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1. SARS-CoV-2 evolution during treatment of chronic infection

Author

Kemp, S. A., Collier, D. A., Datir, R. P., Ferreira, I. A. T. M., Gayed, S., Jahun, A., Hosmillo, M., Rees-Spear, C., Mlcochova, P., Lumb, I. U., Roberts, D. J., Chandra, A., Temperton, N., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., 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, B. J., Fawke, S., Graf, 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., 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, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., De Bie, E. M. D. D., 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, J. D., 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, K. E., Townsend, P., Walker, N., Webster, J., Robson, S. C., Loman, N. J., Connor, T. R., Golubchik, T., Martinez Nunez, R. T., Ludden, C., Corden, S., Johnston, I., Bonsall, D., Smith, C. P., Awan, A. R., Bucca, G., Estee Torok, M., Saeed, K., Prieto, J. A., Jackson, D. K., Hamilton, W. L., Snell, L. B., Moore, C., Harrison, E. M., Goncalves, S., Fairley, D. J., Loose, M. W., Watkins, J., Livett, R., Moses, S., Amato, R., Nicholls, S., Bull, M., Smith, D. L., Barrett, J., Aanensen, D. M., Curran, M. D., Parmar, S., Aggarwal, D., Shepherd, J. G., Parker, M. D., Glaysher, S., Bashton, M., Underwood, A. P., Pacchiarini, N., Loveson, K. F., Carabelli, A. M., Templeton, K. E., Langford, C. F., Sillitoe, J., de Silva, T. I., Wang, D., Kwiatkowski, D., Rambaut, A., O'Grady, J., Cottrell, S., Holden, M. T. G., Thomson, E. C., Osman, H., Andersson, M., Chauhan, A. J., Hassan-Ibrahim, M. O., Lawniczak, M., Alderton, A., Chand, M., Constantinidou, C., Unnikrishnan, M., Darby, A. C., Hiscox, J. A., Paterson, S., Martincorena, I., Robertson, D. L., Volz, E. M., Page, A. J., Pybus, O. G., Bassett, A. R., Ariani, C. V., Spencer Chapman, M. H., K. K., Li, Shah, R. N., Jesudason, N. G., Taha, Y., Mchugh, M. P., Dewar, R., Jahun, A. S., Mcmurray, C., Pandey, S., Mckenna, J. P., Nelson, A., Young, G. R., Mccann, C. M., 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., O'Toole, A., Hesketh, A. R., Stark, R., du Plessis, L., Ruis, C., Adams, H., Bourgeois, Y., Michell, S. L., Gramatopoulos, D., Edgeworth, J., Breuer, J., Todd, J. A., Fraser, C., Buck, D., John, M., Kay, G. L., Palmer, S., Peacock, S. J., Heyburn, D., Weldon, D., Robinson, E., Mcnally, A., Muir, P., Vipond, I. B., Boyes, J., Sivaprakasam, V., Salluja, T., Dervisevic, S., Meader, E. J., Park, N. R., Oliver, K., Jeffries, A. R., Ott, S., da Silva Filipe, A., Simpson, D. A., Williams, C., Masoli, J. A. H., Knight, B. A., Jones, C. R., Koshy, C., Ash, A., Casey, A., Bosworth, A., Ratcliffe, L., Xu-McCrae, L., Pymont, H. M., Hutchings, S., Berry, L., Jones, K., Halstead, F., Davis, T., Holmes, C., Iturriza-Gomara, M., Lucaci, A. O., Randell, P. A., Cox, A., Madona, P., Harris, K. A., Brown, J. R., Mahungu, T. W., Irish-Tavares, D., Haque, T., Hart, J., Witele, E., Fenton, M. L., Liggett, S., Graham, C., Swindells, E., Collins, J., Eltringham, G., Campbell, S., Mcclure, P. C., Clark, G., Sloan, T. J., Jones, C., Lynch, J., Warne, B., Leonard, S., Durham, J., Williams, T., Haldenby, S. T., Storey, N., Alikhan, N. -F., Holmes, N., Carlile, M., Perry, M., Craine, N., Lyons, R. A., Beckett, A. H., Goudarzi, S., Fearn, C., Cook, K., Dent, H., Paul, H., Davies, R., Blane, B., Girgis, S. T., Beale, M. A., Bellis, K. L., Dorman, M. J., Drury, E., Kane, L., Kay, S., Mcguigan, S., Nelson, R., Prestwood, L., Rajatileka, S., Batra, R., Williams, R. J., Kristiansen, M., Green, A., Justice, A., Mahanama, A. I. K., Samaraweera, B., Hadjirin, N. F., Quick, J., Poplawski, R., Kermack, L. M., Reynolds, N., Hall, G., Chaudhry, Y., Pinckert, M. L., Georgana, I., Moll, R. J., Thornton, A., Myers, R., Stockton, J., Williams, C. A., Yew, W. C., Trotter, A. J., 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, J. M., Fina, L., Gilbert, L., Graham, L., Cronin, M., Kumziene-Summerhayes, S., Taylor, S., Jones, S., Groves, D. C., Zhang, P., Gallis, M., Louka, S. F., Starinskij, I., Jackson, C., Gourtovaia, M., Tonkin-Hill, G., Lewis, K., Tovar-Corona, J. M., James, K., Baxter, L., Alam, M. T., Orton, R. J., Hughes, J., Vattipally, S., Ragonnet-Cronin, M., Nascimento, F. F., Jorgensen, D., Boyd, O., Geidelberg, L., Zarebski, A. E., Raghwani, J., Kraemer, M. U. G., Southgate, J., Lindsey, B. B., Freeman, T. M., Keatley, J. -P., Singer, J. B., de Oliveira Martins, L., Yeats, C. A., Abudahab, K., Taylor, B. E. W., Menegazzo, M., Danesh, J., Hogsden, W., Eldirdiri, S., Kenyon, A., Mason, J., Robinson, T. I., Holmes, A., Hartley, J. A., Curran, T., Mather, A. E., Shankar, G., Jones, R., Howe, R., Morgan, S., Wastenge, E., Chapman, M. R., 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, D. T., Wyatt, T., Beaver, C., Foulser, L., Churcher, C. M., Brooks, E., Smith, K. S., Galai, K., Mcmanus, G. M., Bolt, F., Coll, F., Meadows, L., Attwood, S. W., Davies, A., De Lacy, E., Downing, F., Edwards, S., Scarlett, G. P., Jeremiah, S., Smith, N., Leek, D., Sridhar, S., Forrest, S., Cormie, C., Gill, H. K., Dias, J., Higginson, E. E., Maes, M., Young, J., Wantoch, M., Jamrozy, D., Lo, S., Patel, M., Hill, V., Bewshea, C. M., 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, M. O., Gunson, R. N., Bradley, A., Maclean, A., Mollett, G., Blacow, R., Bird, P., Helmer, T., Fallon, K., Tang, J., Hale, A. D., Macfarlane-Smith, L. R., Harper, K. L., Carden, H., Machin, N. W., Jackson, K. A., Ahmad, S. S. Y., George, R. P., Turtle, L., O'Toole, E., Watts, J., Breen, C., Cowell, A., Alcolea-Medina, A., Charalampous, T., Patel, A., Levett, L. J., Heaney, J., Rowan, A., Taylor, G. P., Shah, D., Atkinson, L., Lee, J. C. D., Westhorpe, A. P., Jannoo, R., Lowe, H. L., 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, B. A. I., Burton-Fanning, S., Waugh, S., Raviprakash, V., Sheriff, N., Blakey, V., Williams, L. -A., Moore, J., Stonehouse, S., Smith, L., Davidson, R. K., Bedford, L., Coupland, L., Wright, V., Chappell, J. G., Tsoleridis, T., Ball, J., Khakh, M., Fleming, V. M., Lister, M. M., Howson-Wells, H. C., 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, C. S., Cogger, B. J., Levene, N., Monaghan, L., Keeley, A. J., Partridge, D. G., Raza, M., Evans, C., Johnson, K., Abnizova, I., Aigrain, L., Ali, M., Allen, L., Anderson, R., Ariani, C., Austin-Guest, S., Bala, S., Bassett, A., Battleday, K., Beal, J., Beale, M., 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, S. K., Bush, R., Caetano, C., Cagan, A., Carter, N., Cartwright, J., Monteiro, T. C., 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., Dawson, J., Day, C., Densem, A., Dibling, T., Dockree, C., Dodd, D., Dogga, S., Dougherty, M., Dove, A., Drummond, L., Dudek, M., Durrant, L., Easthope, E., Eckert, S., Ellis, P., Farr, B., Fenton, M., Ferrero, M., Flack, N., Fordham, H., Forsythe, G., Francis, M., Fraser, A., Freeman, A., Galvin, A., Garcia-Casado, M., Gedny, A., Girgis, S., Glover, J., Goodwin, S., Gould, O., 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., Verdejo, C. J., Jones, M., Kallepally, K., Kay, K., Keatley, J., Keith, A., King, A., Kitchin, L., Kleanthous, M., Klimekova, M., Korlevic, P., Krasheninnkova, K., Lane, G., Langford, C., Laverack, A., Law, K., Lensing, S., Lewis-Wade, A., Liddle, J., Lin, Q., Lindsay, S., Linsdell, S., Long, R., Lovell, J., Mack, J., Maddison, M., Makunin, A., Mamun, I., Mansfield, J., Marriott, N., Martin, M., Mayho, M., Mccarthy, S., Mcclintock, J., Mchugh, S., Mcminn, L., Meadows, C., Mobley, E., Moll, R., Morra, M., Morrow, L., Murie, K., Nash, S., Nathwani, C., Naydenova, P., Neaverson, A., Nerou, E., Nicholson, J., Nimz, T., Noell, G. G., O'Meara, S., Ohan, V., Olney, C., Ormond, D., Oszlanczi, A., Pang, Y. F., Pardubska, B., Park, N., Parmar, A., Patel, G., Payne, M., Peacock, S., Petersen, A., Plowman, D., Preston, T., Puethe, C., Quail, M., Rajan, D., 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, E. M., Roopra, D., Rose, M., Rudd, L., Sadri, R., Salmon, N., Saul, D., Schwach, F., Scott, C., Seekings, P., Shirley, L., Simms, A., Sinnott, M., Sivadasan, S., Siwek, B., Sizer, D., Skeldon, K., Skelton, J., Slater-Tunstill, J., Sloper, L., Smerdon, N., Smith, C., Smith, J., Smith, K., Smith, M., Smith, S., Smith, T., Sneade, L., Soria, C. D., Sousa, C., Souster, E., Sparkes, A., Spencer-Chapman, M., Squares, J., 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., Thompson, S., Thompson, M., Thomson, M., Thomson, N., Thurston, S., 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., Wells, A., Wells, E., Westwood, L., Whipp, T., Whiteley, T., Whitton, G., Whitwham, A., Widaa, S., Williams, M., Wilson, M., Wright, S., Farr, B. W., Quail, M. A., Thurston, S. A. J., Bronner, I. F., Redshaw, N. M., Lensing, S. V., Balcazar, C. E., Gallagher, M. D., Williamson, K. A., Stanton, T. D., Michelsen, M. L., Warwick-Dugdale, J., Manley, R., Farbos, A., Harrison, J. W., Sambles, C. M., Studholme, D. J., 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, K. A., Allara, E., Pearson, C., Cheng, J. K. J., Bridgewater, H. E., Frost, L. R., Taylor-Joyce, G., Brown, P. E., Tong, L., Broos, A., Mair, D., Nichols, J., Carmichael, S. N., Smollett, K. L., Nomikou, K., Aranday-Cortes, E., Johnson, N., Nickbakhsh, S., Vamos, E. E., Hughes, M., Rainbow, L., Eccles, R., Nelson, C., Whitehead, M., Gregory, R., Gemmell, M., Wierzbicki, C., Webster, H. J., Fisher, C. L., Signell, A. W., Betancor, G., Wilson, H. D., Nebbia, G., Flaviani, F., Cerda, A. C., Merrill, T. V., Wilson, R. E., Cotic, M., Bayzid, N., Thompson, T., Acheson, E., Rushton, S., O'Brien, S., Baker, D. J., Rudder, S., Aydin, A., Sang, F., Debebe, J., Francois, S., Vasylyeva, T. I., Zamudio, M. E., 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, L. R., Parsons, P. J., Tucker, R. M., Brown, R., Whiteley, M., Rowe, W., Siveroni, I., Le-Viet, T., Gaskin, A., Johnson, R., Sharrocks, K., Blane, E., Modis, Y., Leigh, K. E., Briggs, J. A. G., van Gils, M. J., Smith, K. G. C., Bradley, J. R., Doffinger, R., Ceron-Gutierrez, L., Barcenas-Morales, G., Pollock, D. D., Goldstein, R. A., Smielewska, A., Skittrall, J. P., Gouliouris, T., Goodfellow, I. G., Gkrania-Klotsas, E., Illingworth, C. J. R., Mccoy, L. E., Gupta, R. K., Medical Microbiology and Infection Prevention, AII - Infectious diseases, Collier, Dami A [0000-0001-5446-4423], Jahun, Aminu [0000-0002-4585-1701], Temperton, Nigel [0000-0002-7978-3815], Modis, Yorgo [0000-0002-6084-0429], Briggs, John AG [0000-0003-3990-6910], Goldstein, Richard A [0000-0001-5148-4672], Skittrall, Jordan P [0000-0002-8228-3758], Gkrania-Klotsas, Effrossyni [0000-0002-0930-8330], McCoy, Laura E [0000-0001-9503-7946], Gupta, Ravindra K [0000-0001-9751-1808], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Time Factors, viruses, Passive, Antibodies, Viral, CITIID-NIHR BioResource COVID-19 Collaboration, 2.1 Biological and endogenous factors, Viral, Aetiology, Neutralizing, Lung, Phylogeny, neutralising antibodies, Infectivity, education.field_of_study, Genome, Multidisciplinary, Alanine, biology, High-Throughput Nucleotide Sequencing, Viral Load, Spike Glycoprotein, Virus Shedding, Adenosine Monophosphate, Aged, Antibodies, Neutralizing, COVID-19, Chronic Disease, Genome, Viral, Humans, Immune Evasion, Immune Tolerance, Immunization, Passive, Immunosuppression Therapy, Mutagenesis, Mutant Proteins, Mutation, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Evolution, Molecular, Infectious Diseases, Pneumonia & Influenza, Antibody, Infection, Viral load, Biotechnology, Evolution, General Science & Technology, antibody escape, Convalescent plasma, 030106 microbiology, Population, evasion, Antibodies, Virus, Article, Vaccine Related, resistance, 03 medical and health sciences, Immune system, COVID-19 Genomics UK (COG-UK) Consortium, Biodefense, Genetics, Viral shedding, education, COVID-19 Serotherapy, QR355, Prevention, Wild type, Molecular, Pneumonia, Virology, COVID-19 Drug Treatment, Coronavirus, Emerging Infectious Diseases, Good Health and Well Being, 030104 developmental biology, biology.protein, Immunization, immune suppression, mutation
Abstract

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 (ΔH69/ΔV70) 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 ΔH69/ΔV70 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 ΔH69/ΔV70 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.

Published
2021

2. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies

Author

Collier, D. A., De Marco, A., Ferreira, I. A. T. M., Meng, B., Datir, R. P., Walls, A. C., Kemp, S. A., Bassi, J., Pinto, D., Silacci-Fregni, C., Bianchi, S., Tortorici, M. A., Bowen, J., Culap, K., Jaconi, S., Cameroni, E., Snell, G., Pizzuto, M. S., Pellanda, A. F., Garzoni, C., Riva, A., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., 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, B. J., Fawke, S., Graf, 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., 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, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., De Bie, E. M. D. D., 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, J. D., 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, K. E., Townsend, P., Walker, N., Webster, J., Mccoy, L. E., Smith, K. G. C., Bradley, J. R., Temperton, N., Ceron-Gutierrez, L., Barcenas-Morales, G., Robson, S. C., Loman, N. J., Connor, T. R., Golubchik, T., Martinez Nunez, R. T., Ludden, C., Corden, S., Johnston, I., Bonsall, D., Smith, C. P., Awan, A. R., Bucca, G., Torok, M. E., Saeed, K., Prieto, J. A., Jackson, D. K., Hamilton, W. L., Snell, L. B., Moore, C., Harrison, E. M., Goncalves, S., Fairley, D. J., Loose, M. W., Watkins, J., Livett, R., Moses, S., Amato, R., Nicholls, S., Bull, M., Smith, D. L., Barrett, J., Aanensen, D. M., Curran, M. D., Parmar, S., Aggarwal, D., Shepherd, J. G., Parker, M. D., Glaysher, S., Bashton, M., Underwood, A. P., Pacchiarini, N., Loveson, K. F., Carabelli, A. M., Templeton, K. E., Langford, C. F., Sillitoe, J., de Silva, T. I., Wang, D., Kwiatkowski, D., Rambaut, A., O'Grady, J., Cottrell, S., Holden, M. T. G., Thomson, E. C., Osman, H., Andersson, M., Chauhan, A. J., Hassan-Ibrahim, M. O., Lawniczak, M., Alderton, A., Chand, M., Constantinidou, C., Unnikrishnan, M., Darby, A. C., Hiscox, J. A., Paterson, S., Martincorena, I., Robertson, D. L., Volz, E. M., Page, A. J., Pybus, O. G., Bassett, A. R., Ariani, C. V., Spencer Chapman, M. H., K. K., Li, Shah, R. N., Jesudason, N. G., Taha, Y., Mchugh, M. P., Dewar, R., Jahun, A. S., Mcmurray, C., Pandey, S., Mckenna, J. P., Nelson, A., Young, G. R., Mccann, C. M., 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, A., Hesketh, A. R., Stark, R., du Plessis, L., Ruis, C., Adams, H., Bourgeois, Y., Michell, S. L., Gramatopoulos, D., Edgeworth, J., Breuer, J., Todd, J. A., Fraser, C., Buck, D., John, M., Kay, G. L., Palmer, S., Peacock, S. J., Heyburn, D., Weldon, D., Robinson, E., Mcnally, A., Muir, P., Vipond, I. B., Boyes, J., Sivaprakasam, V., Salluja, T., Dervisevic, S., Meader, E. J., Park, N. R., Oliver, K., Jeffries, A. R., Ott, S., da Silva Filipe, A., Simpson, D. A., Williams, C., Masoli, J. A. H., Knight, B. A., Jones, C. R., Koshy, C., Ash, A., Casey, A., Bosworth, A., Ratcliffe, L., Xu-McCrae, L., Pymont, H. M., Hutchings, S., Berry, L., Jones, K., Halstead, F., Davis, T., Holmes, C., Iturriza-Gomara, M., Lucaci, A. O., Randell, P. A., Cox, A., Madona, P., Harris, K. A., Brown, J. R., Mahungu, T. W., Irish-Tavares, D., Haque, T., Hart, J., Witele, E., Fenton, M. L., Liggett, S., Graham, C., Swindells, E., Collins, J., Eltringham, G., Campbell, S., Mcclure, P. C., Clark, G., Sloan, T. J., Jones, C., Lynch, J., Warne, B., Leonard, S., Durham, J., Williams, T., Haldenby, S. T., Storey, N., Alikhan, N. -F., Holmes, N., Carlile, M., Perry, M., Craine, N., Lyons, R. A., Beckett, A. H., Goudarzi, S., Fearn, C., Cook, K., Dent, H., Paul, H., Davies, R., Blane, B., Girgis, S. T., Beale, M. A., Bellis, K. L., Dorman, M. J., Drury, E., Kane, L., Kay, S., Mcguigan, S., Nelson, R., Prestwood, L., Rajatileka, S., Batra, R., Williams, R. J., Kristiansen, M., Green, A., Justice, A., Mahanama, A. I. K., Samaraweera, B., Hadjirin, N. F., Quick, J., Poplawski, R., Kermack, L. M., Reynolds, N., Hall, G., Chaudhry, Y., Pinckert, M. L., Georgana, I., Moll, R. J., Thornton, A., Myers, R., Stockton, J., Williams, C. A., Yew, W. C., Trotter, A. J., 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, J. M., Fina, L., Gilbert, L., Graham, L., Cronin, M., Kumziene-Summerhayes, S., Taylor, S., Jones, S., Groves, D. C., Zhang, P., Gallis, M., Louka, S. F., Starinskij, I., Jackson, C., Gourtovaia, M., Tonkin-Hill, G., Lewis, K., Tovar-Corona, J. M., James, K., Baxter, L., Alam, M. T., Orton, R. J., Hughes, J., Vattipally, S., Ragonnet-Cronin, M., Nascimento, F. F., Jorgensen, D., Boyd, O., Geidelberg, L., Zarebski, A. E., Raghwani, J., Kraemer, M. U. G., Southgate, J., Lindsey, B. B., Freeman, T. M., Keatley, J. -P., Singer, J. B., de Oliveira Martins, L., Yeats, C. A., Abudahab, K., Taylor, B. E. W., Menegazzo, M., Danesh, J., Hogsden, W., Eldirdiri, S., Kenyon, A., Mason, J., Robinson, T. I., Holmes, A., Hartley, J. A., Curran, T., Mather, A. E., Shankar, G., Jones, R., Howe, R., Morgan, S., Wastenge, E., Chapman, M. R., 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, D. T., Wyatt, T., Beaver, C., Foulser, L., Churcher, C. M., Brooks, E., Smith, K. S., Galai, K., Mcmanus, G. M., Bolt, F., Coll, F., Meadows, L., Attwood, S. W., Davies, A., De Lacy, E., Downing, F., Edwards, S., Scarlett, G. P., Jeremiah, S., Smith, N., Leek, D., Sridhar, S., Forrest, S., Cormie, C., Gill, H. K., Dias, J., Higginson, E. E., Maes, M., Young, J., Wantoch, M., Jamrozy, D., Lo, S., Patel, M., Hill, V., Bewshea, C. M., 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, M. O., Gunson, R. N., Bradley, A., Maclean, A., Mollett, G., Blacow, R., Bird, P., Helmer, T., Fallon, K., Tang, J., Hale, A. D., Macfarlane-Smith, L. R., Harper, K. L., Carden, H., Machin, N. W., Jackson, K. A., Ahmad, S. S. Y., George, R. P., Turtle, L., O'Toole, E., Watts, J., Breen, C., Cowell, A., Alcolea-Medina, A., Charalampous, T., Patel, A., Levett, L. J., Heaney, J., Rowan, A., Taylor, G. P., Shah, D., Atkinson, L., Lee, J. C. D., Westhorpe, A. P., Jannoo, R., Lowe, H. L., 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, B. A. I., Burton-Fanning, S., Waugh, S., Raviprakash, V., Sheriff, N., Blakey, V., Williams, L. -A., Moore, J., Stonehouse, S., Smith, L., Davidson, R. K., Bedford, L., Coupland, L., Wright, V., Chappell, J. G., Tsoleridis, T., Ball, J., Khakh, M., Fleming, V. M., Lister, M. M., Howson-Wells, H. C., 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, C. S., Cogger, B. J., Levene, N., Monaghan, L., Keeley, A. J., Partridge, D. G., Raza, M., Evans, C., Johnson, K., Betteridge, E., Farr, B. W., Goodwin, S., Quail, M. A., Scott, C., Shirley, L., Thurston, S. A. J., Rajan, D., Bronner, I. F., Aigrain, L., Redshaw, N. M., Lensing, S. V., Mccarthy, S., Makunin, A., Balcazar, C. E., Gallagher, M. D., Williamson, K. A., Stanton, T. D., Michelsen, M. L., Warwick-Dugdale, J., Manley, R., Farbos, A., Harrison, J. W., Sambles, C. M., Studholme, D. J., 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, K. A., Allara, E., Pearson, C., Cheng, J. K. J., Bridgewater, H. E., Frost, L. R., Taylor-Joyce, G., Brown, P. E., Tong, L., Broos, A., Mair, D., Nichols, J., Carmichael, S. N., Smollett, K. L., Nomikou, K., Aranday-Cortes, E., Johnson, N., Nickbakhsh, S., Vamos, E. E., Hughes, M., Rainbow, L., Eccles, R., Nelson, C., Whitehead, M., Gregory, R., Gemmell, M., Wierzbicki, C., Webster, H. J., Fisher, C. L., Signell, A. W., Betancor, G., Wilson, H. D., Nebbia, G., Flaviani, F., Cerda, A. C., Merrill, T. V., Wilson, R. E., Cotic, M., Bayzid, N., Thompson, T., Acheson, E., Rushton, S., O'Brien, S., Baker, D. J., Rudder, S., Aydin, A., Sang, F., Debebe, J., Francois, S., Vasylyeva, T. I., Zamudio, M. E., 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, L. R., Parsons, P. J., Tucker, R. M., Brown, R., Whiteley, M., Bonfield, J., Puethe, C., Whitwham, A., Liddle, J., Rowe, W., Siveroni, I., Le-Viet, T., Gaskin, A., Johnson, R., Abnizova, I., Ali, M., Allen, L., Anderson, R., Ariani, C., Austin-Guest, S., Bala, S., Bassett, A., Battleday, K., Beal, J., Beale, M., Bellany, S., Bellerby, T., Bellis, K., Berger, D., Berriman, M., Bevan, P., Binley, S., Bishop, J., Blackburn, K., Boughton, N., Bowker, S., Brendler-Spaeth, T., Bronner, I., Brooklyn, T., Buddenborg, S. K., Bush, R., Caetano, C., Cagan, A., Carter, N., Cartwright, J., Monteiro, T. C., 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., Dawson, J., Day, C., Densem, A., Dibling, T., Dockree, C., Dodd, D., Dogga, S., Dougherty, M., Dove, A., Drummond, L., Dudek, M., Durrant, L., Easthope, E., Eckert, S., Ellis, P., Farr, B., Fenton, M., Ferrero, M., Flack, N., Fordham, H., Forsythe, G., Francis, M., Fraser, A., Freeman, A., Galvin, A., Garcia-Casado, M., Gedny, A., Girgis, S., Glover, J., Gould, O., 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., Verdejo, C. J., Jones, M., Kallepally, K., Kay, K., Keatley, J., Keith, A., King, A., Kitchin, L., Kleanthous, M., Klimekova, M., Korlevic, P., Krasheninnkova, K., Lane, G., Langford, C., Laverack, A., Law, K., Lensing, S., Lewis-Wade, A., Lin, Q., Lindsay, S., Linsdell, S., Long, R., Lovell, J., Mack, J., Maddison, M., Mamun, I., Mansfield, J., Marriott, N., Martin, M., Mayho, M., Mcclintock, J., Mchugh, S., Mcminn, L., Meadows, C., Mobley, E., Moll, R., Morra, M., Morrow, L., Murie, K., Nash, S., Nathwani, C., Naydenova, P., Neaverson, A., Nerou, E., Nicholson, J., Nimz, T., Noell, G. G., O'Meara, S., Ohan, V., Olney, C., Ormond, D., Oszlanczi, A., Pang, Y. F., Pardubska, B., Park, N., Parmar, A., Patel, G., Payne, M., Peacock, S., Petersen, A., Plowman, D., Preston, T., Quail, M., 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, E. M., Roopra, D., Rose, M., Rudd, L., Sadri, R., Salmon, N., Saul, D., Schwach, F., Seekings, P., Simms, A., Sinnott, M., Sivadasan, S., Siwek, B., Sizer, D., Skeldon, K., Skelton, J., Slater-Tunstill, J., Sloper, L., Smerdon, N., Smith, C., Smith, J., Smith, K., Smith, M., Smith, S., Smith, T., Sneade, L., Soria, C. D., Sousa, C., Souster, E., Sparkes, A., Spencer-Chapman, M., Squares, J., 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., Thompson, S., Thompson, M., Thomson, M., Thomson, N., Thurston, S., Toombs, D., Topping, B., Tovar-Corona, J., Ungureanu, D., Uphill, J., Urbanova, J., Van, P. J., Vancollie, V., Voak, P., Walker, D., Walker, M., Waller, M., Ward, G., Weatherhogg, C., Webb, N., Wells, A., Wells, E., Westwood, L., Whipp, T., Whiteley, T., Whitton, G., Widaa, S., Williams, M., Wilson, M., Wright, S., Harvey, W., Virgin, H. W., Lanzavecchia, A., Piccoli, L., Doffinger, R., Wills, M., Veesler, D., Corti, D., and Gupta, R. K.

Subjects
0301 basic medicine, Male, Models, Molecular, Passive, Antibodies, Viral, Neutralization, 0302 clinical medicine, Models, Monoclonal, 80 and over, Viral, Neutralizing antibody, Neutralizing, Aged, 80 and over, Vaccines, Vaccines, Synthetic, Multidisciplinary, biology, Antibodies, Monoclonal, C500, Middle Aged, C700, Spike Glycoprotein, Vaccination, Spike Glycoprotein, Coronavirus, Female, Angiotensin-Converting Enzyme 2, Antibody, Aged, Antibodies, Neutralizing, COVID-19, COVID-19 Vaccines, HEK293 Cells, Humans, Immune Evasion, Immunization, Passive, Mutation, Neutralization Tests, SARS-CoV-2, medicine.drug_class, B100, Monoclonal antibody, Antibodies, Virus, 03 medical and health sciences, Immune system, medicine, COVID-19 Serotherapy, QR355, Synthetic, Molecular, Virology, Coronavirus, 030104 developmental biology, Immunization, biology.protein, 030217 neurology & neurosurgery
Abstract

Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant1, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b22. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.

Published
2021

3. Recurrent SARS-CoV-2 mutations in immunodeficient patients

Author

Wilkinson, S. A. J., Sparks, N., Kele, B., Peacock, T. P., Robson, S. C., Connor, T. R., Loman, N. J., Golubchik, T., Martinez Nunez, R. T., Bonsall, D., Rambaut, A., Snell, L. B., Livett, R., Ludden, C., Corden, S., Nastouli, E., Nebbia, G., Johnston, I., Lythgoe, K., Estee Torok, M., Goodfellow, I. G., Prieto, J. A., Saeed, K., Jackson, D. K., Houlihan, C., Frampton, D., Hamilton, W. L., Witney, A. A., Bucca, G., Pope, C. F., Moore, C., Thomson, E. C., Harrison, E. M., Smith, C. P., Rogan, F., Beckwith, S. M., Murray, A., Singleton, D., Eastick, K., Sheridan, L. A., Randell, P., Jackson, L. M., Ariani, C. V., Gonçalves, S., Fairley, D. J., Loose, M. W., Watkins, J., Moses, S., Nicholls, S., Bull, M., Amato, R., Smith, D. L., Aanensen, D. M., Barrett, J. C., Aggarwal, D., Shepherd, J. G., Curran, M. D., Parmar, S., Parker, M. D., Williams, C., Glaysher, S., Underwood, A. P., Bashton, M., Pacchiarini, N., Loveson, K. F., Byott, M., Carabelli, A. M., Templeton, K. E., de Silva, T. I., Wang, D., Langford, C. F., Sillitoe, J., Gunson, R. N., Cottrell, S., O’Grady, J., Kwiatkowski, D., Lillie, P. J., Cortes, N., Moore, N., Thomas, C., Burns, P. J., Mahungu, T. W., Liggett, S., Beckett, A. H., Holden, M. T. G., Levett, L. J., Osman, H., Hassan-Ibrahim, M. O., Simpson, D. A., Chand, M., Gupta, R. K., Darby, A. C., Paterson, S., Pybus, O. G., Volz, E. M., de Angelis, D., Robertson, D. L., Page, A. J., Martincorena, I., Aigrain, L., Bassett, A. R., Wong, N., Taha, Y., Erkiert, M. J., Spencer Chapman, M. H., Dewar, R., McHugh, M. P., Mookerjee, S., Aplin, S., Harvey, M., Sass, T., Umpleby, H., Wheeler, H., McKenna, J. P., Warne, B., Taylor, J. F., Chaudhry, Y., Izuagbe, R., Jahun, A. S., Young, G. R., McMurray, C., McCann, C. M., Nelson, A., Elliott, S., Price, A., Crown, M. R., Rey, S, Roy, S., Temperton, B., Shaaban, S., Hesketh, A. R., Laing, K. G., Monahan, I. M., Heaney, J., Pelosi, E., Silviera, S., Wilson-Davies, E., Fryer, H., Adams, H., du Plessis, L., Johnson, R., Harvey, W. T., Hughes, J., Orton, R. J., Spurgin, L. G., Bourgeois, Y., Ruis, C., O’Toole, Á., Gourtovaia, M., Sanderson, T., Fraser, C., Edgeworth, J., Breuer, J., Michell, S. L., Todd, J. A., John, M., Buck, D., Gajee, K., Kay, G. L., Peacock, S. J., Heyburn, D., Kitchman, K., McNally, A., Pritchard, D. T., Dervisevic, S., Muir, P., Robinson, E., Vipond, B. B., Ramadan, N. A., Jeanes, C., Weldon, D., Catalan, J., Jones, N., da Silva Filipe, A., Fuchs, M., Miskelly, J., Jeffries, A. R., Oliver, K., Park, N. R., Ash, A., Koshy, C., Barrow, M., Buchan, S. L., Mantzouratou, A., Clark, G., Holmes, C. W., Campbell, S., Davis, T., Tan, N. K., Brown, J. R., Harris, K. A., Kidd, S. P., Grant, P. R., Xu-McCrae, L., Cox, A., Madona, P., Pond, M., Randell, P. A., Withell, K. T., Graham, C., Denton-Smith, R., Swindells, E., Turnbull, R., Sloan, T. J., Bosworth, A., Hutchings, S., Pymont, H. M., Casey, A., Ratcliffe, L., Jones, C. R., Knight, B. A., Haque, T., Hart, J., Irish-Tavares, D., Witele, E., Mower, C., Watson, L. K., Collins, J., Eltringham, G., Crudgington, D., Macklin, B., Iturriza-Gomara, M., Lucaci, A. O., McClure, P. C., Carlile, M., Holmes, N., Storey, N., Rooke, S., Yebra, G., Craine, N., Perry, M., Alikhan, N. F., Bridgett, S., Cook, K. F., Fearn, C., Goudarzi, S., Lyons, R. A., Williams, T., Haldenby, S. T., Durham, J., Leonard, S., Davies, R. M., Batra, R., Blane, B., Spyer, M. J., Smith, P., Yavus, M., Williams, R. J., Mahanama, A. I. K., Samaraweera, B., Girgis, S. T., Hansford, S. E., Green, A., Beaver, C., Bellis, K. L., Dorman, M. J., Kay, S., Prestwood, L., Rajatileka, S., Quick, J., Poplawski, R., Reynolds, N., Mack, A., Morriss, A., Whalley, T., Patel, B., Georgana, I., Hosmillo, M., Pinckert, M. L., Stockton, J., Henderson, J. H., Hollis, A., Stanley, W., Yew, W. C., Myers, R., Thornton, A., Adams, A., Annett, T., Asad, H., Birchley, A., Coombes, J., Evans, J. M., Fina, L., Gatica-Wilcox, B., Gilbert, L., Graham, L., Hey, J., Hilvers, E., Jones, S., Jones, H., Kumziene-Summerhayes, S., McKerr, C., Powell, J., Pugh, G., Taylor, S., Trotter, A. J., Williams, C. A., Kermack, L. M., Foulkes, B. H., Gallis, M., Hornsby, H. R., Louka, S. F., Pohare, M., Wolverson, P., Zhang, P., MacIntyre-Cockett, G., Trebes, A., Moll, R. J., Ferguson, L., Goldstein, E. J., Maclean, A., Tomb, R., Starinskij, I., Thomson, L., Southgate, J., Kraemer, M. U. G., Raghwani, J., Zarebski, A. E., Boyd, O., Geidelberg, L., Illingworth, C. J., Jackson, C., Pascall, D., Vattipally, S., Freeman, T. M., Hsu, S. N., Lindsey, B. B., James, K., Lewis, K., Tonkin-Hill, G., Tovar-Corona, J. M., Cox, M., Abudahab, K., Menegazzo, M., Taylor, B. E. W., Yeats, C. A., Mukaddas, A., Wright, D. W., de Oliveira Martins, L., Colquhoun, R., Hill, V., Jackson, B., McCrone, J. T., Medd, N., Scher, E., Keatley, J. P., Curran, T., Morgan, S., Maxwell, P., Smith, K., Eldirdiri, S., Kenyon, A., Holmes, A. H., Price, J. R., Wyatt, T., Mather, A. E., Skvortsov, T., Hartley, J. A., Guest, M., Kitchen, C., Merrick, I., Munn, R., Bertolusso, B., Lynch, J., Vernet, G., Kirk, S., Wastnedge, E., Stanley, R., Idle, G., Bradley, D. T., Poyner, J., Mori, M., Jones, O., Wright, V., Brooks, E., Churcher, C. M., Fragakis, M., Galai, K., Jermy, A., Judges, S., McManus, G. M., Smith, K. S., Westwick, E., Attwood, S. W., Bolt, F., Davies, A., De Lacy, E., Downing, F., Edwards, S., Meadows, L., Jeremiah, S., Smith, N., Foulser, L., Charalampous, T., Patel, A., Berry, L., Boswell, T., Fleming, V. M., Howson-Wells, H. C., Joseph, A., Khakh, M., Lister, M. M., Bird, P. W., Fallon, K., Helmer, T., McMurray, C. L., Odedra, M., Shaw, J., Tang, J. W., Willford, N. J., Blakey, V., Raviprakash, V., Sheriff, N., Williams, L. A., Feltwell, T., Bedford, L., Cargill, J. 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R., Rey, S, Roy, S., Temperton, B., Shaaban, S., Hesketh, A. R., Laing, K. G., Monahan, I. M., Heaney, J., Pelosi, E., Silviera, S., Wilson-Davies, E., Fryer, H., Adams, H., du Plessis, L., Johnson, R., Harvey, W. T., Hughes, J., Orton, R. J., Spurgin, L. G., Bourgeois, Y., Ruis, C., O’Toole, Á., Gourtovaia, M., Sanderson, T., Fraser, C., Edgeworth, J., Breuer, J., Michell, S. L., Todd, J. A., John, M., Buck, D., Gajee, K., Kay, G. L., Peacock, S. J., Heyburn, D., Kitchman, K., McNally, A., Pritchard, D. T., Dervisevic, S., Muir, P., Robinson, E., Vipond, B. B., Ramadan, N. A., Jeanes, C., Weldon, D., Catalan, J., Jones, N., da Silva Filipe, A., Fuchs, M., Miskelly, J., Jeffries, A. R., Oliver, K., Park, N. R., Ash, A., Koshy, C., Barrow, M., Buchan, S. L., Mantzouratou, A., Clark, G., Holmes, C. W., Campbell, S., Davis, T., Tan, N. K., Brown, J. R., Harris, K. A., Kidd, S. P., Grant, P. R., Xu-McCrae, L., Cox, A., Madona, P., Pond, M., Randell, P. A., Withell, K. T., Graham, C., Denton-Smith, R., Swindells, E., Turnbull, R., Sloan, T. J., Bosworth, A., Hutchings, S., Pymont, H. M., Casey, A., Ratcliffe, L., Jones, C. R., Knight, B. A., Haque, T., Hart, J., Irish-Tavares, D., Witele, E., Mower, C., Watson, L. K., Collins, J., Eltringham, G., Crudgington, D., Macklin, B., Iturriza-Gomara, M., Lucaci, A. O., McClure, P. C., Carlile, M., Holmes, N., Storey, N., Rooke, S., Yebra, G., Craine, N., Perry, M., Alikhan, N. F., Bridgett, S., Cook, K. F., Fearn, C., Goudarzi, S., Lyons, R. A., Williams, T., Haldenby, S. T., Durham, J., Leonard, S., Davies, R. M., Batra, R., Blane, B., Spyer, M. J., Smith, P., Yavus, M., Williams, R. J., Mahanama, A. I. K., Samaraweera, B., Girgis, S. T., Hansford, S. E., Green, A., Beaver, C., Bellis, K. L., Dorman, M. J., Kay, S., Prestwood, L., Rajatileka, S., Quick, J., Poplawski, R., Reynolds, N., Mack, A., Morriss, A., Whalley, T., Patel, B., Georgana, I., Hosmillo, M., Pinckert, M. L., Stockton, J., Henderson, J. H., Hollis, A., Stanley, W., Yew, W. C., Myers, R., Thornton, A., Adams, A., Annett, T., Asad, H., Birchley, A., Coombes, J., Evans, J. M., Fina, L., Gatica-Wilcox, B., Gilbert, L., Graham, L., Hey, J., Hilvers, E., Jones, S., Jones, H., Kumziene-Summerhayes, S., McKerr, C., Powell, J., Pugh, G., Taylor, S., Trotter, A. J., Williams, C. A., Kermack, L. M., Foulkes, B. H., Gallis, M., Hornsby, H. R., Louka, S. F., Pohare, M., Wolverson, P., Zhang, P., MacIntyre-Cockett, G., Trebes, A., Moll, R. J., Ferguson, L., Goldstein, E. J., Maclean, A., Tomb, R., Starinskij, I., Thomson, L., Southgate, J., Kraemer, M. U. G., Raghwani, J., Zarebski, A. E., Boyd, O., Geidelberg, L., Illingworth, C. J., Jackson, C., Pascall, D., Vattipally, S., Freeman, T. M., Hsu, S. N., Lindsey, B. B., James, K., Lewis, K., Tonkin-Hill, G., Tovar-Corona, J. M., Cox, M., Abudahab, K., Menegazzo, M., Taylor, B. E. W., Yeats, C. A., Mukaddas, A., Wright, D. W., de Oliveira Martins, L., Colquhoun, R., Hill, V., Jackson, B., McCrone, J. T., Medd, N., Scher, E., Keatley, J. P., Curran, T., Morgan, S., Maxwell, P., Smith, K., Eldirdiri, S., Kenyon, A., Holmes, A. H., Price, J. R., Wyatt, T., Mather, A. E., Skvortsov, T., Hartley, J. A., Guest, M., Kitchen, C., Merrick, I., Munn, R., Bertolusso, B., Lynch, J., Vernet, G., Kirk, S., Wastnedge, E., Stanley, R., Idle, G., Bradley, D. T., Poyner, J., Mori, M., Jones, O., Wright, V., Brooks, E., Churcher, C. M., Fragakis, M., Galai, K., Jermy, A., Judges, S., McManus, G. M., Smith, K. S., Westwick, E., Attwood, S. W., Bolt, F., Davies, A., De Lacy, E., Downing, F., Edwards, S., Meadows, L., Jeremiah, S., Smith, N., Foulser, L., Charalampous, T., Patel, A., Berry, L., Boswell, T., Fleming, V. M., Howson-Wells, H. C., Joseph, A., Khakh, M., Lister, M. M., Bird, P. W., Fallon, K., Helmer, T., McMurray, C. L., Odedra, M., Shaw, J., Tang, J. W., Willford, N. J., Blakey, V., Raviprakash, V., Sheriff, N., Williams, L. A., Feltwell, T., Bedford, L., Cargill, J. S., Hughes, W., Moore, J., Stonehouse, S., Atkinson, L., Lee, J. C. D., Shah, D., Alcolea-Medina, A., Ohemeng-Kumi, N., Ramble, J., Sehmi, J., Williams, R., Chatterton, W., Pusok, M., Everson, W., Castigador, A., Macnaughton, E., El Bouzidi, K., Lampejo, T., Sudhanva, M., Breen, C., Sluga, G., Ahmad, S. S. Y., George, R. P., Machin, N. W., Binns, D., James, V., Blacow, R., Coupland, L., Smith, L., Barton, E., Padgett, D., Scott, G., Cross, A., Mirfenderesky, M., Greenaway, J., Cole, K., Clarke, P., Duckworth, N., Walsh, S., Bicknell, K., Impey, R., Wyllie, S., Hopes, R., Bishop, C., Chalker, V., Harrison, I., Gifford, L., Molnar, Z., Auckland, C., Evans, C., Johnson, K., Partridge, D. G., Raza, M., Baker, P., Bonner, S., Essex, S., Murray, L. J., Lawton, A. I., Burton-Fanning, S., Payne, B. A. I., Waugh, S., Gomes, A. N., Kimuli, M., Murray, D. R., Ashfield, P., Dobie, D., Ashford, F., Best, A., Crawford, L., Cumley, N., Mayhew, M., Megram, O., Mirza, J., Moles-Garcia, E., Percival, B., Driscoll, M., Ensell, L., Lowe, H. L., Maftei, L., Mondani, M., Chaloner, N. J., Cogger, B. J., Easton, L. J., Huckson, H., Lewis, J., Lowdon, S., Malone, C. S., Munemo, F., Mutingwende, M., Nicodemi, R., Podplomyk, O., Somassa, T., Beggs, A., Richter, A., Cormie, C., Dias, J., Forrest, S., Higginson, E. E., Maes, M., Young, J., Davidson, R. K., Jackson, K. A., Turtle, L., Keeley, A. J., Ball, J., Byaruhanga, T., Chappell, J. G., Dey, J., Hill, J. D., Park, E. J., Fanaie, A., Hilson, R. A., Yaze, G., Lo, S., Afifi, S., Beer, R., Maksimovic, J., McCluggage, K., Spellman, K., Bresner, C., Fuller, W., Marchbank, A., Workman, T., Shelest, E., Debebe, J., Sang, F., Zamudio, M. E., Francois, S., Gutierrez, B., Vasylyeva, T. I., Flaviani, F., Ragonnet-Cronin, M, Smollett, K. L., Broos, A., Mair, D., Nichols, J., Nomikou, K., Tong, L., Tsatsani, I., O’Brien, S., Rushton, S., Sanderson, R., Perkins, J., Cotton, S., Gallagher, A., Allara, E., Pearson, C., Bibby, D., Dabrera, G., Ellaby, N., Gallagher, E., Hubb, J., Lackenby, A., Lee, D., Manesis, N., Mbisa, T., Platt, S., Twohig, K. A., Morgan, M., Aydin, A., Baker, D. J., Foster-Nyarko, E., Prosolek, S. J., Rudder, S., Baxter, C., Carvalho, S. F., Lavin, D., Mariappan, A., Radulescu, C., Singh, A., Tang, M., Morcrette, H., Bayzid, N., Cotic, M., Balcazar, C. E, Gallagher, M. D., Maloney, D., Stanton, T. D., Williamson, K. A., Manley, R., Michelsen, M. L., Sambles, C. M., Studholme, D. J., Warwick-Dugdale, J., Eccles, R., Gemmell, M., Gregory, R., Hughes, M., Nelson, C., Rainbow, L., Vamos, E. E., Webster, H. J., Whitehead, M., Wierzbicki, C., Angyal, A., Green, L. R., Whiteley, M., Betteridge, E., Bronner, I. F., Farr, B. W., Goodwin, S., Lensing, S. V., McCarthy, S. A., Quail, M. A., Rajan, D., Redshaw, N. M., Scott, C., Shirley, L., Thurston, S. A. J., Rowe, W., Gaskin, A., Le-Viet, T., Bonfield, J., Liddle, J., and Whitwham, A.

Abstract

Long-term severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in immunodeficient patients are an important source of variation for the virus but are understudied. Many case studies have been published which describe one or a small number of long-term infected individuals but no study has combined these sequences into a cohesive dataset. This work aims to rectify this and study the genomics of this patient group through a combination of literature searches as well as identifying new case series directly from the COVID-19 Genomics UK (COG-UK) dataset. The spike gene receptor-binding domain and N-terminal domain (NTD) were identified as mutation hotspots. Numerous mutations associated with variants of concern were observed to emerge recurrently. Additionally a mutation in the envelope gene, T30I was determined to be the second most frequent recurrently occurring mutation arising in persistent infections. A high proportion of recurrent mutations in immunodeficient individuals are associated with ACE2 affinity, immune escape, or viral packaging optimisation.There is an apparent selective pressure for mutations that aid cell–cell transmission within the host or persistence which are often different from mutations that aid inter-host transmission, although the fact that multiple recurrent de novo mutations are considered defining for variants of concern strongly indicates that this potential source of novel variants should not be discounted. © The Author(s) 2022. Published by Oxford University Press.

4. A metagenomic prospective cohort study on gut microbiome composition and clinical infection in small bowel transplantation.

Author

Madhav A, Bousfield R, Pereira-Dias J, Cormie C, Forrest S, Keane J, Kermack L, Higginson E, Dougan G, Spiers H, Massey D, Sharkey L, Rutter C, Woodward J, Russell N, Amin I, Butler A, Atkinson K, Dymond T, Bartholdson Scott J, Baker S, and Gkrania-Klotsas E

Subjects
Humans, Metagenome, Prospective Studies, Gastrointestinal Microbiome genetics, Sepsis, Microbiota
Abstract

Two-thirds of small-bowel transplantation (SBT) recipients develop bacteremia, with the majority of infections occurring within 3 months post-transplant. Sepsis-related mortality occurs in 31% of patients and is commonly caused by bacteria of gut origin, which are thought to translocate across the implanted organ. Serial post-transplant surveillance endoscopies provide an opportunity to study whether the composition of the ileal and colonic microbiota can predict the emergence as well as the pathogen of subsequent clinical infections in the SBT patient population. Five participants serially underwent aspiration of ileal and colonic bowel effluents at transplantation and during follow-up endoscopy either until death or for up to 3 months post-SBT. We performed whole-metagenome sequencing (WMS) of 40 bowel effluent samples and compared the results with clinical infection episodes. Microbiome composition was concordant between participants and timepoint-matched ileal and colonic samples. Four out of five (4/5) participants had clinically significant infections thought to be of gut origin. Bacterial translocation from the gut was observed in 3/5 patients with bacterial infectious etiologies. In all three cases, the pathogens had demonstrably colonized the gut between 1-10 days prior to invasive clinical infection. Recipients with better outcomes received donor grafts with higher alpha diversity. There was an increase in the number of antimicrobial resistance genes associated with longer hospital stay for all participants. This metagenomic study provides preliminary evidence to support the pathogen translocation hypothesis of gut-origin sepsis in the SBT cohort. Ileal and colonic microbiome compositions were concordant; therefore, fecal metagenomic analysis could be a useful surveillance tool for impeding infection with specific gut-residing pathogens.

Published
2024
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5. Impact of antimicrobial use on abundance of antimicrobial resistance genes in chicken flocks in Vietnam.

Author

Nhung NT, Dutta A, Higginson E, Kermack L, Yen NTP, Phu DH, Kiet BT, Choisy M, Geskus RB, Baker S, and Carrique-Mas J

Abstract

Objectives: We investigated longitudinally Vietnamese small-scale chicken flocks in order to characterize changes in antimicrobial resistance gene (ARG) content over their life cycle, and the impact of antimicrobial use (AMU) on an intervention consisting of veterinary advice provision., Methods: AMU data and faecal samples were collected from 83 flocks (25 farms) at day-old, mid- and late-production (∼4 month cycle). Using high-throughput real-time PCR, samples were investigated for 94 ARGs. ARG copies were related to 16S rRNA and ng of DNA (ngDNA). Impact of AMU and ARGs in day-olds was investigated by mixed-effects models., Results: Flocks received a mean (standard error, SE) animal daily dose (ADD) of 736.7 (83.0) and 52.1 (9.9) kg in early and late production, respectively. Overall, ARGs/16S rRNA increased from day-old (mean 1.47; SE 0.10) to mid-production (1.61; SE 0.16), further decreasing in end-production (1.60; SE 0.1) (all P  > 0.05). In mid-production, ARGs/16S rRNA increased for aminoglycosides, phenicols, sulphonamides and tetracyclines, decreasing for polymyxins β-lactams and genes that confer resistance to mutiple classes (multi-drug resistance) (MDR). At end-production, aminoglycoside resistance decreased and polymyxin and quinolone resistance increased (all P  < 0.05). Results in relation to ngDNA gave contradictory results. Neither AMU nor ARGs in day-olds had an impact on subsequent ARG abundance. The intervention resulted in 74.2% AMU reduction; its impact on ARGs depended on whether ARGs/ngDNA (+14.8%) or ARGs/16S rRNA metrics (-10.7%) ( P  > 0.05) were computed., Conclusions: The flocks' environment (contaminated water, feed and residual contamination) is likely to play a more important role in transmission of ARGs to flocks than previously thought. Results highlight intriguing differences in the quantification of ARGs depending on the metric chosen., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Published
2023
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6. The Removal of Airborne Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Other Microbial Bioaerosols by Air Filtration on Coronavirus Disease 2019 (COVID-19) Surge Units.

Author

Conway Morris A, Sharrocks K, Bousfield R, Kermack L, Maes M, Higginson E, Forrest S, Pereira-Dias J, Cormie C, Old T, Brooks S, Hamed I, Koenig A, Turner A, White P, Floto RA, Dougan G, Gkrania-Klotsas E, Gouliouris T, Baker S, and Navapurkar V

Subjects
Hospitals, Humans, COVID-19, SARS-CoV-2
Abstract

Airborne severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected in a coronavirus disease 19 (COVID-19) ward before activation of HEPA-air filtration but not during filter operation; SARS-CoV-2 was again detected following filter deactivation. Airborne SARS-CoV-2 was infrequently detected in a COVID-19 intensive care unit. Bioaerosol was also effectively filtered., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Published
2022
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