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

Author

Baker, Stephen, Dougan, Gordon, Hess, Christoph, Kingston, Nathalie, Lehner, Paul J, Lyons, Paul A, Matheson, Nicholas J, Owehand, Willem H, Saunders, Caroline, Summers, Charlotte, Thaventhiran, James ED, Toshner, Mark, Weekes, Michael P, Bucke, Ashlea, Calder, Jo, Canna, Laura, Domingo, Jason, Elmer, Anne, Fuller, Stewart, Harris, Julie, Hewitt, Sarah, Kennet, Jane, Jose, Sherly, Kourampa, Jenny, Meadows, Anne, O’Brien, Criona, Price, Jane, Publico, Cherry, Rastall, Rebecca, Ribeiro, Carla, Rowlands, Jane, Ruffolo, Valentina, Tordesillas, Hugo, Bullman, Ben, Dunmore, Benjamin J, Fawke, Stuart, Gräf, Stefan, Hodgson, Josh, Huang, Christopher, Hunter, Kelvin, Jones, Emma, Legchenko, Ekaterina, Matara, Cecilia, Martin, Jennifer, Mescia, Federica, O’Donnell, Ciara, Pointon, Linda, Pond, Nicole, Shih, Joy, Sutcliffe, Rachel, Tilly, Tobias, Treacy, Carmen, Tong, Zhen, Wood, Jennifer, Wylot, Marta, Bergamaschi, Laura, Betancourt, Ariana, Bower, Georgie, Cossetti, Chiara, De Sa, Aloka, Epping, Madeline, Gleadall, Nick, Grenfell, Richard, Hinch, Andrew, Huhn, Oisin, Jackson, Sarah, Jarvis, Isobel, Lewis, Daniel, Marsden, Joe, Nice, Francesca, Okecha, Georgina, Omarjee, Ommar, Perera, Marianne, Richoz, Nathan, Romashova, Veronika, Yarkoni, Natalia Savinykh, Sharma, Rahul, Stefanucci, Luca, Stephens, Jonathan, Strezlecki, Mateusz, Turner, Lori, De Bie, Eckart MDD, Bunclark, Katherine, Josipovic, Masa, Mackay, Michael, Rossi, Sabrina, Selvan, Mayurun, Spencer, Sarah, Yong, Cissy, Ansaripour, Ali, Michael, Alice, Mwaura, Lucy, Patterson, Caroline, Polwarth, Gary, Polgarova, Petra, di Stefano, Giovanni, Fahey, Codie, Michel, Rachel, and Bong, Sze-How

Subjects
Immunization, Pneumonia & Influenza, Lung, Prevention, Genetics, Vaccine Related, Biotechnology, Pneumonia, Emerging Infectious Diseases, Biodefense, Infectious Diseases, 2.1 Biological and endogenous factors, Aetiology, Infection, Good Health and Well Being, Adenosine Monophosphate, Aged, Alanine, Antibodies, Neutralizing, Antibodies, Viral, COVID-19, Chronic Disease, Evolution, Molecular, Genome, Viral, High-Throughput Nucleotide Sequencing, Humans, Immune Evasion, Immune Tolerance, Immunization, Passive, Immunosuppression Therapy, Male, Mutagenesis, Mutant Proteins, Mutation, Phylogeny, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Time Factors, Viral Load, Virus Shedding, COVID-19 Drug Treatment, COVID-19 Serotherapy, CITIID-NIHR BioResource COVID-19 Collaboration, COVID-19 Genomics UK (COG-UK) Consortium, General Science & Technology
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

3. SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity

Author

Baker, Stephen, Dougan, Gordon, Hess, Christoph, Kingston, Nathalie, Lehner, Paul J., Lyons, Paul A., Matheson, Nicholas J., Owehand, Willem H., Saunders, Caroline, Summers, Charlotte, Thaventhiran, James E.D., Toshner, Mark, Weekes, Michael P., Maxwell, Patrick, Shaw, Ashley, Bucke, Ashlea, Calder, Jo, Canna, Laura, Domingo, Jason, Elmer, Anne, Fuller, Stewart, Harris, Julie, Hewitt, Sarah, Kennet, Jane, Jose, Sherly, Kourampa, Jenny, Meadows, Anne, O’Brien, Criona, Price, Jane, Publico, Cherry, Rastall, Rebecca, Ribeiro, Carla, Rowlands, Jane, Ruffolo, Valentina, Tordesillas, Hugo, Bullman, Ben, Dunmore, Benjamin J., Fawke, Stuart, Gräf, Stefan, Hodgson, Josh, Huang, Christopher, Hunter, Kelvin, Jones, Emma, Legchenko, Ekaterina, Matara, Cecilia, Martin, Jennifer, Mescia, Federica, O’Donnell, Ciara, Pointon, Linda, Shih, Joy, Sutcliffe, Rachel, Tilly, Tobias, Treacy, Carmen, Tong, Zhen, Wood, Jennifer, Wylot, Marta, Betancourt, Ariana, Bower, Georgie, Cossetti, Chiara, De Sa, Aloka, Epping, Madeline, Gleadall, Nick, Grenfell, Richard, Hinch, Andrew, Jackson, Sarah, Jarvis, Isobel, Krishna, Ben, Nice, Francesca, Omarjee, Ommar, Perera, Marianne, Potts, Martin, Richoz, Nathan, Romashova, Veronika, Stefanucci, Luca, Strezlecki, Mateusz, Turner, Lori, De Bie, Eckart M.D.D., Bunclark, Katherine, Josipovic, Masa, Mackay, Michael, Allison, John, Butcher, Helen, Caputo, Daniela, Clapham-Riley, Debbie, Dewhurst, Eleanor, Furlong, Anita, Graves, Barbara, Gray, Jennifer, Ivers, Tasmin, Le Gresley, Emma, Linger, Rachel, Meloy, Sarah, Muldoon, Francesca, Ovington, Nigel, Papadia, Sofia, Phelan, Isabel, Stark, Hannah, Stirrups, Kathleen E., Townsend, Paul, Walker, Neil, Webster, Jennifer, Scholtes, Ingrid, Hein, Sabine, King, Rebecca, Meng, Bo, Datir, Rawlings, Choi, Jinwook, Bradley, John R., Smith, Kenneth G.C., Lee, Joo Hyeon, and Gupta, Ravindra K.

Published
2022
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4. A generative foundation model for antibody sequence understanding

Author

Barton, Justin, primary, Gaspariunas, Aretas, additional, Yadin, David A, additional, Dias, Jorge, additional, Nice, Francesca L, additional, Minns, Danielle H, additional, Snudden, Olivia, additional, Povall, Chelsea, additional, Valle Tomas, Sara, additional, Dobson, Harry, additional, Farmery, James HR, additional, Leem, Jinwoo, additional, and Galson, Jacob D, additional

Published
2024
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6. SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity

Author

Meng, Bo, primary, Datir, Rawlings, additional, Choi, Jinwook, additional, Bradley, John R., additional, Smith, Kenneth G.C., additional, Lee, Joo Hyeon, additional, Gupta, Ravindra K., additional, Baker, Stephen, additional, Dougan, Gordon, additional, Hess, Christoph, additional, Kingston, Nathalie, additional, Lehner, Paul J., additional, Lyons, Paul A., additional, Matheson, Nicholas J., additional, Owehand, Willem H., additional, Saunders, Caroline, additional, Summers, Charlotte, additional, Thaventhiran, James E.D., additional, Toshner, Mark, additional, Weekes, Michael P., additional, Maxwell, Patrick, additional, Shaw, Ashley, additional, Bucke, Ashlea, additional, Calder, Jo, additional, Canna, Laura, additional, Domingo, Jason, additional, Elmer, Anne, additional, Fuller, Stewart, additional, Harris, Julie, additional, Hewitt, Sarah, additional, Kennet, Jane, additional, Jose, Sherly, additional, Kourampa, Jenny, additional, Meadows, Anne, additional, O’Brien, Criona, additional, Price, Jane, additional, Publico, Cherry, additional, Rastall, Rebecca, additional, Ribeiro, Carla, additional, Rowlands, Jane, additional, Ruffolo, Valentina, additional, Tordesillas, Hugo, additional, Bullman, Ben, additional, Dunmore, Benjamin J., additional, Fawke, Stuart, additional, Gräf, Stefan, additional, Hodgson, Josh, additional, Huang, Christopher, additional, Hunter, Kelvin, additional, Jones, Emma, additional, Legchenko, Ekaterina, additional, Matara, Cecilia, additional, Martin, Jennifer, additional, Mescia, Federica, additional, O’Donnell, Ciara, additional, Pointon, Linda, additional, Shih, Joy, additional, Sutcliffe, Rachel, additional, Tilly, Tobias, additional, Treacy, Carmen, additional, Tong, Zhen, additional, Wood, Jennifer, additional, Wylot, Marta, additional, Betancourt, Ariana, additional, Bower, Georgie, additional, Cossetti, Chiara, additional, De Sa, Aloka, additional, Epping, Madeline, additional, Gleadall, Nick, additional, Grenfell, Richard, additional, Hinch, Andrew, additional, Jackson, Sarah, additional, Jarvis, Isobel, additional, Krishna, Ben, additional, Nice, Francesca, additional, Omarjee, Ommar, additional, Perera, Marianne, additional, Potts, Martin, additional, Richoz, Nathan, additional, Romashova, Veronika, additional, Stefanucci, Luca, additional, Strezlecki, Mateusz, additional, Turner, Lori, additional, De Bie, Eckart M.D.D., additional, Bunclark, Katherine, additional, Josipovic, Masa, additional, Mackay, Michael, additional, Allison, John, additional, Butcher, Helen, additional, Caputo, Daniela, additional, Clapham-Riley, Debbie, additional, Dewhurst, Eleanor, additional, Furlong, Anita, additional, Graves, Barbara, additional, Gray, Jennifer, additional, Ivers, Tasmin, additional, Le Gresley, Emma, additional, Linger, Rachel, additional, Meloy, Sarah, additional, Muldoon, Francesca, additional, Ovington, Nigel, additional, Papadia, Sofia, additional, Phelan, Isabel, additional, Stark, Hannah, additional, Stirrups, Kathleen E., additional, Townsend, Paul, additional, Walker, Neil, additional, Webster, Jennifer, additional, Scholtes, Ingrid, additional, Hein, Sabine, additional, and King, Rebecca, additional

Published
2022
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7. SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Author

Mlcochova, Petra, Kemp, Steven A., Dhar, Mahesh Shanker, Papa, Guido, Meng, Bo, Ferreira, Isabella A. T. M., Datir, Rawlings, Collier, Dami A., Albecka, Anna, Singh, Sujeet, Pandey, Rajesh, Brown, Jonathan, Zhou, Jie, Goonawardane, Niluka, Mishra, Swapnil, Whittaker, Charles, Mellan, Thomas, Marwal, Robin, Datta, Meena, Sengupta, Shantanu, Ponnusamy, Kalaiarasan, Radhakrishnan, Venkatraman Srinivasan, Abdullahi, Adam, Charles, Oscar, Chattopadhyay, Partha, Devi, Priti, Caputo, Daniela, Peacock, Tom, Wattal, Chand, Goel, Neeraj, Satwik, Ambrish, Vaishya, Raju, Agarwal, Meenakshi, Chauhan, Himanshu, Dikid, Tanzin, Gogia, Hema, Lall, Hemlata, Verma, Kaptan, Singh, Manoj K., Soni, Namita, Meena, Namonarayan, Madan, Preeti, Singh, Priyanka, Sharma, Ramesh, Sharma, Rajeev, Kabra, Sandhya, Kumar, Sattender, Kumari, Swati, Sharma, Uma, Chaudhary, Urmila, Sivasubbu, Sridhar, Scaria, Vinod, Oberoi, J. K., Raveendran, Reena, Datta, S., Das, Saumitra, Maitra, Arindam, Chinnaswamy, Sreedhar, Biswas, Nidhan Kumar, Parida, Ajay, Raghav, Sunil K., Prasad, Punit, Sarin, Apurva, Mayor, Satyajit, Ramakrishnan, Uma, Palakodeti, Dasaradhi, Seshasayee, Aswin Sai Narain, Thangaraj, K., Bashyam, Murali Dharan, Dalal, Ashwin, Bhat, Manoj, Shouche, Yogesh, Pillai, Ajay, Abraham, Priya, Potdar, Varsha Atul, Cherian, Sarah S., Desai, Anita Sudhir, Pattabiraman, Chitra, Manjunatha, M. V., Mani, Reeta S., Udupi, Gautam Arunachal, Nandicoori, Vinay, Tallapaka, Karthik Bharadwaj, Sowpati, Divya Tej, Kawabata, Ryoko, Morizako, Nanami, Sadamasu, Kenji, Asakura, Hiroyuki, Nagashima, Mami, Yoshimura, Kazuhisa, Ito, Jumpei, Kimura, Izumi, Uriu, Keiya, Kosugi, Yusuke, Suganami, Mai, Oide, Akiko, Yokoyama, Miyabishara, Chiba, Mika, Saito, Akatsuki, Butlertanaka, Erika P., Tanaka, Yuri L., Ikeda, Terumasa, Motozono, Chihiro, Nasser, Hesham, Shimizu, Ryo, Yuan, Yue, Kitazato, Kazuko, Hasebe, Haruyo, Nakagawa, So, Wu, Jiaqi, Takahashi, Miyoko, Fukuhara, Takasuke, Shimizu, Kenta, Tsushima, Kana, Kubo, Haruko, Shirakawa, Kotaro, Kazuma, Yasuhiro, Nomura, Ryosuke, Horisawa, Yoshihito, Takaori-Kondo, Akifumi, Tokunaga, Kenzo, Ozono, Seiya, Baker, Stephen, Dougan, Gordon, Hess, Christoph, Kingston, Nathalie, Lehner, Paul J., Lyons, Paul A., Matheson, Nicholas J., Owehand, Willem H., Saunders, Caroline, Summers, Charlotte, Thaventhiran, James E. D., Toshner, Mark, Weekes, Michael P., Maxwell, Patrick, Shaw, Ashley, Bucke, Ashlea, Calder, Jo, Canna, Laura, Domingo, Jason, Elmer, Anne, Fuller, Stewart, Harris, Julie, Hewitt, Sarah, Kennet, Jane, Jose, Sherly, Kourampa, Jenny, Meadows, Anne, O'Brien, Criona, Price, Jane, Publico, Cherry, Rastall, Rebecca, Ribeiro, Carla, Rowlands, Jane, Ruffolo, Valentina, Tordesillas, Hugo, Bullman, Ben, Dunmore, Benjamin J., Fawke, Stuart, Graf, Stefan, Hodgson, Josh, Huang, Christopher, Hunter, Kelvin, Jones, Emma, Legchenko, Ekaterina, Matara, Cecilia, Martin, Jennifer, Mescia, Federica, O'Donnell, Ciara, Pointon, Linda, Pond, Nicole, Shih, Joy, Sutcliffe, Rachel, Tilly, Tobias, Treacy, Carmen, Tong, Zhen, Wood, Jennifer, Wylot, Marta, Bergamaschi, Laura, Betancourt, Ariana, Bower, Georgie, Cossetti, Chiara, De Sa, Aloka, Epping, Madeline, Gleadall, Nick, Grenfell, Richard, Hinch, Andrew, Huhn, Oisin, Jackson, Sarah, Jarvis, Isobel, Krishna, Ben, Lewis, Daniel, Marsden, Joe, Nice, Francesca, Okecha, Georgina, Omarjee, Ommar, Perera, Marianne, Potts, Martin, Richoz, Nathan, Romashova, Veronika, Yarkoni, Natalia Savinykh, Sharma, Rahul, Stefanucci, Luca, Stephens, Jonathan, Strezlecki, Mateusz, Turner, Lori, De Bie, Eckart M. D. D., Bunclark, Katherine, Josipovic, Masa, Mackay, Michael, Rossi, Sabrina, Selvan, Mayurun, Spencer, Sarah, Yong, Cissy, Allison, John, Butcher, Helen, Clapham-Riley, Debbie, Dewhurst, Eleanor, Furlong, Anita, Graves, Barbara, Gray, Jennifer, Ivers, Tasmin, Kasanicki, Mary, Le Gresley, Emma, Linger, Rachel, Meloy, Sarah, Muldoon, Francesca, Ovington, Nigel, Papadia, Sofia, Phelan, Isabel, Stark, Hannah, Stirrups, Kathleen E., Townsend, Paul, Walker, Neil, Webster, Jennifer, Scholtes, Ingrid, Hein, Sabine, King, Rebecca, Mavousian, Antranik, Lee, Joo Hyeon, Bassi, Jessica, Silacci-Fegni, Chiara, Saliba, Christian, Pinto, Dora, Irie, Takashi, Yoshida, Isao, Hamilton, William L., Sato, Kei, Bhatt, Samir, Flaxman, Seth, James, Leo C., Corti, Davide, Piccoli, Luca, Barclay, Wendy S., Rakshit, Partha, Agrawal, Anurag, Gupta, Ravindra K., (INSACOG), Indian SARS-CoV-2 Genomics Consortium, Consortium, Genotype to Phenotype Japan (G2P-Japan), Collaboration, CITIID-NIHR BioResource COVID-19, Gupta, Ravindra K [0000-0001-9751-1808], Apollo - University of Cambridge Repository, and Gupta, Ravindra K. [0000-0001-9751-1808]

Subjects
Male, COVID-19 Vaccines, medicine.drug_class, Health Personnel, India, Monoclonal antibody, Virus Replication, Antibodies, Cell Line, Cell Fusion, Immune system, 13/100, medicine, Humans, Neutralizing antibody, Antibodies, Neutralizing, Female, Kinetics, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Vaccination, Immune Evasion, Neutralizing, 631/326/596/4130, Syncytium, Multidisciplinary, Cell fusion, biology, article, Vaccine efficacy, 631/250/254, Virology, Spike Glycoprotein, Coronavirus, 13/31, biology.protein, Antibody, Infection
Abstract

The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era., A study of SARS-CoV-2 variants examining their transmission, infectivity, and potential resistance to therapies provides insights into the biology of the Delta variant and its role in the global pandemic.

Published
2022
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8. Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2

Author

Collier, Dami A., Ferreira, Isabella A. T. M., Kotagiri, Prasanti, Datir, Rawlings P., Lim, Eleanor Y., Touizer, Emma, Meng, Bo, Abdullahi, Adam, Elmer, Anne, Kingston, Nathalie, Graves, Barbara, Le Gresley, Emma, Caputo, Daniela, Bergamaschi, Laura, Smith, Kenneth G. C., Bradley, John R., Ceron-Gutierrez, Lourdes, Cortes-Acevedo, Paulina, Barcenas-Morales, Gabriela, Linterman, Michelle A., McCoy, Laura E., Davis, Chris, Thomson, Emma, McKinney, Eoin, Doffinger, Rainer, Wills, Mark, Gupta, Ravindra K., Baker, Stephen, Dougan, Gordon, Hess, Christoph, Lehner, Paul J., Lyons, Paul A., Matheson, Nicholas J., Owehand, Willem H., Saunders, Caroline, Summers, Charlotte, Thaventhiran, James E. D., Toshner, Mark, Weekes, Michael P., Maxwell, Patrick, Shaw, Ashley, Bucke, Ashlea, Calder, Jo, Canna, Laura, Domingo, Jason, Fuller, Stewart, Harris, Julie, Hewitt, Sarah, Kennet, Jane, Jose, Sherly, Kourampa, Jenny, Meadows, Anne, O’Brien, Criona, Price, Jane, Publico, Cherry, Rastall, Rebecca, Ribeiro, Carla, Rowlands, Jane, Ruffolo, Valentina, Tordesillas, Hugo, Bullman, Ben, Dunmore, Benjamin J., Fawke, Stuart, Gräf, Stefan, Hodgson, Josh, Huang, Christopher, Hunter, Kelvin, Jones, Emma, Legchenko, Ekaterina, Matara, Cecilia, Martin, Jennifer, Mescia, Federica, O’Donnell, Ciara, Pointon, Linda, Pond, Nicole, Shih, Joy, Sutcliffe, Rachel, Tilly, Tobias, Treacy, Carmen, Tong, Zhen, Wood, Jennifer, Wylot, Marta, Betancourt, Ariana, Bower, Georgie, Cossetti, Chiara, De Sa, Aloka, Epping, Madeline, Gleadall, Nick, Grenfell, Richard, Hinch, Andrew, Huhn, Oisin, Jackson, Sarah, Jarvis, Isobel, Krishna, Ben, Lewis, Daniel, Marsden, Joe, Nice, Francesca, Okecha, Georgina, Omarjee, Ommar, Perera, Marianne, Potts, Martin, Richoz, Nathan, Romashova, Veronika, Yarkoni, Natalia Savinykh, Sharma, Rahul, Stefanucci, Luca, Stephens, Jonathan, Strezlecki, Mateusz, Turner, Lori, D. D. De Bie, Eckart M., Bunclark, Katherine, Josipovic, Masa, Mackay, Michael, Michael, Alice, Rossi, Sabrina, Selvan, Mayurun, Spencer, Sarah, Yong, Cissy, Ansaripour, Ali, Mwaura, Lucy, Patterson, Caroline, Polwarth, Gary, Polgarova, Petra, Di Stefano, Giovanni, Fahey, Codie, Michel, Rachel, Bong, Sze-How, Coudert, Jerome D., Holmes, Elaine, Allison, John, Butcher, Helen, Clapham-Riley, Debbie, Dewhurst, Eleanor, Furlong, Anita, Gray, Jennifer, Ivers, Tasmin, Kasanicki, Mary, Linger, Rachel, Meloy, Sarah, Muldoon, Francesca, Ovington, Nigel, Papadia, Sofia, Phelan, Isabel, Stark, Hannah, Stirrups, Kathleen E., Townsend, Paul, Walker, Neil, Webster, Jennifer, Collier, Dami A. [0000-0001-5446-4423], Datir, Rawlings P. [0000-0003-0521-2144], Smith, Kenneth G. C. [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
article, 13/106, 38/39, 631/250/2152/2153/1291, 631/326/596/4130, 38
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.

Published
2021
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9. Single-cell multi-omics analysis of the immune response in COVID-19

Author

Stephenson, Emily, Reynolds, Gary, Botting, Rachel A., Calero-Nieto, Fernando J., Morgan, Michael D., Tuong, Zewen Kelvin, Bach, Karsten, Sungnak, Waradon, Worlock, Kaylee B., Yoshida, Masahiro, Kumasaka, Natsuhiko, Kania, Katarzyna, Engelbert, Justin, Olabi, Bayanne, Spegarova, Jarmila Stremenova, Wilson, Nicola K., Mende, Nicole, Jardine, Laura, Gardner, Louis C. S., Goh, Issac, Horsfall, Dave, McGrath, Jim, Webb, Simone, Mather, Michael W., Lindeboom, Rik G. H., Dann, Emma, Huang, Ni, Polanski, Krzysztof, Prigmore, Elena, Gothe, Florian, Scott, Jonathan, Payne, Rebecca P., Baker, Kenneth F., Hanrath, Aidan T., Schim Van Der Loeff, Ina C. D., Barr, Andrew S., Sanchez-Gonzalez, Amada, Bergamaschi, Laura, Mescia, Federica, Barnes, Josephine L., Kilich, Eliz, De Wilton, Angus, Saigal, Anita, Saleh, Aarash, Janes, Sam M., Smith, Claire M., Gopee, Nusayhah, Wilson, Caroline, Coupland, Paul, Coxhead, Jonathan M., Kiselev, Vladimir Yu, Van Dongen, Stijn, Bacardit, Jaume, King, Hamish W., Rostron, Anthony J., Simpson, A. John, Hambleton, Sophie, Laurenti, Elisa, Lyons, Paul A., Meyer, Kerstin B., Nikolić, Marko Z., Duncan, Christopher J. A., Teichmann, Sarah A., Clatworthy, Menna R., Marioni, John C., Göttgens, Berthold, Haniffa, Muzlifah, Baker, Stephen, Bradley, John R., Dougan, Gordon, Goodfellow, Ian G., Gupta, Ravindra K., Hess, Christoph, Kingston, Nathalie, Lehner, Paul J., Matheson, Nicholas J., Owehand, Willem H., Saunders, Caroline, Smith, Kenneth G. C., Summers, Charlotte, Thaventhiran, James E. D., Toshner, Mark, Weekes, Michael P., Bucke, Ashlea, Calder, Jo, Canna, Laura, Domingo, Jason, Elmer, Anne, Fuller, Stewart, Harris, Julie, Hewitt, Sarah, Kennet, Jane, Jose, Sherly, Kourampa, Jenny, Meadows, Anne, O’Brien, Criona, Price, Jane, Publico, Cherry, Rastall, Rebecca, Ribeiro, Carla, Rowlands, Jane, Ruffolo, Valentina, Tordesillas, Hugo, Bullman, Ben, Dunmore, Benjamin J., Fawke, Stuart, Gräf, Stefan, Hodgson, Josh, Huang, Christopher, Hunter, Kelvin, Jones, Emma, Legchenko, Ekaterina, Matara, Cecilia, Martin, Jennifer, O’Donnell, Ciara, Pointon, Linda, Pond, Nicole, Shih, Joy, Sutcliffe, Rachel, Tilly, Tobias, Treacy, Carmen, Tong, Zhen, Wood, Jennifer, Wylot, Marta, Betancourt, Ariana, Bower, Georgie, De Sa, Aloka, Epping, Madeline, Huhn, Oisin, Jackson, Sarah, Jarvis, Isobel, Marsden, Jimmy, Nice, Francesca, Okecha, Georgina, Omarjee, Ommar, Perera, Marianne, Richoz, Nathan, Sharma, Rahul, Turner, Lori, De Bie, Eckart M. D. D., Bunclark, Katherine, Josipovic, Masa, Mackay, Michael, Michael, Alice, Rossi, Sabrina, Selvan, Mayurun, Spencer, Sarah, Yong, Cissy, Ansaripour, Ali, Mwaura, Lucy, Patterson, Caroline, Polwarth, Gary, Polgarova, Petra, Stefano, Giovanni Di, Allison, John, Butcher, Helen, Caputo, Daniela, Clapham-Riley, Debbie, Dewhurst, Eleanor, Furlong, Anita, Graves, Barbara, Gray, Jennifer, Ivers, Tasmin, Kasanicki, Mary, Gresley, Emma Le, Linger, Rachel, Meloy, Sarah, Muldoon, Francesca, Ovington, Nigel, Papadia, Sofia, Phelan, Isabel, Stark, Hannah, Stirrups, Kathleen E., Townsend, Paul, Walker, Neil, Webster, Jennifer, Calero-Nieto, Fernando J. [0000-0003-3358-8253], Morgan, Michael D. [0000-0003-0757-0711], Tuong, Zewen Kelvin [0000-0002-6735-6808], Sungnak, Waradon [0000-0002-0136-4960], Yoshida, Masahiro [0000-0002-3521-5322], Kumasaka, Natsuhiko [0000-0002-3557-0375], Spegarova, Jarmila Stremenova [0000-0002-0710-9266], Wilson, Nicola K. [0000-0003-0865-7333], Mende, Nicole [0000-0002-5078-2333], Gardner, Louis C. S. [0000-0002-7200-978X], Goh, Issac [0000-0002-6397-3518], Horsfall, Dave [0000-0002-8086-812X], Webb, Simone [0000-0003-3058-8952], Mather, Michael W. [0000-0001-7972-7111], Lindeboom, Rik G. H. [0000-0002-3660-504X], Dann, Emma [0000-0002-7400-7438], Polanski, Krzysztof [0000-0002-2586-9576], Payne, Rebecca P. [0000-0002-9037-7367], Baker, Kenneth F. [0000-0002-6735-2911], Schim van der Loeff, Ina C. D. [0000-0003-1196-6196], Barr, Andrew S. [0000-0002-8084-7644], Mescia, Federica [0000-0002-2759-4027], Barnes, Josephine L. [0000-0001-9938-3176], Janes, Sam M. [0000-0002-6634-5939], Smith, Claire M. [0000-0002-8913-0009], Coupland, Paul [0000-0002-2871-3374], Bacardit, Jaume [0000-0002-2692-7205], King, Hamish W. [0000-0001-5972-8926], Rostron, Anthony J. [0000-0002-9336-1723], Simpson, A. John [0000-0003-4731-7294], Hambleton, Sophie [0000-0001-7954-3267], Laurenti, Elisa [0000-0002-9917-9092], Lyons, Paul A. [0000-0001-7035-8997], Meyer, Kerstin B. [0000-0001-5906-1498], Nikolić, Marko Z. [0000-0001-6304-6848], Smith, Kenneth G. C. [0000-0003-3829-4326], Teichmann, Sarah A. [0000-0002-6294-6366], Clatworthy, Menna R. [0000-0002-3340-9828], Marioni, John C. [0000-0001-9092-0852], Göttgens, Berthold [0000-0001-6302-5705], Haniffa, Muzlifah [0000-0002-3927-2084], and Apollo - University of Cambridge Repository

Subjects
692/699/255/2514, 631/208/514/1949, article, 631/250/232, 631/250/254, 631/326/596/4130
Abstract

Funder: Lister Institute of Preventive Medicine; doi: https://doi.org/10.13039/501100001255, Funder: University College London, Birkbeck MRC Doctoral Training Programme, Funder: The Jikei University School of Medicine, Funder: Action Medical Research (GN2779), Funder: NIHR Clinical Lectureship (CL-2017-01-004), Funder: NIHR (ACF-2018-01-004) and the BMA Foundation, Funder: Chan Zuckerberg Initiative (grant 2017-174169) and from Wellcome (WT211276/Z/18/Z and Sanger core grant WT206194), Funder: UKRI Innovation/Rutherford Fund Fellowship allocated by the MRC and the UK Regenerative Medicine Platform (MR/5005579/1 to M.Z.N.). M.Z.N. and K.B.M. have been funded by the Rosetrees Trust (M944), Funder: Barbour Foundation, Funder: ERC Consolidator and EU MRG-Grammar awards, Funder: Versus Arthritis Cure Challenge Research Grant (21777), and an NIHR Research Professorship (RP-2017-08-ST2-002), Funder: European Molecular Biology Laboratory (EMBL), Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.

Published
2021
Full Text
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10. Combined Point-of-Care Nucleic Acid and Antibody Testing for SARS-CoV-2 following Emergence of D614G Spike Variant

Author

Baker, Stephen, Bradley, John, Dougan, Gordon, Goodfellow, Ian, Gupta, Ravi, Lehner, Paul J., Lyons, Paul, Matheson, Nicholas J., Smith, Kenneth G.C., Toshner, Mark, Weekes, Michael P., Brown, Nick, Curran, Martin, Palmar, Surendra, Zhang, Hongyi, Enoch, David, Chapman, Daniel, Shaw, Ashley, Jose, Sherly, Bermperi, Areti, Zerrudo, Julie Ann, Kourampa, Evgenia, Watson, Laura, Worsley, Jieniean, Saunders, Caroline, de Jesus, Ranalie, Domingo, Jason, Pasquale, Ciro, Vergese, Bensi, Vargas, Phoebe, Fabiculana, Marivic, Perales, Marlyn, Mynott, Lee, Blake, Elizabeth, Bates, Amy, Vallier, Anne-Laure, Williams, Alexandra, Phillips, David, Chiu, Edmund, Overhill, Alex, Ramenatte, Nicola, Sipple, Jamal, Frost, Steven, Knock, Helena, Hardy, Richard, Foster, Emily, Davidson, Fiona, Rundell, Viona, Bundi, Purity, Abeseabe, Richmond, Clark, Sarah, Vicente, Isabel, Elmer, Anne, Ribeiro, Carla, Kourampa, Jenny, Kennet, Jane, Rowlands, Jane, Meadows, Anne, O’Brien, Criona, Rastall, Rebecca, Crucusio, Cherry, Hewitt, Sarah, Price, Jane, Calder, Jo, Canna, Laura, Bucke, Ashlea, Tordesillas, Hugo, Harris, Julie, Ruffolo, Valentina, Graves, Barbara, Butcher, Helen, Caputo, Daniela, Le Gresley, Emma, Dunmore, Benjamin J., Martin, Jennifer, Legchenko, Ekaterina, Treacy, Carmen, Huang, Christopher, Wood, Jennifer, Sutcliffe, Rachel, Hodgson, Josh, Shih, Joy, Graf, Stefan, Tong, Zhen, Mescia, Federica, Tilly, Tobias, O’Donnell, Ciara, Hunter, Kelvin, Pointon, Linda, Pond, Nicole, Wylot, Marta, Jones, Emma, Fawke, Stuart, Bullman, Ben, Turner, Lori, Jarvis, Isobel, Omarjee, Ommar, De Sa, Aloka, Marsden, Joe, Betancourt, Ariana, Perera, Marianne, Epping, Maddie, Richoz, Nathan, Bower, Georgie, Sharma, Rahul, Nice, Francesca, Huhn, Oisin, Savoinykh Yarkoni, Natalia, Romashova, Nika, Lewis, Daniel, Hinch, Andrew, Cossetti, Chiara, Strezlecki, Mateusz, Grenfell, Richard, Stark, Hannah, Walker, Neil, Stirrups, Kathy, Ovington, Nigel, Dewhust, Eleanor, Li, Emily, Papadia, Sofia, Kingston, Nathalie, Lever, Andrew, Torok, Estee, Hamilton, William, Hall, Grant, Jahun, Aminu, Chaudhry, Yasmin, Pinckert, Malte, Georgana, Iliana, Yakovleva, Anna, Caller, Laura, Caddy, Sarah, Feltwell, Theresa, Khokhar, Fahad, Meredith, Luke, Holdcroft, Charlotte, Parmar, Surendra, Mlcochova, Petra, Collier, Dami, Ritchie, Allyson, Assennato, Sonny M., Hosmillo, Myra, Goel, Neha, Meng, Bo, Chatterjee, Krishna, Mendoza, Vivien, Temperton, Nigel, Kiss, Leo, James, Leo C., Ciazynska, Katarzyna A., Xiong, Xiaoli, Briggs, John A.G., Nathan, James A., Bergamaschi, Laura, Barmpounakis, Petros, Demeris, Nikos, Skells, Richard, Lyons, Paul A., Baker, Steven, Allain, Jean Pierre, Bousfield, Rachel, Wilson, Michael, Sparkes, Dominic, Amoroso, Glenn, Gkrania-Klotsas, Effrosyni, Hardwick, Susie, Boyle, Adrian, and Gupta, Ravindra K.

Published
2020
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11. SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Author

Mlcochova, Petra, Kemp, Steven A., Dhar, Mahesh Shanker, Papa, Guido, Meng, Bo, Ferreira, Isabella A. T. M., Datir, Rawlings, Collier, Dami A., Albecka, Anna, Singh, Sujeet, Pandey, Rajesh, Brown, Jonathan, Zhou, Jie, Goonawardane, Niluka, Mishra, Swapnil, Whittaker, Charles, Mellan, Thomas, Marwal, Robin, Datta, Meena, Sengupta, Shantanu, Ponnusamy, Kalaiarasan, Radhakrishnan, Venkatraman Srinivasan, Abdullahi, Adam, Charles, Oscar, Chattopadhyay, Partha, Devi, Priti, Caputo, Daniela, Peacock, Tom, Wattal, Chand, Goel, Neeraj, Satwik, Ambrish, Vaishya, Raju, Agarwal, Meenakshi, Chauhan, Himanshu, Dikid, Tanzin, Gogia, Hema, Lall, Hemlata, Verma, Kaptan, Singh, Manoj K., Soni, Namita, Meena, Namonarayan, Madan, Preeti, Singh, Priyanka, Sharma, Ramesh, Sharma, Rajeev, Kabra, Sandhya, Kumar, Sattender, Kumari, Swati, Sharma, Uma, Chaudhary, Urmila, Sivasubbu, Sridhar, Scaria, Vinod, Oberoi, J. K., Raveendran, Reena, Datta, S., Das, Saumitra, Maitra, Arindam, Chinnaswamy, Sreedhar, Biswas, Nidhan Kumar, Parida, Ajay, Raghav, Sunil K., Prasad, Punit, Sarin, Apurva, Mayor, Satyajit, Ramakrishnan, Uma, Palakodeti, Dasaradhi, Seshasayee, Aswin Sai Narain, Thangaraj, K., Bashyam, Murali Dharan, Dalal, Ashwin, Bhat, Manoj, Shouche, Yogesh, Pillai, Ajay, Abraham, Priya, Potdar, Varsha Atul, Cherian, Sarah S., Desai, Anita Sudhir, Pattabiraman, Chitra, Manjunatha, M. V., Mani, Reeta S., Udupi, Gautam Arunachal, Nandicoori, Vinay, Tallapaka, Karthik Bharadwaj, Sowpati, Divya Tej, Kawabata, Ryoko, Morizako, Nanami, Sadamasu, Kenji, Asakura, Hiroyuki, Nagashima, Mami, Yoshimura, Kazuhisa, Ito, Jumpei, Kimura, Izumi, Uriu, Keiya, Kosugi, Yusuke, Suganami, Mai, Oide, Akiko, Yokoyama, Miyabishara, Chiba, Mika, Saito, Akatsuki, Butlertanaka, Erika P., Tanaka, Yuri L., Ikeda, Terumasa, Motozono, Chihiro, Nasser, Hesham, Shimizu, Ryo, Yuan, Yue, Kitazato, Kazuko, Hasebe, Haruyo, Nakagawa, So, Wu, Jiaqi, Takahashi, Miyoko, Fukuhara, Takasuke, Shimizu, Kenta, Tsushima, Kana, Kubo, Haruko, Shirakawa, Kotaro, Kazuma, Yasuhiro, Nomura, Ryosuke, Horisawa, Yoshihito, Takaori-Kondo, Akifumi, Tokunaga, Kenzo, Ozono, Seiya, Baker, Stephen, Dougan, Gordon, Hess, Christoph, Kingston, Nathalie, Lehner, Paul J., Lyons, Paul A., Matheson, Nicholas J., Owehand, Willem H., Saunders, Caroline, Summers, Charlotte, Thaventhiran, James E. D., Toshner, Mark, Weekes, Michael P., Maxwell, Patrick, Shaw, Ashley, Bucke, Ashlea, Calder, Jo, Canna, Laura, Domingo, Jason, Elmer, Anne, Fuller, Stewart, Harris, Julie, Hewitt, Sarah, Kennet, Jane, Jose, Sherly, Kourampa, Jenny, Meadows, Anne, O'Brien, Criona, Price, Jane, Publico, Cherry, Rastall, Rebecca, Ribeiro, Carla, Rowlands, Jane, Ruffolo, Valentina, Tordesillas, Hugo, Bullman, Ben, Dunmore, Benjamin J., Fawke, Stuart, Graf, Stefan, Hodgson, Josh, Huang, Christopher, Hunter, Kelvin, Jones, Emma, Legchenko, Ekaterina, Matara, Cecilia, Martin, Jennifer, Mescia, Federica, O'Donnell, Ciara, Pointon, Linda, Pond, Nicole, Shih, Joy, Sutcliffe, Rachel, Tilly, Tobias, Treacy, Carmen, Tong, Zhen, Wood, Jennifer, Wylot, Marta, Bergamaschi, Laura, Betancourt, Ariana, Bower, Georgie, Cossetti, Chiara, De Sa, Aloka, Epping, Madeline, Gleadall, Nick, Grenfell, Richard, Hinch, Andrew, Huhn, Oisin, Jackson, Sarah, Jarvis, Isobel, Krishna, Ben, Lewis, Daniel, Marsden, Joe, Nice, Francesca, Okecha, Georgina, Omarjee, Ommar, Perera, Marianne, Potts, Martin, Richoz, Nathan, Romashova, Veronika, Yarkoni, Natalia Savinykh, Sharma, Rahul, Stefanucci, Luca, Stephens, Jonathan, Strezlecki, Mateusz, Turner, Lori, De Bie, Eckart M. D. D., Bunclark, Katherine, Josipovic, Masa, Mackay, Michael, Rossi, Sabrina, Selvan, Mayurun, Spencer, Sarah, Yong, Cissy, Allison, John, Butcher, Helen, Clapham-Riley, Debbie, Dewhurst, Eleanor, Furlong, Anita, Graves, Barbara, Gray, Jennifer, Ivers, Tasmin, Kasanicki, Mary, Le Gresley, Emma, Linger, Rachel, Meloy, Sarah, Muldoon, Francesca, Ovington, Nigel, Papadia, Sofia, Phelan, Isabel, Stark, Hannah, Stirrups, Kathleen E., Townsend, Paul, Walker, Neil, Webster, Jennifer, Scholtes, Ingrid, Hein, Sabine, King, Rebecca, Mavousian, Antranik, Lee, Joo Hyeon, Bassi, Jessica, Silacci-Fegni, Chiara, Saliba, Christian, Pinto, Dora, Irie, Takashi, Yoshida, Isao, Hamilton, William L., Sato, Kei, Bhatt, Samir, Flaxman, Seth, James, Leo C., Corti, Davide, Piccoli, Luca, Barclay, Wendy S., Rakshit, Partha, Agrawal, Anurag, Gupta, Ravindra K., Mlcochova, Petra, Kemp, Steven A., Dhar, Mahesh Shanker, Papa, Guido, Meng, Bo, Ferreira, Isabella A. T. M., Datir, Rawlings, Collier, Dami A., Albecka, Anna, Singh, Sujeet, Pandey, Rajesh, Brown, Jonathan, Zhou, Jie, Goonawardane, Niluka, Mishra, Swapnil, Whittaker, Charles, Mellan, Thomas, Marwal, Robin, Datta, Meena, Sengupta, Shantanu, Ponnusamy, Kalaiarasan, Radhakrishnan, Venkatraman Srinivasan, Abdullahi, Adam, Charles, Oscar, Chattopadhyay, Partha, Devi, Priti, Caputo, Daniela, Peacock, Tom, Wattal, Chand, Goel, Neeraj, Satwik, Ambrish, Vaishya, Raju, Agarwal, Meenakshi, Chauhan, Himanshu, Dikid, Tanzin, Gogia, Hema, Lall, Hemlata, Verma, Kaptan, Singh, Manoj K., Soni, Namita, Meena, Namonarayan, Madan, Preeti, Singh, Priyanka, Sharma, Ramesh, Sharma, Rajeev, Kabra, Sandhya, Kumar, Sattender, Kumari, Swati, Sharma, Uma, Chaudhary, Urmila, Sivasubbu, Sridhar, Scaria, Vinod, Oberoi, J. K., Raveendran, Reena, Datta, S., Das, Saumitra, Maitra, Arindam, Chinnaswamy, Sreedhar, Biswas, Nidhan Kumar, Parida, Ajay, Raghav, Sunil K., Prasad, Punit, Sarin, Apurva, Mayor, Satyajit, Ramakrishnan, Uma, Palakodeti, Dasaradhi, Seshasayee, Aswin Sai Narain, Thangaraj, K., Bashyam, Murali Dharan, Dalal, Ashwin, Bhat, Manoj, Shouche, Yogesh, Pillai, Ajay, Abraham, Priya, Potdar, Varsha Atul, Cherian, Sarah S., Desai, Anita Sudhir, Pattabiraman, Chitra, Manjunatha, M. V., Mani, Reeta S., Udupi, Gautam Arunachal, Nandicoori, Vinay, Tallapaka, Karthik Bharadwaj, Sowpati, Divya Tej, Kawabata, Ryoko, Morizako, Nanami, Sadamasu, Kenji, Asakura, Hiroyuki, Nagashima, Mami, Yoshimura, Kazuhisa, Ito, Jumpei, Kimura, Izumi, Uriu, Keiya, Kosugi, Yusuke, Suganami, Mai, Oide, Akiko, Yokoyama, Miyabishara, Chiba, Mika, Saito, Akatsuki, Butlertanaka, Erika P., Tanaka, Yuri L., Ikeda, Terumasa, Motozono, Chihiro, Nasser, Hesham, Shimizu, Ryo, Yuan, Yue, Kitazato, Kazuko, Hasebe, Haruyo, Nakagawa, So, Wu, Jiaqi, Takahashi, Miyoko, Fukuhara, Takasuke, Shimizu, Kenta, Tsushima, Kana, Kubo, Haruko, Shirakawa, Kotaro, Kazuma, Yasuhiro, Nomura, Ryosuke, Horisawa, Yoshihito, Takaori-Kondo, Akifumi, Tokunaga, Kenzo, Ozono, Seiya, Baker, Stephen, Dougan, Gordon, Hess, Christoph, Kingston, Nathalie, Lehner, Paul J., Lyons, Paul A., Matheson, Nicholas J., Owehand, Willem H., Saunders, Caroline, Summers, Charlotte, Thaventhiran, James E. D., Toshner, Mark, Weekes, Michael P., Maxwell, Patrick, Shaw, Ashley, Bucke, Ashlea, Calder, Jo, Canna, Laura, Domingo, Jason, Elmer, Anne, Fuller, Stewart, Harris, Julie, Hewitt, Sarah, Kennet, Jane, Jose, Sherly, Kourampa, Jenny, Meadows, Anne, O'Brien, Criona, Price, Jane, Publico, Cherry, Rastall, Rebecca, Ribeiro, Carla, Rowlands, Jane, Ruffolo, Valentina, Tordesillas, Hugo, Bullman, Ben, Dunmore, Benjamin J., Fawke, Stuart, Graf, Stefan, Hodgson, Josh, Huang, Christopher, Hunter, Kelvin, Jones, Emma, Legchenko, Ekaterina, Matara, Cecilia, Martin, Jennifer, Mescia, Federica, O'Donnell, Ciara, Pointon, Linda, Pond, Nicole, Shih, Joy, Sutcliffe, Rachel, Tilly, Tobias, Treacy, Carmen, Tong, Zhen, Wood, Jennifer, Wylot, Marta, Bergamaschi, Laura, Betancourt, Ariana, Bower, Georgie, Cossetti, Chiara, De Sa, Aloka, Epping, Madeline, Gleadall, Nick, Grenfell, Richard, Hinch, Andrew, Huhn, Oisin, Jackson, Sarah, Jarvis, Isobel, Krishna, Ben, Lewis, Daniel, Marsden, Joe, Nice, Francesca, Okecha, Georgina, Omarjee, Ommar, Perera, Marianne, Potts, Martin, Richoz, Nathan, Romashova, Veronika, Yarkoni, Natalia Savinykh, Sharma, Rahul, Stefanucci, Luca, Stephens, Jonathan, Strezlecki, Mateusz, Turner, Lori, De Bie, Eckart M. D. D., Bunclark, Katherine, Josipovic, Masa, Mackay, Michael, Rossi, Sabrina, Selvan, Mayurun, Spencer, Sarah, Yong, Cissy, Allison, John, Butcher, Helen, Clapham-Riley, Debbie, Dewhurst, Eleanor, Furlong, Anita, Graves, Barbara, Gray, Jennifer, Ivers, Tasmin, Kasanicki, Mary, Le Gresley, Emma, Linger, Rachel, Meloy, Sarah, Muldoon, Francesca, Ovington, Nigel, Papadia, Sofia, Phelan, Isabel, Stark, Hannah, Stirrups, Kathleen E., Townsend, Paul, Walker, Neil, Webster, Jennifer, Scholtes, Ingrid, Hein, Sabine, King, Rebecca, Mavousian, Antranik, Lee, Joo Hyeon, Bassi, Jessica, Silacci-Fegni, Chiara, Saliba, Christian, Pinto, Dora, Irie, Takashi, Yoshida, Isao, Hamilton, William L., Sato, Kei, Bhatt, Samir, Flaxman, Seth, James, Leo C., Corti, Davide, Piccoli, Luca, Barclay, Wendy S., Rakshit, Partha, Agrawal, Anurag, and Gupta, Ravindra K.

Published
2021

12. Combined Point-of-Care Nucleic Acid and Antibody Testing for SARS-CoV-2 following Emergence of D614G Spike Variant

Author

Mlcochova, Petra, primary, Collier, Dami, additional, Ritchie, Allyson, additional, Assennato, Sonny M., additional, Hosmillo, Myra, additional, Goel, Neha, additional, Meng, Bo, additional, Chatterjee, Krishna, additional, Mendoza, Vivien, additional, Temperton, Nigel, additional, Kiss, Leo, additional, James, Leo C., additional, Ciazynska, Katarzyna A., additional, Xiong, Xiaoli, additional, Briggs, John A.G., additional, Nathan, James A., additional, Mescia, Federica, additional, Bergamaschi, Laura, additional, Zhang, Hongyi, additional, Barmpounakis, Petros, additional, Demeris, Nikos, additional, Skells, Richard, additional, Lyons, Paul A., additional, Bradley, John, additional, Baker, Steven, additional, Allain, Jean Pierre, additional, Smith, Kenneth G.C., additional, Bousfield, Rachel, additional, Wilson, Michael, additional, Sparkes, Dominic, additional, Amoroso, Glenn, additional, Gkrania-Klotsas, Effrosyni, additional, Hardwick, Susie, additional, Boyle, Adrian, additional, Goodfellow, Ian, additional, Gupta, Ravindra K., additional, Baker, Stephen, additional, Dougan, Gordon, additional, Gupta, Ravi, additional, Lehner, Paul J., additional, Lyons, Paul, additional, Matheson, Nicholas J., additional, Toshner, Mark, additional, Weekes, Michael P., additional, Brown, Nick, additional, Curran, Martin, additional, Palmar, Surendra, additional, Enoch, David, additional, Chapman, Daniel, additional, Shaw, Ashley, additional, Jose, Sherly, additional, Bermperi, Areti, additional, Zerrudo, Julie Ann, additional, Kourampa, Evgenia, additional, Watson, Laura, additional, Worsley, Jieniean, additional, Saunders, Caroline, additional, de Jesus, Ranalie, additional, Domingo, Jason, additional, Pasquale, Ciro, additional, Vergese, Bensi, additional, Vargas, Phoebe, additional, Fabiculana, Marivic, additional, Perales, Marlyn, additional, Mynott, Lee, additional, Blake, Elizabeth, additional, Bates, Amy, additional, Vallier, Anne-Laure, additional, Williams, Alexandra, additional, Phillips, David, additional, Chiu, Edmund, additional, Overhill, Alex, additional, Ramenatte, Nicola, additional, Sipple, Jamal, additional, Frost, Steven, additional, Knock, Helena, additional, Hardy, Richard, additional, Foster, Emily, additional, Davidson, Fiona, additional, Rundell, Viona, additional, Bundi, Purity, additional, Abeseabe, Richmond, additional, Clark, Sarah, additional, Vicente, Isabel, additional, Elmer, Anne, additional, Ribeiro, Carla, additional, Kourampa, Jenny, additional, Kennet, Jane, additional, Rowlands, Jane, additional, Meadows, Anne, additional, O’Brien, Criona, additional, Rastall, Rebecca, additional, Crucusio, Cherry, additional, Hewitt, Sarah, additional, Price, Jane, additional, Calder, Jo, additional, Canna, Laura, additional, Bucke, Ashlea, additional, Tordesillas, Hugo, additional, Harris, Julie, additional, Ruffolo, Valentina, additional, Graves, Barbara, additional, Butcher, Helen, additional, Caputo, Daniela, additional, Le Gresley, Emma, additional, Dunmore, Benjamin J., additional, Martin, Jennifer, additional, Legchenko, Ekaterina, additional, Treacy, Carmen, additional, Huang, Christopher, additional, Wood, Jennifer, additional, Sutcliffe, Rachel, additional, Hodgson, Josh, additional, Shih, Joy, additional, Graf, Stefan, additional, Tong, Zhen, additional, Tilly, Tobias, additional, O’Donnell, Ciara, additional, Hunter, Kelvin, additional, Pointon, Linda, additional, Pond, Nicole, additional, Wylot, Marta, additional, Jones, Emma, additional, Fawke, Stuart, additional, Bullman, Ben, additional, Turner, Lori, additional, Jarvis, Isobel, additional, Omarjee, Ommar, additional, De Sa, Aloka, additional, Marsden, Joe, additional, Betancourt, Ariana, additional, Perera, Marianne, additional, Epping, Maddie, additional, Richoz, Nathan, additional, Bower, Georgie, additional, Sharma, Rahul, additional, Nice, Francesca, additional, Huhn, Oisin, additional, Savoinykh Yarkoni, Natalia, additional, Romashova, Nika, additional, Lewis, Daniel, additional, Hinch, Andrew, additional, Cossetti, Chiara, additional, Strezlecki, Mateusz, additional, Grenfell, Richard, additional, Stark, Hannah, additional, Walker, Neil, additional, Stirrups, Kathy, additional, Ovington, Nigel, additional, Dewhust, Eleanor, additional, Li, Emily, additional, Papadia, Sofia, additional, Kingston, Nathalie, additional, Lever, Andrew, additional, Torok, Estee, additional, Hamilton, William, additional, Hall, Grant, additional, Jahun, Aminu, additional, Chaudhry, Yasmin, additional, Pinckert, Malte, additional, Georgana, Iliana, additional, Yakovleva, Anna, additional, Caller, Laura, additional, Caddy, Sarah, additional, Feltwell, Theresa, additional, Khokhar, Fahad, additional, Meredith, Luke, additional, Holdcroft, Charlotte, additional, and Parmar, Surendra, additional

Published
2020
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13. A thermostable, closed SARS-CoV-2 spike protein trimer

Author

Xiong, Xiaoli, Qu, Kun, Ciazynska, Katarzyna A., Hosmillo, Myra, Carter, Andrew P., Ebrahimi, Soraya, Ke, Zunlong, Scheres, Sjors H. W., Bergamaschi, Laura, Grice, Guinevere L., Zhang, Ying, Bradley, John, Lyons, Paul A., Smith, Kenneth G. C., Toshner, Mark, Elmer, Anne, Ribeiro, Carla, Kourampa, Jenny, Jose, Sherly, Kennet, Jane, Rowlands, Jane, Meadows, Anne, O’Brien, Criona, Rastall, Rebecca, Crucusio, Cherry, Hewitt, Sarah, Price, Jane, Calder, Jo, Canna, Laura, Bucke, Ashlea, Tordesillas, Hugo, Harris, Julie, Ruffolo, Valentina, Domingo, Jason, Graves, Barbara, Butcher, Helen, Caputo, Daniela, Le Gresley, Emma, Dunmore, Benjamin J., Martin, Jennifer, Legchenko, Ekaterina, Treacy, Carmen, Huang, Christopher, Wood, Jennifer, Sutcliffe, Rachel, Hodgson, Josh, Shih, Joy, Graf, Stefan, Tong, Zhen, Mescia, Federica, Tilly, Tobias, O’Donnell, Ciara, Hunter, Kelvin, Pointon, Linda, Pond, Nicole, Wylot, Marta, Jones, Emma, Fawke, Stuart, Bullman, Ben, Turner, Lori, Jarvis, Isobel, Omarjee, Ommar, De Sa, Aloka, Marsden, Joe, Betancourt, Ariana, Perera, Marianne, Epping, Maddie, Richoz, Nathan, Bower, Georgie, Sharma, Rahul, Nice, Francesca, Huhn, Oisin, Stark, Hannah, Walker, Neil, Stirrups, Kathy, Ovington, Nigel, Dewhust, Eleanor, Li, Emily, Papadia, Sofia, Nathan, James A., Baker, Stephen, James, Leo C., Baxendale, Helen E., Goodfellow, Ian, Doffinger, Rainer, Briggs, John A. G., Hosmillo, Myra [0000-0002-3514-7681], Nathan, James [0000-0002-0248-1632], Baker, Stephen [0000-0003-1308-5755], Goodfellow, Ian [0000-0002-9483-510X], and Apollo - University of Cambridge Repository

Subjects
Models, Molecular, Immunogen, Protein Conformation, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Trimer, Enzyme-Linked Immunosorbent Assay, Receptor binding site, medicine.disease_cause, Protein Engineering, Article, 03 medical and health sciences, Betacoronavirus, 0302 clinical medicine, Protein structure, COVID-19 Testing, Models, Structural Biology, medicine, Humans, Disulfides, Molecular Biology, 030304 developmental biology, Cell entry, 0303 health sciences, Mutation, Clinical Laboratory Techniques, Protein Stability, SARS-CoV-2, Cryoelectron Microscopy, Temperature, Spike Protein, Molecular, Coronavirus Infections, Flow Cytometry, Immunoglobulin G, Protein Multimerization, Spike Glycoprotein, Coronavirus, Spike Glycoprotein, 3. Good health, Coronavirus, Membrane, Biophysics, 030217 neurology & neurosurgery
Abstract

The spike (S) protein of SARS-CoV-2 mediates receptor binding and cell entry and is the dominant target of the immune system. S exhibits substantial conformational flexibility. It transitions from closed to open conformations to expose its receptor binding site, and subsequently from prefusion to postfusion conformations to mediate fusion of viral and cellular membranes. S protein derivatives are components of vaccine candidates and diagnostic assays, as well as tools for research into the biology and immunology of SARS-CoV-2. Here we have designed mutations in S which allow production of thermostable, crosslinked, S protein trimers that are trapped in the closed, pre-fusion, state. We have determined the structures of crosslinked and non-crosslinked proteins, identifying two distinct closed conformations of the S trimer. We demonstrate that the designed, thermostable, closed S trimer can be used in serological assays. This protein has potential applications as a reagent for serology, virology and as an immunogen.

Published
2020
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14. Combined point of care nucleic acid and antibody testing for SARS-CoV-2 following emergence of D614G Spike Variant

Author

Mlcochova, Petra, Collier, Dami, Ritchie, Allyson, Assennato, Sonny M., Hosmillo, Myra, Goel, Neha, Meng, Bo, Chatterjee, Krishna, Mendoza, Vivien, Temperton, Nigel J., Kiss, Leo, James, Leo C., Ciazynska, Katarzyna A., Xiong, Xiaoli, Briggs, John AG., Nathan, James A., Mescia, Federica, Bergamaschi, Laura, Zhang, Hongyi, Barmpounakis, Petros, Demeris, Nikos, Skells, Richard, Lyons, Paul A., Bradley, John, Baker, Steven, Allain, Jean Pierre, Smith, Kenneth GC., Bousfield, Rachel, Wilson, Michael, Sparkes, Dominic, Amoroso, Glenn, Gkrania-Klotsas, Effrosyni, Hardwick, Susie, Boyle, Adrian, Goodfellow, Ian, Gupta, Ravindra K., Baker, Stephen, Dougan, Gordon, Gupta, Ravi, Lehner, Paul J., Lyons, Paul, Matheson, Nicholas J., Smith, Kenneth G.C., Toshner, Mark, Weekes, Michael P., Brown, Nick, Curran, Martin, Palmar, Surendra, Enoch, David, Chapman, Daniel, Shaw, Ashley, Jose, Sherly, Bermperi, Areti, Zerrudo, Julie Ann, Kourampa, Evgenia, Watson, Laura, Worsley, Jieniean, Saunders, Caroline, de Jesus, Ranalie, Domingo, Jason, Pasquale, Ciro, Vergese, Bensi, Vargas, Phoebe, Fabiculana, Marivic, Perales, Marlyn, Mynott, Lee, Blake, Elizabeth, Bates, Amy, Vallier, Anne-Laure, Williams, Alexandra, Phillips, David, Chiu, Edmund, Overhill, Alex, Ramenatte, Nicola, Sipple, Jamal, Frost, Steven, Knock, Helena, Hardy, Richard, Foster, Emily, Davidson, Fiona, Rundell, Viona, Bundi, Purity, Abeseabe, Richmond, Clark, Sarah, Vicente, Isabel, Elmer, Anne, Ribeiro, Carla, Kourampa, Jenny, Kennet, Jane, Rowlands, Jane, Meadows, Anne, O’Brien, Criona, Rastall, Rebecca, Crucusio, Cherry, Hewitt, Sarah, Price, Jane, Calder, Jo, Canna, Laura, Bucke, Ashlea, Tordesillas, Hugo, Harris, Julie, Ruffolo, Valentina, Graves, Barbara, Butcher, Helen, Caputo, Daniela, Le Gresley, Emma, Dunmore, Benjamin J., Martin, Jennifer, Legchenko, Ekaterina, Treacy, Carmen, Huang, Christopher, Wood, Jennifer, Sutcliffe, Rachel, Hodgson, Josh, Shih, Joy, Graf, Stefan, Tong, Zhen, Tilly, Tobias, O’Donnell, Ciara, Hunter, Kelvin, Pointon, Linda, Pond, Nicole, Wylot, Marta, Jones, Emma, Fawke, Stuart, Bullman, Ben, Turner, Lori, Jarvis, Isobel, Omarjee, Ommar, De Sa, Aloka, Marsden, Joe, Betancourt, Ariana, Perera, Marianne, Epping, Maddie, Richoz, Nathan, Bower, Georgie, Sharma, Rahul, Nice, Francesca, Huhn, Oisin, Yarkoni, Natalia Savoinykh, Romashova, Nika, Lewis, Daniel, Hinch, Andrew, Cossetti, Chiara, Strezlecki, Mateusz, Grenfell, Richard, Stark, Hannah, Walker, Neil, Stirrups, Kathy, Ovington, Nigel, Dewhust, Eleanor, Li, Emily, Papadia, Sofia, Mlcochova, Petra, Collier, Dami, Ritchie, Allyson, Assennato, Sonny M., Hosmillo, Myra, Goel, Neha, Meng, Bo, Chatterjee, Krishna, Mendoza, Vivien, Temperton, Nigel J., Kiss, Leo, James, Leo C., Ciazynska, Katarzyna A., Xiong, Xiaoli, Briggs, John AG., Nathan, James A., Mescia, Federica, Bergamaschi, Laura, Zhang, Hongyi, Barmpounakis, Petros, Demeris, Nikos, Skells, Richard, Lyons, Paul A., Bradley, John, Baker, Steven, Allain, Jean Pierre, Smith, Kenneth GC., Bousfield, Rachel, Wilson, Michael, Sparkes, Dominic, Amoroso, Glenn, Gkrania-Klotsas, Effrosyni, Hardwick, Susie, Boyle, Adrian, Goodfellow, Ian, Gupta, Ravindra K., Baker, Stephen, Dougan, Gordon, Gupta, Ravi, Lehner, Paul J., Lyons, Paul, Matheson, Nicholas J., Smith, Kenneth G.C., Toshner, Mark, Weekes, Michael P., Brown, Nick, Curran, Martin, Palmar, Surendra, Enoch, David, Chapman, Daniel, Shaw, Ashley, Jose, Sherly, Bermperi, Areti, Zerrudo, Julie Ann, Kourampa, Evgenia, Watson, Laura, Worsley, Jieniean, Saunders, Caroline, de Jesus, Ranalie, Domingo, Jason, Pasquale, Ciro, Vergese, Bensi, Vargas, Phoebe, Fabiculana, Marivic, Perales, Marlyn, Mynott, Lee, Blake, Elizabeth, Bates, Amy, Vallier, Anne-Laure, Williams, Alexandra, Phillips, David, Chiu, Edmund, Overhill, Alex, Ramenatte, Nicola, Sipple, Jamal, Frost, Steven, Knock, Helena, Hardy, Richard, Foster, Emily, Davidson, Fiona, Rundell, Viona, Bundi, Purity, Abeseabe, Richmond, Clark, Sarah, Vicente, Isabel, Elmer, Anne, Ribeiro, Carla, Kourampa, Jenny, Kennet, Jane, Rowlands, Jane, Meadows, Anne, O’Brien, Criona, Rastall, Rebecca, Crucusio, Cherry, Hewitt, Sarah, Price, Jane, Calder, Jo, Canna, Laura, Bucke, Ashlea, Tordesillas, Hugo, Harris, Julie, Ruffolo, Valentina, Graves, Barbara, Butcher, Helen, Caputo, Daniela, Le Gresley, Emma, Dunmore, Benjamin J., Martin, Jennifer, Legchenko, Ekaterina, Treacy, Carmen, Huang, Christopher, Wood, Jennifer, Sutcliffe, Rachel, Hodgson, Josh, Shih, Joy, Graf, Stefan, Tong, Zhen, Tilly, Tobias, O’Donnell, Ciara, Hunter, Kelvin, Pointon, Linda, Pond, Nicole, Wylot, Marta, Jones, Emma, Fawke, Stuart, Bullman, Ben, Turner, Lori, Jarvis, Isobel, Omarjee, Ommar, De Sa, Aloka, Marsden, Joe, Betancourt, Ariana, Perera, Marianne, Epping, Maddie, Richoz, Nathan, Bower, Georgie, Sharma, Rahul, Nice, Francesca, Huhn, Oisin, Yarkoni, Natalia Savoinykh, Romashova, Nika, Lewis, Daniel, Hinch, Andrew, Cossetti, Chiara, Strezlecki, Mateusz, Grenfell, Richard, Stark, Hannah, Walker, Neil, Stirrups, Kathy, Ovington, Nigel, Dewhust, Eleanor, Li, Emily, and Papadia, Sofia

Abstract

Rapid COVID-19 diagnosis in hospital is essential, though complicated by 30-50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant now dominates the pandemic and it is unclear how serological tests designed to detect anti-Spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95CI 57.8-92.9%) by rapid NAAT alone. Combined point of care antibody test and rapid NAAT is not impacted by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity.

Published
2020

15. Determination of complex subclonal structures of hematological malignancies by multiplexed genotyping of blood progenitor colonies

Author

Nice, Francesca L, Massie, Charlie E, Klampfl, Thorsten, Green, Anthony R, Massie, Charles [0000-0003-2314-4843], Green, Tony [0000-0002-9795-0218], and Apollo - University of Cambridge Repository

Subjects
Erythroid Precursor Cells, Genotyping Techniques, DNA Mutational Analysis, Mutation, Missense, High-Throughput Nucleotide Sequencing, DNA, Neoplasm, Sequence Analysis, DNA, Janus Kinase 2, Polymorphism, Single Nucleotide, Article, Clone Cells, Hematologic Neoplasms, Mutation, Cluster Analysis, Humans, Polycythemia Vera, health care economics and organizations, Alleles, Granulocytes
Abstract

Highlights • Complex clonal hierarchies are difficult to predict computationally from NGS data. • Multiplexed genotyping of BFU-Es based on NGS data allowed for the determination of a complex subclonal composition in a patient with MPN. • Analysis of subclonal composition allowed for the determination of the order of acquisition of mutations., Current next-generation sequencing (NGS) technologies allow unprecedented insights into the mutational profiles of tumors. Recent studies in myeloproliferative neoplasms have further demonstrated that, not only the mutational profile, but also the order in which these mutations are acquired is relevant for our understanding of the disease. Our ability to assign mutation order from NGS data alone is, however, limited. Here, we present a strategy of highly multiplexed genotyping of burst forming unit-erythroid colonies based on NGS results to assess subclonal tumor structure. This allowed for the generation of complex clonal hierarchies and determination of order of mutation acquisition far more accurately than was possible from NGS data alone.

Published
2018

16. Classification and Personalized Prognosis in Myeloproliferative Neoplasms

Author

Grinfeld, Jacob, primary, Nangalia, Jyoti, additional, Baxter, E. Joanna, additional, Wedge, David C., additional, Angelopoulos, Nicos, additional, Cantrill, Robert, additional, Godfrey, Anna L., additional, Papaemmanuil, Elli, additional, Gundem, Gunes, additional, MacLean, Cathy, additional, Cook, Julia, additional, O’Neil, Laura, additional, O’Meara, Sarah, additional, Teague, Jon W., additional, Butler, Adam P., additional, Massie, Charlie E., additional, Williams, Nicholas, additional, Nice, Francesca L., additional, Andersen, Christen L., additional, Hasselbalch, Hans C., additional, Guglielmelli, Paola, additional, McMullin, Mary F., additional, Vannucchi, Alessandro M., additional, Harrison, Claire N., additional, Gerstung, Moritz, additional, Green, Anthony R., additional, and Campbell, Peter J., additional

Published
2018
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17. Classification and Personalized Prognosis in Myeloproliferative Neoplasms

Author

Grinfeld, Jacob, Nangalia, Jyoti, Baxter, E Joanna, Wedge, David C, Angelopoulos, Nicos, Cantrill, Robert, Godfrey, Anna L, Papaemmanuil, Elli, Gundem, Gunes, MacLean, Cathy, Cook, Julia, O'Neil, Laura, O'Meara, Sarah, Teague, Jon W, Butler, Adam P, Massie, Charlie E, Williams, Nicholas, Nice, Francesca L, Andersen, Christen L, Hasselbalch, Hans C, Guglielmelli, Paola, McMullin, Mary F, Vannucchi, Alessandro M, Harrison, Claire N, Gerstung, Moritz, Green, Anthony R, Campbell, Peter J, Grinfeld, Jacob, Nangalia, Jyoti, Baxter, E Joanna, Wedge, David C, Angelopoulos, Nicos, Cantrill, Robert, Godfrey, Anna L, Papaemmanuil, Elli, Gundem, Gunes, MacLean, Cathy, Cook, Julia, O'Neil, Laura, O'Meara, Sarah, Teague, Jon W, Butler, Adam P, Massie, Charlie E, Williams, Nicholas, Nice, Francesca L, Andersen, Christen L, Hasselbalch, Hans C, Guglielmelli, Paola, McMullin, Mary F, Vannucchi, Alessandro M, Harrison, Claire N, Gerstung, Moritz, Green, Anthony R, and Campbell, Peter J

Abstract

BACKGROUND: Myeloproliferative neoplasms, such as polycythemia vera, essential thrombocythemia, and myelofibrosis, are chronic hematologic cancers with varied progression rates. The genomic characterization of patients with myeloproliferative neoplasms offers the potential for personalized diagnosis, risk stratification, and treatment.METHODS: We sequenced coding exons from 69 myeloid cancer genes in patients with myeloproliferative neoplasms, comprehensively annotating driver mutations and copy-number changes. We developed a genomic classification for myeloproliferative neoplasms and multistage prognostic models for predicting outcomes in individual patients. Classification and prognostic models were validated in an external cohort.RESULTS: A total of 2035 patients were included in the analysis. A total of 33 genes had driver mutations in at least 5 patients, with mutations in JAK2, CALR, or MPL being the sole abnormality in 45% of the patients. The numbers of driver mutations increased with age and advanced disease. Driver mutations, germline polymorphisms, and demographic variables independently predicted whether patients received a diagnosis of essential thrombocythemia as compared with polycythemia vera or a diagnosis of chronic-phase disease as compared with myelofibrosis. We defined eight genomic subgroups that showed distinct clinical phenotypes, including blood counts, risk of leukemic transformation, and event-free survival. Integrating 63 clinical and genomic variables, we created prognostic models capable of generating personally tailored predictions of clinical outcomes in patients with chronic-phase myeloproliferative neoplasms and myelofibrosis. The predicted and observed outcomes correlated well in internal cross-validation of a training cohort and in an independent external cohort. Even within individual categories of existing prognostic schemas, our models substantially improved predictive accuracy.CONCLUSIONS: Comprehensive

Published
2018

18. Personalized Prognostic Predictions for Patients with Myeloproliferative Neoplasms through Integration of Comprehensive Genomic and Clinical Information

Author

Grinfeld, Jacob, Nangalia, Jyoti, Baxter, E Joanna, Godfrey, Anna L., Guglielmelli, Paola, Cantrill, Rob, Wedge, David, Angelopoulos, Nicos, Gundem, Gunes, Massie, Charlie, Papaemmanuil, Elli, MacLean, Cathy, Cook, Julia, Nice, Francesca Lauren, Andersen, Christen Lykkegaard, Hasselbalch, Hans Carl, McMullin, Mary Frances, Vannucchi, Alessandro M., Harrison, Claire N., Gerstung, Moritz, Campbell, Peter J, and Green, Anthony R

Published
2017
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19. The Genomic Landscape of Myeloproliferative Neoplasms: Somatic Calr Mutations in the Majority of JAK2-Wildtype Patients

Author

Nangalia, Jyoti, primary, Massie, Charles, additional, Baxter, E Joanna, additional, Nice, Francesca L, additional, Gundem, Gunes, additional, Wedge, David, additional, Avezov, Edward, additional, Li, Juan, additional, Kollmann, Karoline, additional, Kent, David G., additional, Aziz, Athar, additional, Godfrey, Anna L, additional, Hinton, Jonathan, additional, Martincorena, Inigo, additional, Van Loo, Peter, additional, Jones, Amy V, additional, Guglielmelli, Paola, additional, Tarpey, Patrick, additional, Harding, Heather P, additional, Fitzpatrick, John D, additional, Goudie, Calum T, additional, Ortmann, Christina A, additional, Loughran, Stephen J, additional, Raine, Keiran, additional, Jones, David, additional, Butler, Adam, additional, Teague, Jon W, additional, O'Meara, Sarah, additional, McLaren, Stuart, additional, Bianchi, Michele, additional, Silber, Yvonne, additional, Dimitropolou, Danai, additional, Bloxham, David, additional, Mudie, Laura J, additional, Maddison, Mark, additional, Robinson, Ben, additional, Keohane, Clodagh, additional, MacLean, Cathy, additional, Hill, Kate, additional, Orchard, Kim H., additional, Tauro, Sudhir, additional, Du, Ming-Qing, additional, Greaves, Mel, additional, Bowen, David, additional, Huntly, Brian, additional, Harrison, Claire N, additional, Cross, Nicholas C.P., additional, Ron, David, additional, Vannucchi, Alessandro M, additional, Papaemmanuil, Elli, additional, Campbell, Peter J., additional, and Green, Anthony R, additional

Published
2013
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20. DNMT3A mutations occur early or late in patients with myeloproliferative neoplasms and mutation order influences phenotype.

Author

Nangalia J, Nice FL, Wedge DC, Godfrey AL, Grinfeld J, Thakker C, Massie CE, Baxter J, Sewell D, Silber Y, Campbell PJ, and Green AR

Subjects
DNA Methyltransferase 3A, Female, Humans, Male, DNA (Cytosine-5-)-Methyltransferases genetics, Hematologic Neoplasms enzymology, Hematologic Neoplasms genetics, Mutation, Myeloproliferative Disorders enzymology, Myeloproliferative Disorders genetics, Neoplasm Proteins genetics
Published
2015
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