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2. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts tropism and fusogenicity

Author

Meng, B., Abdullahi, A., Ferreira, I., Goonawardane, N., Saito, A., Kimura, I., Yamasoba, D., Gerber, P., Fatihi, S., Rathore, S., Zepeda, S., Papa, G., Kemp, S., Ikeda, T., Toyoda, M., Tan, T., Kuramochi, J., Mitsunaga, S., Ueno, T., Shirakawa, K., Takaori-Kondo, A., Brevini, T., Mallery, D., Charles, O., Collaboration, C., Japan, G., Consortium, E., Bowen, J., Joshi, A., Walls, A., Jackson, L., Martin, D., Smith, K., Bradley, J., Briggs, J., Choi, J., Madissoon, E., Meyer, K., Mlcochova, P., Ceron-Gutierrez, L., Doffinger, R., Teichmann, S., Fisher, A., Pizzuto, M., de Marco, A., Corti, D., Hosmillo, M., Lee, J., James, L., Thukral, L., Veesler, D., Sigal, A., Sampaziotis, F., Goodfellow, I., Matheson, N., Sato, K., and Gupta, R.

Subjects
Immune evasion, SARS-CoV-2
Abstract

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and bears multiple spike mutations2. Here we show that Omicron spike has higher affinity for ACE2 compared to Delta as well as a marked change of antigenicity conferring significant evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralising antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralisation. Importantly, antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lower airway organoids, lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared to Delta. Replication differences mapped to entry efficiency using spike pseudotyped virus (PV) assays. The defect for Omicron PV to enter specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and knock down of TMPRSS2 impacted Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently utilises the cellular protease TMPRSS2 that promotes cell entry via plasma membrane fusion, with greater dependency on cell entry via the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to utilise TMPRSS2, syncytium formation by the Omicron spike was markedly impaired compared to the Delta spike. Omicron’s less efficient spike cleavage at S1/S2 is associated with shift in cellular tropism away from TMPRSS2 expressing cells, with implications for altered pathogenesis., SARS-CoV-2オミクロン株による中和抗体回避と感染指向性の変化. 京都大学プレスリリース. 2022-02-03.

Published
2022

3. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity

Author

Meng, B., Abdullahi, A., Ferreira, I. A. T. M., Goonawardane, N., Saito, A., Kimura, I., Yamasoba, D., Gerber, P. P., Fatihi, S., Rathore, S., Zepeda, S. K., Papa, G., Kemp, S. A., Ikeda, T., Toyoda, M., Tan, T. S., Kuramochi, J., Mitsunaga, S., Ueno, T., Shirakawa, K., Takaori-Kondo, A., Brevini, T., Mallery, D. L., Charles, O. J., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Ouwehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Maxwell, P., Shaw, A., 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., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Fawke, S., Gleadall, N., Grenfell, R., Hinch, A., Jackson, S., Jarvis, I., Krishna, B., Nice, F., Omarjee, O., Perera, M., Potts, M., Richoz, N., Romashova, V., Stefanucci, L., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Butcher, H., Caputo, D., Chandler, M., Chinnery, P., Clapham-Riley, D., Dewhurst, E., Fernandez, C., Furlong, A., Graves, B., Gray, J., Hein, S., Ivers, T., Le Gresley, E., Linger, R., Kasanicki, M., King, R., Meloy, S., Moulton, A., Muldoon, F., Ovington, N., Papadia, S., Penkett, C. J., Phelan, I., Ranganath, V., Paraschiv, R., Sage, A., Sambrook, J., Scholtes, I., Schon, K., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Butlertanaka, E. P., Tanaka, Y. L., Ito, J., Uriu, K., Kosugi, Y., Suganami, M., Oide, A., Yokoyama, M., Chiba, M., Motozono, C., Nasser, H., Shimizu, R., Kitazato, K., Hasebe, H., Irie, T., Nakagawa, S., Wu, J., Takahashi, M., Fukuhara, T., Shimizu, K., Tsushima, K., Kubo, H., Kazuma, Y., Nomura, R., Horisawa, Y., Nagata, K., Kawai, Y., Yanagida, Y., Tashiro, Y., Tokunaga, K., Ozono, S., Kawabata, R., Morizako, N., Sadamasu, K., Asakura, H., Nagashima, M., Yoshimura, K., Cardenas, P., Munoz, E., Barragan, V., Marquez, S., Prado-Vivar, B., Becerra-Wong, M., Caravajal, M., Trueba, G., Rojas-Silva, P., Grunauer, M., Gutierrez, B., Guadalupe, J. J., Fernandez-Cadena, J. C., Andrade-Molina, D., Baldeon, M., Pinos, A., Bowen, J. E., Joshi, A., Walls, A. C., Jackson, L., Martin, D., Smith, K. G. C., Bradley, J., Briggs, J. A. G., Choi, J., Madissoon, E., Meyer, K. B., Mlcochova, P., Ceron-Gutierrez, L., Doffinger, R., Teichmann, S. A., Fisher, A. J., Pizzuto, M. S., de Marco, A., Corti, D., Hosmillo, M., Lee, J. H., James, L. C., Thukral, L., Veesler, D., Sigal, A., Sampaziotis, F., Goodfellow, I. G., Sato, K., and Gupta, R. K.

Subjects
Adult, Male, COVID-19 Vaccines, Virus Replication, Membrane Fusion, Antibodies, Cell Line, Tissue Culture Techniques, Chlorocebus aethiops, 80 and over, Animals, Humans, Viral, Neutralizing, Lung, Aged, Multidisciplinary, Virulence, SARS-CoV-2, Immune Sera, Cell Membrane, Serine Endopeptidases, COVID-19, Convalescence, Middle Aged, Virus Internalization, Spike Glycoprotein, Intestines, Coronavirus, Nasal Mucosa, Mutation, Female, Angiotensin-Converting Enzyme 2, Aged, 80 and over, Antibodies, Neutralizing, Antibodies, Viral, Spike Glycoprotein, Coronavirus
Abstract

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis.

Published
2022
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5. 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

7. Contributors

Author

Ajami, N.J., primary, Angel, J., additional, Angel, M., additional, Arias, C.F., additional, Atmar, R.L., additional, Bányai, K., additional, Brandtzaeg, P., additional, Cheung, W., additional, Choi, J.-M., additional, Crawford, S.E., additional, Cunha, J.B., additional, Desselberger, U., additional, Díaz-Salinas, M.A., additional, Dormitzer, P.R., additional, Elftman, M.D., additional, Estes, M.K., additional, Franco, M.A., additional, Garg, R.R., additional, Gaunt, E., additional, Goodfellow, I., additional, Green, K.Y., additional, Greenberg, H.B., additional, Hagbom, M., additional, Hammarström, L., additional, Harrison, S.C., additional, Herrera, D., additional, Isa, P., additional, Kandasamy, S., additional, Kang, G., additional, Karst, S.M., additional, Khamrin, P., additional, Kolawole, A.O., additional, Larson, G., additional, Le Pendu, J., additional, Lever, A., additional, López, S., additional, López, T., additional, Maneekarn, N., additional, Marcotte, H., additional, Marvin, S., additional, Meliopoulos, V.A., additional, Muhaxhiri, Z., additional, Murillo, A., additional, Nasir, W., additional, Navarro, A., additional, Parra, M., additional, Patton, J.T., additional, Petrosino, J.F., additional, Pitzer, V.E., additional, Venkataram Prasad, B.V., additional, Ramani, S., additional, Rydell, G.E., additional, Saif, L.J., additional, Sastri, N.P., additional, Schultz-Cherry, S., additional, Sen, A., additional, Shanker, S., additional, Silva-Ayala, D., additional, Svensson, L., additional, Taube, S., additional, Ushijima, H., additional, Vesikari, T., additional, Vlasova, A.N., additional, Williamson, L., additional, Wobus, C.E., additional, and Zachos, N.C., additional

Published
2016
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8. Effective control of SARS-CoV-2 transmission between healthcare workers during a period of diminished community prevalence of COVID-19

Author

Jones, N. K., Rivett, L., Sparkes, D., Forrest, S., Sridhar, S., Young, J., Pereira-Dias, J., Cormie, C., Gill, H., Reynolds, N., Wantoch, M., Routledge, M., Warne, B., Levy, J., Jimenez, W. D. C., Samad, F. N. B., Mcnicholas, C., Ferris, M., Gray, J., Gill, M., Curran, M. D., Fuller, S., Chaudhry, A., Shaw, A., Bradley, J. R., Hannon, G. J., Goodfellow, I. G., Dougan, G., Smith, K. G. C., Lehner, P. J., Wright, G., Matheson, N. J., Baker, S., Weekes, M. P., Bradley, J., Goodfellow, I., Gupta, R., Lyons, P. A., Torok, M. E., Toshner, M., Kean, I., Caddy, S., Caller, L., Feltwell, T., Hall, G., Hamilton, W., Hosmillo, M., Houldcroft, C., Jahun, A., Khokhar, F., Meredith, L., Yakovleva, A., Butcher, H., Caputo, D., Clapham-Riley, D., Dolling, H., Furlong, A., Graves, B., Gresley, E. L., Kingston, N., Papadia, S., Stark, H., Stirrups, K. E., Webster, J., Calder, J., Harris, J., Hewitt, S., Kennet, J., Meadows, A., Rastall, R., Brien, C. O., Price, J., Publico, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Hannon, G., Brookes, K., Canna, L., Cruz, I., Dempsey, K., Elmer, A., Escoffery, N., Jones, H., Ribeiro, C., Saunders, C., Wright, A., Nyagumbo, R., Roberts, A., Bucke, A., Hargreaves, S., Johnson, D., Narcorda, A., Read, D., Sparke, C., Worboys, L., Lagadu, K., Mactavous, L., Gould, T., Raine, T., Mather, C., Ramenatte, N., Vallier, A. -L., Kasanicki, M., Eames, P. -J., Thake, L., Bartholomew, N., Brown, N., Curran, M., Parmar, S., Zhang, H., Bowring, A., Martell, G., Quinnell, N., Wright, J., Murphy, H., Dunmore, B. J., Legchenko, E., Graf, S., Huang, C., Hodgson, J., Hunter, K., Martin, J., Mescia, F., Odonnell, C., Pointon, L., Shih, J., Sutcliffe, R., Tilly, T., Tong, Z., Treacy, C., Wood, J., Bergamaschi, L., Betancourt, A., Bowyer, G., De Sa, A., Epping, M., Hinch, A., Huhn, O., Jarvis, I., Lewis, D., Marsden, J., Mccallum, S., Nice, F., Omarjee, O., Perera, M., Romashova, N., Strezlecki, M., Yarkoni, N. S., Turner, L., Bailey, B., Doughton, R., Workman, C., Trotter, C., David, W., Jimenez, C., Jones, Nick K [0000-0003-4475-7761], Sridhar, Sushmita [0000-0001-7453-7482], Hannon, Gregory J [0000-0003-4021-3898], Goodfellow, Ian G [0000-0002-9483-510X], Lehner, Paul J [0000-0001-9383-1054], Matheson, Nicholas J [0000-0002-3318-1851], Weekes, Michael P [0000-0003-3196-5545], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Infectious Disease Transmission, global health, Occupational safety and health, Hospitals, University, Patient-to-Professional, 0302 clinical medicine, COVID-19 Testing, Patient Admission, Nasopharynx, Pandemic, Epidemiology, Prevalence, Medicine, Infection control, Mass Screening, 030212 general & internal medicine, Viral, Biology (General), Family Characteristics, General Neuroscience, Infectious, human biology, virus diseases, General Medicine, Middle Aged, Hospitals, 3. Good health, virology, Community-Acquired Infections, Occupational Diseases, England, epidemiology, Female, medicine.symptom, Symptom Assessment, Coronavirus Infections, Hospital Units, Adult, medicine.medical_specialty, Infectious Disease Transmission, Patient-to-Professional, QH301-705.5, Health Personnel, infectious disease, Science, Pneumonia, Viral, Real-Time Polymerase Chain Reaction, Asymptomatic, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Betacoronavirus, Disease Transmission, Disease Transmission, Infectious, Humans, human, Human Biology and Medicine, Hospitals, Teaching, Pandemics, Mass screening, Asymptomatic Diseases, emerging pathogens, University, Infection Control, General Immunology and Microbiology, business.industry, Clinical Laboratory Techniques, SARS-CoV-2, Teaching, COVID-19, Pneumonia, medicine, occupational health, Contact Tracing, Program Evaluation, 030104 developmental biology, Epidemiology and Global Health, Emergency medicine, business, Research Advance, Contact tracing
Abstract

Previously, we showed that 3% (31/1032)of asymptomatic healthcare workers (HCWs) from a large teaching hospital in Cambridge, UK, tested positive for SARS-CoV-2 in April 2020. About 15% (26/169) HCWs with symptoms of coronavirus disease 2019 (COVID-19) also tested positive for SARS-CoV-2 (Rivett et al., 2020). Here, we show that the proportion of both asymptomatic and symptomatic HCWs testing positive for SARS-CoV-2 rapidly declined to near-zero between 25th April and 24th May 2020, corresponding to a decline in patient admissions with COVID-19 during the ongoing UK ‘lockdown’. These data demonstrate how infection prevention and control measures including staff testing may help prevent hospitals from becoming independent ‘hubs’ of SARS-CoV-2 transmission, and illustrate how, with appropriate precautions, organizations in other sectors may be able to resume on-site work safely.

Published
2020

9. Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease

Author

Bergamaschi, L., Mescia, F., Turner, L., Hanson, A. L., Kotagiri, P., Dunmore, B. J., Ruffieux, H., de Sa, A., Huhn, O., Morgan, M. D., Gerber, P. P., Wills, M. R., Baker, S., Calero-Nieto, F. J., Doffinger, R., Dougan, G., Elmer, A., Goodfellow, I. G., Gupta, R. K., Hosmillo, M., Hunter, K., Kingston, N., Lehner, P. J., Matheson, N. J., Nicholson, J. K., Petrunkina, A. M., Richardson, S., Saunders, C., Thaventhiran, J. E. D., Toonen, E. J. M., Weekes, M. P., Gottgens, B., Toshner, M., Hess, C., Bradley, J. R., Lyons, P. A., Smith, K. G. C., Allison, J., Ansaripour, A., Betancourt, A., Bong, S. -H., Bower, G., Bucke, A., Bullman, B., Bunclark, K., Butcher, H., Calder, J., Canna, L., Caputo, D., Clapham-Riley, D., Cossetti, C., Coudert, J. D., de Bie, E. M. D. D., Dewhurst, E., di Stefano, G., Domingo, J., Epping, M., Fahey, C., Fawke, S., Fuller, S., Furlong, A., Gleadall, N., Graf, S., Graves, B., Gray, J., Grenfell, R., Harris, J., Hewitt, S., Hinch, A., Hodgson, J., Holmes, E., Huang, C., Ivers, T., Jackson, S., Jarvis, I., Jones, E., Kennet, J., Jose, S., Josipovic, M., Kasanicki, M., Kourampa, J., Laurenti, E., Legchenko, E., Le Gresley, E., Lewis, D., Linger, R., Mackay, M., Marioni, J. C., Marsden, J., Martin, J., Matara, C., Meadows, A., Meloy, S., Mende, N., Michael, A., Michel, R., Mwaura, L., Muldoon, F., Nice, F., O'Brien, C., O'Donnell, C., Okecha, G., Omarjee, O., Ovington, N., Owehand, W. H., Papadia, S., Patterson, C., Perera, M., Phelan, I., Pointon, L., Polgarova, P., Polwarth, G., Pond, N., Price, J., Publico, C., Rastall, R., Ribeiro, C., Richoz, N., Romashova, V., Rossi, S., Rowlands, J., Ruffolo, V., Yarkoni, N. S., Sharma, R., Shih, J., Selvan, M., Spencer, S., Stefanucci, L., Stark, H., Stephens, J., Stirrups, K. E., Strezlecki, M., Summers, C., Sutcliffe, R., Tilly, T., Tong, Z., Tordesillas, H., Treacy, C., Townsend, P., Walker, N., Webster, J., Wilson, N. K., Wood, J., Wylot, M., Yong, C., Mescia, Federica [0000-0002-2759-4027], Hanson, Aimee [0000-0002-0231-8771], Ruffieux, Helene [0000-0002-7113-2540], Morgan, Michael [0000-0003-0757-0711], Wills, Mark [0000-0001-8548-5729], Baker, Stephen [0000-0003-1308-5755], Dougan, Gordon [0000-0003-0022-965X], Gupta, Ravindra [0000-0001-9751-1808], Hosmillo, Myra [0000-0002-3514-7681], Kingston, Nathalie [0000-0002-9190-2231], Lehner, Paul [0000-0001-9383-1054], Matheson, Nicholas [0000-0002-3318-1851], Richardson, Sylvia [0000-0003-1998-492X], Thaventhiran, James [0000-0001-8616-074X], Weekes, Michael [0000-0003-3196-5545], Gottgens, Berthold [0000-0001-6302-5705], Toshner, Mark [0000-0002-3969-6143], Bradley, John [0000-0002-7774-8805], Lyons, Paul [0000-0001-7035-8997], Smith, Kenneth [0000-0003-3829-4326], Apollo - University of Cambridge Repository, and Collaboration, Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Immunology, Disease, macromolecular substances, immune pathology, Biology, CD8-Positive T-Lymphocytes, Systemic inflammation, Lymphocyte Activation, Severity of Illness Index, Article, Oxidative Phosphorylation, 03 medical and health sciences, recovery, 0302 clinical medicine, Immunophenotyping, Immune system, Immunopathology, Bystander effect, medicine, Immunology and Allergy, Humans, complement, Longitudinal Studies, systemic inflammation, bystander CD8+ T cell, SARS-CoV-2, Gene Expression Profiling, Interleukin, COVID-19, interferon, Prognosis, TNF-α, Biomarkers, Cytokines, Disease Susceptibility, Host-Pathogen Interactions, Inflammation Mediators, Phenotype, Reactive Oxygen Species, Transcriptome, 030104 developmental biology, Infectious Diseases, 030220 oncology & carcinogenesis, Tumor necrosis factor alpha, medicine.symptom
Abstract

The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing, and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8+ T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)-6. These late immunometabolic and immune defects may have clinical implications., Graphical abstract, The immune changes that underlie COVID-19 severity have not been fully defined. By analyzing a longitudinal cohort of COVID-19 patients and integrating inflammatory factors, immunophenotyping, and transcriptome data, Bergamaschi et al. identify both early and persistent immune changes that distinguish mild and/or asymptomatic from more severe disease.

Published
2021

11. Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission

Author

Rivett, L., Sridhar, S., Sparkes, D., Routledge, M., Jones, N. K., Forrest, S., Young, J., Pereira-Dias, J., Hamilton, W. L., Ferris, M., Torok, M. E., Meredith, L., Curran, M. D., Fuller, S., Chaudhry, A., Shaw, A., Samworth, R. J., Bradley, J. R., Dougan, G., Smith, K. G. C., Lehner, P. J., Matheson, N. J., Wright, G., Goodfellow, I. G., Baker, S., Weekes, M. P., Lyons, P. A., Toshner, M., Warne, B., Scott, J. B., Cormie, C., Gill, H., Kean, I., Maes, M., Reynolds, N., Wantoch, M., Caddy, S., Caller, L., Feltwell, T., Hall, G., Hosmillo, M., Houldcroft, C., Jahun, A., Khokhar, F., Yakovleva, A., Butcher, H., Caputo, D., Clapham-Riley, D., Dolling, H., Furlong, A., Graves, B., Gresley, E. L., Kingston, N., Papadia, S., Stark, H., Stirrups, K. E., Webster, J., Calder, J., Harris, J., Hewitt, S., Kennet, J., Meadows, A., Rastall, R., Brien, C. O., Price, J., Publico, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Brookes, K., Canna, L., Cruz, I., Dempsey, K., Elmer, A., Escoffery, N., Jones, H., Ribeiro, C., Saunders, C., Wright, A., Nyagumbo, R., Roberts, A., Bucke, A., Hargreaves, S., Johnson, D., Narcorda, A., Read, D., Sparke, C., Warboys, L., Lagadu, K., Mactavous, L., Gould, T., Raine, T., Mather, C., Ramenatte, N., Vallier, A. -L., Kasanicki, M., Eames, P. -J., Mcnicholas, C., Thake, L., Bartholomew, N., Brown, N., Parmar, S., Zhang, H., Bowring, A., Martell, G., Quinnell, N., Wright, J., Murphy, H., Dunmore, B. J., Legchenko, E., Graf, S., Huang, C., Hodgson, J., Hunter, K., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Shih, J., Sutcliffe, R., Tilly, T., Tong, Z., Treacy, C., Wood, J., Bergamaschi, L., Betancourt, A., Bowyer, G., A. D., Sa, Epping, M., Hinch, A., Huhn, O., Jarvis, I., Lewis, D., Marsden, J., Mccallum, S., Nice, F., Rivett, Lucy [0000-0002-2781-9345], Lehner, Paul J [0000-0001-9383-1054], Matheson, Nicholas J [0000-0002-3318-1851], Goodfellow, Ian G [0000-0002-9483-510X], Weekes, Michael P [0000-0003-3196-5545], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, medicine, global health, 0302 clinical medicine, COVID-19 Testing, Epidemiology, Pandemic, Health care, Infection control, 030212 general & internal medicine, Viral, Biology (General), Asymptomatic Infections, Nose, 0303 health sciences, Transmission (medicine), COVID-19, SARS-CoV-2, emerging pathogens, epidemiology, human, human biology, infectious disease, occupational health, virology, virus, Betacoronavirus, COVID-19 Vaccines, Coronavirus Infections, Female, Humans, Infection Control, Pandemics, Pneumonia, Viral, Real-Time Polymerase Chain Reaction, United Kingdom, Clinical Laboratory Techniques, Health Personnel, General Neuroscience, virus diseases, General Medicine, 3. Good health, medicine.anatomical_structure, medicine.symptom, Research Article, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), QH301-705.5, Science, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), education, Asymptomatic, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Internal medicine, Throat, Infectious disease (athletes), Human Biology and Medicine, 030304 developmental biology, General Immunology and Microbiology, business.industry, Pneumonia, 030104 developmental biology, Epidemiology and Global Health, Carriage, business
Abstract

Significant differences exist in the availability of healthcare worker (HCW) SARS-CoV-2 testing between countries, and existing programmes focus on screening symptomatic rather than asymptomatic staff. Over a 3 week period (April 2020), 1032 asymptomatic HCWs were screened for SARS-CoV-2 in a large UK teaching hospital. Symptomatic staff and symptomatic household contacts were additionally tested. Real-time RT-PCR was used to detect viral RNA from a throat+nose self-swab. 3% of HCWs in the asymptomatic screening group tested positive for SARS-CoV-2. 17/30 (57%) were truly asymptomatic/pauci-symptomatic. 12/30 (40%) had experienced symptoms compatible with coronavirus disease 2019 (COVID-19)>7 days prior to testing, most self-isolating, returning well. Clusters of HCW infection were discovered on two independent wards. Viral genome sequencing showed that the majority of HCWs had the dominant lineage B∙1. Our data demonstrates the utility of comprehensive screening of HCWs with minimal or no symptoms. This approach will be critical for protecting patients and hospital staff., eLife digest Patients admitted to NHS hospitals are now routinely screened for SARS-CoV-2 (the virus that causes COVID-19), and isolated from other patients if necessary. Yet healthcare workers, including frontline patient-facing staff such as doctors, nurses and physiotherapists, are only tested and excluded from work if they develop symptoms of the illness. However, there is emerging evidence that many people infected with SARS-CoV-2 never develop significant symptoms: these people will therefore be missed by ‘symptomatic-only’ testing. There is also important data showing that around half of all transmissions of SARS-CoV-2 happen before the infected individual even develops symptoms. This means that much broader testing programs are required to spot people when they are most infectious. Rivett, Sridhar, Sparkes, Routledge et al. set out to determine what proportion of healthcare workers was infected with SARS-CoV-2 while also feeling generally healthy at the time of testing. Over 1,000 staff members at a large UK hospital who felt they were well enough to work, and did not fit the government criteria for COVID-19 infection, were tested. Amongst these, 3% were positive for SARS-CoV-2. On closer questioning, around one in five reported no symptoms, two in five very mild symptoms that they had dismissed as inconsequential, and a further two in five reported COVID-19 symptoms that had stopped more than a week previously. In parallel, healthcare workers with symptoms of COVID-19 (and their household contacts) who were self-isolating were also tested, in order to allow those without the virus to quickly return to work and bolster a stretched workforce. Finally, the rates of infection were examined to probe how the virus could have spread through the hospital and among staff – and in particular, to understand whether rates of infection were greater among staff working in areas devoted to COVID-19 patients. Despite wearing appropriate personal protective equipment, healthcare workers in these areas were almost three times more likely to test positive than those working in areas without COVID-19 patients. However, it is not clear whether this genuinely reflects greater rates of patients passing the infection to staff. Staff may give the virus to each other, or even acquire it at home. Overall, this work implies that hospitals need to be vigilant and introduce broad screening programmes across their workforces. It will be vital to establish such approaches before ‘lockdown’ is fully lifted, so healthcare institutions are prepared for any second peak of infections.

Published
2020

12. The Church Socialist League 1906-1923 : origins, development and disintegration

Author

Goodfellow, I.

Subjects
100, Philosophy
Abstract

This thesis, in examining the life cycle of the Church Socialist League provides a case study in Christian Socialism. The C. S. L. was the third Anglican Society to be founded in the phase of Christian Socialism that arose in the last quarter of the nineteenth century: it emerged within that tradition in response to the increasing political momentum of the Labour Movement which first achieved significant Parliamentary presence in the 1906 General Election. This study examines the context in which the League arose, the membership, organisational development and life of the League and the conflicts and circumstances which led to its dissolution. The society was distinguished from its predecessors by an explicit avowal of Socialism combined with an open attitude in theology and churchmanship. Within the League's membership three elements may be detected - Socialist, Catholic and Intellectual. The history of the League demonstrates the interplay between these elements in the context of the circumstances of the time, notably developments within the general field of the Labour and Socialist movement and the war and its aftermath. As a result the character of the League changed markedly in the course of its existence. Each of the three elements made a bid to control the League. As a result of internal tensions and external circumstances the League broke up: it was a failure in synthesis. In its full commitment to political and economic Socialism it posed acutely the central problem of Christian. Socialism - the relation between secular political principles and Christian theology - and demonstrated the difficulty, and perhaps the impossibility, of giving stable and effective institutional expression to the relationship between two 'ideologies'.

Published
1983

13. An integrated national scale SARS-CoV-2 genomic surveillance network

Author

Aanensen, DM, Abudahab, K, Adams, A, Afifi, S, Alam, MT, Alderton, A, Alikhan, N-F, Allan, J, Almsaud, M, Alrezaihi, A, Alruwaili, M, Amato, R, Andersson, M, Angyal, A, Aranday-Cortes, E, Ariani, C, Armstrong, SD, Asamaphan, P, Attwood, S, Aydin, A, Badhan, A, Baker, D, Baker, P, Balcazar, CE, Ball, J, Barton, AE, Bashton, M, Baxter, L, Beale, M, Beaver, C, Beckett, A, Beer, R, Beggs, A, Bell, A, Bellis, KL, Bentley, EG, Berriman, M, Betteridge, E, Bibby, D, Bicknell, K, Birchley, A, Black, G, Blane, B, Bloomfield, S, Bolt, F, Bonsall, DG, Bosworth, A, Bourgeois, Y, Boyd, O, Bradshaw, D, Breuer, J, Bridgewater, H, Brooks, T, Broos, A, Brown, JR, Brown, RL, Brunker, K, Bucca, G, Buck, D, Bull, M, Butcher, E, Caddy, SL, Caller, LG, Cambell, S, Carlile, M, Carmichael, S, Carrilero, L, Castellano, S, Chaloner, J, Chand, M, Chapman, MR, Chappell, J, Charles, I, Chauhan, AJ, Chawla, A, Cheng, E, Churcher, CM, Clark, G, Clark, JJ, Collins, J, Colquhoun, R, Connor, TR, Constantinidou, C, Coombes, J, Corden, S, Cottrell, S, Cowell, A, Curran, MD, Curran, T, Dabrera, G, Danesh, J, Darby, AC, De Cesare, M, Martins, LDO, De Silva, TI, Debebe, B, Dervisevic, S, Dewar, RA, Dia, M, Dorman, M, Dougan, G, Dover, L, Downing, F, Drury, E, Du Plessis, L, Dyal, PL, Eccles, R, Edwards, S, Ellaby, N, Elliott, S, Eltringham, G, Elumogo, N, Essex, S, Evans, CM, Evans, J, Nascimento, FF, Fairley, DJ, Farr, B, Feltwell, T, Ferguson, N, Filipe, ADS, Findlay, J, Forrest, LM, Forrest, S, Foulser, L, Francois, S, Fraser, C, Frost, L, Gallagher, E, Gallagher, MD, Garcia-Dorival, I, Gaskin, A, Gatica-Wilcox, B, Gavriil, A, Geidelberg, L, Gemmell, M, Gerada, A, Gifford, L, Gilbert, L, Gilmore, P, Gilroy, R, Girgis, S, Glaysher, S, Golubchik, T, Goncalves, S, Goodfellow, I, Goodwin, S, Graham, C, Graham, L, Grammatopoulos, D, Green, A, Green, LR, Greenaway, J, Gregory, R, Groves, DC, Groves, N, Guest, M, Gunson, R, Haldenby, S, Hall, G, Hamilton, WL, Han, X, Harris, KA, Harrison, EM, Hartley, C, Herrera, C, Hesketh, A, Heyburn, D, Hill, V, Hiscox, JA, Holden, M, Holmes, A, Holmes, N, Holt, GS, Hopes, R, Hosmillo, M, Houldcroft, CJ, Howson-Wells, H, Hubb, J, Hughe, J, Hughes, M, Hutchings, S, Impey, R, Iturriza-Gomara, M, Jackson, A, Jackson, B, Jackson, DK, Jahun, AS, James, K, Jamrozy, D, Jeffries, A, Jesudason, N, John, M, Johnson, J, Johnson, KJ, Johnson, N, Johnston, I, Jones, B, Jones, R, Jones, S, Jorgensen, D, Kane, L, Kay, GL, Kay, S, Keatley, J-P, Keeley, AJ, Khakh, M, Khokhar, FA, Kitchen, C, Knight, B, Kolyva, A, Kraemer, M, Kristiansen, M, Kumziene-Summerhayes, S, Kwiatkowski, D, Lackenby, A, Langford, C, Lawniczak, M, Thanh, L-V, Lee, D, Letchford, L, Li, K, Li, L, Liggett, S, Lindsey, BB, Livett, R, Lloyd, A, Lo, S, Lockhart, M, Loh, J, Loman, NJ, Loose, M, Lucaci, A, Ludden, C, Luu, L, Lyons, RA, MacIntyre-Cockett, G, MacLean, A, Mair, D, Maksimovic, J, Manley, R, Manso, C, Manson, J, Martincorena, I, Masoli, J, Mather, AE, Mbisa, T, McCluggage, K, McClure, P, McCrone, JT, McDonald, S, McHugh, MP, McKenna, JM, McMinn, L, McMurray, C, Meadows, L, Menegazzo, M, Meredith, LW, Merrick, I, Mestek-Boukhibar, L, Miah, S, Michell, S, Michelsen, ML, Molnar, Z, Moore, C, Moore, N, Morgan, M, Morgan, S, Muddyman, D, Muir, DA, Muir, P, Myers, R, Nastouli, E, Naydenova, P, Nelson, A, Nelson, C, Nelson, R, Nicholls, S, Nichols, J, Niebel, M, Niola, P, Nomikou, K, O'Grady, J, O'Toole, AN, O'Toole, E, Olateju, C, Orton, RJ, Osman, H, Ott, S, Pacchiarini, N, Padgett, D, Page, AJ, Palmer, S, Panchbhaya, YN, Pandey, S, Park, N, Parker, MD, Parkhill, J, Parr, YA, Parsons, PJ, Partridge, DG, Patel, M, Patterson, S, Payne, B, Peacock, SJ, Penrice-Randal, R, Perry, M, Platt, S, Poplawski, R, Prakash, R, Prestwood, L, Price, A, Price, JR, Puethe, C, Pybus, O, Pymont, H, Quail, M, Quick, J, Raghwani, J, Ragonnet-Cronin, M, Rahman, S, Rainbow, L, Rajatileka, S, Rambaut, A, Ramsay, M, Randell, PA, Randle, NP, Raviprakash, V, Raza, M, Silva, PR, Rey, S, Richter, A, Robertson, DL, Robinson, TI, Robson, SC, Rooke, S, Rowan, A, Rowe, W, Roy, S, Rudder, S, Ruis, C, Sang, F, Scarlett, G, Schaefer, U, Scott, C, Scott, G, Sethi, D, Shaaban, S, Shah, R, Sharma, P, Shawli, GT, Shepherd, J, Sherriff, N, Shirley, L, Sillitoe, J, Simpson, DA, Singer, JB, Siveroni, I, Smith, C, Smith, CP, Smith, DL, Smith, N, Smith, W, Smith-Palmer, A, Smollett, K, Southgate, J, Spellman, K, Spencer-Chapman, M, Sridhar, S, Stanley, R, Stark, R, Stewart, JP, Stockton, J, Stuart, C, Studholme, D, Swainston, N, Swindells, E, Taha, Y, Tariq, MA, Taylor, B, Taylor, GP, Taylor, S, Taylor-Joyce, G, Tedim, AP, Temperton, B, Templeton, KE, Thomson, EC, Thomson, NM, Thornton, A, Thurston, S, Todd, J, Tong, L, Tonkin-Hill, G, Torok, ME, Trebes, A, Trotter, AJ, Tsoleridis, T, Tucker, RM, Tutill, HJ, Underwood, A, Unnikrishnan, M, Vamos, E, Vasylyeva, T, Vattipally, S, Victoria, A, Vipond, B, Volz, EM, Wain, J, Wang, D, Warwick-Dugdale, J, Wastnedge, E, Watkins, J, Watts, J, Webber, M, Weeks, S, Weldon, D, Whitehead, M, Williams, CA, Williams, C, Williams, D, Williams, R, Williams, TC, Wise, E, Wright, V, Wyles, MD, Wyllie, S, Yakovleva, A, Yasir, M, Yeats, C, Yew, WC, Young, GR, Yu, X, and Zarebski, A

Subjects
Microbiology (medical), Scale (ratio), SARS-CoV-2, viruses, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19, COVID-19 Genomics UK (COG-UK) consortiumcontact@cogconsortium.uk, C500, Genome, Viral, Genomics, Biology, C700, Microbiology, Article, Infectious Diseases, Virology, Humans, Cartography
Abstract

The Coronavirus Disease 2019 (COVID-19) Genomics UK Consortium (COG-UK) was launched in March, 2020, with £20 million support from UK Research and Innovation, the UK Department of Health and Social Care, and Wellcome Trust. The goal of this consortium is to sequence severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for up to 230 000 patients, health-care workers, and other essential workers in the UK with COVID-19, which will help to enable the tracking of SARS-CoV-2 transmission, identify viral mutations, and integrate with health data to assess how the viral genome interacts with cofactors and consequences of COVID-19.

Published
2020
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14. Imperceptible, Robust, and Targeted Adversarial Examples for Automatic Speech Recognition

Author

Qin, Y., Carlini, N., Goodfellow, I., Garrison Cottrell, and Raffel, C.

Subjects
FOS: Computer and information sciences, Computer Science - Machine Learning, Sound (cs.SD), Statistics - Machine Learning, Audio and Speech Processing (eess.AS), FOS: Electrical engineering, electronic engineering, information engineering, Machine Learning (stat.ML), Computer Science - Sound, Electrical Engineering and Systems Science - Audio and Speech Processing, Machine Learning (cs.LG)
Abstract

Adversarial examples are inputs to machine learning models designed by an adversary to cause an incorrect output. So far, adversarial examples have been studied most extensively in the image domain. In this domain, adversarial examples can be constructed by imperceptibly modifying images to cause misclassification, and are practical in the physical world. In contrast, current targeted adversarial examples applied to speech recognition systems have neither of these properties: humans can easily identify the adversarial perturbations, and they are not effective when played over-the-air. This paper makes advances on both of these fronts. First, we develop effectively imperceptible audio adversarial examples (verified through a human study) by leveraging the psychoacoustic principle of auditory masking, while retaining 100% targeted success rate on arbitrary full-sentence targets. Next, we make progress towards physical-world over-the-air audio adversarial examples by constructing perturbations which remain effective even after applying realistic simulated environmental distortions., Comment: International Conference on Machine Learning (ICML), 2019

Published
2019
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15. A domain agnostic measure for monitoring and evaluating GANs

Author

Grnarova, P., Levy, K. Y., Aurelien Lucchi, Perraudin, N., Goodfellow, I., Hofmann, T., and Krause, A.

Subjects
FOS: Computer and information sciences, Computer Science - Machine Learning, Statistics - Machine Learning, Machine Learning (stat.ML), Machine Learning (cs.LG)
Abstract

Generative Adversarial Networks (GANs) have shown remarkable results in modeling complex distributions, but their evaluation remains an unsettled issue. Evaluations are essential for: (i) relative assessment of different models and (ii) monitoring the progress of a single model throughout training. The latter cannot be determined by simply inspecting the generator and discriminator loss curves as they behave non-intuitively. We leverage the notion of duality gap from game theory to propose a measure that addresses both (i) and (ii) at a low computational cost. Extensive experiments show the effectiveness of this measure to rank different GAN models and capture the typical GAN failure scenarios, including mode collapse and non-convergent behaviours. This evaluation metric also provides meaningful monitoring on the progression of the loss during training. It highly correlates with FID on natural image datasets, and with domain specific scores for text, sound and cosmology data where FID is not directly suitable. In particular, our proposed metric requires no labels or a pretrained classifier, making it domain agnostic.

Published
2018

16. Targeting macrophage and intestinal epithelial cell specific microRNAs against norovirus restricts replication in vivo

Author

Thorne, L, Lu, J, Chaudhry, Y, Bailey, D, and Goodfellow, I

Subjects
viruses, Macrophages, Norovirus, Epithelial Cells, Virus Replication, Antiviral Agents, Article, Cell Line, Rodent Diseases, Mice, MicroRNAs, Viral Tropism, Disease Transmission, Infectious, Animals, Caliciviridae Infections
Abstract

Until recently, our understanding of the cellular tropism of human norovirus (HuNoV), a major cause of viral gastroenteritis, has been limited. Immune cells and intestinal epithelial cells (IECs) have been proposed as targets of HuNoV replication in vivo, although the contribution of each to pathogenesis and transmission is unknown. Murine norovirus (MNV) is widely used as a surrogate model for HuNoV, as it replicates in cultured immune cells. The importance of the complete MNV immune cell tropism in vivo has not been determined. Recent work has linked replication in IECs to viral persistence in vivo. MNV provides a model to assess the relative contribution of each cell tropism to viral replication in immunocompetent native hosts. Here we exploited cell-specific microRNAs to control MNV replication, through insertion of microRNA target sequences into the MNV genome. We demonstrated the utility of this approach for MNV in vitro by selectively reducing replication in microglial cells, using microglial-specific miR-467c. We then showed that inserting a target sequence for the haematopoietic-specific miR-142-3p abrogated replication in a macrophage cell line. The presence of a target sequence for either miR-142-3p or IEC miR-215 significantly reduced viral secretion during the early stages of a persistent infection in immunocompetent mice, confirming that both cell types support viral replication in vivo. This study provides additional evidence that MNV shares the IEC tropism of HuNoVs in vivo, and now provides a model to dissect the contribution of replication in each cell type to viral pathogenesis and transmission in a native host.

Published
2018

17. Activation of COX-2/PGE2 Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production

Author

Alfajaro, MM, Choi, J-S, Kim, D-S, Seo, J-Y, Kim, J-Y, Park, J-G, Soliman, M, Baek, Y-B, Cho, E-H, Kwon, J, Kwon, H-J, Park, S-J, Lee, WS, Kang, M-I, Hosmillo, M, Goodfellow, I, Cho, K-O, Hosmillo, Myra [0000-0002-3514-7681], Goodfellow, Ian [0000-0002-9483-510X], and Apollo - University of Cambridge Repository

Subjects
prostaglandin E2, Cyclooxygenase 2 Inhibitors, Swine, Gene Expression, Nitric Oxide, Virus Replication, Dinoprostone, Sapovirus, Cell Line, Bile Acids and Salts, caliciviruses, cyclooxygenases, Cyclooxygenase 2, Cyclooxygenase 1, Animals, RNA Interference, RNA, Small Interfering, Cells, Cultured, Caliciviridae Infections, Signal Transduction
Abstract

Enteric caliciviruses in the genera Norovirus and Sapovirus are important pathogens that cause severe acute gastroenteritis in both humans and animals. Cyclooxygenases (COXs) and their final product, prostaglandin E2 (PGE2), are known to play important roles in the modulation of both the host response to infection and the replicative cycles of several viruses. However, the precise mechanism(s) by which the COX/PGE2 pathway regulates sapovirus replication remains largely unknown. In this study, infection with porcine sapovirus (PSaV) strain Cowden, the only cultivable virus within the genus Sapovirus, markedly increased COX-2 mRNA and protein levels at 24 and 36 h postinfection (hpi), with only a transient increase in COX-1 levels seen at 24 hpi. The treatment of cells with pharmacological inhibitors, such as nonsteroidal anti-inflammatory drugs or small interfering RNAs (siRNAs) against COX-1 and COX-2, significantly reduced PGE2 production, as well as PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE2 pathway. We observed that pharmacological inhibition of COX-2 dramatically increased NO production, causing a reduction in PSaV replication that could be restored by inhibition of nitric oxide synthase via the inhibitor N-nitro-l-methyl-arginine ester. This study identified a pivotal role for the COX/PGE2 pathway in the regulation of NO production during the sapovirus life cycle, providing new insights into the life cycle of this poorly characterized family of viruses. Our findings also reveal potential new targets for treatment of sapovirus infection. IMPORTANCE: Sapoviruses are among the major etiological agents of acute gastroenteritis in both humans and animals, but little is known about sapovirus host factor requirements. Here, using only cultivable porcine sapovirus (PSaV) strain Cowden, we demonstrate that PSaV induced the vitalization of the cyclooxygenase (COX) and prostaglandin E2 (PGE2) pathway. Targeting of COX-1/2 using nonsteroidal anti-inflammatory drugs (NSAIDs) such as the COX-1/2 inhibitor indomethacin and the COX-2-specific inhibitors NS-398 and celecoxib or siRNAs targeting COXs, inhibited PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE2 pathway. We further demonstrate that the production of PGE2 provides a protective effect against the antiviral effector mechanism of nitric oxide. Our findings uncover a new mechanism by which PSaV manipulates the host cell to provide an environment suitable for efficient viral growth, which in turn can be a new target for treatment of sapovirus infection.

Published
2017

19. Virus genomes reveal factors that spread and sustained the Ebola epidemic

Author

Dudas, G. (Gytis), Carvalho, L.M. (Luiz Max), Bedford, T. (Trevor), Tatem, A.J. (Andrew J.), Baele, G. (Guy), Faria, R. (Rui), Park, D.J. (Daniel J.), Ladner, J.T. (Jason T.), Arias, A., Asogun, D. (Danny), Bielejec, F. (Filip), Caddy, S.L., Cotten, M. (Matthew), D'Ambrozio, J. (Jonathan), Dellicour, S. (Simon), Di Caro, A. (Antonino), Diclaro, J.W. (Joseph W.), Duraffour, S. (Sophie), Elmore, M.J. (Michael J.), Fakoli, L.S. (Lawrence S.), Faye, O. (Ousmane), Gilbert, M.L. (Merle L.), Gevao, S.M. (Sahr M.), Gire, S. (Stephen), Gladden-Young, A. (Adrianne), Gnirke, A. (Andreas), Goba, A. (Augustine), Grant, D.S. (Donald S.), Haagmans, B.L. (Bart), Hiscox, J.A. (Julian A.), Jah, U., Kugelman, J.R. (Jeffrey R.), Liu, D. (Di), Lu, J. (Jia), Malboeuf, C.M. (Christine M.), Mate, S. (Suzanne), Matthews, D.A. (David A.), Matranga, C.B. (Christian B.), Meredith, L.W. (Luke W.), Qu, J. (James), Quick, J. (Joshua), Pas, S.D. (Suzan), Phan, M.V.T. (My V. T.), Pollakis, G. (G.), Reusken, C.B.E.M. (Chantal), Sanchez-Lockhart, M. (Mariano), Schaffner, S.F. (Stephen F.), Schieffelin, J.S. (John S.), Sealfon, R.S. (Rachel S.), Simon-Loriere, E. (Etienne), Smits, S.L. (Saskia), Stoecker, K. (Kilian), Thorne, L. (Lucy), Tobin, E.A. (Ekaete Alice), Vandi, M.A. (Mohamed A.), Watson, S.J. (Simon J.), West, K. (Kendra), Whitmer, S. (Shannon), Wiley, M.R. (Michael R.), Winnicki, S.M. (Sarah M.), Wohl, S. (Shirlee), Wölfel, R. (Roman), Yozwiak, N.L. (Nathan L.), Andersen, K.G. (Kristian G.), Blyden, S.O. (Sylvia O.), Bolay, F. (Fatorma), Carroll, M.W. (Miles W.), Dahn, B. (Bernice), Diallo, B. (Boubacar), Formenty, P. (Pierre), Fraser, C. (Christophe), Gao, G.F. (George F.), Garry, R.F. (Robert F.), Goodfellow, I. (Ian), Günther, S. (Stephan), Happi, C.T. (Christian T.), Holmes, E.C. (Edward C.), Kargbo, B. (Brima), Keïta, S. (Sakoba), Kellam, P. (Paul), Koopmans D.V.M., M.P.G. (Marion), Kuhn, J.H. (Jens H.), Loman, N.J. (Nicholas J.), Magassouba, N. (N'Faly), Naidoo, D. (Dhamari), Nichol, S.T. (Stuart T.), Nyenswah, T. (Tolbert), Palacios, G. (Gustavo), Pybus, O. (Oliver), Sabeti, P.C. (Pardis C.), Sall, A. (Amadou), Ströher, U. (Ute), Wurie, I., Suchard, M.A. (Marc), Lemey, P. (Philippe), Rambaut, A. (Andrew), Dudas, G. (Gytis), Carvalho, L.M. (Luiz Max), Bedford, T. (Trevor), Tatem, A.J. (Andrew J.), Baele, G. (Guy), Faria, R. (Rui), Park, D.J. (Daniel J.), Ladner, J.T. (Jason T.), Arias, A., Asogun, D. (Danny), Bielejec, F. (Filip), Caddy, S.L., Cotten, M. (Matthew), D'Ambrozio, J. (Jonathan), Dellicour, S. (Simon), Di Caro, A. (Antonino), Diclaro, J.W. (Joseph W.), Duraffour, S. (Sophie), Elmore, M.J. (Michael J.), Fakoli, L.S. (Lawrence S.), Faye, O. (Ousmane), Gilbert, M.L. (Merle L.), Gevao, S.M. (Sahr M.), Gire, S. (Stephen), Gladden-Young, A. (Adrianne), Gnirke, A. (Andreas), Goba, A. (Augustine), Grant, D.S. (Donald S.), Haagmans, B.L. (Bart), Hiscox, J.A. (Julian A.), Jah, U., Kugelman, J.R. (Jeffrey R.), Liu, D. (Di), Lu, J. (Jia), Malboeuf, C.M. (Christine M.), Mate, S. (Suzanne), Matthews, D.A. (David A.), Matranga, C.B. (Christian B.), Meredith, L.W. (Luke W.), Qu, J. (James), Quick, J. (Joshua), Pas, S.D. (Suzan), Phan, M.V.T. (My V. T.), Pollakis, G. (G.), Reusken, C.B.E.M. (Chantal), Sanchez-Lockhart, M. (Mariano), Schaffner, S.F. (Stephen F.), Schieffelin, J.S. (John S.), Sealfon, R.S. (Rachel S.), Simon-Loriere, E. (Etienne), Smits, S.L. (Saskia), Stoecker, K. (Kilian), Thorne, L. (Lucy), Tobin, E.A. (Ekaete Alice), Vandi, M.A. (Mohamed A.), Watson, S.J. (Simon J.), West, K. (Kendra), Whitmer, S. (Shannon), Wiley, M.R. (Michael R.), Winnicki, S.M. (Sarah M.), Wohl, S. (Shirlee), Wölfel, R. (Roman), Yozwiak, N.L. (Nathan L.), Andersen, K.G. (Kristian G.), Blyden, S.O. (Sylvia O.), Bolay, F. (Fatorma), Carroll, M.W. (Miles W.), Dahn, B. (Bernice), Diallo, B. (Boubacar), Formenty, P. (Pierre), Fraser, C. (Christophe), Gao, G.F. (George F.), Garry, R.F. (Robert F.), Goodfellow, I. (Ian), Günther, S. (Stephan), Happi, C.T. (Christian T.), Holmes, E.C. (Edward C.), Kargbo, B. (Brima), Keïta, S. (Sakoba), Kellam, P. (Paul), Koopmans D.V.M., M.P.G. (Marion), Kuhn, J.H. (Jens H.), Loman, N.J. (Nicholas J.), Magassouba, N. (N'Faly), Naidoo, D. (Dhamari), Nichol, S.T. (Stuart T.), Nyenswah, T. (Tolbert), Palacios, G. (Gustavo), Pybus, O. (Oliver), Sabeti, P.C. (Pardis C.), Sall, A. (Amadou), Ströher, U. (Ute), Wurie, I., Suchard, M.A. (Marc), Lemey, P. (Philippe), and Rambaut, A. (Andrew)

Abstract

The 2013-2016 West African epidemic caused by the Ebola virus was of unprecedented magnitude, duration and impact. Here we reconstruct the dispersal, proliferation and decline of Ebola virus throughout the region by analysing 1,610 Ebola virus genomes, which represent over 5% of the known cases. We test the association of geography, climate and demography with viral movement among administrative regions, inferring a classic 'gravity' model, with intense dispersal between larger and closer populations. Despite attenuation of international dispersal after border closures, cross-border transmission had already sown the seeds for an international epidemic, rendering these measures ineffective at curbing the epidemic. We address why the epidemic did not spread into neighbouring countries, showing that these countries were susceptible to substantial outbreaks but at lower risk of introductions. Finally, we reveal that this large epidemic was a heterogeneous and spatially dissociated collection of transmission clusters of varying size, duration and connectivity. These insights will help to inform interventions in future epidemics.

Published
2017
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20. Neurodevelopmental protein Musashi-1 interacts with the Zika genome and promotes viral replication

Author

Chavali, P.L., Stojic, L., Meredith, L.W., Joseph, N., Nahorski, M.S., Sanford, T.J., Sweeney, T.R., Krishna, B.A., Hosmillo, M., Firth, A.E., Bayliss, R., Marcelis, C.L.M., Lindsay, S., Goodfellow, I., Woods, C.G., Gergely, F., Chavali, P.L., Stojic, L., Meredith, L.W., Joseph, N., Nahorski, M.S., Sanford, T.J., Sweeney, T.R., Krishna, B.A., Hosmillo, M., Firth, A.E., Bayliss, R., Marcelis, C.L.M., Lindsay, S., Goodfellow, I., Woods, C.G., and Gergely, F.

Abstract

Item does not contain fulltext, A recent outbreak of Zika virus in Brazil has led to a simultaneous increase in reports of neonatal microcephaly. Zika targets cerebral neural precursors, a cell population essential for cortical development, but the cause of this neurotropism remains obscure. Here we report that the neural RNA-binding protein Musashi-1 (MSI1) interacts with the Zika genome and enables viral replication. Zika infection disrupts the binding of MSI1 to its endogenous targets, thereby deregulating expression of factors implicated in neural stem cell function. We further show that MSI1 is highly expressed in neural progenitors of the human embryonic brain and is mutated in individuals with autosomal recessive primary microcephaly. Selective MSI1 expression in neural precursors could therefore explain the exceptional vulnerability of these cells to Zika infection.

Published
2017

21. Virus genomes reveal the factors that spread and sustained the West African Ebola epidemic

Author

Dudas, G, Carvalho, LM, Bedford, T, Tatem, A, Baele, G, Faria, N, Park, D, Ladner, J, Arias, A, Asogun, D, Bielejec, F, Caddy, S, Cotten, M, Dambrozio, J, Dellicour, S, Di Caro, A, Diclaro, J, Duraffour, S, Elmore, M, Fakoli, L, Gilbert, M, Gevao, S, Gire, S, Gladden-Young, A, Gnirke, A, Goba, A, Grant, D, Haagmans, B, Hiscox, J, Jah, U, Kargbo, B, Kugelman, J, Liu, D, Lu, J, Malboeuf, C, Mate, S, Matthews, D, Matranga, C, Meredith, L, Qu, J, Quick, J, Pas, S, Phan, MVT, Poliakis, G, Reusken, C, Sanchez-Lockhart, M, Schaffner, S, Schieffelin, J, Sealfon, R, Simon-Loriere, E, Smits, S, Stoecker, K, Thorne, L, Tobin, E, Vandi, M, Watson, S, West, K, Whitmer, S, Wiley, M, Winnicki, S, Wohl, S, Wölfel, R, Yozwiak, N, Andersen, K, Blyden, S, Bolay, F, Carroll, M, Dahn, B, Diallo, B, Formenty, P, Fraser, C, Gao, G, Garry, R, Goodfellow, I, Günther, S, Happi, C, Holmes, E, Kellam, P, Koopmans, MPG, Loman, N, Magassouba, N, Naidoo, D, Nichol, S, Nyenswah, T, Palacios, G, Pybus, O, Sabeti, P, Sall, A, Sakoba, K, Ströeher, U, Wurie, I, Suchard, M, Lemey, P, Rambaut, A, and Wellcome Trust

Subjects
viruses
Abstract

Summary The 2013-2016 epidemic of Ebola virus disease in West Africa was of unprecedented magnitude, duration and impact. Extensive collaborative sequencing projects have produced a large collection of over 1600 Ebola virus genomes, representing over 5% of known cases, unmatched for any single human epidemic. In this comprehensive analysis of this entire dataset, we reconstruct in detail the history of migration, proliferation and decline of Ebola virus throughout the region. We test the association of geography, climate, administrative boundaries, demography and culture with viral movement among 56 administrative regions. Our results show that during the outbreak viral lineages moved according to a classic ‘gravity’ model, with more intense migration between larger and more proximate population centers. Notably, we find that despite a strong attenuation of international dispersal after border closures, localized cross-border transmission beforehand had already set the seeds for an international epidemic, rendering these measures relatively ineffective in curbing the epidemic. We use this empirical evidence to address why the epidemic did not spread into neighboring countries, showing that although these regions were susceptible to developing significant outbreaks, they were also at lower risk of viral introductions. Finally, viral genome sequence data uniquely reveals this large epidemic to be a heterogeneous and spatially dissociated collection of transmission clusters of varying size, duration and connectivity. These insights will help inform approaches to intervention in such epidemics in the future.

Published
2016

22. Ebola virus disease cluster — Northern Sierra Leone, January 2016

Author

Alpren, C., Sloan, M., Boegler, K. A., Martin, D. W., Ervin, E., Washburn, F., Rickert, R., Singh, T., Redd, J. T., Bangalie, A., Bass, M., Bennett, S. D., Boateng, I. A., Campbell, D., Cassell, C., Cotton, M., Duffy, N., Goodfellow, I., Hersey, S., Jackson, E. L., Jah, U., Jimissa, A. S., Kamara, A. S., Kamara, F., Kellam, P., Levine, R., Luke Meredith, Miller, L. A., Moody-Geissler, S., Musoke, R., Naidoo, D., Ndyahikayo, J., Njie, G., Phan, M., Rambaut, A., and Sesay, F.

Subjects
Health Information Management, Epidemiology, Health, Toxicology and Mutagenesis, Health(social science)
Published
2016
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23. The RNA Helicase eIF4A is required for Sapovirus translation

Author

Hosmillo, M, Sweeney, TR, Chaudhry, Y, Leen, E, Curry, S, Goodfellow, I, Cho, K-O, Sweeney, Trevor [0000-0003-4016-7326], Goodfellow, Ian [0000-0002-9483-510X], Apollo - University of Cambridge Repository, and Biotechnology and Biological Sciences Research Council (BBSRC)

Subjects
VPG, Science & Technology, Reticulocytes, Swine, 11 Medical And Health Sciences, Genome, Viral, 06 Biological Sciences, Virus Replication, Sapovirus, INITIATION, Sterols, Viral Proteins, Virology, BINDING, Eukaryotic Initiation Factor-4A, Mutation, Animals, RNA, Viral, MESSENGER-RNAS, 07 Agricultural And Veterinary Sciences, Rabbits, 5' Untranslated Regions, Life Sciences & Biomedicine, PORCINE ENTERIC CALICIVIRUS, Protein Binding
Abstract

The eukaryotic initiation factor (eIF) 4A is a DEAD-box helicase that unwinds RNA structure in the 5´-untranslated region (UTR) of mRNAs. Here, we investigated the role of eIF4A in porcine sapovirus VPg-dependent translation. Using inhibitors and dominant negative mutants, we found that eIF4A is required for viral translation and infectivity, suggesting that despite the presence of a very short 5´-UTR, eIF4A is required to unwind RNA structure in the sapovirus genome to facilitate virus translation.

Published
2016

24. Evidence for human norovirus infection of dogs in the UK

Author

Caddy, S L, De Rougemont, A, Emmott, E, El-Attar, L M R, Mitchell, J A, Hollinshead, M, Belliot, G, Brownlie, J, Le Pendu, J, and Goodfellow, I

Abstract

Human noroviruses (HuNoVs) are a major cause of viral gastroenteritis, with an estimated 3 million cases per year in the United Kingdom. HuNoVs have recently been isolated from pet dogs in Europe (M. Summa, C.-H. von Bonsdorff, and L. Maunula, J Clin Virol 53:244–247, 2012, http://dx.doi.org/10.1016/j.jcv.2011.12.014), raising concerns about potential zoonotic infections. With 31% of United Kingdom households owning a dog, this could prove to be an important transmission route. To examine this risk, canine tissues were studied for their ability to bind to HuNoV in vitro. In addition, canine stool samples were analyzed for the presence of viral nucleic acid, and canine serum samples were tested for the presence of anti-HuNoV antibodies. The results showed that seven different genotypes of HuNoV virus-like particles (VLPs) can bind to canine gastrointestinal tissue, suggesting that infection is at least theoretically possible. Although HuNoV RNA was not identified in stool samples from 248 dogs, serological evidence of previous exposure to HuNoV was obtained in 43/325 canine serum samples. Remarkably, canine seroprevalence for different HuNoV genotypes mirrored the seroprevalence in the human population. Though entry and replication within cells have not been demonstrated, the canine serological data indicate that dogs produce an immune response to HuNoV, implying productive infection. In conclusion, this study reveals zoonotic implications for HuNoV, and to elucidate the significance of this finding, further epidemiological and molecular investigations will be essential.

Published
2015

25. Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial

Author

von Seidlein, L, Dunning, J, Sahr, F, Rojek, A, Gannon, F, Carson, G, Idriss, B, Massaquoi, T, Gandi, R, Joseph, S, Osman, HK, Brooks, TJG, Simpson, AJH, Goodfellow, I, Thorne, L, Arias, A, Merson, L, Castle, L, Howell-Jones, R, Pardinaz-Solis, R, Hope-Gill, B, Ferri, M, Grove, J, Kowalski, M, Stepniewska, K, Lang, T, Whitehead, J, Olliaro, P, Samai, M, Horby, PW, von Seidlein, L, Dunning, J, Sahr, F, Rojek, A, Gannon, F, Carson, G, Idriss, B, Massaquoi, T, Gandi, R, Joseph, S, Osman, HK, Brooks, TJG, Simpson, AJH, Goodfellow, I, Thorne, L, Arias, A, Merson, L, Castle, L, Howell-Jones, R, Pardinaz-Solis, R, Hope-Gill, B, Ferri, M, Grove, J, Kowalski, M, Stepniewska, K, Lang, T, Whitehead, J, Olliaro, P, Samai, M, and Horby, PW

Abstract

BACKGROUND: TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. METHODS AND FINDINGS: In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of ≤0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 × 109 RNA copies/ml plasma (95% CI 7.52 × 108, 6.66 × 109). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died. CONCLUSIONS: Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201501000997429.

Published
2016

26. Laboratory support during and after the Ebola virus endgame: Towards a sustained laboratory infrastructure

Author

Goodfellow, I., Reusken, C.B.E.M. (Chantal), Koopmans D.V.M., M.P.G. (Marion), Goodfellow, I., Reusken, C.B.E.M. (Chantal), and Koopmans D.V.M., M.P.G. (Marion)

Abstract

The Ebola virus epidemic in West Africa is on the brink of entering a second phase in which the (inter)national efforts to slow down virus transmission will be engaged to end the epidemic. The response community must consider the longevity of their current laboratory support, as it is essential that diagnostic capacity in the affected countries be supported beyond the end of the epidemic. The emergency laboratory response should be used to support building structural diagnostic and outbreak surveillance capacity.

Published
2015

27. Genotypic anomaly in ebola virus strains circulating in magazine wharf Area, Freetown, Sierra Leone, 2015

Author

Smits, S.L. (Saskia), Pas, S.D. (Suzan), Reusken, C.B.E.M. (Chantal), Haagmans, B.L. (Bart), Pertile, P., Cancedda, C., Dierberg, K., Wurie, I., Kamara, A., Kargbo, D., Caddy, S.L., Arias, A., Thorne, L., Lu, J., Jah, U., Goodfellow, I., Koopmans D.V.M., M.P.G. (Marion), Smits, S.L. (Saskia), Pas, S.D. (Suzan), Reusken, C.B.E.M. (Chantal), Haagmans, B.L. (Bart), Pertile, P., Cancedda, C., Dierberg, K., Wurie, I., Kamara, A., Kargbo, D., Caddy, S.L., Arias, A., Thorne, L., Lu, J., Jah, U., Goodfellow, I., and Koopmans D.V.M., M.P.G. (Marion)

Abstract

The Magazine Wharf area, Freetown, Sierra Leone was a focus of ongoing Ebola virus transmission from late June 2015. Viral genomes linked to this area contain a series of 13 T to C substitutions in a 150 base pair intergenic region downstream of viral protein 40 open reading frame, similar to the Ebolavirus/H.sapienswt/ SLE/2014/Makona-J0169 strain (J0169) detected in the same town in November 2014. This suggests that recently circulating viruses from Freetown descend from a J0169-like virus.

Published
2015
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28. Genotypic anomaly in Ebola virus strains circulating in Magazine Wharf area, Freetown, Sierra Leone, 2015

Author

Smits, Saskia, Pas, Suzan, Reusken, Chantal, Haagmans, Bart, Pertile, P, Cancedda, C, Dierberg, K, Wurie, I, Kamara, A, Kargbo, D, Caddy, SL, Arias, A, Thorne, L, Lu, J, Jah, U, Goodfellow, I, Koopmans, Marion, Smits, Saskia, Pas, Suzan, Reusken, Chantal, Haagmans, Bart, Pertile, P, Cancedda, C, Dierberg, K, Wurie, I, Kamara, A, Kargbo, D, Caddy, SL, Arias, A, Thorne, L, Lu, J, Jah, U, Goodfellow, I, and Koopmans, Marion

Abstract

The Magazine Wharf area, Freetown, Sierra Leone was a focus of ongoing Ebola virus transmission from late June 2015. Viral genomes linked to this area contain a series of 13 T to C substitutions in a 150 base pair intergenic region downstream of viral protein 40 open reading frame, similar to the Ebolavirus/H. sapienswt/SLE/2014/Makona-J0169 strain (J0169) detected in the same town in November 2014. This suggests that recently circulating viruses from Freetown descend from a J0169-like virus.

Published
2015

29. Hepatitis E in southern Vietnam: Seroepidemiology in humans and molecular epidemiology in pigs.

Author

Berto, A., Pham, H. A., Thao, T. T. N., Vy, N. H. T., Caddy, S. L., Hiraide, R., Tue, N. T., Goodfellow, I., Carrique‐Mas, J. J., Thwaites, G. E., Baker, S., Boni, M. F., and the VIZIONS consortium

Subjects
HEPATITIS E virus, SEROPREVALENCE, ZOONOSES, MOLECULAR epidemiology, DISEASE risk factors
Abstract

Summary: Viral pathogens account for a significant proportion of the burden of emerging infectious diseases in humans. The Wellcome Trust‐Vietnamese Initiative on Zoonotic Infections (WT‐VIZIONS) is aiming to understand the circulation of viral zoonotic pathogens in animals that pose a potential risk to human health. Evidence suggests that human exposure and infections with hepatitis E virus (HEV) genotypes (GT) 3 and 4 results from zoonotic transmission. Hypothesising that HEV GT3 and GT4 are circulating in the Vietnamese pig population and can be transmitted to humans, we aimed to estimate the seroprevalence of HEV exposure in a population of farmers and the general population. We additionally performed sequence analysis of HEV in pig populations in the same region to address knowledge gaps regarding HEV circulation and to evaluate if pigs were a potential source of HEV exposure. We found a high prevalence of HEV GT3 viral RNA in pigs (19.1% in faecal samples and 8.2% in rectal swabs) and a high HEV seroprevalence in pig farmers (16.0%) and a hospital‐attending population (31.7%) in southern Vietnam. The hospital population was recruited as a general‐population proxy even though this particular population subgroup may introduce bias. The detection of HEV RNA in pigs indicates that HEV may be a zoonotic disease risk in this location, although a larger sample size is required to infer an association between HEV positivity in pigs and seroprevalence in humans. [ABSTRACT FROM AUTHOR]

Published
2018
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38. Human CD55 domains 3 & 4

Author

Williams, P., primary, Chaudhry, Y., additional, Goodfellow, I., additional, Billington, J., additional, Spiller, B., additional, Evans, D.J., additional, and Lea, S.M., additional

Published
2003
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39. Nitazoxanide Is an Ineffective Treatment of Chronic Norovirus in Patients With X-Linked Agammaglobulinemia and May Yield False-Negative Polymerase Chain Reaction Findings in Stool Specimens.

Author

Kempf, Bjoern, Edgar, J. David, Mc Caughey, Conall, Devlin, Lisa A., Thorne, L., and Goodfellow, I.

Subjects
AGAMMAGLOBULINEMIA, ANTIVIRAL agents, X-linked genetic disorders, GENETIC mutation, POLYMERASE chain reaction, RNA viruses, THIAZOLES, NOROVIRUS diseases
Published
2017
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43. Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

Author

Alm E., Broberg E.K., Connor T., Hodcroft E.B., Komissarov A.B., Maurer-Stroh S., Melidou A., Neher R.A., O'Toole A., Pereyaslov D., Beerenwinkel N., Posada-Cespedes S., Jablonski K.P., Ferreira P.F., Topolsky I., Avsic-Zupanc T., Korva M., Poljak M., Zakotnik S., Zorec T.M., Bragstad K., Hungnes O., Stene-Johansen K., Reusken C., Meijer A., Vennema H., Ruiz-Roldan L., Bracho M.A., Garcia-Gonzalez N., Chiner-Oms A., Cancino-Munoz I., Comas I., Goig G.A., Torres-Puente M., Lopez M.G., Martinez-Priego L., D'Auria G., Ruiz-Hueso P., Ferrus-Abad L., de Marco G., Galan-Vendrell I., Carbo-Ramirez S., Ruiz-Rodriguez P., Coscolla M., Polackova K., Kramna L., Cinek O., Richter J., Krashias G., Tryfonos C., Bashiardes S., Koptides D., Christodoulou C., Bartolini B., Gruber C.E., Di Caro A., Castilletti C., Stefani F., Rimoldi S.G., Romeri F., Salerno F., Polesello S., Nagy A., Jirincova H., Vecerova J., Novakova L., Cordey S., Murtskhvaladze M., Kotaria N., Schar T., Beisel C., Vugrek O., Rokic F., Trgovec-Greif L., Jurak I., Rukavina T., Sucic N., Schonning K., Karst S.M., Kirkegaard R.H., Michaelsen T.Y., Sorensen E.A., Knutson S., Brandt J., Le-Quy V., Sorensen T., Petersen C., Pedersen M.S., Larsen S.L., Skov M.N., Rasmussen M., Fonager J., Fomsgaard A., Maksyutov R.A., Gavrilova E.V., Pyankov O.V., Bodnev S.A., Tregubchak T.V., Shvalov A.N., Antonets D.V., Resende P.C., Goya S., Perrin A., Lee R.T., Yadahalli S., Han A.X., Russell C.A., Schmutz S., Zaheri M., Kufner V., Huber M., Trkola A., Antwerpen M., Walter M.C., van der Werf S., Gambaro F., Behillil S., Enouf V., Donati F., Ustinova M., Rovite V., Klovins J., Savicka O., Wienecke-Baldacchino A.K., Ragimbeau C., Fournier G., Mossong J., Aberle S.W., Haukland M., Enkirch T., Advani A., Karlberg M.L., Lindsjo O.K., Broddesson S., Slavikova M., Lickova M., Klempa B., Staronova E., Ticha E., Szemes T., Rusnakova D., Stadler T., Quer J., Anton A., Andres C., Pinana M., Garcia-Cehic D., Pumarola T., Izopet J., Gioula G., Exindari M., Papa A., Chatzidimitriou D., Metallidis S., Pappa S., Macek M., Geryk J., Broz P., Briksi A., Hubacek P., Drevinek P., Zajac M., Kvapil P., Holub M., Kvapilova K., Novotny A., Kasny M., Klempt P., Vapalahti O., Smura T., Sironen T., Selhorst P., Anthony C., Arien K., Simon-Loriere E., Rabalski L., Bienkowska-Szewczyk K., Borges V., Isidro J., Gomes J.P., Guiomar R., Pechirra P., Costa I., Duarte S., Vieira L., Pyrc K., Zuckerman N.S., Turdikulova S., Abdullaev A., Dalimova D., Abdurakhimov A., Tagliabracci A., Alessandrini F., Melchionda F., Onofri V., Turchi C., Bagnarelli P., Menzo S., Caucci S., Di Sante L., Popa A., Genger J.-W., Agerer B., Lercher A., Endler L., Smyth M., Penz T., Schuster M., Senekowitsch M., Laine J., Bock C., Bergthaler A., Shevtsov A., Kalendar R., Ramanculov Y., Graf A., Muenchhoff M., Keppler O.T., Krebs S., Blum H., Marcello A., Licastro D., D'Agaro P., Laubscher F., Vidanovic D., Tesovic B., Volkening J., Clementi N., Mancini N., Rupnik M., Mahnic A., Walker A., Houwaart T., Wienemann T., Vasconcelos M.K., Strelow D., Jensen B.-E.O., Senff T., Hulse L., Adams O., Andree M., Hauka S., Feldt T., Keitel V., Kindgen-Milles D., Timm J., Pfeffer K., Dilthey A.T., Moore C., Ozdarendeli A., Pavel S.T.I., Yetiskin H., Aydin G., Holyavkin C., Uygut M.A., Cevik C., Shchetinin A., Gushchin V., Dinler-Doganay G., Doganay L., Kizilboga-Akgun T., Karacan I., Pancer K., Maes P., Marti-Carreras J., Wawina-Bokalanga T., Vanmechelen B., Thurmer A., Wedde M., Durrwald R., von Kleist M., Drechsel O., Wolff T., Fuchs S., Kmiecinski R., Michel J., Nitsche A., Casas I., Caballero M.I., Zaballos A., Jimenez P., Jimenez M., Fernandez S.M., Fernandez S.V., de la Plaza I.C., Fadeev A., Ivanova A., Sergeeva M., Stefanelli P., Estee Torok M., Hall G., da Silva Filipe A., Turtle L., Afifi S., McCluggage K., Beer R., Ledesma J., Maksimovic J., Spellman K., Hamilton W.L., Marchbank A., Southgate J.A., Underwood A., Taylor B., Yeats C., Abudahab K., Gemmell M.R., Eccles R., Lucaci A., Nelson C.A., Rainbow L., Whitehead M., Gregory R., Haldenby S., Paterson S., Hughes M.A., Curran M.D., Baker D., Tucker R., Green L.R., Feltwell T., Halstead F.D., Wyles M., Jahun A.S., Ahmad S.S.Y., Georgana I., Goodfellow I., Yakovleva A., Meredith L.W., Gavriil A., Awan A.R., Fisher C., Edgeworth J., Lynch J., Moore N., Williams R., Kidd S.P., Cortes N., Brunker K., McCrone J.T., Quick J., Duckworth N., Walsh S., Sloan T., Ludden C., George R.P., Eltringham G., Brown J.R., Aranday-Cortes E., Shepherd J.G., Hughes J., Li K.K., Williams T.C., Johnson N., Jesudason N., Mair D., Thomson E., Shah R., Parr Y.A., Carmichael S., Robertson D.L., Nomikou K., Broos A., Niebel M., Smollett K., Tong L., Miah S., Wittner A., Phillips N., Payne B., Dewar R., Holmes A., Bolt F., Price J.R., Mookerjee S., Sethi D.K., Potter W., Stanley R., Prakash R., Dervisevic S., Graham J.C., Nelson A., Smith D., Young G.R., Yew W.C., Todd J.A., Trebes A., Andersson M., Bull M., Watkins J., Birchley A., Gatica-Wilcox B., Gilbert L., Kumziene-Summerhayes S., Rey S., Chauhan A., Butcher E., Bicknell K., Elliott S., Glaysher S., Lackenby A., Bibby D., Platt S., Mohamed H., Machin N.W., Mbisa J.L., Evans J., Perry M., Pacchiarini N., Corden S., Adams A.G., Gaskin A., Coombs J., Graham L.J., Cottrell S., Morgan M., Gifford L., Kolyva A., Rudder S.J., Trotter A.J., Mather A.E., Aydin A., Page A.J., Kay G.L., de Oliveira Martins L., Yasir M., Alikhan N.-F., Thomson N.M., Gilroy R., Kingsley R.A., O'Grady J., Gutierrez A.V., Diaz M., Viet T.L., Tedim A.P., Adriaenssens E.M., Patrick Mcclure C., Sang F., Clark G., Howson-Wells H.C., Debebe J., Ball J., Chappell J., Khakh M., Carlile M., Loose M., Lister M.M., Holmes N., Tsoleridis T., Fleming V.M., Wright V., Smith W., Gallagher M.D., Parker M., Partridge D.G., Evans C., Baker P., Essex S., Liggett S., Keeley A.J., Bashton M., Rooke S., Dervisavic S., Meader E.J., Lopez C.E.B., Angyal A., Kristiansen M., Tutill H.J., Findlay J., Mestek-Boukhibar L., Forrest L., Dyal P., Williams R.J., Panchbhaya Y., Williams C.A., Roy S., Pandey S., Stockton J., Loman N.J., Poplawski R., Nicholls S., Rowe W.P.M., Khokhar F., Pinckert M.L., Hosmillo M., Chaudhry Y., Caller L.G., Davidson R.K., Griffith L., Rambaut A., Jackson B., Colquhoun R., Hill V., Nichols J., Asamaphan P., Darby A., Jackson K.A., Iturriza-Gomara M., Vamos E.E., Green A., Aanensen D., Bonsall D., Buck D., Macintyre-Cockett G., de Cesare M., Pybus O., Golubchik T., Scarlett G., Loveson K.F., Robson S.C., Beckett A., Lindsey B., Groves D.C., Parsons P.J., McHugh M.P., Barnes J.D., Manso C.F., Grammatopoulos D., Menger K.E., Harrison E., Gunson R., Peacock S.J., Gonzalez G., Carr M., Mihaela L., Popovici O., Brytting M., Bresner C., Fuller W., Workman T., Mentis A.F., Kossyvakis A., Karamitros T., Pogka V., Kalliaropoulos A., Horefti E., Kontou A., Martinez-Gonzalez B., Labropoulou V., Voulgari-Kokota A., Evangelidou M., Bizta P., Belimezi M., Lambrechts L., Doymaz M.Z., Yazici M.K., Cetin N.S., Karaaslan E., Kallio-Kokko H., Virtanen J., Suvanto M., Nguyen P.T., Ellonen P., Hannula S., Kangas H., Sreenu V.B., Burian K., Terhes G., Gombos K., Gyenesei A., Urban P., Herczeg R., Jakab F., Kemenesi G., Toth G.E., Somogyi B., Zana B., Zeghbib S., Kuczmog A., Foldes F., Lanszki Z., Madai M., Papp H., Pereszlenyi C.I., Babinszky G.C., Dudas G., Csoma E., Abou Tayoun A.N., Alsheikh-Ali A.A., Loney T., Nowotny N., Abdul-Wahab O., Gonzalez-Candelas F., Andersen M.H., Taylor S., MARTI CARRERAS, Joan, Vanmechelen, Bert, Wawina, Tony, Medical Microbiology and Infection Prevention, AII - Infectious diseases, WHO European Region Sequencing Lab, GISAID EpiCoV Grp, Erik, Alm, Eeva K, Broberg, Thomas, Connor, Emma B, Hodcroft, Andrey B, Komissarov, Sebastian, Maurer-Stroh, Angeliki, Melidou, Richard A, Neher, Áine, O’Toole, Dmitriy, Pereyaslov, WHO European Region sequencing laboratories and GISAID EpiCoV group (Niko Beerenwinkel, The, Posada-Céspedes, Susana, Philipp, Kim, Jablonski, Falé Ferreira, Pedro, Topolsky, Ivan, Avšičžupanc, Tatjana, Korva, Miša, Poljak, Mario, Zakotnik, Samo, Tomaž, Zorec, Mark, Bragstad, Karoline, Hungnes, Olav, Stene-Johansen, Kathrine, Reusken, Chantal, Meijer, Adam, Vennema, Harry, Ruiz-Roldán, Lidia, Alma Bracho, María, García-González, Neri, Chiner-Oms, Álvaro, Cancino-Muñoz, Irving, Comas, Iñaki, A Goig, Galo, Torres-Puente, Manuela, G López, Mariana, Martínez-Priego, Llúcia, D’Auria, Giuseppe, LoretoFerrús-Abad, de Marco, Griselda, Galan-Vendrell, Inmaculada, Carbó-Ramirez, Sandra, Ruíz-Hueso, Paula, Coscollá, Mireia, Polackova, Katerina, Kramna, Lenka, Cinek, Ondrej, Richter, Jan, Krashias, George, Tryfonos, Christina, Bashiardes, Stavro, Koptides, Dana, Christodoulou, Christina, Bartolini, Barbara, Em Gruber, Cesare, Di Caro, Antonino, Castilletti, Concetta, Stefani, Fabrizio, Giordana Rimoldi, Sara, Romeri, Francesca, Salerno, Franco, Polesello, Stefano, Nagy, Alexander, Jirincova, Helena, Vecerova, Jaromira, Novakova, Ludmila, Cordey, Samuel, Murtskhvaladze, Marine, Kotaria, Nato, Schär, Tobia, Beisel, Christian, Vugrek, Oliver, Rokić, Filip, Trgovecgreif, Lovro, Jurak, Igor, Rukavina, Tomislav, Sučić, Neven, Schønning, Kristian, M Karst, Søren, H Kirkegaard, Rasmu, Y Michaelsen, Thoma, Aa Sørensen, Emil, Knutson, Simon, Brandt, Jakob, Le-Quy, Vang, Sørensen, Trine, Petersen, Celine, Schou Pedersen, Martin, Løkkegaard Larsen, Sanne, Nielsine Skov, Marianne, Rasmussen, Morten, Fonager, Jannik, Fomsgaard, Ander, Amirovich Maksyutov, Rinat, Vasil’Evna Gavrilova, Elena, Victorovich Pyankov, Oleg, Alexandrovich Bodnev, Sergey, Vladimirovna Tregubchak, Tatyana, Nikolayevich Shvalov, Alexander, Victorovich Antonets, Deni, Cristina Resende, Paola, Goya, Stephanie, Perrin, Amandine, Tc Lee, Raphael, Yadahalli, Shilpa, X Han, Alvin, A Russell, Colin, Schmutz, Stefan, Zaheri, Maryam, Kufner, Verena, Huber, Michael, Trkola, Alexandra, Antwerpen, Marku, C Walter, Mathia, van der Werf, Sylvie, Gambaro, Fabiana, Behillil, Sylvie, Enouf, Vincent, Donati, Flora, Ustinova, Monta, Rovite, Vita, Klovins, Jani, Savicka, Oksana, K Wienecke-Baldacchino, Anke, Ragimbeau, Catherine, Fournier, Guillaume, Mossong, Joël, W Aberle, Stephan, Haukland, Mattia, Enkirch, Theresa, Advani, Abdolreza, Lind Karlberg, Maria, Karlsson Lindsjö, Oskar, Broddesson, Sandra, Sláviková, Monika, Ličková, Martina, Klempa, Bori, Staroňová, Edita, Tichá, Elena, Szemes, Tomáš, Rusňáková, Diana, Stadler, Tanja, Quer, Josep, Anton, Andre, Andres, Cristina, Piñana, Maria, Garcia-Cehic, Damir, Pumarola, Toma, Izopet, Jacque, Gioula, Georgia, Exindari, Maria, Papa, Anna, Chatzidimitriou, Dimitrio, Metallidis, Symeon, Pappa, Stella, Macek Jr, Milan, Geryk, Jan, Brož, Petr, Briksí, Aleš, Hubáček, Petr, Dřevínek, Pavel, Zajac, Miroslav, Kvapil, Petr, Holub, Michal, Kvapilová, Kateřina, Novotný, Adam, Kašný, Martin, Klempt, Petr, Vapalahti, Olli, Smura, Teemu, Sironen, Tarja, Selhorst, Philippe, Anthony, Colin, Ariën, Kevin, Simon-Loriere, Etienne, Rabalski, Lukasz, Bienkowska-Szewczyk, Krystyna, Borges, Vítor, Isidro, Joana, Paulo Gomes, João, Guiomar, Raquel, Pechirra, Pedro, Costa, Inê, Duarte, Sílvia, Vieira, Luí, Pyrc, Krzysztof, S Zuckerman, Neta, Turdikulova, Shahlo, Abdullaev, Alisher, Dalimova, Dilbar, Abdurakhimov, Abror, Tagliabracci, Adriano, Alessandrini, Federica, Melchionda, Filomena, Onofri, Valerio, Turchi, Chiara, Bagnarelli, Patrizia, Menzo, Stefano, Caucci, Sara, Di Sante, Laura, Popa, Alexandra, Genger, Jakob-Wendelin, Agerer, Benedikt, Lercher, Alexander, Endler, Luka, Smyth, Mark, Penz, Thoma, Schuster, Michael, Senekowitsch, Martin, Laine, Jan, Bock, Christoph, Bergthaler, Andrea, Shevtsov, Alexandr, Kalendar, Ruslan, Ramanculov, Yerlan, Graf, Alexander, Muenchhoff, Maximilian, T Keppler, Oliver, Krebs, Stefan, Blum, Helmut, Marcello, Alessandro, Licastro, Danilo, D’Agaro, Pierlanfranco, Laubscher, Florian, Vidanovic, Dejan, Tesovic, Bojana, Volkening, Jeremy, Clementi, Nicola, Mancini, Nicasio, Rupnik, Maja, Mahnic, Aleksander, Walker, Andrea, Houwaart, Torsten, Wienemann, Tobia, Kohns Vasconcelos, Malte, Strelow, Daniel, Ole Jensen, Björn-Erik, Senff, Tina, Hülse, Lisanna, Adams, Ortwin, Andree, Marcel, Hauka, Sandra, Feldt, Torsten, Keitel, Verena, Kindgen-Milles, Detlef, Timm, Jörg, Pfeffer, Klau, T Dilthey, Alexander, Moore, Catherine, Ozdarendeli, Aykut, Terkis Islam Pavel, Shaikh, Yetiskin, Hazel, Aydin, Gunsu, Holyavkin, Can, Ali Uygut, Muhammet, Cevik, Ceren, Shchetinin, Alexey, Gushchin, Vladimir, Dinler-Doganay, Gizem, Doganay, Levent, Kizilboga-Akgun, Tugba, Karacan, Ilker, Pancer, Katarzyna, Maes, Piet, Martí-Carreras, Joan, Wawina-Bokalanga, Tony, Thürmer, Andrea, Wedde, Marianne, Dürrwald, Ralf, Von Kleist, Max, Drechsel, Oliver, Wolff, Thorsten, Fuchs, Stephan, Kmiecinski, Rene, Michel, Janine, Nitsche, Andrea, Casas, Inmaculada, Iglesias Caballero, María, Zaballos, Ángel, Jiménez, Pilar, Jiménez, Mercede, Monzón Fernández, Sara, Varona Fernández, Sarai, Cuesta De La Plaza, Isabel, Fadeev, Artem, Ivanova, Anna, Sergeeva, Mariia, Stefanelli, Paola, Estee Torok, M, Hall, Grant, da Silva Filipe, Ana, Turtle, Lance, Afifi, Safiah, Mccluggage, Kathryn, Beer, Robert, Ledesma, Juan, Maksimovic, Joshua, Spellman, Karla, L Hamilton, William, Marchbank, Angela, Alexander Southgate, Joel, Underwood, Anthony, Taylor, Ben, Yeats, Corin, Abudahab, Khalil, R Gemmell, Matthew, Eccles, Richard, Lucaci, Anita, Abigail Nelson, Charlotte, Rainbow, Lucille, Whitehead, Mark, Gregory, Richard, Haldenby, Sam, Paterson, Steve, A Hughes, Margaret, D Curran, Martin, Baker, David, Tucker, Rachel, R Green, Luke, Feltwell, Theresa, D Halstead, Fenella, Wyles, Matthew, S Jahun, Aminu, Y Ahmad, Shazaad S, Georgana, Iliana, Goodfellow, Ian, Yakovleva, Anna, W Meredith, Luke, Gavriil, Artemi, Raza Awan, Ali, Fisher, Chloe, Jonathan, European Centre for Disease Prevention and Control [Stockholm, Sweden] (ECDC), Cardiff University, Public Health Wales [Cardiff, Royaume uni], University of Basel (Unibas), Research Institute of Influenza, St. Petersburg, Russia, Agency for science, technology and research [Singapore] (A*STAR), National University of Singapore (NUS), University of Edinburgh, WHO Regional Office for Europe [Copenhagen], We gratefully acknowledge the authors, originating and submitting laboratories of the sequences from GISAID’s EpiCoV Database used in the phylogenetic analysis. We gratefully acknowledge all the staff working with sample collection, sample preparation, sequencing, data analysis and data sharing in all laboratories in the WHO European Region for making this work possible, The WHO European Region sequencing laboratories and GISAID EpiCoV group*: Niko Beerenwinkel, Susana Posada-Céspedes, Kim Philipp Jablonski, Pedro Falé Ferreira, Ivan Topolsky, Tatjana Avšič-Županc, Miša Korva, Mario Poljak, Samo Zakotnik, Tomaž Mark Zorec, Karoline Bragstad, Olav Hungnes, Kathrine Stene-Johansen, Chantal Reusken, Adam Meijer, Harry Vennema, Lidia Ruiz-Roldán, María Alma Bracho, Neris García-González, Álvaro Chiner-Oms, Irving Cancino-Muñoz, Iñaki Comas, Galo A Goig, Manuela Torres-Puente, Mariana G López, Llúcia Martínez-Priego, Giuseppe D'Auria, Paula Ruíz-Hueso, Loreto Ferrús-Abad, Griselda de Marco, Inmaculada Galan-Vendrell, Sandra Carbó-Ramirez, Paula Ruiz-Rodriguez, Mireia Coscollá, Katerina Polackova, Lenka Kramna, Ondrej Cinek, Jan Richter, George Krashias, Christina Tryfonos, Stavros Bashiardes, Dana Koptides, Christina Christodoulou, Barbara Bartolini, Cesare Em Gruber, Antonino Di Caro, Concetta Castilletti, Fabrizio Stefani, Sara Giordana Rimoldi, Francesca Romeri, Franco Salerno, Stefano Polesello, Alexander Nagy, Helena Jirincova, Jaromira Vecerova, Ludmila Novakova, Samuel Cordey, Marine Murtskhvaladze, Nato Kotaria, Tobias Schär, Christian Beisel, Oliver Vugrek, Filip Rokić, Lovro Trgovec-Greif, Igor Jurak, Tomislav Rukavina, Neven Sučić, Kristian Schønning, Søren M Karst, Rasmus H Kirkegaard, Thomas Y Michaelsen, Emil Aa Sørensen, Simon Knutson, Jakob Brandt, Vang Le-Quy, Trine Sørensen, Celine Petersen, Martin Schou Pedersen, Sanne Løkkegaard Larsen, Marianne Nielsine Skov, Morten Rasmussen, Jannik Fonager, Anders Fomsgaard, Rinat Amirovich Maksyutov, Elena Vasil'Evna Gavrilova, Oleg Victorovich Pyankov, Sergey Alexandrovich Bodnev, Tatyana Vladimirovna Tregubchak, Alexander Nikolayevich Shvalov, Denis Victorovich Antonets, Paola Cristina Resende, Stephanie Goya, Amandine Perrin, Raphael Tc Lee, Shilpa Yadahalli, Alvin X Han, Colin A Russell, Stefan Schmutz, Maryam Zaheri, Verena Kufner, Michael Huber, Alexandra Trkola, Markus Antwerpen, Mathias C Walter, Sylvie van der Werf, Fabiana Gambaro, Sylvie Behillil, Vincent Enouf, Flora Donati, Monta Ustinova, Vita Rovite, Janis Klovins, Oksana Savicka, Anke K Wienecke-Baldacchino, Catherine Ragimbeau, Guillaume Fournier, Joël Mossong, Stephan W Aberle, Mattias Haukland, Theresa Enkirch, Abdolreza Advani, Maria Lind Karlberg, Oskar Karlsson Lindsjö, Sandra Broddesson, Monika Sláviková, Martina Ličková, Boris Klempa, Edita Staroňová, Elena Tichá, Tomáš Szemes, Diana Rusňáková, Tanja Stadler, Josep Quer, Andres Anton, Cristina Andres, Maria Piñana, Damir Garcia-Cehic, Tomas Pumarola, Jacques Izopet, Georgia Gioula, Maria Exindari, Anna Papa, Dimitrios Chatzidimitriou, Symeon Metallidis, Stella Pappa, Milan Macek Jr, Jan Geryk, Petr Brož, Aleš Briksí, Petr Hubáček, Pavel Dřevínek, Miroslav Zajac, Petr Kvapil, Michal Holub, Kateřina Kvapilová, Adam Novotný, Martin Kašný, Petr Klempt, Olli Vapalahti, Teemu Smura, Tarja Sironen, Philippe Selhorst, Colin Anthony, Kevin Ariën, Etienne Simon-Loriere, Lukasz Rabalski, Krystyna Bienkowska-Szewczyk, Vítor Borges, Joana Isidro, João Paulo Gomes, Raquel Guiomar, Pedro Pechirra, Inês Costa, Sílvia Duarte, Luís Vieira, Krzysztof Pyrc, Neta S Zuckerman, Shahlo Turdikulova, Alisher Abdullaev, Dilbar Dalimova, Abror Abdurakhimov, Adriano Tagliabracci, Federica Alessandrini, Filomena Melchionda, Valerio Onofri, Chiara Turchi, Patrizia Bagnarelli, Stefano Menzo, Sara Caucci, Laura Di Sante, Alexandra Popa, Jakob-Wendelin Genger, Benedikt Agerer, Alexander Lercher, Lukas Endler, Mark Smyth, Thomas Penz, Michael Schuster, Martin Senekowitsch, Jan Laine, Christoph Bock, Andreas Bergthaler, Alexandr Shevtsov, Ruslan Kalendar, Yerlan Ramanculov, Alexander Graf, Maximilian Muenchhoff, Oliver T Keppler, Stefan Krebs, Helmut Blum, Alessandro Marcello, Danilo Licastro, Pierlanfranco D'Agaro, Florian Laubscher, Dejan Vidanovic, Bojana Tesovic, Jeremy Volkening, Nicola Clementi, Nicasio Mancini, Maja Rupnik, Aleksander Mahnic, Andreas Walker, Torsten Houwaart, Tobias Wienemann, Malte Kohns Vasconcelos, Daniel Strelow, Björn-Erik Ole Jensen, Tina Senff, Lisanna Hülse, Ortwin Adams, Marcel Andree, Sandra Hauka, Torsten Feldt, Verena Keitel, Detlef Kindgen-Milles, Jörg Timm, Klaus Pfeffer, Alexander T Dilthey, Catherine Moore, Aykut Ozdarendeli, Shaikh Terkis Islam Pavel, Hazel Yetiskin, Gunsu Aydin, Can Holyavkin, Muhammet Ali Uygut, Ceren Cevik, Alexey Shchetinin, Vladimir Gushchin, Gizem Dinler-Doganay, Levent Doganay, Tugba Kizilboga-Akgun, Ilker Karacan, Katarzyna Pancer, Piet Maes, Joan Martí-Carreras, Tony Wawina-Bokalanga, Bert Vanmechelen, Andrea Thürmer, Marianne Wedde, Ralf Dürrwald, Max Von Kleist, Oliver Drechsel, Thorsten Wolff, Stephan Fuchs, Rene Kmiecinski, Janine Michel, Andreas Nitsche, Inmaculada Casas, María Iglesias Caballero, Ángel Zaballos, Pilar Jiménez, Mercedes Jiménez, Sara Monzón Fernández, Sarai Varona Fernández, Isabel Cuesta De La Plaza, Artem Fadeev, Anna Ivanova, Mariia Sergeeva, Paola Stefanelli, M Estee Torok, Grant Hall, Ana da Silva Filipe, Lance Turtle, Safiah Afifi, Kathryn Mccluggage, Robert Beer, Juan Ledesma, Joshua Maksimovic, Karla Spellman, William L Hamilton, Angela Marchbank, Joel Alexander Southgate, Anthony Underwood, Ben Taylor, Corin Yeats, Khalil Abudahab, Matthew R Gemmell, Richard Eccles, Anita Lucaci, Charlotte Abigail Nelson, Lucille Rainbow, Mark Whitehead, Richard Gregory, Sam Haldenby, Steve Paterson, Margaret A Hughes, Martin D Curran, David Baker, Rachel Tucker, Luke R Green, Theresa Feltwell, Fenella D Halstead, Matthew Wyles, Aminu S Jahun, Shazaad S Y Ahmad, Iliana Georgana, Ian Goodfellow, Anna Yakovleva, Luke W Meredith, Artemis Gavriil, Ali Raza Awan, Chloe Fisher, Jonathan Edgeworth, Jessica Lynch, 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Ethan Butcher, Kelly Bicknell, Scott Elliott, Sharon Glaysher, Angie Lackenby, David Bibby, Steven Platt, Hodan Mohamed, Nicholas William Machin, Jean Lutamyo Mbisa, Jonathan Evans, Malorie Perry, Nicole Pacchiarini, Sally Corden, Alexander Geraint Adams, Amy Gaskin, Jason Coombs, Lee John Graham, Simon Cottrell, Mari Morgan, Laura Gifford, Anastasia Kolyva, Steven John Rudder, Alexander J Trotter, Alison E Mather, Alp Aydin, Andrew J Page, Gemma L Kay, Leonardo de Oliveira Martins, Muhammad Yasir, Nabil-Fareed Alikhan, Nicholas M Thomson, Rachel Gilroy, Robert A Kingsley, Justin O'Grady, Ana Victoria Gutierrez, Maria Diaz, Thanh Le Viet, Ana P Tedim, Evelien M Adriaenssens, C Patrick Mcclure, Christopher Moore, Fei Sang, Gemma Clark, Hannah C Howson-Wells, Johnny Debebe, Jonathan Ball, Joseph Chappell, Manjinder Khakh, Matthew Carlile, Matthew Loose, Michelle M Lister, Nadine Holmes, Theocharis Tsoleridis, Vicki M Fleming, Victoria Wright, Wendy Smith, Michael D Gallagher, Matthew 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A., Cevik, C., Shchetinin, A., Gushchin, V., Dinler-Doganay, G., Doganay, L., Kizilboga-Akgun, T., Karacan, I., Pancer, K., Maes, P., Marti-Carreras, J., Wawina-Bokalanga, T., Vanmechelen, B., Thurmer, A., Wedde, M., Durrwald, R., von Kleist, M., Drechsel, O., Wolff, T., Fuchs, S., Kmiecinski, R., Michel, J., Nitsche, A., Casas, I., Caballero, M. I., Zaballos, A., Jimenez, P., Jimenez, M., Fernandez, S. M., Fernandez, S. V., de la Plaza, I. C., Fadeev, A., Ivanova, A., Sergeeva, M., Stefanelli, P., Estee Torok, M., Hall, G., da Silva Filipe, A., Turtle, L., Afifi, S., Mccluggage, K., Beer, R., Ledesma, J., Maksimovic, J., Spellman, K., Hamilton, W. L., Marchbank, A., Southgate, J. A., Underwood, A., Taylor, B., Yeats, C., Abudahab, K., Gemmell, M. R., Eccles, R., Lucaci, A., Nelson, C. A., Rainbow, L., Whitehead, M., Gregory, R., Haldenby, S., Paterson, S., Hughes, M. A., Curran, M. D., Baker, D., Tucker, R., Green, L. R., Feltwell, T., Halstead, F. D., Wyles, M., Jahun, A. S., Ahmad, S. S. Y., Georgana, I., Goodfellow, I., Yakovleva, A., Meredith, L. W., Gavriil, A., Awan, A. R., Fisher, C., Edgeworth, J., Lynch, J., Moore, N., Williams, R., Kidd, S. P., Cortes, N., Brunker, K., Mccrone, J. T., Quick, J., Duckworth, N., Walsh, S., Sloan, T., Ludden, C., George, R. P., Eltringham, G., Brown, J. R., Aranday-Cortes, E., Shepherd, J. G., Hughes, J., Li, K. K., Williams, T. C., Johnson, N., Jesudason, N., Mair, D., Thomson, E., Shah, R., Parr, Y. A., Carmichael, S., Robertson, D. L., Nomikou, K., Broos, A., Niebel, M., Smollett, K., Tong, L., Miah, S., Wittner, A., Phillips, N., Payne, B., Dewar, R., Holmes, A., Bolt, F., Price, J. R., Mookerjee, S., Sethi, D. K., Potter, W., Stanley, R., Prakash, R., Dervisevic, S., Graham, J. C., Nelson, A., Smith, D., Young, G. R., Yew, W. C., Todd, J. A., Trebes, A., Andersson, M., Bull, M., Watkins, J., Birchley, A., Gatica-Wilcox, B., Gilbert, L., Kumziene-Summerhayes, S., Rey, S., Chauhan, A., Butcher, E., Bicknell, K., Elliott, S., Glaysher, S., Lackenby, A., Bibby, D., Platt, S., Mohamed, H., Machin, N. W., Mbisa, J. L., Evans, J., Perry, M., Pacchiarini, N., Corden, S., Adams, A. G., Gaskin, A., Coombs, J., Graham, L. J., Cottrell, S., Morgan, M., Gifford, L., Kolyva, A., Rudder, S. J., Trotter, A. J., Mather, A. E., Aydin, A., Page, A. J., Kay, G. L., de Oliveira Martins, L., Yasir, M., Alikhan, N. -F., Thomson, N. M., Gilroy, R., Kingsley, R. A., O'Grady, J., Gutierrez, A. V., Diaz, M., Viet, T. L., Tedim, A. P., Adriaenssens, E. M., Patrick Mcclure, C., Sang, F., Clark, G., Howson-Wells, H. C., Debebe, J., Ball, J., Chappell, J., Khakh, M., Carlile, M., Loose, M., Lister, M. M., Holmes, N., Tsoleridis, T., Fleming, V. M., Wright, V., Smith, W., Gallagher, M. D., Parker, M., Partridge, D. G., Evans, C., Baker, P., Essex, S., Liggett, S., Keeley, A. J., Bashton, M., Rooke, S., Dervisavic, S., Meader, E. J., Lopez, C. E. B., Angyal, A., Kristiansen, M., Tutill, H. J., Findlay, J., Mestek-Boukhibar, L., Forrest, L., Dyal, P., Williams, R. J., Panchbhaya, Y., Williams, C. A., Roy, S., Pandey, S., Stockton, J., Loman, N. J., Poplawski, R., Nicholls, S., Rowe, W. P. M., Khokhar, F., Pinckert, M. L., Hosmillo, M., Chaudhry, Y., Caller, L. G., Davidson, R. K., Griffith, L., Rambaut, A., Jackson, B., Colquhoun, R., Hill, V., Nichols, J., Asamaphan, P., Darby, A., Jackson, K. A., Iturriza-Gomara, M., Vamos, E. E., Green, A., Aanensen, D., Bonsall, D., Buck, D., Macintyre-Cockett, G., de Cesare, M., Pybus, O., Golubchik, T., Scarlett, G., Loveson, K. F., Robson, S. C., Beckett, A., Lindsey, B., Groves, D. C., Parsons, P. J., Mchugh, M. P., Barnes, J. D., Manso, C. F., Grammatopoulos, D., Menger, K. E., Harrison, E., Gunson, R., Peacock, S. J., Gonzalez, G., Carr, M., Mihaela, L., Popovici, O., Brytting, M., Bresner, C., Fuller, W., Workman, T., Mentis, A. F., Kossyvakis, A., Karamitros, T., Pogka, V., Kalliaropoulos, A., Horefti, E., Kontou, A., Martinez-Gonzalez, B., Labropoulou, V., Voulgari-Kokota, A., Evangelidou, M., Bizta, P., Belimezi, M., Lambrechts, L., Doymaz, M. Z., Yazici, M. K., Cetin, N. S., Karaaslan, E., Kallio-Kokko, H., Virtanen, J., Suvanto, M., Nguyen, P. T., Ellonen, P., Hannula, S., Kangas, H., Sreenu, V. B., Burian, K., Terhes, G., Gombos, K., Gyenesei, A., Urban, P., Herczeg, R., Jakab, F., Kemenesi, G., Toth, G. E., Somogyi, B., Zana, B., Zeghbib, S., Kuczmog, A., Foldes, F., Lanszki, Z., Madai, M., Papp, H., Pereszlenyi, C. I., Babinszky, G. C., Dudas, G., Csoma, E., Abou Tayoun, A. N., Alsheikh-Ali, A. A., Loney, T., Nowotny, N., Abdul-Wahab, O., Gonzalez-Candelas, F., Andersen, M. H., Taylor, S., European Centre for Disease Prevention and Control (ECDC), Public Health Wales Microbiology Cardiff, Faculty of Agriculture and Forestry, Department of Agricultural Sciences, and Institute of Biotechnology

Subjects
Infecções Respiratórias, 0301 basic medicine, MESH: Coronavirus Infections, Epidemiology, [SDV]Life Sciences [q-bio], Distribution (economics), Wastewater, MESH: Base Sequence, Severe Acute Respiratory Syndrome, MESH: World Health Organization, Pandemic, MESH: Coronavirus, MESH: COVID-19, Sequencing, Viral, Clade, Nomenclature, Genome, biology, COVID-19, Europe, NGS, SARS-CoV-2, WGS, nomenclature, sequencing, Base Sequence, Betacoronavirus, Coronavirus, Coronavirus Infections, Genome, Viral, Humans, Phylogeography, Pneumonia, Viral, RNA, Viral, RNA-Dependent RNA Polymerase, Spatio-Temporal Analysis, World Health Organization, Pandemics, C500, European region, 3. Good health, Geography, MESH: Phylogeography, MESH: RNA-Dependent RNA Polymerase, MESH: RNA, Viral, MESH: Betacoronavirus, Spatio-Temporal Analysi, MESH: Genome, Viral, Cartography, Human, Bioquímica, MESH: Pandemics, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Coronaviru, 030106 microbiology, 03 medical and health sciences, MESH: Spatio-Temporal Analysis, MESH: Severe Acute Respiratory Syndrome, Virology, MESH: SARS-CoV-2, Whole genome sequencing, MESH: Humans, Whole Genome Sequencing, Betacoronaviru, Coronavirus Infection, business.industry, Public Health, Environmental and Occupational Health, Pneumonia, biology.organism_classification, B900, 030104 developmental biology, MESH: Pneumonia, Viral, RNA, SARS_CoV-2, 3111 Biomedicine, MESH: Europe, Human medicine, business
Abstract

8 páginas, 3 figuras, We show the distribution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three genomic nomenclature systems to all sequence data from the World Health Organization European Region available until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation, compare the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2., We gratefully acknowledge the authors, originating and submitting laboratories of the sequences from GISAID’s EpiCoV Database used in the phylogenetic analysis. We gratefully acknowledge all the staff working with sample collection, sample preparation, sequencing, data analysis and data sharing in all laboratories in the WHO European Region for making this work possible.

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45. Hepatitis E in southern Vietnam: Seroepidemiology in humans and molecular epidemiology in pigs

Author

Berto, A, Pham, HA, Thao, TTN, Vy, NHT, Caddy, SL, Hiraide, R, Tue, NT, Goodfellow, I, Carrique-Mas, JJ, Thwaites, GE, Baker, S, Boni, MF, and VIZIONS Consortium

Subjects
Swine Diseases, Molecular Epidemiology, Farmers, seroprevalence, Swine, viruses, prevalence, virus diseases, pigs, hepatitis E virus, zoonosis, digestive system diseases, 3. Good health, Hepatitis E, Vietnam, Seroepidemiologic Studies, Zoonoses, Animals, Humans, RNA, Viral, human
Abstract

Viral pathogens account for a significant proportion of the burden of emerging infectious diseases in humans. The Wellcome Trust-Vietnamese Initiative on Zoonotic Infections (WT-VIZIONS) is aiming to understand the circulation of viral zoonotic pathogens in animals that pose a potential risk to human health. Evidence suggests that human exposure and infections with hepatitis E virus (HEV) genotypes (GT) 3 and 4 results from zoonotic transmission. Hypothesising that HEV GT3 and GT4 are circulating in the Vietnamese pig population and can be transmitted to humans, we aimed to estimate the seroprevalence of HEV exposure in a population of farmers and the general population. We additionally performed sequence analysis of HEV in pig populations in the same region to address knowledge gaps regarding HEV circulation and to evaluate if pigs were a potential source of HEV exposure. We found a high prevalence of HEV GT3 viral RNA in pigs (19.1% in faecal samples and 8.2% in rectal swabs) and a high HEV seroprevalence in pig farmers (16.0%) and a hospital-attending population (31.7%) in southern Vietnam. The hospital population was recruited as a general-population proxy even though this particular population subgroup may introduce bias. The detection of HEV RNA in pigs indicates that HEV may be a zoonotic disease risk in this location, although a larger sample size is required to infer an association between HEV positivity in pigs and seroprevalence in humans.

46. Norovirus Polymerase Fidelity Contributes to Viral Transmission In Vivo

Author

Arias, A, Thorne, L, Ghurburrun, E, Bailey, D, and Goodfellow, I

Subjects
viruses, polymerase fidelity, RNA polymerases, quasispecies, virus transmission, noroviruses, 3. Good health
Abstract

Intrahost genetic diversity and replication error rates are intricately linked to RNA virus pathogenesis, with alterations in viral polymerase fidelity typically leading to attenuation during infections in vivo. We have previously shown that norovirus intrahost genetic diversity also influences viral pathogenesis using the murine norovirus model, as increasing viral mutation frequency using a mutagenic nucleoside resulted in clearance of a persistent infection in mice. Given the role of replication fidelity and genetic diversity in pathogenesis, we have now investigated whether polymerase fidelity can also impact virus transmission between susceptible hosts. We have identified a high-fidelity norovirus RNA-dependent RNA polymerase mutant (I391L) which displays delayed replication kinetics in vivo but not in cell culture. The I391L polymerase mutant also exhibited lower transmission rates between susceptible hosts than the wild-type virus and, most notably, another replication defective mutant that has wild-type levels of polymerase fidelity. These results provide the first experimental evidence that norovirus polymerase fidelity contributes to virus transmission between hosts and that maintaining diversity is important for the establishment of infection. This work supports the hypothesis that the reduced polymerase fidelity of the pandemic GII.4 human norovirus isolates may contribute to their global dominance. IMPORTANCE Virus replication fidelity and hence the intrahost genetic diversity of viral populations are known to be intricately linked to viral pathogenesis and tropism as well as to immune and antiviral escape during infection. In this study, we investigated whether changes in replication fidelity can impact the ability of a virus to transmit between susceptible hosts by the use of a mouse model for norovirus. We show that a variant encoding a high-fidelity polymerase is transmitted less efficiently between mice than the wild-type strain. This constitutes the first experimental demonstration that the polymerase fidelity of viruses can impact transmission of infection in their natural hosts. These results provide further insight into potential reasons for the global emergence of pandemic human noroviruses that display alterations in the replication fidelity of their polymerases compared to nonpandemic strains.

47. Activation of COX-2/PGE2 Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production

Author

Alfajaro, MM, Choi, J-S, Kim, D-S, Seo, J-Y, Kim, J-Y, Park, J-G, Soliman, M, Baek, Y-B, Cho, E-H, Kwon, J, Kwon, H-J, Park, S-J, Lee, WS, Kang, M-I, Hosmillo, M, Goodfellow, I, and Cho, K-O

Subjects
prostaglandin E2, Cyclooxygenase 2 Inhibitors, Swine, Gene Expression, Nitric Oxide, Virus Replication, Dinoprostone, Sapovirus, 3. Good health, Cell Line, Bile Acids and Salts, caliciviruses, cyclooxygenases, Cyclooxygenase 2, Cyclooxygenase 1, Animals, RNA Interference, RNA, Small Interfering, Cells, Cultured, Caliciviridae Infections, Signal Transduction
Abstract

Enteric caliciviruses in the genera Norovirus and Sapovirus are important pathogens that cause severe acute gastroenteritis in both humans and animals. Cyclooxygenases (COXs) and their final product, prostaglandin E2 (PGE2), are known to play important roles in the modulation of both the host response to infection and the replicative cycles of several viruses. However, the precise mechanism(s) by which the COX/PGE2 pathway regulates sapovirus replication remains largely unknown. In this study, infection with porcine sapovirus (PSaV) strain Cowden, the only cultivable virus within the genus Sapovirus, markedly increased COX-2 mRNA and protein levels at 24 and 36 h postinfection (hpi), with only a transient increase in COX-1 levels seen at 24 hpi. The treatment of cells with pharmacological inhibitors, such as nonsteroidal anti-inflammatory drugs or small interfering RNAs (siRNAs) against COX-1 and COX-2, significantly reduced PGE2 production, as well as PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE2 pathway. We observed that pharmacological inhibition of COX-2 dramatically increased NO production, causing a reduction in PSaV replication that could be restored by inhibition of nitric oxide synthase via the inhibitor N-nitro-l-methyl-arginine ester. This study identified a pivotal role for the COX/PGE2 pathway in the regulation of NO production during the sapovirus life cycle, providing new insights into the life cycle of this poorly characterized family of viruses. Our findings also reveal potential new targets for treatment of sapovirus infection. IMPORTANCE: Sapoviruses are among the major etiological agents of acute gastroenteritis in both humans and animals, but little is known about sapovirus host factor requirements. Here, using only cultivable porcine sapovirus (PSaV) strain Cowden, we demonstrate that PSaV induced the vitalization of the cyclooxygenase (COX) and prostaglandin E2 (PGE2) pathway. Targeting of COX-1/2 using nonsteroidal anti-inflammatory drugs (NSAIDs) such as the COX-1/2 inhibitor indomethacin and the COX-2-specific inhibitors NS-398 and celecoxib or siRNAs targeting COXs, inhibited PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE2 pathway. We further demonstrate that the production of PGE2 provides a protective effect against the antiviral effector mechanism of nitric oxide. Our findings uncover a new mechanism by which PSaV manipulates the host cell to provide an environment suitable for efficient viral growth, which in turn can be a new target for treatment of sapovirus infection.

48. Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial

Author

J. Cutler, A, Oliveira, J, C. Ferreira, R, Challis, B, M. Walker, N, Caddy, S, Lu, J, E. Stevens, H, J. Smyth, D, L. Pekalski, M, Kennet, J, M.D. Hunter, K, Goodfellow, I, S. Wicker, L, A. Todd, J, and Waldron-Lynch, F

Subjects
2 Aetiology, Inflammatory and immune system, 3207 Medical Microbiology, hemic and immune systems, chemical and pharmacologic phenomena, 32 Biomedical and Clinical Sciences, FOS: Health sciences, 3. Good health, 3204 Immunology, Vaccine Related, Infectious Diseases, Emerging Infectious Diseases, Clinical Research, 2.1 Biological and endogenous factors, Digestive Diseases, Infection
Abstract

Background: The infection of a participant with norovirus during the adaptive study of interleukin-2 dose on regulatory T cells in type 1 diabetes (DILT1D) allowed a detailed insight into the cellular and cytokine immune responses to this prevalent gastrointestinal pathogen. Methods: Serial blood, serum and peripheral blood mononuclear cell (PBMC) samples were collected pre-, and post-development of the infection. To differentiate between the immune response to norovirus and to control for the administration of a single dose of aldesleukin (recombinant interleukin-2, rIL-2) alone, samples from five non-infected participants administered similar doses were analysed in parallel. Results: Norovirus infection was self-limited and resolved within 24 hours, with the subsequent development of anti-norovirus antibodies. Serum pro- and anti-inflammatory cytokine levels, including IL-10, peaked during the symptomatic period of infection, coincident with increased frequencies of monocytes and neutrophils. At the same time, the frequency of regulatory CD4+ T cell (Treg), effector T cell (Teff) CD4+ and CD8+ subsets were dynamically reduced, rebounding to baseline levels or above at the next sampling point 24 hours later. NK cells and NKT cells transiently increased CD69 expression and classical monocytes expressed increased levels of CD40, HLA-DR and SIGLEC-1, biomarkers of an interferon response. We also observed activation and mobilisation of Teffs, where increased frequencies of CD69+ and Ki-67+ effector memory Teffs were followed by the emergence of memory CD8+ Teff expressing the mucosal tissue homing markers CD103 and β7 integrin. Treg responses were coincident with the innate cell, Teff and cytokine response. Key Treg molecules FOXP3, CTLA-4, and CD25 were upregulated following infection, alongside an increase in frequency of Tregs with the capacity to home to tissues. Conclusions: The results illustrate the innate, adaptive and counter-regulatory immune responses to norovirus infection. Low-dose IL-2 administration induces many of the Treg responses observed during infection.

49. 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. 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. 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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.

50. COVID-19 due to the B.1.617.2 (Delta) variant compared to B.1.1.7 (Alpha) variant of SARS-CoV-2: a prospective observational cohort study

Author

Kläser, K., Molteni, E., Graham, M., Canas, L. S., Österdahl, M. F., Antonelli, M., Chen, L., Deng, J., Murray, B., Kerfoot, E., Wolf, J., May, A., Fox, B., Capdevila, J., Aanensen, D. M., Abudahab, K., Adams, H., Adams, A., Afifi, S., Aggarwal, D., Ahmad, S. S. Y., Aigrain, L., Alcolea-Medina, A., Alikhan, N-F, Allara, E., Amato, R., Angyal, A., Annett, T., Aplin, S., Ariani, C. V., Asad, H., Ash, A., Ashfield, P., Ashford, F., Atkinson, L., Attwood, S. W., Auckland, C., Aydin, A., Baker, D. J., Baker, P., Balcazar, C. E., Ball, J., Barrett, J. C., Barrow, M., Barton, E., Bashton, M., Bassett, A. R., Batra, R., Baxter, C., Bayzid, N., Beaver, C., Beckett, A. H., Beckwith, S. M., Bedford, L., Beer, R., Beggs, A., Bellis, K. L., Berry, L., Bertolusso, B., Best, A., Betteridge, E., Bibby, D., Bicknell, K., Binns, D., Birchley, A., Bird, P. W., Bishop, C., Blacow, R., Blakey, V., Blane, B., Bolt, F., Bonfield, J., Bonner, S., Bonsall, D., Boswell, T., Bosworth, A., Bourgeois, Y., Boyd, O., Bradley, D. T., Breen, C., Bresner, C., Breuer, J., Bridgett, S., Bronner, I. F., Brooks, E., Broos, A., Brown, J. R., Bucca, G., Buchan, S. L., Buck, D., Bull, M., Burns, P. J., Burton-Fanning, S., Byaruhanga, T., Byott, M., Campbell, S., Carabelli, A. M., Cargill, J. S., Carlile, M., Carvalho, S. F., Casey, A., Castigador, A., Catalan, J., Chalker, V., Chaloner, N. J., Chand, M., Chappell, J. G., Charalampous, T., Chatterton, W., Chaudhry, Y., Churcher, C. M., Clark, G., Clarke, P., Cogger, B. J., Cole, K., Collins, J., Colquhoun, R., Connor, T. R., Cook, K. F., Coombes, J., Corden, S., Cormie, C., Cortes, N., Cotic, M., Cotton, S., Cottrell, S., Coupland, L., Cox, M. G., Cox, A., Craine, N., Crawford, L., Cross, A., Crown, M. R., Crudgington, D., Cumley, N., Curran, T., Curran, M. D., da Silva Filipe, A., Dabrera, G., Darby, A. C., Davidson, R. K., Davies, A., Davies, R. M., Davis, T., de Angelis, D., De Lacy, E., de Oliveira Martins, L., de Silva, T. I., Debebe, J., Denton-Smith, R., Dervisevic, S., Dewar, R., Dey, J., Dias, J., Dobie, D., Dorman, M. J., Downing, F., Driscoll, M., du Plessis, L., Duckworth, N., Durham, J., Eastick, K., Easton, L. J., Eccles, R., Edgeworth, J., Edwards, S., Bouzidi, K. E., Eldirdiri, S., Ellaby, N., Elliott, S., Eltringham, G., Ensell, L., Erkiert, M. J., Zamudio, M. E., Essex, S., Evans, J. M., Evans, C., Everson, W., Fairley, D. J., Fallon, K., Fanaie, A., Farr, B. W., Fearn, C., Feltwell, T., Ferguson, L., Fina, L., Flaviani, F., Fleming, V. M., Forrest, S., Foster-Nyarko, E., Foulkes, B. H., Foulser, L., Fragakis, M., Frampton, D., Francois, S., Fraser, C., Freeman, T. M., Fryer, H., Fuchs, M., Fuller, W., Gajee, K., Galai, K., Gallagher, A., Gallagher, E., Gallagher, M. D., Gallis, M., Gaskin, A., Gatica-Wilcox, B., Geidelberg, L., Gemmell, M., Georgana, I., George, R. P., Gifford, L., Gilbert, L., Girgis, S. T., Glaysher, S., Goldstein, E. J., Golubchik, T., Gomes, A. N., Gonçalves, S., Goodfellow, I. G., Goodwin, S., Goudarzi, S., Gourtovaia, M., Graham, C. A., Graham, L., Grant, P. R., Green, L. R., Green, A., Greenaway, J., Gregory, R., Guest, M., Gunson, R. N., Gupta, R. K., Gutierrez, B., Haldenby, S. T., Hamilton, W. L., Hansford, S. E., Haque, T., Harris, K. A., Harrison, I., Harrison, E. M., Hart, J., Hartley, .J. A., Harvey, W. T., Harvey, M., Hassan-Ibrahim, M. O., Heaney, J., Helmer, T., Henderson, J. H., Hesketh, A. R., Hey, J., Heyburn, D., Higginson, E. E., Hill, V., Hill, J. D., Hilson, R. A., Hilvers, E., Holden, M. T. G., Hollis, A., Holmes, C. W., Holmes, N., Holmes, A. H., Hopes, R., Hornsby, H. R., Hosmillo, M., Houlihan, C., Howson-Wells, H. C., Hsu, S. 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G., Cox, A., Craine, N., Crawford, L., Cross, A., Crown, M. R., Crudgington, D., Cumley, N., Curran, T., Curran, M. D., da Silva Filipe, A., Dabrera, G., Darby, A. C., Davidson, R. K., Davies, A., Davies, R. M., Davis, T., de Angelis, D., De Lacy, E., de Oliveira Martins, L., de Silva, T. I., Debebe, J., Denton-Smith, R., Dervisevic, S., Dewar, R., Dey, J., Dias, J., Dobie, D., Dorman, M. J., Downing, F., Driscoll, M., du Plessis, L., Duckworth, N., Durham, J., Eastick, K., Easton, L. J., Eccles, R., Edgeworth, J., Edwards, S., Bouzidi, K. E., Eldirdiri, S., Ellaby, N., Elliott, S., Eltringham, G., Ensell, L., Erkiert, M. J., Zamudio, M. E., Essex, S., Evans, J. M., Evans, C., Everson, W., Fairley, D. J., Fallon, K., Fanaie, A., Farr, B. W., Fearn, C., Feltwell, T., Ferguson, L., Fina, L., Flaviani, F., Fleming, V. M., Forrest, S., Foster-Nyarko, E., Foulkes, B. H., Foulser, L., Fragakis, M., Frampton, D., Francois, S., Fraser, C., Freeman, T. 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R., Hosmillo, M., Houlihan, C., Howson-Wells, H. C., Hsu, S. 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A., Yebra, G., Yew, W. C., Young, G. R., Young, J., Zarebski, A. E., Zhang, P., Modat, M., Hammers, A., Spector, T. D., Steves, C. J., Sudre, C. H., Ourselin, S., and Duncan, E. L.

Abstract

The Delta (B.1.617.2) variant was the predominant UK circulating SARS-CoV-2 strain between May and December 2021. How Delta infection compares with previous variants is unknown. This prospective observational cohort study assessed symptomatic adults participating in the app-based COVID Symptom Study who tested positive for SARS-CoV-2 from May 26 to July 1, 2021 (Delta overwhelmingly the predominant circulating UK variant), compared (1:1, age- and sex-matched) with individuals presenting from December 28, 2020 to May 6, 2021 (Alpha (B.1.1.7) the predominant variant). We assessed illness (symptoms, duration, presentation to hospital) during Alpha- and Delta-predominant timeframes; and transmission, reinfection, and vaccine effectiveness during the Delta-predominant period. 3581 individuals (aged 18 to 100 years) from each timeframe were assessed. The seven most frequent symptoms were common to both variants. Within the first 28 days of illness, some symptoms were more common with Delta versus Alpha infection (including fever, sore throat, and headache) and some vice versa (dyspnoea). Symptom burden in the first week was higher with Delta versus Alpha infection; however, the odds of any given symptom lasting ≥ 7 days was either lower or unchanged. Illness duration ≥ 28 days was lower with Delta versus Alpha infection, though unchanged in unvaccinated individuals. Hospitalisation for COVID-19 was unchanged. The Delta variant appeared more (1.49) transmissible than Alpha. Re-infections were low in all UK regions. Vaccination markedly reduced the risk of Delta infection (by 69-84%). We conclude that COVID-19 from Delta or Alpha infections is similar. The Delta variant is more transmissible than Alpha; however, current vaccines showed good efficacy against disease. This research framework can be useful for future comparisons with new emerging variants. © 2022, The Author(s).

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