We report SARS-CoV-2 spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of the receptor binding motif replacements such as N439K and Y453F known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro , we show that whilst ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of S proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of H69 and V70 residues in B.1.1.7 spike (where ΔH69/V70 naturally occurs) impairs spike incorporation and entry efficiency of B.1.1.7 spike pseudotyped virus. B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted.

SARS-CoV-2 Spike 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 deletion in the S gene, which results in loss of two amino acids: H69 and V70. Of particular note this deletion, 𝚫H69/V70, often co-occurs with the receptor binding motif amino acid replacements N501Y, N439K and Y453F. One of the 𝚫H69/V70+ N501Y lineages, B.1.1.7, is comprised of over 4000 SARS-CoV-2 genome sequences from the UK and includes eight other S gene mutations: RBD (N501Y and A570D), S1 (𝚫H69/V70 and 𝚫144/145) and S2 (P681H, T716I, S982A and D1118H). Some of these mutations have presumably arisen as a result of the virus evolving from immune selection pressure in infected individuals and at least one, lineage B.1.1.7, potentially from a chronic infection. Given our recent evidence that delH69/V70 enhances viral infectivity (Kemp et al. 2020), its effect on virus fitness appears to be independent to the RBD changes. Enhanced surveillance for the delH69/V70 deletion with and without RBD mutations should be considered as a priority. Permissive mutations such as delH69/V70 have the potential to enhance the ability of SARS-CoV-2 to generate new variants, including vaccine escape variants, that would have otherwise significantly reduced viral infectivity.

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