Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70

• Published in: bioRxiv
• Main Authors: Kemp, Steven A, Meng, Bo, Ferriera, Isabella Atm, Rawlings Datir, Harvey, William T, Papa, Guido, Lytras, Spyros, Collier, Dami A, Ahmed, Mohamed, Gallo, Giulia, Thakur, Nazia, The Covid-19 Genomics Uk (Cog-Uk) Consortium, Carabelli, Alessandro M, Kenyon, Julia C, Lever, Andrew M, De Marco, Anna, Saliba, Christian, Culap, Katja, Cameroni, Elisabetta, Piccoli, Luca, Corti, Davide, James, Leo C, Bailey, Dalan, Robertson, David L, Gupta, Ravindra K
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 08.03.2021
• Subjects: Amino acids; Cell fusion; Gene deletion; Infectivity; Mutation; S gene; Severe acute respiratory syndrome coronavirus 2; Spike protein; Vaccines; Virions
• DOI: 10.1101/2020.12.14.422555

Abstract SARS-CoV-2 amino acid replacements in the receptor binding domain (RBD) occur relatively frequently and some have a consequence for immune recognition. Here we report recurrent emergence and significant onward transmission of a six-nucleotide out of frame deletion in the S gene, which results in loss of two amino acids: H69 and V70. We report that in human infections ΔH69/V70 often co-occurs with the receptor binding motif amino acid replacements N501Y, N439K and Y453F, and in the latter two cases has followed the RBD mutation. One of the ΔH69/V70+ N501Y lineages, now known as B.1.1.7, has undergone rapid expansion and includes eight S gene mutations: RBD (N501Y and A570D), S1 (ΔH69/V70 and Δ144) and S2 (P681H, T716I, S982A and D1118H). In vitro, we show that ΔH69/V70 does not reduce serum neutralisation across multiple convalescent sera. However, ΔH69/V70 increases infectivity and is associated with increased incorporation of cleaved spike into virions. ΔH69/V70 is able to compensate for small infectivity defects induced by RBD mutations N501Y, N439K and Y453F. In addition, replacement of H69 and V70 residues in the B.1.1.7 spike reduces its infectivity and spike mediated cell-cell fusion. Based on our data ΔH69/V70 likely acts as a permissive mutation that allows acquisition of otherwise deleterious immune escape mutations. Enhanced surveillance for the ΔH69/V70 deletion with and without RBD mutations should be considered as a global priority not only as a marker for the B.1.1.7 variant, but potentially also for other emerging variants of concern. Vaccines designed to target the deleted spike protein could mitigate against its emergence as increased selective forces from immunity and vaccines increase globally. Highlights * ΔH69/V70 is present in at least 28 SARS-CoV-2 lineages * ΔH69/V70 does not confer escape from convalescent sera * ΔH69/V70 increases spike infectivity and compensates for RBD mutations * ΔH69/V70 is associated with greater spike cleavage * B.1.1.7 requires ΔH69/V70 for optimal spike cleavage and infectivity Competing Interest Statement RKG has received consulting fees from UMOVIS lab, Gilead Sciences and ViiV Healthcare, and a research grant from InvisiSmart Technologies. Footnotes * ↵8 https://www.cogconsortium.uk. Full list of consortium names and affiliations are in Appendix * additional data on del69/70 impact on infectivity, spike incorporation and impact in the B.1.1.7 spike background