kosugi  6 , Keiya Uriu  6 , Izumi Kimura  6 , Kotaro Shirakawa  5 , Adam Abdullahi  1   2 , Anurag Agarwal  7 , Seiya Ozono  8 , Kenzo Tokunaga  8 , Kei Sato  6   9 , Ravindra K Gupta  1   2   10 ; CITIID-NIHR BioResource COVID-19 Collaboration, Indian SARS-CoV-2 Genomics Consortium; Genotype to Phenotype Japan (G2P-Japan) Consortium
Affiliations

SARS-CoV-2 B.1.617 Mutations L452R and E484Q Are Not Synergistic for Antibody Evasion

Isabella A T M Ferreira et al. J Infect Dis. .

Abstract

The SARS-CoV-2 B.1.617 variant emerged in the Indian state of Maharashtra in late 2020. There have been fears that 2 key mutations seen in the receptor-binding domain, L452R and E484Q, would have additive effects on evasion of neutralizing antibodies. We report that spike bearing L452R and E484Q confers modestly reduced sensitivity to BNT162b2 mRNA vaccine-elicited antibodies following either first or second dose. The effect is similar in magnitude to the loss of sensitivity conferred by L452R or E484Q alone. These data demonstrate reduced sensitivity to vaccine-elicited neutralizing antibodies by L452R and E484Q but lack of synergistic loss of sensitivity.

Keywords: B.1.617; COVID-19; Indian variant; SARS-CoV-2; antibody escape; evasion; fitness; infectivity; neutralizing antibodies; resistance; spike mutation.

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Figures

Figure 1.
Figure 1.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.617 variant emerging in India A, Maximum-likelihood phylogeny of lineages bearing L452R in spike. All sequences with the L452R mutation were downloaded from https://gisaid.org and manually aligned to reference strain MN908947.3 with mafft. Sequences were deduplicated and a random subset of 400 global sequences and 100 US sequences were then selected with seqtk. All sequence lineages were assigned using pangolin version 2.4. Major lineages are indicated as straight lines adjacent to the heatmap, alongside mutations of current interest. The phylogeny was inferred with IQTREE2 version 2.1.3. B, The number of B.1617 cases per month in India in the first half of 2021.
Figure 2.
Figure 2.
Entry efficiency and neutralization sensitivity of B.1.617 mutant pseudotyped viruses following mRNA vaccination A, Surface representation of the spike protein in open formation with neutralizing antibody H4 (pink spheres, Protein Data Bank 7L58, [8] ) bound to 1 monomer of the spike protein. Residues L452 and E484 are indicated with red and green spheres, respectively. Ribbon is a representation of the interaction between the neutralizing antibody H4 and the receptor-binding domain of a spike monomer. Neutralization by (B) first-dose and (C) second-dose mRNA vaccine-elicited sera against wild type (WT) and mutant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike pseudotyped viruses. Reciprocal geometric mean titer shown with 95% confidence interval. *P < .05, ***P < .001, ****P < .0001. D, Virus infectivity of pseudotyped virus (PV) bearing indicated spike mutations. PVs were generated in 293T cells and used to infect HOS cells transduced with ACE2 and TMPRSS2. Input virus was normalized for protein expression. Data are technical triplicates and mean with SE is plotted. Data are representative of 2 independent experiments.
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References

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