Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7

• DOI: 10.1016/j.celrep.2021.109292
• Publication Date: 2021-06-08T07:58:30Z
• Authors: Bo Meng; Steven A. Kemp; Guido Papa; Rawlings Datir; Isabella A.T.M. F...; Sara Marelli; William T. Harvey; Spyros Lytras; Ahmed Mohamed; Giulia Gallo; Nazia Thakur; Dami A. Collier; Petra Mlcochova; Samuel C. Robson; Nicholas J. Loman; Thomas R. Connor; Tanya Golubchik; Rocio T. Martinez...; Catherine Ludden; Sally Corden; Ian Johnston; David Bonsall; Colin P. Smith; Ali R. Awan; Giselda Bucca; M. Estee Torok; Kordo Saeed; Jacqui A. Prieto; David K. Jackson; William L. Hamilton; Luke B. Snell; Catherine Moore; Ewan M. Harrison; Sonia Goncalves; Derek J. Fairley; Matthew W. Loose; Joanne Watkins; Rich Livett; Samuel Moses; Roberto Amato; Sam Nicholls; Matthew Bull; Darren L. Smith; Jeff Barrett; David M. Aanensen; Martin D. Curran; Surendra Parmar; Dinesh Aggarwal; James G. Shepherd; Matthew D. Parker; Sharon Glaysher; Matthew Bashton; Anthony P. Underwood; Nicole Pacchiarini; Katie F. Loveson; Kate E. Templeton; Cordelia F. Langford; John Sillitoe; Thushan I. de Silva; Dennis Wang; Dominic Kwiatkowski; Andrew Rambaut; Justin O’Grady; Simon Cottrell; Matthew T.G. Holden; Emma C. Thomson; Husam Osman; Monique Andersson; Anoop J. Chauhan; Mohammed O. Hassa...; Mara Lawniczak; Alex Alderton; Meera Chand; Chrystala Constan...; Meera Unnikrishnan; Alistair C. Darby; Julian A. Hiscox; Steve Paterson; Inigo Martincorena; Erik M. Volz; Andrew J. Page; Oliver G. Pybus; Andrew R. Bassett; Cristina V. Ariani; Michael H. Spence...; Kathy K. Li; Rajiv N. Shah; Natasha G. Jesudason; Yusri Taha; Martin P. McHugh; Rebecca Dewar; Aminu S. Jahun; Claire McMurray; Sarojini Pandey; James P. McKenna; Andrew Nelson; Gregory R. Young; Clare M. McCann; Scott Elliott; Hannah Lowe; Ben Temperton; Sunando Roy; Anna Price; Sara Rey; Matthew Wyles; Stefan Rooke; Sharif Shaaban; Mariateresa de Ce...; Laura Letchford; Siona Silveira; Emanuela Pelosi; Eleri Wilson-Davies; Myra Hosmillo; Áine O’Toole; Andrew R. Hesketh; Richard Stark; Louis du Plessis; Chris Ruis; Helen Adams; Yann Bourgeois; Stephen L. Michell; Dimitris Grammato...; Jonathan Edgeworth; Judith Breuer; John A. Todd; Christophe Fraser; David Buck; Michaela John; Gemma L. Kay; Steve Palmer; Sharon J. Peacock; David Heyburn; Danni Weldon; Esther Robinson; Alan McNally; Peter Muir; Ian B. Vipond; John Boyes; Venkat Sivaprakasam; Tranprit Salluja; Samir Dervisevic; Emma J. Meader; Naomi R. Park; Karen Oliver; Aaron R. Jeffries; Sascha Ott; Ana da Silva Filipe; David A. Simpson; Chris Williams; Jane A.H. Masoli; Bridget A. Knight; Christopher R. Jones; Cherian Koshy; Amy Ash; Anna Casey; Andrew Bosworth; Liz Ratcliffe; Li Xu-McCrae; Hannah M. Pymont; Stephanie Hutchings; Lisa Berry; Katie Jones; Fenella Halstead; Thomas Davis; Christopher Holmes; Miren Iturriza-Go...; Anita O. Lucaci; Paul Anthony Randell; Alison Cox; Pinglawathee Madona; Kathryn Ann Harris; Julianne Rose Brown; Tabitha W. Mahungu; Dianne Irish-Tavares; Tanzina Haque; Jennifer Hart; Eric Witele; Melisa Louise Fenton; Steven Liggett; Clive Graham; Emma Swindells; Jennifer Collins; Gary Eltringham; Sharon Campbell; Patrick C. McClure; Gemma Clark; Tim J. Sloan; Carl Jones; Jessica Lynch; Ben Warne; Steven Leonard; Jillian Durham; Thomas Williams; Sam T. Haldenby; Nathaniel Storey; Nabil-Fareed Alikhan; Nadine Holmes; Christopher Moore; Matthew Carlile; Malorie Perry; Noel Craine; Ronan A. Lyons; Angela H. Beckett; Salman Goudarzi; Christopher Fearn; Kate Cook; Hannah Dent; Hannah Paul; Robert Davies; Beth Blane; Sophia T. Girgis; Mathew A. Beale; Katherine L. Bellis; Matthew J. Dorman; Eleanor Drury; Leanne Kane; Sally Kay; Samantha McGuigan; Rachel Nelson; Liam Prestwood; Shavanthi Rajatileka; Rahul Batra; Rachel J. Williams; Mark Kristiansen; Angie Green; Anita Justice; Adhyana I.K. Maha...; Buddhini Samaraweera; Nazreen F. Hadjirin; Joshua Quick; Radoslaw Poplawski; Leanne M. Kermack; Nicola Reynolds; Grant Hall; Yasmin Chaudhry; Malte L. Pinckert; Iliana Georgana; Robin J. Moll; Alicia Thornton; Richard Myers; Joanne Stockton; Charlotte A. Will...; Wen C. Yew; Alexander J. Trotter; Amy Trebes; George MacIntyre-...; Alec Birchley; Alexander Adams; Amy Plimmer; Bree Gatica-Wilcox; Caoimhe McKerr; Ember Hilvers; Hannah Jones; Hibo Asad; Jason Coombes; Johnathan M. Evans; Laia Fina; Lauren Gilbert; Lee Graham; Michelle Cronin; Sara Kumziene-Sum...; Sarah Taylor; Sophie Jones; Danielle C. Groves; Peijun Zhang; Marta Gallis; Stavroula F. Louka; Igor Starinskij; Chris Jackson; Marina Gourtovaia; Gerry Tonkin-Hill; Kevin Lewis; Jaime M. Tovar-Co...; Keith James; Laura Baxter; Mohammad T. Alam; Richard J. Orton; Joseph Hughes; Sreenu Vattipally; Manon Ragonnet-Cr...; Fabricia F. Nasci...; David Jorgensen; Olivia Boyd; Lily Geidelberg; Alex E. Zarebski; Jayna Raghwani; Moritz U.G. Kraemer; Joel Southgate; Benjamin B. Lindsey; Timothy M. Freeman; Jon-Paul Keatley; Joshua B. Singer; Leonardo de Olive...; Corin A. Yeats; Khalil Abudahab; Ben E.W. Taylor; Mirko Menegazzo; John Danesh; Wendy Hogsden; Sahar Eldirdiri; Anita Kenyon; Jenifer Mason; Trevor I. Robinson; Alison Holmes; James Price; John A. Hartley; Tanya Curran; Alison E. Mather; Giri Shankar; Rachel Jones; Robin Howe; Sian Morgan; Elizabeth Wastenge; Michael R. Chapman; Siddharth Mookerjee; Rachael Stanley; Wendy Smith; Timothy Peto; David Eyre; Derrick Crook; Gabrielle Vernet; Christine Kitchen; Huw Gulliver; Ian Merrick; Martyn Guest; Robert Munn; Declan T. Bradley; Tim Wyatt; Charlotte Beaver; Luke Foulser; Sophie Palmer; Carol M. Churcher; Ellena Brooks; Kim S. Smith; Katerina Galai; Georgina M. McManus; Frances Bolt; Francesc Coll; Lizzie Meadows; Stephen W. Attwood; Alisha Davies; Elen De Lacy; Fatima Downing; Sue Edwards; Garry P. Scarlett; Sarah Jeremiah; Nikki Smith; Danielle Leek; Sushmita Sridhar; Sally Forrest; Claire Cormie; Harmeet K. Gill; Joana Dias; Ellen E. Higginson; Mailis Maes; Jamie Young; Michelle Wantoch; Dorota Jamrozy; Stephanie Lo; Minal Patel; Verity Hill; Claire M. Bewshea; Sian Ellard; Cressida Auckland; Ian Harrison; Chloe Bishop; Vicki Chalker; Alex Richter; Andrew Beggs; Angus Best; Benita Percival; Jeremy Mirza; Oliver Megram; Megan Mayhew; Liam Crawford; Fiona Ashcroft; Emma Moles-Garcia; Nicola Cumley; Richard Hopes; Patawee Asamaphan; Marc O. Niebel; Rory N. Gunson; Amanda Bradley; Alasdair Maclean; Guy Mollett; Rachel Blacow; Paul Bird; Thomas Helmer; Karlie Fallon; Julian Tang; Antony D. Hale; Louissa R. Macfar...; Katherine L. Harper; Holli Carden; Nicholas W. Machin; Kathryn A. Jackson; Shazaad S.Y. Ahmad; Ryan P. George; Lance Turtle; Elaine O’Toole; Joanne Watts; Cassie Breen; Angela Cowell; Adela Alcolea-Medina; Themoula Charalam...; Amita Patel; Lisa J. Levett; Judith Heaney; Aileen Rowan; Graham P. Taylor; Divya Shah; Laura Atkinson; Jack C.D. Lee; Adam P. Westhorpe; Riaz Jannoo; Helen L. Lowe; Angeliki Karamani; Leah Ensell; Wendy Chatterton; Monika Pusok; Ashok Dadrah; Amanda Symmonds; Graciela Sluga; Zoltan Molnar; Paul Baker; Stephen Bonner; Sarah Essex; Edward Barton; Debra Padgett; Garren Scott; Jane Greenaway; Brendan A.I. Payne; Shirelle Burton-F...; Sheila Waugh; Veena Raviprakash; Nicola Sheriff; Victoria Blakey; Lesley-Anne Williams; Jonathan Moore; Susanne Stonehouse; Louise Smith; Rose K. Davidson; Luke Bedford; Lindsay Coupland; Victoria Wright; Joseph G. Chappell; Theocharis Tsoler...; Jonathan Ball; Manjinder Khakh; Vicki M. Fleming; Michelle M. Lister; Hannah C. Howson-...; Louise Berry; Tim Boswell; Amelia Joseph; Iona Willingham; Nichola Duckworth; Sarah Walsh; Emma Wise; Nathan Moore; Matilde Mori; Nick Cortes; Stephen Kidd; Rebecca Williams; Laura Gifford; Kelly Bicknell; Sarah Wyllie; Allyson Lloyd; Robert Impey; Cassandra S. Malone; Benjamin J. Cogger; Nick Levene; Lynn Monaghan; Alexander J. Keeley; David G. Partridge; Mohammad Raza; Cariad Evans; Kate Johnson; Emma Betteridge; Ben W. Farr; Scott Goodwin; Michael A. Quail; Carol Scott; Lesley Shirley; Scott A.J. Thurston; Diana Rajan; Iraad F. Bronner; Louise Aigrain; Nicholas M. Redshaw; Stefanie V. Lensing; Shane McCarthy; Alex Makunin; Carlos E. Balcazar; Michael D. Gallagher; Kathleen A. Willi...; Thomas D. Stanton; Michelle L. Miche...; Joanna Warwick-Du...; Robin Manley; Audrey Farbos; James W. Harrison; Christine M. Sambles; David J. Studholme; Angie Lackenby; Tamyo Mbisa; Steven Platt; Shahjahan Miah; David Bibby; Carmen Manso; Jonathan Hubb; Gavin Dabrera; Mary Ramsay; Daniel Bradshaw; Ulf Schaefer; Natalie Groves; Eileen Gallagher; David Lee; David Williams; Nicholas Ellaby; Hassan Hartman; Nikos Manesis; Vineet Patel; Juan Ledesma; Katherine A. Twohig; Elias Allara; Clare Pearson; Jeffrey K.J. Cheng; Hannah E. Bridgew...; Lucy R. Frost; Grace Taylor-Joyce; Paul E. Brown; Lily Tong; Alice Broos; Daniel Mair; Jenna Nichols; Stephen N. Carmic...; Katherine L. Smol...; Kyriaki Nomikou; Elihu Aranday-Cortes; Natasha Johnson; Seema Nickbakhsh; Edith E. Vamos; Margaret Hughes; Lucille Rainbow; Richard Eccles; Charlotte Nelson; Mark Whitehead; Richard Gregory; Matthew Gemmell; Claudia Wierzbicki; Hermione J. Webster; Chloe L. Fisher; Adrian W. Signell; Gilberto Betancor; Harry D. Wilson; Gaia Nebbia; Flavia Flaviani; Alberto C. Cerda; Tammy V. Merrill; Rebekah E. Wilson; Marius Cotic; Nadua Bayzid; Thomas Thompson; Erwan Acheson; Steven Rushton; Sarah O’Brien; David J. Baker; Steven Rudder; Alp Aydin; Fei Sang; Johnny Debebe; Sarah Francois; Tetyana I. Vasylyeva; Marina Escalera Z...; Bernardo Gutierrez; Angela Marchbank; Joshua Maksimovic; Karla Spellman; Kathryn McCluggage; Mari Morgan; Robert Beer; Safiah Afifi; Trudy Workman; William Fuller; Catherine Bresner; Adrienn Angyal; Luke R. Green; Paul J. Parsons; Rachel M. 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• Keywords: 0301 basic medicine; Medical Physiology; Resistance; MC UU 1201412; Antibodies, Viral; MR/R024758/1; Recurrence; Chlorocebus aethiops; Viral; deletion; Biology (General); Lung; Neutralizing; Phylogeny; infectivity; MC_UU_12014/12; C500; C700; Spike Glycoprotein; UKRI; 3. Good health; MRC; Antibody Escape; Infectious Diseases; Spike Glycoprotein, Coronavirus; antibody escape; Covid-19; Protein Binding; 570; QH301-705.5; Sars-cov-2; 610; Antibodies; Article; Cell Line; Deletion; resistance; /dk/atira/pure/subjectarea/asjc/1300; 03 medical and health sciences; COVID-19 Genomics UK (COG-UK) Consortium; spike mutation; Alpha Variant; Animals; Humans; neutralizing antibodies; B.1.1.7; Pandemics; Vero Cells; Immune Evasion; Biochemistry, Genetics and Molecular Biology(all); SARS-CoV-2; COVID-19; Pneumonia; MR/P008801/1; Antibodies, Neutralizing; Coronavirus; Emerging Infectious Diseases; Good Health and Well Being; HEK293 Cells; Infectivity; Alpha variant; Mutation; Spike Mutation; Biochemistry and Cell Biology; Neutralizing Antibodies

We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of 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, although 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 spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant 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.