SARS-CoV-2 evolution during treatment of chronic infection

Kemp SA, Collier DA, Datir RP, Ferreira IATM, Gayed S, Jahun A, Hosmillo M, Rees-Spear C, Mlcochova P, Lumb IU, Roberts DJ, Chandra A, Temperton N, Baker S, Dougan G, Hess C, Kingston N, Lehner PJ, Lyons PA, Matheson NJ, Owehand WH, Saunders C, Summers C, Thaventhiran JED, Toshner M, Weekes MP, Bucke A, Calder J, Canna L, Domingo J, Elmer A, Fuller S, Harris J, Hewitt S, Kennet J, Jose S, Kourampa J, Meadows A, O?Brien C, Price J, Publico C, Rastall R, Ribeiro C, Rowlands J, Ruffolo V, Tordesillas H, Bullman B, Dunmore BJ, Fawke S, Gräf S, Hodgson J, Huang C, Hunter K, Jones E, Legchenko E, Matara C, Martin J, Mescia F, O?Donnell C, Pointon L, Pond N, Shih J, Sutcliffe R, Tilly T, Treacy C, Tong Z, Wood J, Wylot M, Bergamaschi L, Betancourt A, Bower G, Cossetti C, De Sa A, Epping M, Fawke S, Gleadall N, Grenfell R, Hinch A, Huhn O, Jackson S, Jarvis I, Lewis D, Marsden J, Nice F, Okecha G, Omarjee O, Perera M, Richoz N, Romashova V, Yarkoni NS, Sharma R, Stefanucci L, Stephens J, Strezlecki M, Turner L, De Bie EMDD, Bunclark K, Josipovic M, Mackay M, Rossi S, Selvan M, Spencer S, Yong C, Ansaripour A, Michael A, Mwaura L, Patterson C, Polwarth G, Polgarova P, di Stefano G, Fahey C, Michel R, Bong S-H, Coudert JD, Holmes E, Allison J, Butcher H, Caputo D, Clapham-Riley D, Dewhurst E, Furlong A, Graves B, Gray J, Ivers T, Kasanicki M, Le Gresley E, Linger R, Meloy S, Muldoon F, Ovington N, Papadia S, Phelan I, Stark H, Stirrups KE, Townsend P, Walker N, Webster J, Robson SC, Loman NJ, Connor TR, Golubchik T, Martinez Nunez RT, Ludden C, Corden S, Johnston I, Bonsall D, Smith CP, Awan AR, Bucca G, Estee Torok M, Saeed K, Prieto JA, Jackson DK, Hamilton WL, Snell LB, Moore C, Harrison EM, Goncalves S, Fairley DJ, Loose MW, Watkins J, Livett R, Moses S, Amato R, Nicholls S, Bull M, Smith DL, Barrett J, Aanensen DM, Curran MD, Parmar S, Aggarwal D, Shepherd JG, Parker MD, Glaysher S, Bashton M, Underwood AP, Pacchiarini N, Loveson KF, Carabelli AM, Templeton KE, Langford CF, Sillitoe J, de Silva TI, Wang D, Kwiatkowski D, Rambaut A, O?Grady J, Cottrell S, Holden MTG, Thomson EC, Osman H, Andersson M, Chauhan AJ, Hassan-Ibrahim MO, Lawniczak M, Alderton A, Chand M, Constantinidou C, Unnikrishnan M, Darby AC, Hiscox JA, Paterson S, Martincorena I, Robertson DL, Volz EM, Page AJ, Pybus OG, Bassett AR, Ariani CV, Spencer Chapman MH, Li KK, Shah RN, Jesudason NG, Taha Y, McHugh MP, Dewar R, Jahun AS, McMurray C, Pandey S, McKenna JP, Nelson A, Young GR, McCann CM, Elliott S, Lowe H, Temperton B, Roy S, Price A, Rey S, Wyles M, Rooke S, Shaaban S, de Cesare M, Letchford L, Silveira S, Pelosi E, Wilson-Davies E, Hosmillo M, O?Toole Á, Hesketh AR, Stark R, du Plessis L, Ruis C, Adams H, Bourgeois Y, Michell SL, Gramatopoulos D, Edgeworth J, Breuer J, Todd JA, Fraser C, Buck D, John M, Kay GL, Palmer S, Peacock SJ, Heyburn D, Weldon D, Robinson E, McNally A, Muir P, Vipond IB, Boyes J, Sivaprakasam V, Salluja T, Dervisevic S, Meader EJ, Park NR, Oliver K, Jeffries AR, Ott S, da Silva Filipe A, Simpson DA, Williams C, Masoli JAH, Knight BA, Jones CR, Koshy C, Ash A, Casey A, Bosworth A, Ratcliffe L, Xu-McCrae L, Pymont HM, Hutchings S, Berry L, Jones K, Halstead F, Davis T, Holmes C, Iturriza-Gomara M, Lucaci AO, Randell PA, Cox A, Madona P, Harris KA, Brown JR, Mahungu TW, Irish-Tavares D, Haque T, Hart J, Witele E, Fenton ML, Liggett S, Graham C, Swindells E, Collins J, Eltringham G, Campbell S, McClure PC, Clark G, Sloan TJ, Jones C, Lynch J, Warne B, Leonard S, Durham J, Williams T, Haldenby ST, Storey N, Alikhan N-F, Holmes N, Moore C, Carlile M, Perry M, Craine N, Lyons RA, Beckett AH, Goudarzi S, Fearn C, Cook K, Dent H, Paul H, Davies R, Blane B, Girgis ST, Beale MA, Bellis KL, Dorman MJ, Drury E, Kane L, Kay S, McGuigan S, Nelson R, Prestwood L, Rajatileka S, Batra R, Williams RJ, Kristiansen M, Green A, Justice A, Mahanama AIK, Samaraweera B, Hadjirin NF, Quick J, Poplawski R, Kermack LM, Reynolds N, Hall G, Chaudhry Y, Pinckert ML, Georgana I, Moll RJ, Thornton A, Myers R, Stockton J, Williams CA, Yew WC, Trotter AJ, Trebes A, MacIntyre-Cockett G, Birchley A, Adams A, Plimmer A, Gatica-Wilcox B, McKerr C, Hilvers E, Jones H, Asad H, Coombes J, Evans JM, Fina L, Gilbert L, Graham L, Cronin M, Kumziene-Summerhayes S, Taylor S, Jones S, Groves DC, Zhang P, Gallis M, Louka SF, Starinskij I, Jackson C, Gourtovaia M, Tonkin-Hill G, Lewis K, Tovar-Corona JM, James K, Baxter L, Alam MT, Orton RJ, Hughes J, Vattipally S, Ragonnet-Cronin M, Nascimento FF, Jorgensen D, Boyd O, Geidelberg L, Zarebski AE, Raghwani J, Kraemer MUG, Southgate J, Lindsey BB, Freeman TM, Keatley J-P, Singer JB, de Oliveira Martins L, Yeats CA, Abudahab K, Taylor BEW, Menegazzo M, Danesh J, Hogsden W, Eldirdiri S, Kenyon A, Mason J, Robinson TI, Holmes A, Price J, Hartley JA, Curran T, Mather AE, Shankar G, Jones R, Howe R, Morgan S, Wastenge E, Chapman MR, Mookerjee S, Stanley R, Smith W, Peto T, Eyre D, Crook D, Vernet G, Kitchen C, Gulliver H, Merrick I, Guest M, Munn R, Bradley DT, Wyatt T, Beaver C, Foulser L, Palmer S, Churcher CM, Brooks E, Smith KS, Galai K, McManus GM, Bolt F, Coll F, Meadows L, Attwood SW, Davies A, De Lacy E, Downing F, Edwards S, Scarlett GP, Jeremiah S, Smith N, Leek D, Sridhar S, Forrest S, Cormie C, Gill HK, Dias J, Higginson EE, Maes M, Young J, Wantoch M, Jamrozy D, Lo S, Patel M, Hill V, Bewshea CM, Ellard S, Auckland C, Harrison I, Bishop C, Chalker V, Richter A, Beggs A, Best A, Percival B, Mirza J, Megram O, Mayhew M, Crawford L, Ashcroft F, Moles-Garcia E, Cumley N, Hopes R, Asamaphan P, Niebel MO, Gunson RN, Bradley A, Maclean A, Mollett G, Blacow R, Bird P, Helmer T, Fallon K, Tang J, Hale AD, Macfarlane-Smith LR, Harper KL, Carden H, Machin NW, Jackson KA, Ahmad SSY, George RP, Turtle L, O?Toole E, Watts J, Breen C, Cowell A, Alcolea-Medina A, Charalampous T, Patel A, Levett LJ, Heaney J, Rowan A, Taylor GP, Shah D, Atkinson L, Lee JCD, Westhorpe AP, Jannoo R, Lowe HL, Karamani A, Ensell L, Chatterton W, Pusok M, Dadrah A, Symmonds A, Sluga G, Molnar Z, Baker P, Bonner S, Essex S, Barton E, Padgett D, Scott G, Greenaway J, Payne BAI, Burton-Fanning S, Waugh S, Raviprakash V, Sheriff N, Blakey V, Williams L-A, Moore J, Stonehouse S, Smith L, Davidson RK, Bedford L, Coupland L, Wright V, Chappell JG, Tsoleridis T, Ball J, Khakh M, Fleming VM, Lister MM, Howson-Wells HC, Berry L, Boswell T, Joseph A, Willingham I, Duckworth N, Walsh S, Wise E, Moore N, Mori M, Cortes N, Kidd S, Williams R, Gifford L, Bicknell K, Wyllie S, Lloyd A, Impey R, Malone CS, Cogger BJ, Levene N, Monaghan L, Keeley AJ, Partridge DG, Raza M, Evans C, Johnson K, Abnizova I, Aigrain L, Alderton A, Ali M, Allen L, Amato R, Anderson R, Ariani C, Austin-Guest S, Bala S, Barrett J, Bassett A, Battleday K, Beal J, Beale M, Beaver C, Bellany S, Bellerby T, Bellis K, Berger D, Berriman M, Betteridge E, Bevan P, Binley S, Bishop J, Blackburn K, Bonfield J, Boughton N, Bowker S, Brendler-Spaeth T, Bronner I, Brooklyn T, Buddenborg SK, Bush R, Caetano C, Cagan A, Carter N, Cartwright J, Monteiro TC, Chapman L, Chillingworth T-J, Clapham P, Clark R, Clarke A, Clarke C, Cole D, Cook E, Coppola M, Cornell L, Cornwell C, Corton C, Crackett A, Cranage A, Craven H, Craw S, Crawford M, Cutts T, Dabrowska M, Davies M, Davies R, Dawson J, Day C, Densem A, Dibling T, Dockree C, Dodd D, Dogga S, Dorman M, Dougan G, Dougherty M, Dove A, Drummond L, Drury E, Dudek M, Durham J, Durrant L, Easthope E, Eckert S, Ellis P, Farr B, Fenton M, Ferrero M, Flack N, Fordham H, Forsythe G, Foulser L, Francis M, Fraser A, Freeman A, Galvin A, Garcia-Casado M, Gedny A, Girgis S, Glover J, Goncalves S, Goodwin S, Gould O, Gourtovaia M, Gray A, Gray E, Griffiths C, Gu Y, Guerin F, Hamilton W, Hanks H, Harrison E, Harrott A, Harry E, Harvison J, Heath P, Hernandez-Koutoucheva A, Hobbs R, Holland D, Holmes S, Hornett G, Hough N, Huckle L, Hughes-Hallet L, Hunter A, Inglis S, Iqbal S, Jackson A, Jackson D, James K, Jamrozy D, Verdejo CJ, Johnston I, Jones M, Kallepally K, Kane L, Kay K, Kay S, Keatley J, Keith A, King A, Kitchin L, Kleanthous M, Klimekova M, Korlevic P, Krasheninnkova K, Lane G, Langford C, Laverack A, Law K, Lawniczak M, Lensing S, Leonard S, Letchford L, Lewis K, Lewis-Wade A, Liddle J, Lin Q, Lindsay S, Linsdell S, Livett R, Lo S, Long R, Lovell J, Lovell J, Ludden C, Mack J, Maddison M, Makunin A, Mamun I, Mansfield J, Marriott N, Martin M, Martincorena I, Mayho M, McCarthy S, McClintock J, McGuigan S, McHugh S, McMinn L, Meadows C, Mobley E, Moll R, Morra M, Morrow L, Murie K, Nash S, Nathwani C, Naydenova P, Neaverson A, Nelson R, Nerou E, Nicholson J, Nimz T, Noell GG, O?Meara S, Ohan V, Oliver K, Olney C, Ormond D, Oszlanczi A, Palmer S, Pang YF, Pardubska B, Park N, Parmar A, Patel G, Patel M, Payne M, Peacock S, Petersen A, Plowman D, Preston T, Prestwood L, Puethe C, Quail M, Rajan D, Rajatileka S, Rance R, Rawlings S, Redshaw N, Reynolds J, Reynolds M, Rice S, Richardson M, Roberts C, Robinson K, Robinson M, Robinson D, Rogers H, Rojo EM, Roopra D, Rose M, Rudd L, Sadri R, Salmon N, Saul D, Schwach F, Scott C, Seekings P, Shirley L, Sillitoe J, Simms A, Sinnott M, Sivadasan S, Siwek B, Sizer D, Skeldon K, Skelton J, Slater-Tunstill J, Sloper L, Smerdon N, Smith C, Smith C, Smith J, Smith K, Smith M, Smith S, Smith T, Sneade L, Soria CD, Sousa C, Souster E, Sparkes A, Spencer-Chapman M, Squares J, Stanley R, Steed C, Stickland T, Still I, Stratton M, Strickland M, Swann A, Swiatkowska A, Sycamore N, Swift E, Symons E, Szluha S, Taluy E, Tao N, Taylor K, Taylor S, Thompson S, Thompson M, Thomson M, Thomson N, Thurston S, Tonkin-Hill G, Toombs D, Topping B, Tovar-Corona J, Ungureanu D, Uphill J, Urbanova J, Jansen Van P, Vancollie V, Voak P, Walker D, Walker M, Waller M, Ward G, Weatherhogg C, Webb N, Weldon D, Wells A, Wells E, Westwood L, Whipp T, Whiteley T, Whitton G, Whitwham A, Widaa S, Williams M, Wilson M, Wright S, Betteridge E, Farr BW, Goodwin S, Quail MA, Scott C, Shirley L, Thurston SAJ, Rajan D, Bronner IF, Aigrain L, Redshaw NM, Lensing SV, McCarthy S, Makunin A, Balcazar CE, Gallagher MD, Williamson KA, Stanton TD, Michelsen ML, Warwick-Dugdale J, Manley R, Farbos A, Harrison JW, Sambles CM, Studholme DJ, Lackenby A, Mbisa T, Platt S, Miah S, Bibby D, Manso C, Hubb J, Dabrera G, Ramsay M, Bradshaw D, Schaefer U, Groves N, Gallagher E, Lee D, Williams D, Ellaby N, Hartman H, Manesis N, Patel V, Ledesma J, Twohig KA, Allara E, Pearson C, Cheng JKJ, Bridgewater HE, Frost LR, Taylor-Joyce G, Brown PE, Tong L, Broos A, Mair D, Nichols J, Carmichael SN, Smollett KL, Nomikou K, Aranday-Cortes E, Johnson N, Nickbakhsh S, Vamos EE, Hughes M, Rainbow L, Eccles R, Nelson C, Whitehead M, Gregory R, Gemmell M, Wierzbicki C, Webster HJ, Fisher CL, Signell AW, Betancor G, Wilson HD, Nebbia G, Flaviani F, Cerda AC, Merrill TV, Wilson RE, Cotic M, Bayzid N, Thompson T, Acheson E, Rushton S, O?Brien S, Baker DJ, Rudder S, Aydin A, Sang F, Debebe J, Francois S, Vasylyeva TI, Zamudio ME, Gutierrez B, Marchbank A, Maksimovic J, Spellman K, McCluggage K, Morgan M, Beer R, Afifi S, Workman T, Fuller W, Bresner C, Angyal A, Green LR, Parsons PJ, Tucker RM, Brown R, Whiteley M, Bonfield J, Puethe C, Whitwham A, Liddle J, Rowe W, Siveroni I, Le-Viet T, Gaskin A, Johnson R, Sharrocks K, Blane E, Modis Y, Leigh KE, Briggs JAG, van Gils MJ, Smith KGC, Bradley JR, Smith C, Doffinger R, Ceron-Gutierrez L, Barcenas-Morales G, Pollock DD, Goldstein RA, Smielewska A, Skittrall JP, Gouliouris T, Goodfellow IG, Gkrania-Klotsas E, Illingworth CJR, McCoy LE, Gupta RK, The CITIID-NIHR BioResource COVID-19 Collaboration, Principal investigators, CRF & volunteer research nurses, Sample logistics, Sample processing

(2021) Nature 592, 277-282.

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (?H69/?V70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ?H69/?V70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ?H69/?V70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

 
Andrew Rambaut, 2007