Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants

James W Saville,Inna Sekirov,Sriram Subramaniam,Dhiraj Mannar,Katharine S Tuttle,Wei Li,Andrew Kim,Shanti S Srivastava,Steven Zhou,Jean-Philippe Demers,Dimiter S Dimitrov,Xing Zhu,Alison M Berezuk

doi:10.1038/s41467-022-28324-6

James W Saville, Inna Sekirov + Show 11 more

Open Access

https://doi.org/10.1038/s41467-022-28324-6

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Abstract

The Delta and Kappa variants of SARS-CoV-2 co-emerged in India in late 2020, with the Delta variant underlying the resurgence of COVID-19, even in countries with high vaccination rates. In this study, we assess structural and biochemical aspects of viral fitness for these two variants using cryo-electron microscopy (cryo-EM), ACE2-binding and antibody neutralization analyses. Both variants demonstrate escape of antibodies targeting the N-terminal domain, an important immune hotspot for neutralizing epitopes. Compared to wild-type and Kappa lineages, Delta variant spike proteins show modest increase in ACE2 affinity, likely due to enhanced electrostatic complementarity at the RBD-ACE2 interface, which we characterize by cryo-EM. Unexpectedly, Kappa variant spike trimers form a structural head-to-head dimer-of-trimers assembly, which we demonstrate is a result of the E484Q mutation and with unknown biological implications. The combination of increased antibody escape and enhanced ACE2 binding provides an explanation, in part, for the rapid global dominance of the Delta variant.

Highlights

The Delta and Kappa variants of SARS-CoV-2 co-emerged in India in late 2020, with the Delta variant underlying the resurgence of COVID-19, even in countries with high vaccination rates
We present a comparative analysis of the effects of the Delta and Kappa variant S protein mutations on aspects of viral fitness
As discussed below, is that in the context of antibody evasion and ACE2 affinity, the Delta and Kappa variants do not differ to a great degree, and that the global dominance of the Delta variant is likely a result of enhancements in other aspects of viral fitness

Summary

Introduction

The Delta and Kappa variants of SARS-CoV-2 co-emerged in India in late 2020, with the Delta variant underlying the resurgence of COVID-19, even in countries with high vaccination rates. In March 2021, genomic sequencing of SARS-CoV-2 samples in Maharashtra, India revealed an increased prevalence of E484Q, L452R and P681R co-mutation in the Spike glycoprotein (S protein)[1–3] This variant was called the double mutant by the global news media and was later designated as lineage B.1.617.1 and the Kappa variant of interest by the World Health Organization[4]. How the combinatorial effect of the Delta and Kappa S protein mutations contribute towards increased viral fitness remains superficially characterised relative to previously emerged variants of concern (Alpha, Beta and Gamma). We report cryo-electron microscopy (cryo-EM) structures of Delta and Kappa variant S protein trimers – both in the unbound state and in complex with the ACE2 receptor – to gain insight into how their mutations underlie changes in ACE2 binding and antibody neutralisation escape. We go on to report two additional structures of S proteins containing novel substitutions at position 484 (I484 and A484) to dissect the chemical nature of this dimerisation event

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