Author: "Ceron-Gutierrez, L." - Searchworks@Jio Institute Digital Library Search Results

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33 results on '"Ceron-Gutierrez, L."'

1. High incidence of anti-cytokine autoantibodies in dogs with immune diseases suggests important immuno-regulatory functions

Author: Autran-Martínez, M., Cortes-Acevedo, P., Cerón-Gutiérrez, L., Davies, S., Mendoza-Elvira, E.S., Martínez-Rodríguez, H.A., Liboni, C., Pérez-Valencia, V., Döffinger, R., and Barcenas-Morales, G.
Published: 2019
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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

4. Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2

Author: Collier, D. A., Ferreira, I. A. T. M., Kotagiri, P., Datir, R. P., Lim, E. Y., Touizer, E., Meng, B., Abdullahi, A., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., 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., 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., Krishna, B., Lewis, D., Marsden, J., Nice, F., Okecha, G., Omarjee, O., Perera, M., Potts, M., Richoz, N., Romashova, V., Yarkoni, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., D. D. De Bie E. M., Bunclark, K., Josipovic, M., Mackay, M., Michael, A., Rossi, S., Selvan, M., Spencer, S., Yong, C., Ansaripour, 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., Smith, K. G. C., Bradley, J. R., Ceron-Gutierrez, L., Cortes-Acevedo, P., Barcenas-Morales, G., Linterman, M. A., Mccoy, L. E., Davis, C., Thomson, E., Mckinney, E., Doffinger, R., Wills, M., Gupta, R. K., Collier, Dami A [0000-0001-5446-4423], Datir, Rawlings P [0000-0003-0521-2144], Smith, Kenneth GC [0000-0003-3829-4326], Linterman, Michelle A [0000-0001-6047-1996], McCoy, Laura E [0000-0001-9503-7946], Thomson, Emma [0000-0003-1482-0889], Lyons, Paul A [0000-0001-7035-8997], Gupta, Ravindra K [0000-0001-9751-1808], and Apollo - University of Cambridge Repository
Subjects: Male, 0301 basic medicine, Aging, Secondary, T-Lymphocytes, Antibodies, Viral, Neutralization, 0302 clinical medicine, 80 and over, Medicine, Viral, Neutralizing, Adult, Aged, Aged, 80 and over, Antibodies, Neutralizing, Autoantibodies, B-Lymphocytes, BNT162 Vaccine, COVID-19 Vaccines, Female, Health Personnel, Humans, Immunization, Secondary, Immunoglobulin A, Immunoglobulin Class Switching, Immunoglobulin G, Immunologic Memory, Inflammation, Interferon-gamma, Interleukin-2, Middle Aged, SARS-CoV-2, Somatic Hypermutation, Immunoglobulin, Spike Glycoprotein, Coronavirus, Vaccination, Vaccines, Synthetic, Immunity, Sars-Cov-2, Vaccines, education.field_of_study, Multidisciplinary, biology, Spike Glycoprotein, 030220 oncology & carcinogenesis, Antibody, Population, Article, Antibodies, 03 medical and health sciences, Immune system, Immunoglobulin, education, business.industry, Synthetic, Somatic Hypermutation, Vaccine efficacy, Coronavirus, 030104 developmental biology, Immunization, Immunology, biology.protein, business
Abstract: Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating., Nature, 596 (7872), ISSN:0028-0836, ISSN:1476-4687
Published: 2021

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

6. SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies

Author: Collier, Dami A, De Marco, Anna, Ferreira, Isabella ATM, Meng, Bo, Datir, Rawlings, Walls, Alexandra C, Kemp S, Steven A, Bassi, Jessica, Pinto, Dora, Fregni, Chiara Silacci, Bianchi, Siro, Tortorici, M Alejandra, Bowen, John, Culap, Katja, Jaconi, Stefano, Cameroni, Elisabetta, Snell, Gyorgy, Pizzuto, Matteo S, Pellanda, Alessandra Franzetti, Garzoni, Christian, Riva, Agostino, CITIID-NIHR BioResource COVID-19 Collaboration, Elmer, Anne, Kingston, Nathalie, Graves, Barbara, McCoy, Laura E, Smith, Kenneth Gc, Bradley, John R, Temperton, Nigel, Ceron-Gutierrez L, Lourdes, Barcenas-Morales, Gabriela, COVID-19 Genomics UK (COG-UK) Consortium, Harvey, William, Virgin, Herbert W, Lanzavecchia, Antonio, Piccoli, Luca, Doffinger, Rainer, Wills, Mark, Veesler, David, Corti, Davide, Gupta, Ravindra K, Datir, Rawlings [0000-0003-0521-2144], Smith, Kenneth [0000-0003-3829-4326], Bradley, John [0000-0002-7774-8805], Wills, Mark [0000-0001-8548-5729], and Apollo - University of Cambridge Repository
Subjects: The COVID-19 Genomics UK (COG-UK) consortium, The CITIID-NIHR BioResource COVID-19 Collaboration
Abstract: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission is uncontrolled in many parts of the world, compounded in some areas by higher transmission potential of the B1.1.7 variant now seen in 50 countries. It is unclear whether responses to SARS-CoV-2 vaccines based on the prototypic strain will be impacted by mutations found in B.1.1.7. Here we assessed immune responses following vaccination with mRNA-based vaccine BNT162b2. We measured neutralising antibody responses following a single immunization using pseudoviruses expressing the wild-type Spike protein or the 8 amino acid mutations found in the B.1.1.7 spike protein. The vaccine sera exhibited a broad range of neutralising titres against the wild-type pseudoviruses that were modestly reduced against B.1.1.7 variant. This reduction was also evident in sera from some convalescent patients. Decreased B.1.1.7 neutralisation was also observed with monoclonal antibodies targeting the N-terminal domain (9 out of 10), the Receptor Binding Motif (RBM) (5 out of 31), but not in neutralising mAbs binding outside the RBM. Introduction of the E484K mutation in a B.1.1.7 background to reflect newly emerging viruses in the UK led to a more substantial loss of neutralising activity by vaccine-elicited antibodies and mAbs (19 out of 31) over that conferred by the B.1.1.7 mutations alone. E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b.
Published: 2022
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7. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies

Author: Collier, D. A., De Marco, A., Ferreira, I. A. T. M., Meng, B., Datir, R. P., Walls, A. C., Kemp, S. A., Bassi, J., Pinto, D., Silacci-Fregni, C., Bianchi, S., Tortorici, M. A., Bowen, J., Culap, K., Jaconi, S., Cameroni, E., Snell, G., Pizzuto, M. S., Pellanda, A. F., Garzoni, C., Riva, A., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O'Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Fawke, S., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Pond, N., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Bergamaschi, L., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Grenfell, R., Hinch, A., Huhn, O., Jackson, S., Jarvis, I., Lewis, D., Marsden, J., Nice, F., Okecha, G., Omarjee, O., Perera, M., Richoz, N., Romashova, V., Yarkoni, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Rossi, S., Selvan, M., Spencer, S., Yong, C., Ansaripour, A., Michael, A., Mwaura, L., Patterson, C., Polwarth, G., Polgarova, P., di Stefano, G., Fahey, C., Michel, R., Bong, S. -H., Coudert, J. D., Holmes, E., Allison, J., Butcher, H., Caputo, D., Clapham-Riley, D., Dewhurst, E., Furlong, A., Graves, B., Gray, J., Ivers, T., Kasanicki, M., Le Gresley, E., Linger, R., Meloy, S., Muldoon, F., Ovington, N., Papadia, S., Phelan, I., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Mccoy, L. E., Smith, K. G. C., Bradley, J. R., Temperton, N., Ceron-Gutierrez, L., Barcenas-Morales, G., Robson, S. C., Loman, N. J., Connor, T. R., Golubchik, T., Martinez Nunez, R. T., Ludden, C., Corden, S., Johnston, I., Bonsall, D., Smith, C. P., Awan, A. R., Bucca, G., Torok, M. E., Saeed, K., Prieto, J. A., Jackson, D. K., Hamilton, W. L., Snell, L. B., Moore, C., Harrison, E. M., Goncalves, S., Fairley, D. J., Loose, M. W., Watkins, J., Livett, R., Moses, S., Amato, R., Nicholls, S., Bull, M., Smith, D. L., Barrett, J., Aanensen, D. M., Curran, M. D., Parmar, S., Aggarwal, D., Shepherd, J. G., Parker, M. D., Glaysher, S., Bashton, M., Underwood, A. P., Pacchiarini, N., Loveson, K. F., Carabelli, A. M., Templeton, K. E., Langford, C. F., Sillitoe, J., de Silva, T. I., Wang, D., Kwiatkowski, D., Rambaut, A., O'Grady, J., Cottrell, S., Holden, M. T. G., Thomson, E. C., Osman, H., Andersson, M., Chauhan, A. J., Hassan-Ibrahim, M. O., Lawniczak, M., Alderton, A., Chand, M., Constantinidou, C., Unnikrishnan, M., Darby, A. C., Hiscox, J. A., Paterson, S., Martincorena, I., Robertson, D. L., Volz, E. M., Page, A. J., Pybus, O. G., Bassett, A. R., Ariani, C. V., Spencer Chapman, M. H., K. K., Li, Shah, R. N., Jesudason, N. G., Taha, Y., Mchugh, M. P., Dewar, R., Jahun, A. S., Mcmurray, C., Pandey, S., Mckenna, J. P., Nelson, A., Young, G. R., Mccann, C. M., Elliott, S., Lowe, H., Temperton, B., Roy, S., Price, A., Rey, S., Wyles, M., Rooke, S., Shaaban, S., de Cesare, M., Letchford, L., Silveira, S., Pelosi, E., Wilson-Davies, E., Hosmillo, M., O'Toole, A., Hesketh, A. R., Stark, R., du Plessis, L., Ruis, C., Adams, H., Bourgeois, Y., Michell, S. L., Gramatopoulos, D., Edgeworth, J., Breuer, J., Todd, J. A., Fraser, C., Buck, D., John, M., Kay, G. L., Palmer, S., Peacock, S. J., Heyburn, D., Weldon, D., Robinson, E., Mcnally, A., Muir, P., Vipond, I. B., Boyes, J., Sivaprakasam, V., Salluja, T., Dervisevic, S., Meader, E. J., Park, N. R., Oliver, K., Jeffries, A. R., Ott, S., da Silva Filipe, A., Simpson, D. A., Williams, C., Masoli, J. A. H., Knight, B. A., Jones, C. R., Koshy, C., Ash, A., Casey, A., Bosworth, A., Ratcliffe, L., Xu-McCrae, L., Pymont, H. M., Hutchings, S., Berry, L., Jones, K., Halstead, F., Davis, T., Holmes, C., Iturriza-Gomara, M., Lucaci, A. O., Randell, P. A., Cox, A., Madona, P., Harris, K. A., Brown, J. R., Mahungu, T. W., Irish-Tavares, D., Haque, T., Hart, J., Witele, E., Fenton, M. L., Liggett, S., Graham, C., Swindells, E., Collins, J., Eltringham, G., Campbell, S., Mcclure, P. C., Clark, G., Sloan, T. J., Jones, C., Lynch, J., Warne, B., Leonard, S., Durham, J., Williams, T., Haldenby, S. T., Storey, N., Alikhan, N. -F., Holmes, N., Carlile, M., Perry, M., Craine, N., Lyons, R. A., Beckett, A. H., Goudarzi, S., Fearn, C., Cook, K., Dent, H., Paul, H., Davies, R., Blane, B., Girgis, S. T., Beale, M. A., Bellis, K. L., Dorman, M. J., Drury, E., Kane, L., Kay, S., Mcguigan, S., Nelson, R., Prestwood, L., Rajatileka, S., Batra, R., Williams, R. J., Kristiansen, M., Green, A., Justice, A., Mahanama, A. I. K., Samaraweera, B., Hadjirin, N. F., Quick, J., Poplawski, R., Kermack, L. M., Reynolds, N., Hall, G., Chaudhry, Y., Pinckert, M. L., Georgana, I., Moll, R. J., Thornton, A., Myers, R., Stockton, J., Williams, C. A., Yew, W. C., Trotter, A. J., Trebes, A., MacIntyre-Cockett, G., Birchley, A., Adams, A., Plimmer, A., Gatica-Wilcox, B., Mckerr, C., Hilvers, E., Jones, H., Asad, H., Coombes, J., Evans, J. M., Fina, L., Gilbert, L., Graham, L., Cronin, M., Kumziene-Summerhayes, S., Taylor, S., Jones, S., Groves, D. C., Zhang, P., Gallis, M., Louka, S. F., Starinskij, I., Jackson, C., Gourtovaia, M., Tonkin-Hill, G., Lewis, K., Tovar-Corona, J. M., James, K., Baxter, L., Alam, M. T., Orton, R. J., Hughes, J., Vattipally, S., Ragonnet-Cronin, M., Nascimento, F. F., Jorgensen, D., Boyd, O., Geidelberg, L., Zarebski, A. E., Raghwani, J., Kraemer, M. U. G., Southgate, J., Lindsey, B. B., Freeman, T. M., Keatley, J. -P., Singer, J. B., de Oliveira Martins, L., Yeats, C. A., Abudahab, K., Taylor, B. E. W., Menegazzo, M., Danesh, J., Hogsden, W., Eldirdiri, S., Kenyon, A., Mason, J., Robinson, T. I., Holmes, A., Hartley, J. A., Curran, T., Mather, A. E., Shankar, G., Jones, R., Howe, R., Morgan, S., Wastenge, E., Chapman, M. R., Mookerjee, S., Stanley, R., Smith, W., Peto, T., Eyre, D., Crook, D., Vernet, G., Kitchen, C., Gulliver, H., Merrick, I., Guest, M., Munn, R., Bradley, D. T., Wyatt, T., Beaver, C., Foulser, L., Churcher, C. M., Brooks, E., Smith, K. S., Galai, K., Mcmanus, G. M., Bolt, F., Coll, F., Meadows, L., Attwood, S. W., Davies, A., De Lacy, E., Downing, F., Edwards, S., Scarlett, G. P., Jeremiah, S., Smith, N., Leek, D., Sridhar, S., Forrest, S., Cormie, C., Gill, H. K., Dias, J., Higginson, E. E., Maes, M., Young, J., Wantoch, M., Jamrozy, D., Lo, S., Patel, M., Hill, V., Bewshea, C. M., Ellard, S., Auckland, C., Harrison, I., Bishop, C., Chalker, V., Richter, A., Beggs, A., Best, A., Percival, B., Mirza, J., Megram, O., Mayhew, M., Crawford, L., Ashcroft, F., Moles-Garcia, E., Cumley, N., Hopes, R., Asamaphan, P., Niebel, M. O., Gunson, R. N., Bradley, A., Maclean, A., Mollett, G., Blacow, R., Bird, P., Helmer, T., Fallon, K., Tang, J., Hale, A. D., Macfarlane-Smith, L. R., Harper, K. L., Carden, H., Machin, N. W., Jackson, K. A., Ahmad, S. S. Y., George, R. P., Turtle, L., O'Toole, E., Watts, J., Breen, C., Cowell, A., Alcolea-Medina, A., Charalampous, T., Patel, A., Levett, L. J., Heaney, J., Rowan, A., Taylor, G. P., Shah, D., Atkinson, L., Lee, J. C. D., Westhorpe, A. P., Jannoo, R., Lowe, H. L., Karamani, A., Ensell, L., Chatterton, W., Pusok, M., Dadrah, A., Symmonds, A., Sluga, G., Molnar, Z., Baker, P., Bonner, S., Essex, S., Barton, E., Padgett, D., Scott, G., Greenaway, J., Payne, B. A. I., Burton-Fanning, S., Waugh, S., Raviprakash, V., Sheriff, N., Blakey, V., Williams, L. -A., Moore, J., Stonehouse, S., Smith, L., Davidson, R. K., Bedford, L., Coupland, L., Wright, V., Chappell, J. G., Tsoleridis, T., Ball, J., Khakh, M., Fleming, V. M., Lister, M. M., Howson-Wells, H. C., Boswell, T., Joseph, A., Willingham, I., Duckworth, N., Walsh, S., Wise, E., Moore, N., Mori, M., Cortes, N., Kidd, S., Williams, R., Gifford, L., Bicknell, K., Wyllie, S., Lloyd, A., Impey, R., Malone, C. S., Cogger, B. J., Levene, N., Monaghan, L., Keeley, A. J., Partridge, D. G., Raza, M., Evans, C., Johnson, K., Betteridge, E., Farr, B. W., Goodwin, S., Quail, M. A., Scott, C., Shirley, L., Thurston, S. A. J., Rajan, D., Bronner, I. F., Aigrain, L., Redshaw, N. M., Lensing, S. V., Mccarthy, S., Makunin, A., Balcazar, C. E., Gallagher, M. D., Williamson, K. A., Stanton, T. D., Michelsen, M. L., Warwick-Dugdale, J., Manley, R., Farbos, A., Harrison, J. W., Sambles, C. M., Studholme, D. J., Lackenby, A., Mbisa, T., Platt, S., Miah, S., Bibby, D., Manso, C., Hubb, J., Dabrera, G., Ramsay, M., Bradshaw, D., Schaefer, U., Groves, N., Gallagher, E., Lee, D., Williams, D., Ellaby, N., Hartman, H., Manesis, N., Patel, V., Ledesma, J., Twohig, K. A., Allara, E., Pearson, C., Cheng, J. K. J., Bridgewater, H. E., Frost, L. R., Taylor-Joyce, G., Brown, P. E., Tong, L., Broos, A., Mair, D., Nichols, J., Carmichael, S. N., Smollett, K. L., Nomikou, K., Aranday-Cortes, E., Johnson, N., Nickbakhsh, S., Vamos, E. E., Hughes, M., Rainbow, L., Eccles, R., Nelson, C., Whitehead, M., Gregory, R., Gemmell, M., Wierzbicki, C., Webster, H. J., Fisher, C. L., Signell, A. W., Betancor, G., Wilson, H. D., Nebbia, G., Flaviani, F., Cerda, A. C., Merrill, T. V., Wilson, R. E., Cotic, M., Bayzid, N., Thompson, T., Acheson, E., Rushton, S., O'Brien, S., Baker, D. J., Rudder, S., Aydin, A., Sang, F., Debebe, J., Francois, S., Vasylyeva, T. I., Zamudio, M. E., Gutierrez, B., Marchbank, A., Maksimovic, J., Spellman, K., Mccluggage, K., Morgan, M., Beer, R., Afifi, S., Workman, T., Fuller, W., Bresner, C., Angyal, A., Green, L. R., Parsons, P. J., Tucker, R. M., Brown, R., Whiteley, M., Bonfield, J., Puethe, C., Whitwham, A., Liddle, J., Rowe, W., Siveroni, I., Le-Viet, T., Gaskin, A., Johnson, R., Abnizova, I., Ali, M., Allen, L., Anderson, R., Ariani, C., Austin-Guest, S., Bala, S., Bassett, A., Battleday, K., Beal, J., Beale, M., Bellany, S., Bellerby, T., Bellis, K., Berger, D., Berriman, M., Bevan, P., Binley, S., Bishop, J., Blackburn, K., Boughton, N., Bowker, S., Brendler-Spaeth, T., Bronner, I., Brooklyn, T., Buddenborg, S. K., Bush, R., Caetano, C., Cagan, A., Carter, N., Cartwright, J., Monteiro, T. C., Chapman, L., Chillingworth, T. -J., Clapham, P., Clark, R., Clarke, A., Clarke, C., Cole, D., Cook, E., Coppola, M., Cornell, L., Cornwell, C., Corton, C., Crackett, A., Cranage, A., Craven, H., Craw, S., Crawford, M., Cutts, T., Dabrowska, M., Davies, M., Dawson, J., Day, C., Densem, A., Dibling, T., Dockree, C., Dodd, D., Dogga, S., Dougherty, M., Dove, A., Drummond, L., Dudek, M., Durrant, L., Easthope, E., Eckert, S., Ellis, P., Farr, B., Fenton, M., Ferrero, M., Flack, N., Fordham, H., Forsythe, G., Francis, M., Fraser, A., Freeman, A., Galvin, A., Garcia-Casado, M., Gedny, A., Girgis, S., Glover, J., Gould, O., Gray, A., Gray, E., Griffiths, C., Gu, Y., Guerin, F., Hamilton, W., Hanks, H., Harrison, E., Harrott, A., Harry, E., Harvison, J., Heath, P., Hernandez-Koutoucheva, A., Hobbs, R., Holland, D., Holmes, S., Hornett, G., Hough, N., Huckle, L., Hughes-Hallet, L., Hunter, A., Inglis, S., Iqbal, S., Jackson, A., Jackson, D., Verdejo, C. J., Jones, M., Kallepally, K., Kay, K., Keatley, J., Keith, A., King, A., Kitchin, L., Kleanthous, M., Klimekova, M., Korlevic, P., Krasheninnkova, K., Lane, G., Langford, C., Laverack, A., Law, K., Lensing, S., Lewis-Wade, A., Lin, Q., Lindsay, S., Linsdell, S., Long, R., Lovell, J., Mack, J., Maddison, M., Mamun, I., Mansfield, J., Marriott, N., Martin, M., Mayho, M., Mcclintock, J., Mchugh, S., Mcminn, L., Meadows, C., Mobley, E., Moll, R., Morra, M., Morrow, L., Murie, K., Nash, S., Nathwani, C., Naydenova, P., Neaverson, A., Nerou, E., Nicholson, J., Nimz, T., Noell, G. G., O'Meara, S., Ohan, V., Olney, C., Ormond, D., Oszlanczi, A., Pang, Y. F., Pardubska, B., Park, N., Parmar, A., Patel, G., Payne, M., Peacock, S., Petersen, A., Plowman, D., Preston, T., Quail, M., Rance, R., Rawlings, S., Redshaw, N., Reynolds, J., Reynolds, M., Rice, S., Richardson, M., Roberts, C., Robinson, K., Robinson, M., Robinson, D., Rogers, H., Rojo, E. M., Roopra, D., Rose, M., Rudd, L., Sadri, R., Salmon, N., Saul, D., Schwach, F., Seekings, P., Simms, A., Sinnott, M., Sivadasan, S., Siwek, B., Sizer, D., Skeldon, K., Skelton, J., Slater-Tunstill, J., Sloper, L., Smerdon, N., Smith, C., Smith, J., Smith, K., Smith, M., Smith, S., Smith, T., Sneade, L., Soria, C. D., Sousa, C., Souster, E., Sparkes, A., Spencer-Chapman, M., Squares, J., Steed, C., Stickland, T., Still, I., Stratton, M., Strickland, M., Swann, A., Swiatkowska, A., Sycamore, N., Swift, E., Symons, E., Szluha, S., Taluy, E., Tao, N., Taylor, K., Thompson, S., Thompson, M., Thomson, M., Thomson, N., Thurston, S., Toombs, D., Topping, B., Tovar-Corona, J., Ungureanu, D., Uphill, J., Urbanova, J., Van, P. J., Vancollie, V., Voak, P., Walker, D., Walker, M., Waller, M., Ward, G., Weatherhogg, C., Webb, N., Wells, A., Wells, E., Westwood, L., Whipp, T., Whiteley, T., Whitton, G., Widaa, S., Williams, M., Wilson, M., Wright, S., Harvey, W., Virgin, H. W., Lanzavecchia, A., Piccoli, L., Doffinger, R., Wills, M., Veesler, D., Corti, D., and Gupta, R. K.
Subjects: 0301 basic medicine, Male, Models, Molecular, Passive, Antibodies, Viral, Neutralization, 0302 clinical medicine, Models, Monoclonal, 80 and over, Viral, Neutralizing antibody, Neutralizing, Aged, 80 and over, Vaccines, Vaccines, Synthetic, Multidisciplinary, biology, Antibodies, Monoclonal, C500, Middle Aged, C700, Spike Glycoprotein, Vaccination, Spike Glycoprotein, Coronavirus, Female, Angiotensin-Converting Enzyme 2, Antibody, Aged, Antibodies, Neutralizing, COVID-19, COVID-19 Vaccines, HEK293 Cells, Humans, Immune Evasion, Immunization, Passive, Mutation, Neutralization Tests, SARS-CoV-2, medicine.drug_class, B100, Monoclonal antibody, Antibodies, Virus, 03 medical and health sciences, Immune system, medicine, COVID-19 Serotherapy, QR355, Synthetic, Molecular, Virology, Coronavirus, 030104 developmental biology, Immunization, biology.protein, 030217 neurology & neurosurgery
Abstract: Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant1, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b22. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.
Published: 2021

8. SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies

Author: Isabella Ferreira, Herbert W. Virgin, M. Alejandra Tortorici, Christian Garzoni, Laura E. McCoy, Elisabetta Cameroni, Rainer Doffinger, Bo Meng, Dami A. Collier, Nathalie Kingston, Siro Bianchi, Ceron Ceron-Gutierrez L, Gyorgy Snell, John Bradley, John E. Bowen, Mark R. Wills, Davide Corti, David Veesler, Jessica Bassi, Alexandra C. Walls, Dora Pinto, Ravindra K. Gupta, Alessandra Franzetti Pellanda, Steven A. Kemp S, Barbara J. Graves, Katja Culap, Kenneth G. C. Smith, Luca Piccoli, Antonio Lanzavecchia, Matteo Samuele Pizzuto, Chiara Silacci Fregni, Anna De Marco, Anne Elmer, Stefano Jaconi, Gabriela Barcenas-Morales, Agostino Riva, and Rawlings Datir
Subjects: Mutation, biology, SARS-CoV-2, medicine.drug_class, COVID-19, Monoclonal antibody, medicine.disease_cause, Virology, Article, Neutralization, Vaccination, Immune system, variant, Immunization, antibody, vaccine, medicine, biology.protein, Potency, mutation, Antibody, neutralising antibodies
Abstract: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission is uncontrolled in many parts of the world, compounded in some areas by higher transmission potential of the B1.1.7 variant now seen in 50 countries. It is unclear whether responses to SARS-CoV-2 vaccines based on the prototypic strain will be impacted by mutations found in B.1.1.7. Here we assessed immune responses following vaccination with mRNA-based vaccine BNT162b2. We measured neutralising antibody responses following a single immunization using pseudoviruses expressing the wild-type Spike protein or the 8 amino acid mutations found in the B.1.1.7 spike protein. The vaccine sera exhibited a broad range of neutralising titres against the wild-type pseudoviruses that were modestly reduced against B.1.1.7 variant. This reduction was also evident in sera from some convalescent patients. Decreased B.1.1.7 neutralisation was also observed with monoclonal antibodies targeting the N-terminal domain (9 out of 10), the Receptor Binding Motif (RBM) (5 out of 31), but not in neutralising mAbs binding outside the RBM. Introduction of the E484K mutation in a B.1.1.7 background to reflect newly emerging viruses in the UK led to a more substantial loss of neutralising activity by vaccine-elicited antibodies and mAbs (19 out of 31) over that conferred by the B.1.1.7 mutations alone. E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b.
Published: 2021

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

Author: Collier, Dami A., De Marco, Anna, Ferreira, Isabella A.T.M., Meng, Bo, Datir, Rawlings, Walls, Alexandra C., Kemp S, Steven A., Bassi, Jessica, Pinto, Dora, Fregni, Chiara Silacci, Bianchi, Siro, Tortorici, M. Alejandra, Bowen, John, Culap, Katja, Jaconi, Stefano, Cameroni, Elisabetta, Snell, Gyorgy, Pizzuto, Matteo S., Pellanda, Alessandra Franzetti, Garzoni, Christian, Riva, Agostino, Elmer, Anne, Kingston, Nathalie, Graves, Barbara, McCoy, Laura E., Smith, Kenneth G. C., Bradley, John R., Temperton, Nigel J., Lourdes Ceron-Gutierrez, L., Barcenas-Morales, Gabriela, Harvey, William, Virgin, Herbert W., Lanzavecchia, Antonio, Piccoli, Luca, Doffinger, Rainer, Wills, Mark, Veesler, David, Corti, Davide, Gupta, Ravindra K., Collier, Dami A., De Marco, Anna, Ferreira, Isabella A.T.M., Meng, Bo, Datir, Rawlings, Walls, Alexandra C., Kemp S, Steven A., Bassi, Jessica, Pinto, Dora, Fregni, Chiara Silacci, Bianchi, Siro, Tortorici, M. Alejandra, Bowen, John, Culap, Katja, Jaconi, Stefano, Cameroni, Elisabetta, Snell, Gyorgy, Pizzuto, Matteo S., Pellanda, Alessandra Franzetti, Garzoni, Christian, Riva, Agostino, Elmer, Anne, Kingston, Nathalie, Graves, Barbara, McCoy, Laura E., Smith, Kenneth G. C., Bradley, John R., Temperton, Nigel J., Lourdes Ceron-Gutierrez, L., Barcenas-Morales, Gabriela, Harvey, William, Virgin, Herbert W., Lanzavecchia, Antonio, Piccoli, Luca, Doffinger, Rainer, Wills, Mark, Veesler, David, Corti, Davide, and Gupta, Ravindra K.
Abstract: SARS-CoV-2 transmission is uncontrolled in many parts of the world, compounded in some areas by higher transmission potential of the B1.1.7 variant1 now reported in 94 countries. It is unclear whether responses to SARS-CoV-2 vaccines based on the prototypic strain will be impacted by mutations found in B.1.1.7. Here we assessed immune responses following vaccination with mRNA-based vaccine BNT162b22. We measured neutralising antibody responses following first and second immunisations using pseudoviruses expressing the wild-type Spike protein or the 8 amino acid mutations found in the B.1.1.7 spike protein. The vaccine sera exhibited a broad range of neutralising titres against the wild-type pseudoviruses that were modestly reduced against B.1.1.7 variant. This reduction was also evident in sera from some convalescent patients. Decreased B.1.1.7 neutralisation was also observed with monoclonal antibodies targeting the N-terminal domain (9 out of 10), the RBM (5 out of 31), but not in RBD neutralising mAbs binding outside the RBM. Introduction of the E484K mutation in a B.1.1.7 background to reflect a newly emergent Variant of Concern (VOC 202102/02) led to a more substantial loss of neutralising activity by vaccine-elicited antibodies and mAbs (19 out of 31) over that conferred by the B.1.1.7 mutations alone. E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b.
Published: 2021

10. Critical care workers have lower seroprevalence of SARS-CoV-2 IgG compared with non-patient facing staff in first wave of COVID19

Author: Baxendale, H.E., primary, Wells, D., additional, Gronlund, J., additional, Nadesalingam, A., additional, Paloniemi, M., additional, Carnell, G., additional, Tonks, P., additional, Ceron-Gutierrez, L., additional, Ebrahimi, S., additional, Sayer, A., additional, Briggs, J.A.G., additional, Xiong, X., additional, Nathan, J.A., additional, Grice, G.L., additional, James, L.C., additional, Luptak, J., additional, Pai, S., additional, Heeney, J.L., additional, and Doffinger, R., additional
Published: 2020
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11. Disseminated Mycobacterium tuberculosis infection due to interferon γ deficiency. Response to replacement therapy

Author: Seneviratne, Suranjith Luke, Doffinger, Rainer, Macfarlane, John, Ceron-Gutierrez, L, Kashipaz, M R Amel, Robbins, A, Patel, T, Powell, P T, Kumararatne, D S, and Powell, Richard J
Published: 2007

12. Disseminated Mycobacterium tuberculosis infection due to interferon (gamma) deficiency. Response to replacement therapy

Author: Seneviratne, Suranjith Luke, Doffinger, Rainer, Macfarlane, John, Ceron-Gutierrez, L., Kashipaz, M.R. Amel, Robbins, A., Patel, T., Powell, P.T., Kumararatne, D.S., and Powell, Richard J.
Subjects: Mycobacterium tuberculosis -- Case studies, Mycobacterium tuberculosis -- Care and treatment, Mycobacterium tuberculosis -- Diagnosis, Interferon gamma -- Abnormalities, Interferon gamma -- Case studies, Drug therapy -- Patient outcomes, Health
Published: 2007

13. THU0043 Targeted medicine: therapeutic use of functional cytokine assays in complex inflammatory arthritis

Author: Htut, EEP, primary, Ceron-Gutierrez, L, additional, Doffinger, R, additional, and Rees, J, additional
Published: 2017
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14. IRF8 mutations and human dendritic-cell immunodeficiency

Author: Hambleton S, Salem S, Bustamante J, Bigley V, Boisson-Dupuis S, Azevedo J, Fortin A, Haniffa M, Ceron-Gutierrez L, Bacon CM, Menon G, Trouillet C, McDonald D, Carey P, Ginhoux F, Alsina L, Zumwalt TJ, Kong XF, Kumararatne D, Butler K, Hubeau M, Feinberg J, Al-Muhsen S, Cant A, Abel L, Chaussabel D, Doffinger R, Talesnik E, Grumach A, Duarte A, Abarca K, Moraes-Vasconcelos D, Burk D, Berghuis A, Geissmann F, Collin M, Casanova JL, and Gros P
Published: 2011

15. Disseminated Mycobacterium tuberculosis infection due to interferon deficiency. Response to replacement therapy

Author: Luke Seneviratne, S., primary, Doffinger, R., additional, Macfarlane, J., additional, Ceron-Gutierrez, L, additional, Amel Kashipaz, M R, additional, Robbins, A, additional, Patel, T, additional, Powell, P T, additional, Kumararatne, D S, additional, and Powell, R. J, additional
Published: 2007
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16. Disseminated Mycobacterium tuberculosis Infection Due to IFN-γ Deficiency. Response to Replacement Therapy

Author: Seneviratne, S.L., Macfarlane, J., Doffinger, R., Ceron-Gutierrez, L., Kashipaz, M. Amel, Robbins, A., Patel, T., Powell, P.T., Kumararatne, D.S., and Powell, R.J.
Published: 2006
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17. Neutralizing Autoantibodies against Interleukin-10 in Inflammatory Bowel Disease.

Author: Griffin H, Ceron-Gutierrez L, Gharahdaghi N, Ebrahimi S, Davies S, Loo PS, Szabo A, Williams E, Mukhopadhyay A, McLoughlin L, Irwin S, Travis S, Klenerman P, Bunn S, Cant AJ, Hambleton S, Uhlig HH, and Doffinger R
Subjects: Female, Humans, Infant, Male, B-Lymphocytes drug effects, B-Lymphocytes immunology, Immunoglobulins, Intravenous administration & dosage, Glucocorticoids administration & dosage, Drug Therapy, Combination methods, Infliximab administration & dosage, Child, Preschool, Severity of Illness Index, Treatment Outcome, Antibodies, Neutralizing immunology, Antibodies, Neutralizing blood, Autoantibodies immunology, Autoantibodies blood, Inflammatory Bowel Diseases blood, Inflammatory Bowel Diseases diagnosis, Inflammatory Bowel Diseases drug therapy, Inflammatory Bowel Diseases immunology, Interleukin-10 immunology
Abstract: We discovered high-titer neutralizing autoantibodies against interleukin-10 in a child with infantile-onset inflammatory bowel disease (IBD), a phenocopy of inborn errors of interleukin-10 signaling. After B-cell-depletion therapy and an associated decrease in the anti-interleukin-10 titer, conventional IBD therapy could be withdrawn. A second child with neutralizing anti-interleukin-10 autoantibodies had a milder course of IBD and has been treated without B-cell depletion. We conclude that neutralizing anti-interleukin-10 autoantibodies may be a causative or modifying factor in IBD, with potential implications for therapy. (Funded by the National Institute for Health and Care Research and others.)., (Copyright © 2024 Massachusetts Medical Society.)
Published: 2024
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18. Atypical B cells and impaired SARS-CoV-2 neutralization following heterologous vaccination in the elderly.

Author: Ferreira IATM, Lee CYC, Foster WS, Abdullahi A, Dratva LM, Tuong ZK, Stewart BJ, Ferdinand JR, Guillaume SM, Potts MOP, Perera M, Krishna BA, Peñalver A, Cabantous M, Kemp SA, Ceron-Gutierrez L, Ebrahimi S, Lyons P, Smith KGC, Bradley J, Collier DA, McCoy LE, van der Klaauw A, Thaventhiran JED, Farooqi IS, Teichmann SA, MacAry PA, Doffinger R, Wills MR, Linterman MA, Clatworthy MR, and Gupta RK
Subjects: Aged, Humans, COVID-19 Vaccines, ChAdOx1 nCoV-19, SARS-CoV-2, Vaccination, COVID-19 prevention & control
Abstract: Suboptimal responses to a primary vaccination course have been reported in the elderly, but there is little information regarding the impact of age on responses to booster third doses. Here, we show that individuals 70 years or older (median age 73, range 70-75) who received a primary two-dose schedule with AZD1222 and booster third dose with mRNA vaccine achieve significantly lower neutralizing antibody responses against SARS-CoV-2 spike pseudotyped virus compared with those younger than 70 (median age 66, range 54-69) at 1 month post booster. Impaired neutralization potency and breadth post third dose in the elderly is associated with circulating "atypical" spike-specific B cells expressing CD11c and FCRL5. However, when considering individuals who received three doses of mRNA vaccine, we did not observe differences in neutralization or enrichment in atypical B cells. This work highlights the finding that AdV and mRNA COVID-19 vaccine formats differentially instruct the memory B cell response., Competing Interests: Declaration of interests R.K.G. has received honoraria for consulting and educational activities from Gilead, GSK, Janssen, and Moderna., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2023
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19. Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade.

Author: Yam-Puc JC, Hosseini Z, Horner EC, Gerber PP, Beristain-Covarrubias N, Hughes R, Lulla A, Rust M, Boston R, Ali M, Fischer K, Simmons-Rosello E, O'Reilly M, Robson H, Booth LH, Kahanawita L, Correa-Noguera A, Favara D, Ceron-Gutierrez L, Keller B, Craxton A, Anderson GSF, Sun XM, Elmer A, Saunders C, Bermperi A, Jose S, Kingston N, Mulroney TE, Piñon LPG, Chapman MA, Grigoriadou S, MacFarlane M, Willis AE, Patil KR, Spencer S, Staples E, Warnatz K, Buckland MS, Hollfelder F, Hyvönen M, Döffinger R, Parkinson C, Lear S, Matheson NJ, and Thaventhiran JED
Subjects: Humans, Immune Checkpoint Inhibitors, COVID-19 Vaccines, SARS-CoV-2, Vaccination, Antigen-Antibody Complex, Antibodies, Viral, Immunity, Humoral, COVID-19 prevention & control
Abstract: Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination., (© 2023. The Author(s).)
Published: 2023
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20. Accelerated waning of the humoral response to COVID-19 vaccines in obesity.

Author: van der Klaauw AA, Horner EC, Pereyra-Gerber P, Agrawal U, Foster WS, Spencer S, Vergese B, Smith M, Henning E, Ramsay ID, Smith JA, Guillaume SM, Sharpe HJ, Hay IM, Thompson S, Innocentin S, Booth LH, Robertson C, McCowan C, Kerr S, Mulroney TE, O'Reilly MJ, Gurugama TP, Gurugama LP, Rust MA, Ferreira A, Ebrahimi S, Ceron-Gutierrez L, Scotucci J, Kronsteiner B, Dunachie SJ, Klenerman P, Park AJ, Rubino F, Lamikanra AA, Stark H, Kingston N, Estcourt L, Harvala H, Roberts DJ, Doffinger R, Linterman MA, Matheson NJ, Sheikh A, Farooqi IS, and Thaventhiran JED
Subjects: Humans, COVID-19 Vaccines, Longitudinal Studies, Prospective Studies, SARS-CoV-2, Obesity epidemiology, Antibodies, Neutralizing, Antibodies, Viral, Vaccination, Obesity, Morbid, COVID-19 epidemiology, COVID-19 prevention & control
Abstract: Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI > 40 kg/m 2 ) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60-1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5-24.9 kg/m 2 ). We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI (P = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies., (© 2023. The Author(s).)
Published: 2023
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21. Author Correction: Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies.

Author: Collier DA, De Marco A, Ferreira IATM, Meng B, Datir RP, Walls AC, Kemp SA, Bassi J, Pinto D, Silacci-Fregni C, Bianchi S, Tortorici MA, Bowen J, Culap K, Jaconi S, Cameroni E, Snell G, Pizzuto MS, Pellanda AF, Garzoni C, Riva A, Elmer A, Kingston N, Graves B, McCoy LE, Smith KGC, Bradley JR, Temperton N, Ceron-Gutierrez L, Barcenas-Morales G, Harvey W, Virgin HW, Lanzavecchia A, Piccoli L, Doffinger R, Wills M, Veesler D, Corti D, and Gupta RK
Published: 2022
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22. Author Correction: SARS-CoV-2 evolution during treatment of chronic infection.

Author: Kemp SA, Collier DA, Datir RP, Ferreira IATM, Gayed S, Jahun A, Hosmillo M, Rees-Spear C, Mlcochova P, Lumb IU, Roberts DJ, Chandra A, Temperton N, Sharrocks K, Blane E, Modis Y, Leigh KE, Briggs JAG, van Gils MJ, Smith KGC, Bradley JR, Smith C, Doffinger R, Ceron-Gutierrez L, Barcenas-Morales G, Pollock DD, Goldstein RA, Smielewska A, Skittrall JP, Gouliouris T, Goodfellow IG, Gkrania-Klotsas E, Illingworth CJR, McCoy LE, and Gupta RK
Published: 2022
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23. Defective Interferon-Gamma Production Is Common in Chronic Pulmonary Aspergillosis.

Author: Colombo SAP, Hashad R, Denning DW, Kumararatne DS, Ceron-Gutierrez L, Barcenas-Morales G, MacDonald AS, Harris C, Doffinger R, and Kosmidis C
Subjects: Cytokines, Female, Humans, Interleukin-12, Interleukin-18, Lipopolysaccharides, Male, Middle Aged, Tumor Necrosis Factor-alpha, beta-Glucans, Interferon-gamma, Pulmonary Aspergillosis
Abstract: Background: Immune defects in chronic pulmonary aspergillosis (CPA) are poorly characterized. We compared peripheral blood cytokine profiles in patients with CPA versus healthy controls and explored the relationship with disease severity., Methods: Interferon-gamma (IFNγ), interleukin (IL)-17, tumor necrosis factor-α, IL-6, IL-12, and IL-10 were measured after in vitro stimulation of whole blood with lipopolysaccharide (LPS), phytohemagglutinin, β-glucan, zymosan (ZYM), IL-12 or IL-18, and combinations. Clinical parameters and mortality were correlated with cytokine production., Results: Cytokine profiles were evaluated in 133 patients (57.1% male, mean age 61 years). In comparison to controls, patients with CPA had significantly reduced production of IFNγ in response to stimulation with β-glucan + IL-12 (312 vs 988 pg/mL), LPS + IL-12 (252 vs 1033 pg/mL), ZYM + IL-12 (996 vs 2347 pg/mL), and IL-18 + IL-12 (7193 vs 12 330 pg/mL). Age >60 (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.00-2.91; P = .05) and chronic obstructive pulmonary disease (HR, 1.69; 95% CI, 1.03-2.78; P = .039) were associated with worse survival, whereas high IFNγ production in response to beta-glucan + IL-12 stimulation (HR, 0.48; 95% CI, .25-0.92; P = .026) was associated with reduced mortality., Conclusions: Patients with CPA show impaired IFNγ production in peripheral blood in response to stimuli. Defective IFNγ production ability correlates with worse outcomes. Immunotherapy with IFNγ could be beneficial for patients showing impaired IFNγ production in CPA., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
Published: 2022
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24. Critical Care Workers Have Lower Seroprevalence of SARS-CoV-2 IgG Compared with Non-patient Facing Staff in First Wave of COVID19.

Author: Baxendale HE, Wells D, Gronlund J, Nadesalingham A, Paloniemi M, Carnell G, Tonks P, Ceron-Gutierrez L, Ebrahimi S, Sayer A, Briggs JAG, Ziong X, Nathan JA, Grice G, James LC, Luptak J, Pai S, Heeney JL, Lear S, and Doffinger R
Abstract: Introduction: In early 2020, at first surge of the coronavirus disease 2019 (COVID-19) pandemic, many health care workers (HCW) were re-deployed to critical care environments to support intensive care teams looking after patients with severe COVID-19. There was considerable anxiety of increased risk of COVID-19 for these staff. To determine whether critical care HCW were at increased risk of hospital acquired infection, we explored the relationship between workplace, patient facing role and evidence of immune exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within a quaternary hospital providing a regional critical care response. Routine viral surveillance was not available at this time., Methods: We screened over 500 HCW (25% of the total workforce) for history of clinical symptoms of possible COVID19, assigning a symptom severity score, and quantified SARS-CoV-2 serum antibodies as evidence of immune exposure to the virus., Results: Whilst 45% of the cohort reported symptoms that they consider may have represented COVID-19, 14% had evidence of immune exposure. Staffs in patient facing critical care roles were least likely to be seropositive (9%) and staff working in non-patient facing roles most likely to be seropositive (22%). Anosmia and fever were the most discriminating symptoms for seropositive status. Older males presented with more severe symptoms. Of the 12 staff screened positive by nasal swab (10 symptomatic), 3 showed no evidence of seroconversion in convalescence., Conclusions: Patient facing staff working in critical care do not appear to be at increased risk of hospital acquired infection however the risk of nosocomial infection from non-patient facing staff may be more significant than previous recognised. Most symptoms ascribed to possible COVID-19 were found to have no evidence of immune exposure however seroprevalence may underrepresent infection frequency. Older male staff were at the greatest risk of more severe symptoms., Competing Interests: Conflict of interest None to declare., (© 2021 Helen E. Baxendale, David Wells, Jessica Gronlund, Angalee Nadesalingham, Mina Paloniemi, George Carnell, Paul Tonks, Lourdes Ceron-Gutierrez, Soraya Ebrahimi, Ashleigh Sayer, John A.G. Briggs, Xiaoli Ziong, James A Nathan, Guinevere Grice, Leo C James, Jakub Luptak, Sumita Pai, Jonathan L Heeney, Sara Lear, Rainer Doffinger, published by Sciendo.)
Published: 2021
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25. SARS-CoV-2 Spike Protein Stabilized in the Closed State Induces Potent Neutralizing Responses.

Author: Carnell GW, Ciazynska KA, Wells DA, Xiong X, Aguinam ET, McLaughlin SH, Mallery D, Ebrahimi S, Ceron-Gutierrez L, Asbach B, Einhauser S, Wagner R, James LC, Doffinger R, Heeney JL, and Briggs JAG
Subjects: Animals, COVID-19 Vaccines chemistry, COVID-19 Vaccines immunology, HEK293 Cells, Humans, Mice, Protein Stability, Angiotensin-Converting Enzyme 2 chemistry, Angiotensin-Converting Enzyme 2 immunology, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing immunology, Antibodies, Viral chemistry, Antibodies, Viral immunology, Epitopes chemistry, Epitopes immunology, SARS-CoV-2 chemistry, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus immunology
Abstract: The majority of SARS-CoV-2 vaccines in use or advanced development are based on the viral spike protein (S) as their immunogen. S is present on virions as prefusion trimers in which the receptor binding domain (RBD) is stochastically open or closed. Neutralizing antibodies have been described against both open and closed conformations. The long-term success of vaccination strategies depends upon inducing antibodies that provide long-lasting broad immunity against evolving SARS-CoV-2 strains. Here, we have assessed the results of immunization in a mouse model using an S protein trimer stabilized in the closed state to prevent full exposure of the receptor binding site and therefore interaction with the receptor. We compared this with other modified S protein constructs, including representatives used in current vaccines. We found that all trimeric S proteins induced a T cell response and long-lived, strongly neutralizing antibody responses against 2019 SARS-CoV-2 and variants of concern P.1 and B.1.351. Notably, the protein binding properties of sera induced by the closed spike differed from those induced by standard S protein constructs. Closed S proteins induced more potent neutralizing responses than expected based on the degree to which they inhibit interactions between the RBD and ACE2. These observations suggest that closed spikes recruit different, but equally potent, immune responses than open spikes and that this is likely to include neutralizing antibodies against conformational epitopes present in the closed conformation. We suggest that closed spikes, together with their improved stability and storage properties, may be a valuable component of refined, next-generation vaccines. IMPORTANCE Vaccines in use against SARS-CoV-2 induce immune responses against the spike protein. There is intense interest in whether the antibody response induced by vaccines will be robust against new variants, as well as in next-generation vaccines for use in previously infected or immunized individuals. We assessed the use as an immunogen of a spike protein engineered to be conformationally stabilized in the closed state where the receptor binding site is occluded. Despite occlusion of the receptor binding site, the spike induces potently neutralizing sera against multiple SARS-CoV-2 variants. Antibodies are raised against a different pattern of epitopes to those induced by other spike constructs, preferring conformational epitopes present in the closed conformation. Closed spikes, or mRNA vaccines based on their sequence, can be a valuable component of next-generation vaccines.
Published: 2021
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26. SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies.

Author: Collier DA, De Marco A, Ferreira IATM, Meng B, Datir R, Walls AC, Kemp S SA, Bassi J, Pinto D, Fregni CS, Bianchi S, Tortorici MA, Bowen J, Culap K, Jaconi S, Cameroni E, Snell G, Pizzuto MS, Pellanda AF, Garzoni C, Riva A, Elmer A, Kingston N, Graves B, McCoy LE, Smith KG, Bradley JR, Temperton N, Ceron-Gutierrez L L, Barcenas-Morales G, Harvey W, Virgin HW, Lanzavecchia A, Piccoli L, Doffinger R, Wills M, Veesler D, Corti D, and Gupta RK
Abstract: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission is uncontrolled in many parts of the world, compounded in some areas by higher transmission potential of the B1.1.7 variant now seen in 50 countries. It is unclear whether responses to SARS-CoV-2 vaccines based on the prototypic strain will be impacted by mutations found in B.1.1.7. Here we assessed immune responses following vaccination with mRNA-based vaccine BNT162b2. We measured neutralising antibody responses following a single immunization using pseudoviruses expressing the wild-type Spike protein or the 8 amino acid mutations found in the B.1.1.7 spike protein. The vaccine sera exhibited a broad range of neutralising titres against the wild-type pseudoviruses that were modestly reduced against B.1.1.7 variant. This reduction was also evident in sera from some convalescent patients. Decreased B.1.1.7 neutralisation was also observed with monoclonal antibodies targeting the N-terminal domain (9 out of 10), the Receptor Binding Motif (RBM) (5 out of 31), but not in neutralising mAbs binding outside the RBM. Introduction of the E484K mutation in a B.1.1.7 background to reflect newly emerging viruses in the UK led to a more substantial loss of neutralising activity by vaccine-elicited antibodies and mAbs (19 out of 31) over that conferred by the B.1.1.7 mutations alone. E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b., Competing Interests: Competing interests A.D.M., J.B., D.P., C.S.F., S.B., K.C., N.S., E.C., G.S., S.J., A.L., H.W.V., M.S.P., L.P. and D.C. are employees of Vir Biotechnology and may hold shares in Vir Biotechnology. H.W.V. is a founder of PierianDx and Casma Therapeutics. Neither company provided funding for this work or is performing related work. D.V. is a consultant for Vir Biotechnology Inc. The Veesler laboratory has received a sponsored research agreement from Vir Biotechnology Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. RKG has received consulting fees from UMOVIS Lab, Gilead and ViiV.
Published: 2021
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27. Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation.

Author: Kemp SA, Collier DA, Datir R, Ferreira I, Gayed S, Jahun A, Hosmillo M, Rees-Spear C, Mlcochova P, Lumb IU, Roberts DJ, Chandra A, Temperton N, Sharrocks K, Blane E, Briggs J, van GM, Smith K, Bradley JR, Smith C, Doffinger R, Ceron-Gutierrez L, Barcenas-Morales G, Pollock DD, Goldstein RA, Smielewska A, Skittrall JP, Gouliouris T, Goodfellow IG, Gkrania-Klotsas E, Illingworth C, McCoy LE, and Gupta RK
Abstract: SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2, and amino acid variation in Spike is increasingly appreciated. Given both vaccines and therapeutics are designed around Wuhan-1 Spike, this raises the theoretical possibility of virus escape, particularly in immunocompromised individuals where prolonged viral replication occurs. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences by both short and long read technologies over 23 time points spanning 101 days. Although little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days, N501Y in Spike was transiently detected at day 55 and V157L in RdRp emerged. However, following convalescent plasma we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and Δ H69/ Δ V70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro , the Spike escape double mutant bearing Δ H69/ Δ V70 and D796H conferred decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility, but incurred an infectivity defect. The Δ H69/ Δ V70 single mutant had two-fold higher infectivity compared to wild type and appeared to compensate for the reduced infectivity of D796H. Consistent with the observed mutations being outside the RBD, monoclonal antibodies targeting the RBD were not impacted by either or both mutations, but a non RBD binding monoclonal antibody was less potent against Δ H69/ Δ V70 and the double mutant. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with reduced susceptibility to neutralising antibodies.
Published: 2020
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28. Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report.

Author: Buckland MS, Galloway JB, Fhogartaigh CN, Meredith L, Provine NM, Bloor S, Ogbe A, Zelek WM, Smielewska A, Yakovleva A, Mann T, Bergamaschi L, Turner L, Mescia F, Toonen EJM, Hackstein CP, Akther HD, Vieira VA, Ceron-Gutierrez L, Periselneris J, Kiani-Alikhan S, Grigoriadou S, Vaghela D, Lear SE, Török ME, Hamilton WL, Stockton J, Quick J, Nelson P, Hunter M, Coulter TI, Devlin L, Bradley JR, Smith KGC, Ouwehand WH, Estcourt L, Harvala H, Roberts DJ, Wilkinson IB, Screaton N, Loman N, Doffinger R, Lyons PA, Morgan BP, Goodfellow IG, Klenerman P, Lehner PJ, Matheson NJ, and Thaventhiran JED
Subjects: Adenosine Monophosphate therapeutic use, Adult, Alanine therapeutic use, Antiviral Agents therapeutic use, COVID-19 virology, Fever prevention & control, Humans, Immunity, Humoral immunology, Lymphocyte Count, Male, SARS-CoV-2 immunology, SARS-CoV-2 physiology, Treatment Outcome, Adenosine Monophosphate analogs & derivatives, Alanine analogs & derivatives, Immunity, Humoral drug effects, SARS-CoV-2 drug effects
Abstract: The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients.
Published: 2020
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29. Inherited salt-losing tubulopathies are associated with immunodeficiency due to impaired IL-17 responses.

Author: Evans RDR, Antonelou M, Sathiananthamoorthy S, Rega M, Henderson S, Ceron-Gutierrez L, Barcenas-Morales G, Müller CA, Doffinger R, Walsh SB, and Salama AD
Subjects: Adolescent, Adult, Aged, 80 and over, Animals, Child, Preschool, Chronic Disease, Cohort Studies, Female, Genetic Diseases, Inborn, Humans, Magnesium metabolism, Male, Middle Aged, Potassium metabolism, Salts metabolism, Salts therapeutic use, Sodium metabolism, Sodium Chloride metabolism, Sodium Chloride, Dietary therapeutic use, Th17 Cells metabolism, Th2 Cells metabolism, Young Adult, Immunologic Deficiency Syndromes etiology, Interleukin-17 metabolism, Kidney Tubules, Distal pathology
Abstract: Increased extracellular sodium activates Th17 cells, which provide protection from bacterial and fungal infections. Whilst high salt diets have been shown to worsen autoimmune disease, the immunological consequences of clinical salt depletion are unknown. Here, we investigate immunity in patients with inherited salt-losing tubulopathies (SLT). Forty-seven genotyped SLT patients (with Bartter, Gitelman or EAST Syndromes) are recruited. Clinical features of dysregulated immunity are recorded with a standardised questionnaire and immunological investigations of IL-17 responsiveness undertaken. The effects of altering extracellular ionic concentrations on immune responses are then assessed. Patients are hypokalaemic and hypomagnesaemic, with reduced interstitial sodium stores determined by 23 Na-magnetic resonance imaging. SLT patients report increased mucosal infections and allergic disease compared to age-matched controls. Aligned with their clinical phenotype, SLT patients have an increased ratio of Th2:Th17 cells. SLT Th17 and Tc17 polarisation is reduced in vitro, yet STAT1 and STAT3 phosphorylation and calcium flux following T cell activation are unaffected. In control cells, the addition of extracellular sodium (+40 mM), potassium (+2 mM), or magnesium (+1 mM) reduces Th2:Th17 ratio and augments Th17 polarisation. Our results thus show that the ionic environment typical in SLT impairs IL-17 immunity, but the intracellular pathways that mediate salt-driven Th17 polarisation are intact and in vitro IL-17 responses can be reinvigorated by increasing extracellular sodium concentration. Whether better correction of extracellular ions can rescue the immunophenotype in vivo in SLT patients remains unknown.
Published: 2020
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30. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation.

Author: Cuchet-Lourenço D, Eletto D, Wu C, Plagnol V, Papapietro O, Curtis J, Ceron-Gutierrez L, Bacon CM, Hackett S, Alsaleem B, Maes M, Gaspar M, Alisaac A, Goss E, AlIdrissi E, Siegmund D, Wajant H, Kumararatne D, AlZahrani MS, Arkwright PD, Abinun M, Doffinger R, and Nejentsev S
Subjects: Alleles, Arthritis immunology, Cytokines metabolism, Female, Fibroblasts metabolism, Fibroblasts pathology, Humans, Inflammatory Bowel Diseases immunology, Lymphopenia genetics, Male, Mitogen-Activated Protein Kinases metabolism, Pedigree, Severe Combined Immunodeficiency immunology, Arthritis genetics, Inflammatory Bowel Diseases genetics, Receptor-Interacting Protein Serine-Threonine Kinases genetics, Severe Combined Immunodeficiency genetics
Abstract: RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Published: 2018
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31. Protein microarrays identify disease-specific anti-cytokine autoantibody profiles in the landscape of immunodeficiency.

Author: Rosenberg JM, Price JV, Barcenas-Morales G, Ceron-Gutierrez L, Davies S, Kumararatne DS, Döffinger R, and Utz PJ
Subjects: Humans, Immunologic Deficiency Syndromes blood, Protein Array Analysis, Autoantibodies blood, Cytokines immunology, Immunologic Deficiency Syndromes immunology
Abstract: Background: Anti-cytokine autoantibodies (ACAAs) are pathogenic in a handful of rare immunodeficiencies. However, the prevalence and significance of other ACAAs across immunodeficiencies have not yet been described., Objective: We profiled ACAAs in a diverse cohort of serum samples from patients with immunodeficiency and assessed the sensitivity and specificity of protein microarrays for ACAA identification and discovery., Methods: Highly multiplexed protein microarrays were designed and fabricated. Blinded serum samples from a cohort of 58 immunodeficiency patients and healthy control subjects were used to probe microarrays. Unsupervised hierarchical clustering was used to identify clusters of reactivity, and after unblinding, significance analysis of microarrays was used to identify disease-specific autoantibodies. A bead-based assay was used to validate protein microarray results. Blocking activity of serum containing ACAAs was measured in vitro., Results: Protein microarrays were highly sensitive and specific for the detection of ACAAs in patients with autoimmune polyendocrine syndrome type I and pulmonary alveolar proteinosis, detecting ACAA levels consistent with those reported in the published literature. Protein microarray results were validated by using an independent bead-based assay. To confirm the functional significance of these ACAAs, we tested and confirmed the blocking activity of select ACAAs in vitro., Conclusion: Protein microarrays are a powerful tool for ACAA detection and discovery, and they hold promise as a diagnostic for the evaluation and monitoring of clinical immunodeficiency., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
Published: 2016
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32. Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans.

Author: Schoenmakers E, Agostini M, Mitchell C, Schoenmakers N, Papp L, Rajanayagam O, Padidela R, Ceron-Gutierrez L, Doffinger R, Prevosto C, Luan J, Montano S, Lu J, Castanet M, Clemons N, Groeneveld M, Castets P, Karbaschi M, Aitken S, Dixon A, Williams J, Campi I, Blount M, Burton H, Muntoni F, O'Donovan D, Dean A, Warren A, Brierley C, Baguley D, Guicheney P, Fitzgerald R, Coles A, Gaston H, Todd P, Holmgren A, Khanna KK, Cooke M, Semple R, Halsall D, Wareham N, Schwabe J, Grasso L, Beck-Peccoz P, Ogunko A, Dattani M, Gurnell M, and Chatterjee K
Subjects: Adult, Aged, Amino Acid Sequence, Animals, Azoospermia genetics, Base Sequence, Child, Child, Preschool, Codon, Nonsense, DNA genetics, Female, Hearing Loss, Sensorineural genetics, Humans, Insulin Resistance genetics, Male, Mice, Middle Aged, Models, Molecular, Molecular Sequence Data, Muscular Dystrophies genetics, Mutation, Missense, Pedigree, Photosensitivity Disorders genetics, RNA-Binding Proteins chemistry, RNA-Binding Proteins metabolism, Reactive Oxygen Species metabolism, Selenocysteine metabolism, Selenoproteins metabolism, Sequence Homology, Amino Acid, Spermatogenesis genetics, T-Lymphocytes immunology, Mutation, RNA-Binding Proteins genetics, Selenoproteins deficiency
Abstract: Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as selenocysteine (Sec), generating a family of selenoproteins. Sec incorporation is mediated by a multiprotein complex that includes Sec insertion sequence-binding protein 2 (SECISBP2; also known as SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a complex phenotype. Azoospermia, with failure of the latter stages of spermatogenesis, was associated with a lack of testis-enriched selenoproteins. An axial muscular dystrophy was also present, with features similar to myopathies caused by mutations in selenoprotein N (SEPN1). Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation-induced oxidative damage may mediate the observed photosensitivity. Reduced levels of selenoproteins in peripheral blood cells were associated with impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, and telomere shortening. Paradoxically, raised ROS in affected subjects was associated with enhanced systemic and cellular insulin sensitivity, similar to findings in mice lacking the antioxidant selenoenzyme glutathione peroxidase 1 (GPx1). Thus, mutation of SECISBP2 is associated with a multisystem disorder with defective biosynthesis of many selenoproteins, highlighting their role in diverse biological processes.
Published: 2010
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33. Autoantibodies to interferon-gamma in a patient with selective susceptibility to mycobacterial infection and organ-specific autoimmunity.

Author: Döffinger R, Helbert MR, Barcenas-Morales G, Yang K, Dupuis S, Ceron-Gutierrez L, Espitia-Pinzon C, Barnes N, Bothamley G, Casanova JL, Longhurst HJ, and Kumararatne DS
Subjects: Autoimmunity, Diabetes Mellitus, Type 1 etiology, Disease Susceptibility, Humans, Hypothyroidism etiology, Male, Middle Aged, Mycobacterium Infections, Nontuberculous complications, Mycobacterium chelonae drug effects, Mycobacterium tuberculosis drug effects, Tuberculosis complications, Autoantibodies blood, Immunoglobulin G blood, Interferon-gamma immunology, Mycobacterium Infections, Nontuberculous immunology, Tuberculosis immunology
Abstract: We evaluated a patient with disseminated Mycobacterium tuberculosis and Mycobacterium chelonae infection, of which he died. He also developed autoimmune (type I) diabetes and primary hypothyroidism. His serum contained a high titer of immunoglobulin G autoantibody to interferon-gamma (IFN-gamma) capable of blocking in vitro responses to this cytokine by peripheral blood mononuclear cells from normal donors. These results suggest that autoantibodies to IFN-gamma can induce susceptibility to disseminated mycobacterial infection, which may be refractory to chemotherapy.
Published: 2004
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33 results on '"Ceron-Gutierrez, L."'

1. High incidence of anti-cytokine autoantibodies in dogs with immune diseases suggests important immuno-regulatory functions

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

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

4. Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2

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

6. SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies

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

8. SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies

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

10. Critical care workers have lower seroprevalence of SARS-CoV-2 IgG compared with non-patient facing staff in first wave of COVID19

11. Disseminated Mycobacterium tuberculosis infection due to interferon γ deficiency. Response to replacement therapy

12. Disseminated Mycobacterium tuberculosis infection due to interferon (gamma) deficiency. Response to replacement therapy

13. THU0043 Targeted medicine: therapeutic use of functional cytokine assays in complex inflammatory arthritis

14. IRF8 mutations and human dendritic-cell immunodeficiency

15. Disseminated Mycobacterium tuberculosis infection due to interferon deficiency. Response to replacement therapy

16. Disseminated Mycobacterium tuberculosis Infection Due to IFN-γ Deficiency. Response to Replacement Therapy

17. Neutralizing Autoantibodies against Interleukin-10 in Inflammatory Bowel Disease.

18. Atypical B cells and impaired SARS-CoV-2 neutralization following heterologous vaccination in the elderly.

19. Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade.

20. Accelerated waning of the humoral response to COVID-19 vaccines in obesity.

21. Author Correction: Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies.

22. Author Correction: SARS-CoV-2 evolution during treatment of chronic infection.

23. Defective Interferon-Gamma Production Is Common in Chronic Pulmonary Aspergillosis.

24. Critical Care Workers Have Lower Seroprevalence of SARS-CoV-2 IgG Compared with Non-patient Facing Staff in First Wave of COVID19.

25. SARS-CoV-2 Spike Protein Stabilized in the Closed State Induces Potent Neutralizing Responses.

26. SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies.

27. Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation.

28. Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report.

29. Inherited salt-losing tubulopathies are associated with immunodeficiency due to impaired IL-17 responses.

30. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation.

31. Protein microarrays identify disease-specific anti-cytokine autoantibody profiles in the landscape of immunodeficiency.

32. Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans.

33. Autoantibodies to interferon-gamma in a patient with selective susceptibility to mycobacterial infection and organ-specific autoimmunity.

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