Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape

McCarthy, K.; Rennick, Linda J.; Nambulli, Sham; Robinson-McCarthy, Lindsey R.; Bain, William; Haidar, Ghady; Duprex, W. Paul

doi:10.1101/2020.11.19.389916

Cited by 104 publications

(150 citation statements)

References 46 publications

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“…Deletions in the N-terminal domain (NTD) of Spike S1 are also being increasingly recognised, both within hosts 7 and across individuals 8 . The evolutionary basis for the emergence of deletions is unclear at present, and could be related to escape from immunity or to enhanced fitness/transmission.…”

Section: Introductionmentioning

confidence: 99%

Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation

Kemp

Collier

Datir

et al. 2020

Preprint

160

145

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SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2, and amino acid variation in Spike is increasingly appreciated. Given both vaccines and therapeutics are designed around Wuhan-1 Spike, this raises the theoretical possibility of virus escape, particularly in immunocompromised individuals where prolonged viral replication occurs. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences by both short and long read technologies over 23 time points spanning 101 days. Although little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days, N501Y in Spike was transiently detected at day 55 and V157L in RdRp emerged. However, following convalescent plasma we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility, but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type and appeared to compensate for the reduced infectivity of D796H. Consistent with the observed mutations being outside the RBD, monoclonal antibodies targeting the RBD were not impacted by either or both mutations, but a non RBD binding monoclonal antibody was less potent against ΔH69/ΔV70 and the double mutant. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with reduced susceptibility to neutralising antibodies.

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Section: Introductionmentioning

confidence: 99%

Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation

Kemp

Collier

Datir

et al. 2020

Preprint

160

145

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“…1A). While variants with deletions in this region of Spike are observed in GISAID 13 , the earliest unambiguous sequence that includes the H69/V70 was detected in Sweden in April 2020, an independent deletion event relative to other H69/V70 variants. The prevalence of H69/V70 has since increased since August 2020 ( Fig.…”

Section: Resultsmentioning

confidence: 98%

“…Protein structure modelling indicates this mutation could also contribute to antibody evasion as suggested for other NTD deletions 13 .…”

mentioning

confidence: 80%

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Recurrent independent emergence and transmission of SARS-CoV-2 Spike amino acid H69/V70 deletions

Gupta

Kemp

Harvey

et al. 2021

Preprint

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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 𝚫H69/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 𝚫H69/V70 deletion with and without RBD mutations should be considered as a priority. Permissive mutations such as 𝚫H69/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 fitness.

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“…Overall, these results suggest that when the neutralizing activity of potent human sera is rapidly eroded by viral evolution this is often due to mutations within the RBD, but that antigenic evolution also occurs elsewhere in the spike. In this respect, it is worth noting that while the neutralizing activity of SARS-CoV-2 immunity elicited by infection primarily targets the RBD (Piccoli et al, 2020), mutations to the NTD also reduce neutralization by some antibodies and sera (Chi et al, 2020;Kemp et al, 2020;Liu et al, 2020a;McCarthy et al, 2020;Weisblum et al, 2020;Zhou et al, 2019)-and some regions of the NTD undergo significant sequence evolution in 229E ( Figure 4A).…”

Section: Much Of the Antigenic Evolution Is Due To Mutations In The Smentioning

confidence: 99%

A human coronavirus evolves antigenically to escape antibody immunity

Eguia

Crawford

Stevens-Ayers

et al. 2020

Preprint

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There is intense interest in antibody immunity to coronaviruses. However, it is unknown if coronaviruses evolve to escape such immunity, and if so, how rapidly. Here we address this question by characterizing the historical evolution of human coronavirus 229E. We identify human sera from the 1980s and 1990s that have neutralizing titers against contemporaneous 229E that are comparable to the anti-SARS-CoV-2 titers induced by SARS-CoV-2 infection or vaccination. We test these sera against 229E strains isolated after sera collection, and find that neutralizing titers are lower against these “future” viruses. In some cases, sera that neutralize contemporaneous 229E viral strains with titers >1:100 do not detectably neutralize strains isolated 8–17 years later. The decreased neutralization of “future” viruses is due to antigenic evolution of the viral spike, especially in the receptor-binding domain. If these results extrapolate to other coronaviruses, then it may be advisable to periodically update SARS-CoV-2 vaccines.

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Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape

Cited by 104 publications

References 46 publications

Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation

Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation

Recurrent independent emergence and transmission of SARS-CoV-2 Spike amino acid H69/V70 deletions

A human coronavirus evolves antigenically to escape antibody immunity

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