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1. Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study

Author

Mark S Graham, PhD, Carole H Sudre, PhD, Anna May, MA, Michela Antonelli, PhD, Benjamin Murray, MSc, Thomas Varsavsky, MSc, Kerstin Kläser, MSc, Liane S Canas, PhD, Erika Molteni, PhD, Marc Modat, PhD, David A Drew, PhD, Long H Nguyen, MD, Lorenzo Polidori, MSc, Somesh Selvachandran, MSc, Christina Hu, MA, Joan Capdevila, PhD, Alexander Hammers, ProfPhD, Andrew T Chan, ProfMD, Jonathan Wolf, MA, Tim D Spector, ProfPhD, Claire J Steves, PhD, Sebastien Ourselin, ProfPhD, Cherian Koshy, Amy Ash, Emma Wise, Nathan Moore, Matilde Mori, Nick Cortes, Jessica Lynch, Stephen Kidd, Derek J Fairley, Tanya Curran, James P McKenna, Helen Adams, Christophe Fraser, Tanya Golubchik, David Bonsall, Mohammed O Hassan-Ibrahim, Cassandra S Malone, Benjamin J Cogger, Michelle Wantoch, Nicola Reynolds, Ben Warne, Joshua Maksimovic, Karla Spellman, Kathryn McCluggage, Michaela John, Robert Beer, Safiah Afifi, Sian Morgan, Angela Marchbank, Anna Price, Christine Kitchen, Huw Gulliver, Ian Merrick, Joel Southgate, Martyn Guest, Robert Munn, Trudy Workman, Thomas R Connor, William Fuller, Catherine Bresner, Luke B Snell, Amita Patel, Themoula Charalampous, Gaia Nebbia, Rahul Batra, Jonathan Edgeworth, Samuel C Robson, Angela H Beckett, David M Aanensen, Anthony P Underwood, Corin A Yeats, Khalil Abudahab, Ben EW Taylor, Mirko Menegazzo, Gemma Clark, Wendy Smith, Manjinder Khakh, Vicki M Fleming, Michelle M Lister, Hannah C Howson-Wells, Louise Berry, Tim Boswell, Amelia Joseph, Iona Willingham, Carl Jones, Christopher Holmes, Paul Bird, Thomas Helmer, Karlie Fallon, Julian Tang, Veena Raviprakash, Sharon Campbell, Nicola Sheriff, Victoria Blakey, Lesley-Anne Williams, Matthew W Loose, Nadine Holmes, Christopher Moore, Matthew Carlile, Victoria Wright, Fei Sang, Johnny Debebe, Francesc Coll, Adrian W Signell, Gilberto Betancor, Harry D Wilson, Sahar Eldirdiri, Anita Kenyon, Thomas Davis, Oliver G Pybus, Louis du Plessis, Alex E Zarebski, Jayna Raghwani, Moritz UG Kraemer, Sarah Francois, Stephen W Attwood, Tetyana I Vasylyeva, Marina Escalera Zamudio, Bernardo Gutierrez, M. Estee Torok, William L Hamilton, Ian G Goodfellow, Grant Hall, Aminu S Jahun, Yasmin Chaudhry, Myra Hosmillo, Malte L Pinckert, Iliana Georgana, Samuel Moses, Hannah Lowe, Luke Bedford, Jonathan Moore, Susanne Stonehouse, Chloe L Fisher, Ali R Awan, John BoYes, Judith Breuer, Kathryn Ann Harris, Julianne Rose Brown, Divya Shah, Laura Atkinson, Jack CD Lee, Nathaniel Storey, Flavia Flaviani, Adela Alcolea-Medina, Rebecca Williams, Gabrielle Vernet, Michael R Chapman, Lisa J Levett, Judith Heaney, Wendy Chatterton, Monika Pusok, Li Xu-McCrae, Darren L Smith, Matthew Bashton, Gregory R Young, Alison Holmes, Paul Anthony Randell, Alison Cox, Pinglawathee Madona, Frances Bolt, James Price, Siddharth Mookerjee, Manon Ragonnet-Cronin, Fabricia F. Nascimento, David Jorgensen, Igor Siveroni, Rob Johnson, Olivia Boyd, Lily Geidelberg, Erik M Volz, Aileen Rowan, Graham P Taylor, Katherine L Smollett, Nicholas J Loman, Joshua Quick, Claire McMurray, Joanne Stockton, Sam Nicholls, Will Rowe, Radoslaw Poplawski, Alan McNally, Rocio T Martinez Nunez, Jenifer Mason, Trevor I Robinson, Elaine O'Toole, Joanne Watts, Cassie Breen, Angela Cowell, Graciela Sluga, Nicholas W Machin, Shazaad S Y Ahmad, Ryan P George, Fenella Halstead, Venkat Sivaprakasam, Wendy Hogsden, Chris J Illingworth, Chris Jackson, Emma C Thomson, James G Shepherd, Patawee Asamaphan, Marc O Niebel, Kathy K Li, Rajiv N Shah, Natasha G Jesudason, Lily Tong, Alice Broos, Daniel Mair, Jenna Nichols, Stephen N Carmichael, Kyriaki Nomikou, Elihu Aranday-Cortes, Natasha Johnson, Igor Starinskij, Ana da Silva Filipe, David L Robertson, Richard J Orton, Joseph Hughes, Sreenu Vattipally, Joshua B Singer, Seema Nickbakhsh, Antony D Hale, Louissa R Macfarlane-Smith, Katherine L Harper, Holli Carden, Yusri Taha, Brendan AI Payne, Shirelle Burton-Fanning, Sheila Waugh, Jennifer Collins, Gary Eltringham, Steven Rushton, Sarah O'Brien, Amanda Bradley, Alasdair Maclean, Guy Mollett, Rachel Blacow, Kate E Templeton, Martin P McHugh, Rebecca Dewar, Elizabeth Wastenge, Samir Dervisevic, Rachael Stanley, Emma J Meader, Lindsay Coupland, Louise Smith, Clive Graham, Edward Barton, Debra Padgett, Garren Scott, Emma Swindells, Jane Greenaway, Andrew Nelson, Clare M McCann, Wen C Yew, Monique Andersson, Timothy Peto, Anita Justice, David Eyre, Derrick Crook, Tim J Sloan, Nichola Duckworth, Sarah Walsh, Anoop J Chauhan, Sharon Glaysher, Kelly Bicknell, Sarah Wyllie, Scott Elliott, Allyson Lloyd, Robert Impey, Nick Levene, Lynn Monaghan, Declan T Bradley, Tim Wyatt, Elias Allara, Clare Pearson, Husam Osman, Andrew Bosworth, Esther Robinson, Peter Muir, Ian B Vipond, Richard Hopes, Hannah M Pymont, Stephanie Hutchings, Martin D Curran, Surendra Parmar, Angie Lackenby, Tamyo Mbisa, Steven Platt, Shahjahan Miah, David Bibby, Carmen Manso, Jonathan Hubb, Meera Chand, Gavin Dabrera, Mary Ramsay, Daniel Bradshaw, Alicia Thornton, Richard Myers, Ulf Schaefer, Natalie Groves, Eileen Gallagher, David Lee, David Williams, Nicholas Ellaby, Ian Harrison, Hassan Hartman, Nikos Manesis, Vineet Patel, Chloe Bishop, Vicki Chalker, Juan Ledesma, Katherine A Twohig, Matthew T.G. Holden, Sharif Shaaban, Alec Birchley, Alexander Adams, Alisha Davies, Amy Gaskin, Amy Plimmer, Bree Gatica-Wilcox, Caoimhe McKerr, Catherine Moore, Chris Williams, David Heyburn, Elen De Lacy, Ember Hilvers, Fatima Downing, Giri Shankar, Hannah Jones, Hibo Asad, Jason Coombes, Joanne Watkins, Johnathan M Evans, Laia Fina, Laura Gifford, Lauren Gilbert, Lee Graham, Malorie Perry, Mari Morgan, Matthew Bull, Michelle Cronin, Nicole Pacchiarini, Noel Craine, Rachel Jones, Robin Howe, Sally Corden, Sara Rey, Sara Kumziene-SummerhaYes, Sarah Taylor, Simon Cottrell, Sophie Jones, Sue Edwards, Justin O'Grady, Andrew J Page, Alison E Mather, David J Baker, Steven Rudder, Alp Aydin, Gemma L Kay, Alexander J Trotter, Nabil-Fareed Alikhan, Leonardo de Oliveira Martins, Thanh Le-Viet, Lizzie Meadows, Anna Casey, Liz Ratcliffe, David A Simpson, Zoltan Molnar, Thomas Thompson, Erwan Acheson, Jane AH Masoli, Bridget A Knight, Sian Ellard, Cressida Auckland, Christopher R Jones, Tabitha W Mahungu, Dianne Irish-Tavares, Tanzina Haque, Jennifer Hart, Eric Witele, Melisa Louise Fenton, Ashok Dadrah, Amanda Symmonds, Tranprit Saluja, Yann Bourgeois, Garry P Scarlett, Katie F Loveson, Salman Goudarzi, Christopher Fearn, Kate Cook, Hannah Dent, Hannah Paul, David G Partridge, Mohammad Raza, Cariad Evans, Kate Johnson, Steven Liggett, Paul Baker, Stephen Bonner, Sarah Essex, Ronan A Lyons, Kordo Saeed, Adhyana I.K Mahanama, Buddhini Samaraweera, Siona Silveira, Emanuela Pelosi, Eleri Wilson-Davies, Rachel J Williams, Mark Kristiansen, Sunando Roy, Charlotte A Williams, Marius Cotic, Nadua Bayzid, Adam P Westhorpe, John A Hartley, Riaz Jannoo, Helen L Lowe, Angeliki Karamani, Leah Ensell, Jacqui A Prieto, Sarah Jeremiah, Dimitris Grammatopoulos, Sarojini Pandey, Lisa Berry, Katie Jones, Alex Richter, Andrew Beggs, Angus Best, Benita Percival, Jeremy Mirza, Oliver Megram, Megan Mayhew, Liam Crawford, Fiona Ashcroft, Emma Moles-Garcia, Nicola Cumley, Colin P Smith, Giselda Bucca, Andrew R Hesketh, Beth Blane, Sophia T Girgis, Danielle Leek, Sushmita Sridhar, Sally Forrest, Claire Cormie, Harmeet K Gill, Joana Dias, Ellen E Higginson, Mailis Maes, Jamie Young, Leanne M Kermack, Ravi Kumar Gupta, Catherine Ludden, Sharon J Peacock, Sophie Palmer, Carol M Churcher, Nazreen F Hadjirin, Alessandro M Carabelli, Ellena Brooks, Kim S Smith, Katerina Galai, Georgina M McManus, Chris Ruis, Rose K Davidson, Andrew Rambaut, Thomas Williams, Carlos E Balcazar, Michael D Gallagher, Áine O'Toole, Stefan Rooke, Verity Hill, Kathleen A Williamson, Thomas D Stanton, Stephen L Michell, Claire M Bewshea, Ben Temperton, Michelle L Michelsen, Joanna Warwick-Dugdale, Robin Manley, Audrey Farbos, James W Harrison, Christine M Sambles, David J Studholme, Aaron R Jeffries, Alistair C Darby, Julian A Hiscox, Steve Paterson, Miren Iturriza-Gomara, Kathryn A Jackson, Anita O Lucaci, Edith E Vamos, Margaret Hughes, Lucille Rainbow, Richard Eccles, Charlotte Nelson, Mark Whitehead, Lance Turtle, Sam T Haldenby, Richard Gregory, Matthew Gemmell, Claudia Wierzbicki, Hermione J Webster, Thushan I de Silva, Nikki Smith, Adrienn Angyal, Benjamin B Lindsey, Danielle C Groves, Luke R Green, Dennis Wang, Timothy M Freeman, Matthew D Parker, Alexander J Keeley, Paul J Parsons, Rachel M Tucker, Rebecca Brown, Matthew Wyles, Max Whiteley, Peijun Zhang, Marta Gallis, Stavroula F Louka, Chrystala Constantinidou, Meera Unnikrishnan, Sascha Ott, Jeffrey K.J. Cheng, Hannah E. Bridgewater, Lucy R. Frost, Grace Taylor-Joyce, Richard Stark, Laura Baxter, Mohammad T. Alam, Paul E Brown, Dinesh Aggarwal, Alberto C Cerda, Tammy V Merrill, Rebekah E Wilson, Patrick C McClure, Joseph G Chappell, Theocharis Tsoleridis, Jonathan Ball, David Buck, John A Todd, Angie Green, Amy Trebes, George MacIntyre-Cockett, Mariateresa de Cesare, Alex Alderton, Roberto Amato, Cristina V Ariani, Mathew A Beale, Charlotte Beaver, Katherine L Bellis, Emma Betteridge, James Bonfield, John Danesh, Matthew J Dorman, Eleanor Drury, Ben W Farr, Luke Foulser, Sonia Goncalves, Scott Goodwin, Marina Gourtovaia, Ewan M Harrison, David K Jackson, Dorota Jamrozy, Ian Johnston, Leanne Kane, Sally Kay, Jon-Paul Keatley, Dominic Kwiatkowski, Cordelia F Langford, Mara Lawniczak, Laura Letchford, Rich Livett, Stephanie Lo, Inigo Martincorena, Samantha McGuigan, Rachel Nelson, Steve Palmer, Naomi R Park, Minal Patel, Liam Prestwood, Christoph Puethe, Michael A Quail, Shavanthi Rajatileka, Carol Scott, Lesley Shirley, John Sillitoe, Michael H Spencer Chapman, Scott AJ Thurston, Gerry Tonkin-Hill, Danni Weldon, Diana Rajan, Iraad F Bronner, Louise Aigrain, Nicholas M Redshaw, Stefanie V Lensing, Robert Davies, Andrew Whitwham, Jennifier Liddle, Kevin Lewis, Jaime M Tovar-Corona, Steven Leonard, Jillian Durham, Andrew R Bassett, Shane McCarthy, Robin J Moll, Keith James, Karen Oliver, Alex Makunin, Jeff Barrett, and Rory N Gunson

Subjects
Public aspects of medicine, RA1-1270
Abstract

Summary: Background: The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods: We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, Rt, for the two incidence estimates. Findings: From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the Rt of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, Rt fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation: The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding: Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society.

Published
2021
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2. A low FODMAP diet is associated with changes in the microbiota and reduction in breath hydrogen but not colonic volume in healthy subjects.

Author

Tim J Sloan, Jonna Jalanka, Giles A D Major, Shanthi Krishnasamy, Sue Pritchard, Salah Abdelrazig, Katri Korpela, Gulzar Singh, Claire Mulvenna, Caroline L Hoad, Luca Marciani, David A Barrett, Miranda C E Lomer, Willem M de Vos, Penny A Gowland, and Robin C Spiller

Subjects
Medicine, Science
Abstract

BACKGROUND & AIMS:Ingestion of poorly digested, fermentable carbohydrates (fermentable oligo-, di-, mono-saccharides and polyols; FODMAPs) have been implicated in exacerbating intestinal symptoms and the reduction of intake with symptom alleviation. Restricting FODMAP intake is believed to relieve colonic distension by reducing colonic fermentation but this has not been previously directly assessed. We performed a randomised controlled trial comparing the effect of a low FODMAP diet combined with either maltodextrin or oligofructose on colonic contents, metabolites and microbiota. METHODS:A parallel randomised controlled trial in healthy adults (n = 37). All subjects followed a low FODMAP diet for a week and supplemented their diet with either maltodextrin (MD) or oligofructose (OF) 7g twice daily. Fasted assessments performed pre- and post-diet included MRI to assess colonic volume, breath testing for hydrogen and methane, and stool collection for microbiota analysis. RESULTS:The low FODMAP diet was associated with a reduction in Bifidobacterium and breath hydrogen, which was reversed by oligofructose supplementation. The difference in breath hydrogen between groups post-intervention was 27ppm (95% CI 7 to 50, P

Published
2018
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3. Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Author

S. Cotton, M.P. McHugh, R. Dewar, J.G. Haas, K. Templeton, Samuel C. Robson, Thomas R. Connor, Nicholas J. Loman, Tanya Golubchik, Rocio T. Martinez Nunez, David Bonsall, Andrew Rambaut, Luke B. Snell, Rich Livett, Catherine Ludden, Sally Corden, Eleni Nastouli, Gaia Nebbia, Ian Johnston, Jacqui A. Prieto, Kordo Saeed, David K. Jackson, Catherine Houlihan, Dan Frampton, William L. Hamilton, Adam A. Witney, Giselda Bucca, Cassie F. Pope, Catherine Moore, Emma C. Thomson, Teresa Cutino-Moguel, Ewan M. Harrison, Colin P. Smith, Fiona Rogan, Shaun M. Beckwith, Abigail Murray, Dawn Singleton, Kirstine Eastick, Liz A. Sheridan, Paul Randell, Leigh M. Jackson, Cristina V. Ariani, Sónia Gonçalves, Derek J. Fairley, Matthew W. Loose, Joanne Watkins, Samuel Moses, Sam Nicholls, Matthew Bull, Roberto Amato, Darren L. Smith, David M. Aanensen, Jeffrey C. Barrett, Beatrix Kele, Dinesh Aggarwal, James G. Shepherd, Martin D. Curran, Surendra Parmar, Matthew D. Parker, Catryn Williams, Sharon Glaysher, Anthony P. Underwood, Matthew Bashton, Nicole Pacchiarini, Katie F. Loveson, Matthew Byott, Alessandro M. Carabelli, Kate E. Templeton, Sharon J. Peacock, Thushan I. de Silva, Dennis Wang, Cordelia F. Langford, John Sillitoe, Rory N. Gunson, Simon Cottrell, Justin O’Grady, Dominic Kwiatkowski, Patrick J. Lillie, Nicholas Cortes, Nathan Moore, Claire Thomas, Phillipa J. Burns, Tabitha W. Mahungu, Steven Liggett, Angela H. Beckett, Matthew TG. Holden, Lisa J. Levett, Husam Osman, Mohammed O. Hassan-Ibrahim, David A. Simpson, Meera Chand, Ravi K. Gupta, Alistair C. Darby, Steve Paterson, Oliver G. Pybus, Erik M. Volz, Daniela de Angelis, David L. Robertson, Andrew J. Page, Inigo Martincorena, Louise Aigrain, Andrew R. Bassett, Nick Wong, Yusri Taha, Michelle J. Erkiert, Michael H. Spencer Chapman, Rebecca Dewar, Martin P. McHugh, Siddharth Mookerjee, Stephen Aplin, Matthew Harvey, Thea Sass, Helen Umpleby, Helen Wheeler, James P. McKenna, Ben Warne, Joshua F. Taylor, Yasmin Chaudhry, Rhys Izuagbe, Aminu S. Jahun, Gregory R. Young, Claire McMurray, Clare M. McCann, Andrew Nelson, Scott Elliott, Hannah Lowe, Anna Price, Matthew R. Crown, Sara Rey, Sunando Roy, Ben Temperton, Sharif Shaaban, Andrew R. Hesketh, Kenneth G. Laing, Irene M. Monahan, Judith Heaney, Emanuela Pelosi, Siona Silviera, Eleri Wilson-Davies, Helen Fryer, Helen Adams, Louis du Plessis, Rob Johnson, William T. Harvey, Joseph Hughes, Richard J. Orton, Lewis G. Spurgin, Yann Bourgeois, Chris Ruis, Áine O'Toole, Marina Gourtovaia, Theo Sanderson, Christophe Fraser, Jonathan Edgeworth, Judith Breuer, Stephen L. Michell, John A. Todd, Michaela John, David Buck, Kavitha Gajee, Gemma L. Kay, David Heyburn, Themoula Charalampous, Adela Alcolea-Medina, Katie Kitchman, Alan McNal, David T. Pritch, Samir Dervisevic, Peter Muir, Esther Robinson, Barry B. Vipond, Newara A. Ramadan, Christopher Jeanes, Danni Weldon, Jana Catalan, Neil Jones, Ana da Silva Filipe, Chris Williams, Marc Fuchs, Julia Miskelly, Aaron R. Jeffries, Karen Oliver, Naomi R. Park, Amy Ash, Cherian Koshy, Magdalena Barrow, Sarah L. Buchan, Anna Mantzouratou, Gemma Clark, Christopher W. Holmes, Sharon Campbell, Thomas Davis, Ngee Keong Tan, Julianne R. Brown, Kathryn A. Harris, Stephen P. Kidd, Paul R. Grant, Li Xu-McCrae, Alison Cox, Pinglawathee Madona, Marcus Pond, Paul A. Randell, Karen T. Withell, Cheryl Williams, Clive Graham, Rebecca Denton-Smith, Emma Swindells, Robyn Turnbull, Tim J. Sloan, Andrew Bosworth, Stephanie Hutchings, Hannah M. Pymont, Anna Casey, Liz Ratcliffe, Christopher R. Jones, Bridget A. Knight, Tanzina Haque, Jennifer Hart, Dianne Irish-Tavares, Eric Witele, Craig Mower, Louisa K. Watson DipHE, Jennifer Collins, Gary Eltringham, Dorian Crudgington, Ben Macklin, Miren Iturriza-Gomara, Anita O. Lucaci, Patrick C. McClure, Matthew Carlile, Nadine Holmes, Christopher Moore, Nathaniel Storey, Stefan Rooke, Gonzalo Yebra, Noel Craine, Malorie Perry, Nabil-Fareed Alikhan, Stephen Bridgett, Kate F. Cook, Christopher Fearn, Salman Goudarzi, Ronan A. Lyons, Thomas Williams, Sam T. Haldenby, Jillian Durham, Steven Leonard, Robert M. Davies, Rahul Batra, Beth Blane, Moira J. Spyer, Perminder Smith, Mehmet Yavus, Rachel J. Williams, Adhyana IK. Mahanama, Buddhini Samaraweera, Sophia T. Girgis, Samantha E. Hansford, Angie Green, Charlotte Beaver, Katherine L. Bellis, Matthew J. Dorman, Sally Kay, Liam Prestwood, Shavanthi Rajatileka, Joshua Quick, Radoslaw Poplawski, Nicola Reynolds, Andrew Mack, Arthur Morriss, Thomas Whalley, Bindi Patel, Iliana Georgana, Myra Hosmillo, Malte L. Pinckert, Joanne Stockton, John H. Henderson, Amy Hollis, William Stanley, Wen C. Yew, Richard Myers, Alicia Thornton, Alexander Adams, Tara Annett, Hibo Asad, Alec Birchley, Jason Coombes, Johnathan M. Evans, Laia Fina, Bree Gatica-Wilcox, Lauren Gilbert, Lee Graham, Jessica Hey, Ember Hilvers, Sophie Jones, Hannah Jones, Sara Kumziene-Summerhayes, Caoimhe McKerr, Jessica Powell, Georgia Pugh, Sarah Taylor, Alexander J. Trotter, Charlotte A. Williams, Leanne M. Kermack, Benjamin H. Foulkes, Marta Gallis, Hailey R. Hornsby, Stavroula F. Louka, Manoj Pohare, Paige Wolverson, Peijun Zhang, George MacIntyre-Cockett, Amy Trebes, Robin J. Moll, Lynne Ferguson, Emily J. Goldstein, Alasdair Maclean, Rachael Tomb, Igor Starinskij, Laura Thomson, Joel Southgate, Moritz UG. Kraemer, Jayna Raghwani, Alex E. Zarebski, Olivia Boyd, Lily Geidelberg, Chris J. Illingworth, Chris Jackson, David Pascall, Sreenu Vattipally, Timothy M. Freeman, Sharon N. Hsu, Benjamin B. Lindsey, Keith James, Kevin Lewis, Gerry Tonkin-Hill, Jaime M. Tovar-Corona, MacGregor Cox, Khalil Abudahab, Mirko Menegazzo, Ben EW. Taylor, Corin A. Yeats, Afrida Mukaddas, Derek W. Wright, Leonardo de Oliveira Martins, Rachel Colquhoun, Verity Hill, Ben Jackson, J.T. McCrone, Nathan Medd, Emily Scher, Jon-Paul Keatley, Tanya Curran, Sian Morgan, Patrick Maxwell, Ken Smith, Sahar Eldirdiri, Anita Kenyon, Alison H. Holmes, James R. Price, Tim Wyatt, Alison E. Mather, Timofey Skvortsov, John A. Hartley, Martyn Guest, Christine Kitchen, Ian Merrick, Robert Munn, Beatrice Bertolusso, Jessica Lynch, Gabrielle Vernet, Stuart Kirk, Elizabeth Wastnedge, Rachael Stanley, Giles Idle, Declan T. Bradley, Nicholas F. Killough, Jennifer Poyner, Matilde Mori, Owen Jones, Victoria Wright, Ellena Brooks, Carol M. Churcher, Laia Delgado Callico, Mireille Fragakis, Katerina Galai, Andrew Jermy, Sarah Judges, Anna Markov, Georgina M. McManus, Kim S. Smith, Peter MD. Thomas-McEwen, Elaine Westwick, Stephen W. Attwood, Frances Bolt, Alisha Davies, Elen De Lacy, Fatima Downing, Sue Edwards, Lizzie Meadows, Sarah Jeremiah, Nikki Smith, Luke Foulser, Amita Patel, Louise Berry, Tim Boswell, Vicki M. Fleming, Hannah C. Howson-Wells, Amelia Joseph, Manjinder Khakh, Michelle M. Lister, Paul W. Bird, Karlie Fallon, Thomas Helmer, Claire L. McMurray, Mina Odedra, Jessica Shaw, Julian W. Tang, Nicholas J. Willford, Victoria Blakey, Veena Raviprakash, Nicola Sheriff, Lesley-Anne Williams, Theresa Feltwell, Luke Bedford, James S. Cargill, Warwick Hughes, Jonathan Moore, Susanne Stonehouse, Laura Atkinson, Jack CD. Lee, Divya Shah, Natasha Ohemeng-Kumi, John Ramble, Jasveen Sehmi, Rebecca Williams, Wendy Chatterton, Monika Pusok, William Everson, Anibolina Castigador, Emily Macnaughton, Kate El Bouzidi, Temi Lampejo, Malur Sudhanva, Cassie Breen, Graciela Sluga, Shazaad SY. Ahmad, Ryan P. George, Nicholas W. Machin, Debbie Binns, Victoria James, Rachel Blacow, Lindsay Coupland, Louise Smith, Edward Barton, Debra Padgett, Garren Scott, Aidan Cross, Mariyam Mirfenderesky, Jane Greenaway, Kevin Cole, Phillip Clarke, Nichola Duckworth, Sarah Walsh, Kelly Bicknell, Robert Impey, Sarah Wyllie, Richard Hopes, Chloe Bishop, Vicki Chalker, Ian Harrison, Laura Gifford, Zoltan Molnar, Cressida Auckland, Cariad Evans, Kate Johnson, David G. Partridge, Mohammad Raza, Paul Baker, Stephen Bonner, Sarah Essex, Leanne J. Murray, Andrew I. Lawton, Shirelle Burton-Fanning, Brendan AI. Payne, Sheila Waugh, Andrea N. Gomes, Maimuna Kimuli, Darren R. Murray, Paula Ashfield, Donald Dobie, Fiona Ashford, Angus Best, Liam Crawford, Nicola Cumley, Megan Mayhew, Oliver Megram, Jeremy Mirza, Emma Moles-Garcia, Benita Percival, Megan Driscoll, Leah Ensell, Helen L. Lowe, Laurentiu Maftei, Matteo Mondani, Nicola J. Chaloner, Benjamin J. Cogger, Lisa J. Easton, Hannah Huckson, Jonathan Lewis, Sarah Lowdon, Cassandra S. Malone, Florence Munemo, Manasa Mutingwende, Roberto Nicodemi, Olga Podplomyk FD, Thomas Somassa, Andrew Beggs, Alex Richter, Claire Cormie, Joana Dias, Sally Forrest, Ellen E. Higginson, Mailis Maes, Jamie Young, Rose K. Davidson, Kathryn A. Jackson, Alexander J. Keeley, Jonathan Ball, Timothy Byaruhanga, Joseph G. Chappell, Jayasree Dey, Jack D. Hill, Emily J. Park, Arezou Fanaie, Rachel A. Hilson, Geraldine Yaze, Stephanie Lo, Safiah Afifi, Robert Beer, Joshua Maksimovic, Kathryn McCluggage, Karla Spellman, Catherine Bresner, William Fuller, Angela Marchbank, Trudy Workma, Ekaterina Shelest, Johnny Debebe, Fei Sang, Sarah Francois, Bernardo Gutierrez, Tetyana I. Vasylyeva, Flavia Flaviani, Manon Ragonnet-Cronin, Katherine L. Smollett, Alice Broos, Daniel Mair, Jenna Nichols, Kyriaki Nomikou, Lily Tong, Ioulia Tsatsani, Sarah O'Brien, Steven Rushton, Roy Sanderson, Jon Perkins, Seb Cotton, Abbie Gallagher, Elias Allara, Clare Pearson, David Bibby, Gavin Dabrer, Nicholas Ellaby, Eileen Gallagher, Jonathan Hubb, Angie Lackenby, David Lee, Nikos Manesis, Tamyo Mbisa, Steven Platt, Katherine A. Twohig, Mari Morgan, Alp Aydin, David J. Baker, Ebenezer Foster-Nyarko, Sophie J. Prosolek, Steven Rudder, Chris Baxter, Sílvia F. Carvalho, Deborah Lavin, Arun Mariappan, Clara Radulescu, Aditi Singh, Miao Tang, Helen Morcrette, Nadua Bayzid, Marius Cotic, Carlos E. Balcazar, Michael D. Gallagher, Daniel Maloney, Thomas D. Stanton, Kathleen A. Williamson, Robin Manley, Michelle L. Michelsen, Christine M. Sambles, David J. Studholme, Joanna Warwick-Dugdale, Richard Eccles, Matthew Gemmell, Richard Gregory, Margaret Hughes, Charlotte Nelson, Lucille Rainbow, Edith E. Vamos, Hermione J. Webster, Mark Whitehead, Claudia Wierzbicki, Adrienn Angyal, Luke R. Green, Max Whiteley, Emma Betteridge, Iraad F. Bronner, Ben W. Farr, Scott Goodwin, Stefanie V. Lensing, Shane A. McCarthy, Michael A. Quail, Diana Rajan, Nicholas M. Redshaw, Carol Scott, Lesley Shirley, Scott AJ. Thurston, Will Rowe, Amy Gaskin, Thanh Le-Viet, James Bonfield, Jennifier Liddle, Andrew Whitwham, University of St Andrews. School of Medicine, University of St Andrews. Infection and Global Health Division, and Apollo - University of Cambridge Repository

Subjects
Microbiology (medical), MCC, Introduction, SARS-CoV-2, NDAS, COVID-19, Care homes, General Medicine, NIS, Patient Discharge, Hospitals, Hospitalization, Infectious Diseases, SDG 3 - Good Health and Well-being, RA0421, RA0421 Public health. Hygiene. Preventive Medicine, Humans, Hospital discharge
Abstract

COG-UK is supported by funding from the MRC part of UK Research & Innovation, the National Institute of Health Research (Grant code MC_PC_19027), and Genome Research Limited, operating as the Welcome Sanger Institute. Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine. Publisher PDF

Published
2023

4. Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study

Author

Harry D Wilson, Elaine O'Toole, Andrew Bassett, Moritz U. G. Kraemer, Beth Blane, Scott Goodwin, Giri Shankar, Joseph Hughes, Lucy R. Frost, Alicia Thornton, Scott Elliott, Tammy V Merrill, Sheila Waugh, Alexander Adams, Peter Muir, Graciela Sluga, Rebecca Williams, Hannah Dent, Christophe Fraser, Shavanthi Rajatileka, John C. Hartley, Luke B Snell, Benjamin J Cogger, Lance Turtle, Alex Makunin, John A. Todd, Victoria Wright, Daniela De Angelis, James McKenna, Dinesh Aggarwal, Jonathan K. Ball, Jillian Durham, Garren Scott, Thushan I de Silva, Veena Raviprakash, Hannah M Pymont, Jason Coombes, Anita Lucaci, Luke R. Green, Leigh M Jackson, Hermione J. Webster, Louis du Plessis, David A. Jackson, Minal Patel, Áine O'Toole, Ravi Gupta, Marc Niebel, Garry Scarlett, Rajiv Shah, Guy Mollett, Kathy Li, Rory Gunson, Matthew Bashton, Carl Jones, Sara Kumziene-Summerhayes, Zoltan Molnar, Siona Silveira, Malte L Pinckert, Catherine Ludden, Angeliki Karamani, Leanne Kane, Brendan A I Payne, Alan McNally, Clare M. McCann, Holli Carden, Mohammad Raza, Alison E. Mather, Kate B. Cook, Amy Gaskin, David J. Williams, Shaun R. Seaman, Christopher I. Jones, Gilberto Betancor, Matthew T. G. Holden, Jennifier Liddle, Meera Unnikrishnan, Angie Green, Ben Taylor, Kelly Bicknell, Alexander J. Trotter, Emma Meader, Leanne M Kermack, Nathaniel Storey, Michelle Cronin, Sally Forrest, Sarah Jeremiah, Asad Zaidi, M Morgan, Alasdair MacLean, Thomas R. Connor, Johnathan M Evans, Rachael Stanley, Ryan P George, Nadine Holmes, Richard H. Myers, Christine Sambles, Bernardo Gutierrez, Jeffrey K. J. Cheng, Tim Wyatt, Natasha Jesudason, Lindsay Coupland, Monika Pusok, Manon Ragonnet-Cronin, Jenifer Mason, Joshua Maksimovic, Russell Hope, Alison Holmes, David Simpson, Radoslaw Poplawski, Amelia Joseph, Erwan Acheson, James Bonfield, Mara K. N. Lawniczak, Sascha Ott, Lesley-Anne Williams, Jessica Lynch, Graham P. Taylor, Anita Kenyon, Elizabeth Wastenge, Megan Mayhew, Adhyana I K Mahanama, Stavroula F Louka, Chloe Bishop, Esther Robinson, Darren Smith, Anne M. Presanis, Matthew Carlile, Thomas D Stanton, Dennis Wang, Katerina Galai, Adam P Westhorpe, Flavia Flaviani, Michelle Wantoch, Max Whiteley, Yann Bourgeois, Matthew Gemmell, Mary Ramsay, A Lloyd, Simon Thelwall, Hannah C. Howson-Wells, Joseph G. Chappell, Steve Paterson, Gary Eltringham, Robert Impey, Siddharth Mookerjee, Steven Platt, Emma Swindells, Laura Letchford, Alex Alderton, Lee Graham, Safiah Afifi, David C. Lee, Cassie Breen, Melisa Louise Fenton, Benita Percival, Adrian W Signell, Tanya Golubchik, Ian B Vipond, Eleri Wilson-Davies, Angie Lackenby, Laura Atkinson, Sarojini Pandey, Nazreen F. Hadjirin, Michael A Chapman, Huw Gulliver, Joana Dias, Grant Hall, Antony D Hale, Hassan Hartman, Alp Aydin, Louise Smith, Ashok Dadrah, Johnny Debebe, Sarah Walsh, Stephanie W. Lo, Andrew Bosworth, Bridget Knight, Hannah E Bridgewater, Nadua Bayzid, Gemma L. Kay, Richard Gregory, Sally Kay, Ellena Brooks, Andre Charlett, Georgina M McManus, Riaz Jannoo, Victoria Blakey, Carol Scott, Rachel Nelson, Liz Ratcliffe, Gerry Tonkin-Hill, Verity Hill, Joanne D. Stockton, Danielle Leek, Steven Leonard, Stephanie Hutchings, Jonathan D. Moore, Kathryn Ann Harris, Sophie Jones, Venkat Sivaprakasam, Amy Plimmer, Tanzina Haque, Katherine L. Bellis, Khalil Abudahab, Dianne Irish-Tavares, Gaia Nebbia, Kathryn A Jackson, Stephen W Attwood, Daniel Mair, Sreenu Vattipally, Susanne Stonehouse, Ian Merrick, Lucille Rainbow, Mathew A. Beale, Angela Helen Beckett, Ember Hilvers, Thomas Helmer, Jenna Nichols, Giselda Bucca, Salman Goudarzi, Christopher Ruis, Surendra Parmar, Angela Cowell, Alberto C Cerda, Divya K. Shah, Judith Heaney, E. Thomson, Kyriaki Nomikou, Nicole Pacchiarini, Katherine L Harper, Fatima Downing, M. Estée Török, Michelle L Michelsen, Aaron R. Jeffries, Jennifer Collins, Christopher Williams, Katie F. Loveson, Steven Rudder, Theocharis Tsoleridis, Robert Davies, David Robertson, Katherine Smollett, Kathryn McCluggage, Liam Crawford, Inigo Martincorena, Charlotte Beaver, Oliver Megram, Karla Spellman, Sam Haldenby, Emma Betteridge, William D. Fuller, Will P. M. Rowe, Cherian Koshy, Tim E. A. Peto, Alison Cox, Natasha Johnson, Tanya Curran, Sharif Shaaban, Tamyo Mbisa, Cordelia Langford, Eric Witele, Andrew J. Page, Christoph Puethe, Nicola Reynolds, Paul W Bird, Louise Aigrain, Ronan Lyons, Amy Trebes, Sally Corden, Steven Rushton, Jack Cd Lee, Jane Greenaway, Hibo Asad, Amanda Bradley, Mohammed O Hassan-Ibrahim, Shane McCarthy, Fei Sang, Matthew Loose, Hannah Jones, Keith D. James, Chloe L Fisher, Chrystala Constantinidou, Alex G. Richter, Jane A. H. Masoli, Michael Gallagher, Vicki M. Fleming, Anna Price, Amy Ash, Michaela John, Alex Zarebski, Fenella D. Halstead, John Danesh, Christine Kitchen, Aminu S Jahun, Mark Whitehead, Julianne R Brown, Catherine Bresner, Marius Cotic, Stefanie V Lensing, Nick Levene, Louissa R Macfarlane-Smith, Wendy Hogsden, Cressida Auckland, Eleanor Drury, Richard Eccles, Jennifer Hart, Seema Nickbakhsh, Alisha Davies, David M. Aanensen, Shirelle Burton-Fanning, Ben Farr, Buddhini Samaraweera, Sarah Wyllie, Hannah Lowe, Richard J. Orton, Martin D. Curran, Carol Churcher, Karen Oliver, Elihu Aranday-Cortes, Wen Yew, Thanh Le-Viet, Matthew Parker, Katherine A Twohig, Shahjahan Miah, Samuel M. Nicholls, G MacIntyre-Cockett, Tranprit Saluja, Charlotte Nelson, Vicki Chalker, Roberto Amato, Ellen Higginson, Timothy M. Freeman, Christopher W Holmes, Yasmin Chaudhry, Elias Allara, Alec Birchley, Iraad Bronner, Emma Moles-Garcia, Angus I. Best, Anna L. Casey, Audrey Farbos, Nicholas W Machin, David W Eyre, Tim Boswell, Charlotte A Williams, Elen De Lacy, Matthew J. Bull, Matilde Mori, Carmen F. Manso, Peijun Zhang, Sahar Eldirdiri, Dimitris Grammatopoulos, Corin Yeats, Claudia Wierzbicki, David G Partridge, Kordo Saeed, Nichola Duckworth, David J. Studholme, Harmeet K Gill, Juan Ledesma, Thomas R. A. Davis, Sushmita Sridhar, Clive Graham, Husam Osman, Julian A. Hiscox, Helen Adams, Christopher Fearn, Fabrícia F. Nascimento, Ulf Schaefer, James W. Harrison, Andrew J. Nelson, Joshua Quick, Mohammad Tauqeer Alam, Liam Prestwood, Nikos Manesis, Julian Tang, Justin O'Grady, Sophia T Girgis, Louise Berry, Gemma Clark, Marina Escalera Zamudio, Karlie Fallon, Tim J Sloan, Joanne Watkins, Clare Pearson, Andrew D Beggs, Rachel Williams, Luke Bedford, Trevor Robinson, Nicholas M Redshaw, Richard Hopes, Mirko Menegazzo, Katherine Twohig, Gabrielle Vernet, Steven Liggett, Mariateresa de Cesare, Derrick W. Crook, Dominic P. Kwiatkowski, Mark Kristiansen, Miren Iturriza-Gomara, Christopher I. Moore, Claire Cormie, Olivia Boyd, Nikki Smith, Noel Craine, Kathleen A. Williamson, John Boyes, Sian Ellard, Cristina V. Ariani, Wendy Chatterton, David Bonsall, Kevin Lewis, David Jorgensen, Ian Harrison, Christopher Jackson, Martin P McHugh, Danni Weldon, Michael A. Quail, Amita Patel, Lily Geidelberg, Myra Hosmillo, Judith Breuer, Cariad Evans, Edward Barton, Trudy Workman, Derek Fairley, Vineet Patel, Daniel Bradshaw, Robin Manley, Scott Aj Thurston, John Sillitoe, Monique Andersson, Sharon J. Peacock, Jamie Lopez-Bernal, Thomas Thompson, Nabil-Fareed Alikhan, Ben Temperton, Paul Baker, Robin J Moll, Laura Gifford, Nicholas J. Loman, Jayna Raghwani, Jacqui Prieto, Andrew Hesketh, Oliver G. Pybus, Adela Alcolea-Medina, David Buck, Gregory R Young, Alistair C. Darby, Sónia Gonçalves, Aileen G. Rowan, Tabitha Mahungu, Nicholas Ellaby, Jon-Paul Keatley, Lily Tong, Robert Beer, Martyn Guest, Lisa J Levett, Ali R Awan, Iliana Georgana, Paul E Brown, Li Xu-McCrae, Stephen P. Kidd, Sara Rey, Shazaad Ahmad, Danielle C. Groves, Tetyana I. Vasylyeva, David F. Bibby, Nathan Moore, Fiona Ashcroft, Igor Starinskij, Hannah Paul, Claire McMurray, Michael Spencer Chapman, Carlos Balcazar, Joanna Warwick-Dugdale, Pinglawathee Madona, Edith Vamos, Lesley Shirley, Kate Templeton, Luke Foulser, Igor Siveroni, Ewan M. Harrison, Sian Morgan, Diana Rajan, S Taylor, Laia Fina, Naomi Park, Sarah J. O'Brien, Alessandro M Carabelli, Angela Marchbank, Sunando Roy, Leonardo de Oliveira Martins, Steve Palmer, Jonathan Hubb, Alexander J Keeley, Francesc Coll, Malorie Perry, Paul J. Parsons, Anthony Underwood, Patawee Asamaphan, William L Hamilton, Tommy Nyberg, Sophie Palmer, Amanda Symmonds, Anoop Chauhan, Robert Johnson, Christopher J. R. Illingworth, James Shepherd, Wendy Smith, Rich Livett, Rachel Blacow, Margaret Hughes, Jeremy Mirza, Joanne Watts, Jonathan D. Edgeworth, Sarah François, Sue Edwards, Adrienn Angyal, Thomas N. Williams, Marta Gallis, Lauren Gilbert, Paul Randell, Kate Johnson, Eileen Gallagher, Nick Cortes, Yusri Taha, Leah Ensell, Emanuela Pelosi, Stefan Rooke, Michelle Lister, Ana da Silva Filipe, Cassandra S Malone, Themoula Charalampous, Benjamin B Lindsey, Natalie Groves, Colin Smith, Ross J Harris, Rebekah E Wilson, Stephen Bonner, Richard Stark, Sharon Campbell, Nicola Sheriff, Helen L Lowe, Rachel Jones, Ben Warne, Rose K Davidson, Declan Bradley, Ian Johnston, Jeffrey C. Barrett, Joshua B Singer, Shirin Aliabadi, Andrew Whitwham, Patrick McClure, Samuel Robson, Sharon Glaysher, Robert J. Munn, Emma L. Wise, Laura Baxter, Kim S Smith, Catherine Moore, Bree Gatica-Wilcox, Alice Broos, Sarah Essex, David Baker, Manjinder Khakh, Dorota Jamrozy, Rachel Tucker, Ian Goodfellow, S.E. Moses, Nicola Cumley, Robin Howe, Meera Chand, James I. Price, Marina Gourtovaia, Debra Padgett, Jaime Tovar-Corona, Stephen L. Michell, Matthew J. Dorman, Lizzie Meadows, David Heyburn, Iona Willingham, Rocio Martinez Nunez, Grace Taylor-Joyce, Claire M Bewshea, Anita Justice, Simon Cottrell, Rebecca C H Brown, Jamie Young, Gavin Dabrera, Matthew Wyles, Stephen Carmichael, Lisa Berry, Frances Bolt, Andrew Rambaut, Samir Dervisevic, Erik M. Volz, Rahul Batra, Caoimhe McKerr, Samantha McGuigan, Katie Jones, Mailis Maes, Rebecca Dewar, Mary Sinnathamby, Joel Southgate, and Lynn Monaghan

Subjects
medicine.medical_specialty, business.industry, Proportional hazards model, Public health, Hazard ratio, Attendance, C500, Vaccination, Infectious Diseases, Relative risk, Internal medicine, Cohort, medicine, business, Cohort study
Abstract

Background: \ud The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes.\ud \ud Methods: \ud This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status.\ud \ud Findings: \ud Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low.\ud \ud Interpretation: \ud This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant.\ud \ud Funding: \ud Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.

Published
2022

5. Exponential growth, high prevalence of SARS-CoV-2, and vaccine effectiveness associated with the Delta variant

Author

Mohammad Raza, Alison E. Mather, Gilberto Betancor, Ian Merrick, Ben Taylor, Mathew A. Beale, Helen Ward, Samir Dervisevic, Michelle Cronin, Aaron R. Jeffries, Louise Smith, Steven Rudder, Mara K. N. Lawniczak, Sascha Ott, Ashok Dadrah, Luke Bedford, Gabrielle Vernet, Erik M. Volz, Rahul Batra, Johnny Debebe, Caoimhe McKerr, Samantha McGuigan, Oliver Megram, Katie Jones, Mailis Maes, Rebecca Dewar, Emma Swindells, Robert E. Johnson, Myra Hosmillo, Wen C Yew, Vineet Patel, Scott Aj Thurston, Matthew Bashton, Luke B Snell, Lynn Monaghan, David Buck, Gregory R Young, Garren Scott, Louis du Plessis, Sara Kumziene-Summerhayes, David M. Aanensen, Carl Jones, Nadine Holmes, Bernardo Gutierrez, Elizabeth Wastenge, Stavroula F Louka, Dennis Wang, Richard I. Gregory, M. Estée Török, Alistair C. Darby, Ulf Schaefer, Marc Niebel, David Robertson, E. Thomson, Carol Churcher, Patrick C McClure, Scott Elliott, Sarah Jeremiah, Katerina Galai, Matthew W. Loose, Megan Mayhew, Adhyana I K Mahanama, Angeliki Karamani, Naomi R Park, David J. Williams, Lance Turtle, Lucy R. Frost, Alicia Thornton, Jennifier Liddle, M Morgan, Tim Wyatt, Paul W Bird, Chloe Bishop, Esther Robinson, Alasdair MacLean, Inigo Martincorena, Bridget A. Knight, Emma Meader, Thomas R. Connor, Hermione J. Webster, Peter Muir, Sarah Walsh, Stephanie W. Lo, Andrew Bosworth, Hannah E Bridgewater, David Simpson, Radoslaw Poplawski, Angus I. Best, David Baker, Laura Letchford, Cassie Breen, Yann Bourgeois, Matthew Gemmell, Nikki Smith, Alison Holmes, Iliana Georgana, Christophe Fraser, Natasha Jesudason, Johnathan M Evans, Rachael Stanley, Lesley-Anne Williams, Jessica Lynch, Hannah Lowe, Eleri Wilson-Davies, Paul A. Baker, Alex Makunin, James Bonfield, Helen Adams, Christopher Fearn, Peter J. Diggle, Harry D Wilson, Carmen F. Manso, Nichola Duckworth, D Haw, Anna L. Casey, Audrey Farbos, Sam Haldenby, Vicki Chalker, Roberto Amato, Elen De Lacy, Ben Farr, Eric Witele, Buddhini Samaraweera, G MacIntyre-Cockett, Husam Osman, Jane Greenaway, Justin O'Grady, Sally Forrest, Andrew Nelson, Monika Pusok, A Lloyd, Edward Barton, James W. Harrison, Sophie Palmer, Amanda Symmonds, James Shepherd, Nazreen F. Hadjirin, Stephen L. Michell, Mohammed O Hassan-Ibrahim, Fiona Ashcroft, Daniel Mair, Richard H. Myers, Dianne Irish-Tavares, Hannah C. Howson-Wells, Jacqui Prieto, Christine Sambles, Andrew Hesketh, Alp Aydin, Sónia Gonçalves, Tabitha Mahungu, Tanzina Haque, Nicholas Ellaby, Karen Oliver, Hannah Paul, Joanne Watts, Claire McMurray, Lisa J Levett, Darren Smith, Simon Cottrell, Joanna Warwick-Dugdale, Pinglawathee Madona, Matthew J. Dorman, Lizzie Meadows, Ali R Awan, Leanne M Kermack, Jennifer Hart, Angie Lackenby, Carol Scott, Michael Spencer Chapman, Lucille Rainbow, Kyriaki Nomikou, Julianne R Brown, Juan Ledesma, Adam P Westhorpe, Giri Shankar, Karlie Fallon, Tim J Sloan, Joanne Watkins, Robert Impey, Sue Edwards, Rebecca C H Brown, Robin J Moll, Karla Spellman, Laura Gifford, Jamie Young, Adrienn Angyal, Graham Phillip Taylor, Robin Manley, Gavin Dabrera, Michelle Wantoch, Rachel Williams, David Heyburn, Mirko Menegazzo, Derrick W. Crook, Gaia Nebbia, Rachel Nelson, Elaine O'Toole, Luke Foulser, Katherine L Harper, Fatima Downing, Hassan Hartman, Nathan Moore, Gemma L. Kay, Matthew Wyles, Thanh Le-Viet, Edith Vamos, John Sillitoe, Lesley Shirley, Nicholas J. Loman, Iona Willingham, Elihu Aranday-Cortes, Ian B Vipond, Jeremy Mirza, Alberto C Cerda, Michelle L Michelsen, Steven Riley, Alison Cox, Igor Siveroni, Nadua Bayzid, Shavanthi Rajatileka, Giselda Bucca, Benjamin J Cogger, Tim Boswell, Matthew J. Bull, Stephen Carmichael, Lisa Berry, Frances Bolt, Kylie E. C. Ainslie, Martyn Guest, Sarojini Pandey, Katherine L. Bellis, Shane A. McCarthy, Christopher Ruis, Fei Sang, David Bonsall, Danni Weldon, Alex Alderton, Lee Graham, Amy Trebes, Sally Corden, Adrian W Signell, Tanya Golubchik, Huw Gulliver, Rocio Martinez Nunez, Dinesh Aggarwal, Tanya Curran, Jonathan K. Ball, Sharif Shaaban, Paul Randell, Jillian Durham, Alec Birchley, Matilde Mori, Joana Dias, Katherine A Twohig, Grant Hall, Antony D Hale, Alan McNally, Jonathan D. Edgeworth, Safiah Afifi, Andrew Rambaut, Katherine Smollett, David N. Lee, Tamyo Mbisa, Shahjahan Miah, Steven Rushton, Grace Taylor-Joyce, Hannah M Pymont, Chloe L Fisher, Cordelia Langford, Alex G. Richter, Jane A. H. Masoli, Michael Gallagher, Vicki M. Fleming, Kathleen A. Williamson, Anna Price, Holli Carden, Khalil Abudahab, Joanne D. Stockton, Meera Unnikrishnan, Jennifer Collins, Emma Moles-Garcia, Michaela John, Christine Kitchen, Tranprit Saluja, Ian Harrison, Lily Tong, Thomas G. Thompson, Thomas Helmer, Amita Patel, Siona Silveira, Deborah Ashby, Claire M Bewshea, Anita Justice, Brendan A I Payne, Alexander J. Trotter, Nikos Manesis, Katie F. Loveson, Cristina V. Ariani, Wendy Chatterton, Robert J. Munn, Julian A. Hiscox, Robert Beer, Judith Breuer, Caroline E. Walters, Liam Crawford, Ara Darzi, Will P. M. Rowe, Cariad Evans, Matthew Parker, Tammy V Merrill, Louise Aigrain, Joshua Quick, Leigh M Jackson, Samuel M. Nicholls, Jonathan W. Moore, John A Hartley, Graham P. Taylor, Cherian Koshy, Shirelle Burton-Fanning, Sheila Waugh, Catherine Moore, Danielle C. Groves, Peijun Zhang, Sahar Eldirdiri, Derek Fairley, Tim E. A. Peto, Jack Cd Lee, Sharon Glaysher, Liam Prestwood, Hannah Dent, Anita Kenyon, Stephen P. Kidd, Nick Levene, Igor Starinskij, Joseph G. Chappell, Steve Paterson, Gary Eltringham, Laia Fina, Angela Marchbank, Daniel Bradshaw, Marina Escalera Zamudio, Scott Goodwin, Andrew D Beggs, Seema Nickbakhsh, Trevor Robinson, Christina Atchison, David K. Jackson, Kathy Li, Rory Gunson, Sunando Roy, Graham S Cooke, Steven Liggett, Yasmin Chaudhry, Anoop Chauhan, Ben Temperton, Mariateresa de Cesare, Paul E Brown, Li Xu-McCrae, Martin P McHugh, Catherine Ludden, Wendy Smith, Danielle Leek, Divya K. Shah, Judith Heaney, Dominic P. Kwiatkowski, Kate M. Johnson, Robin Howe, Malorie Perry, Tetyana I. Vasylyeva, David F. Bibby, Haowei Wang, Steve Palmer, Nicholas W Machin, Charlotte A Williams, Bree Gatica-Wilcox, Angie Green, John A. Todd, Paul Elliott, Noel Craine, Jeffrey K. J. Cheng, Kate Templeton, Jonathan Hubb, Joshua Maksimovic, Christl A. Donnelly, Monique Andersson, Christopher Holmes, Dimitris Grammatopoulos, Christopher B. Williams, David G Partridge, Aminu S Jahun, Alexander Adams, Marius Cotic, Sarah Essex, Christopher J. Moore, Trudy Workman, Nicola Sheriff, Helen L Lowe, Ewan M. Harrison, Dorota Jamrozy, Rachel Jones, Ellen Higginson, Erwan Acheson, Christopher R. Jones, Oliver G. Pybus, Francesc Coll, Sian Morgan, Paul J. Parsons, Patawee Asamaphan, Veena Raviprakash, Andrew R. Bassett, Declan Bradley, Laura Atkinson, Anthony Underwood, Graciela Sluga, Sally Kay, Ellena Brooks, Oliver Eales, Andrew Whitwham, Surendra Parmar, Angela Cowell, Nicole Pacchiarini, Theocharis Tsoleridis, Jason Coombes, Robert Davies, Flavia Flaviani, Benita Percival, Jenna Nichols, Natasha M. Johnson, Salman Goudarzi, Hibo Asad, Amanda Bradley, Hannah Jones, Chrystala Constantinidou, Georgina M McManus, Minal Patel, Steven Leonard, Rebecca Williams Bmbs, Andrew J. Page, Christoph Puethe, Nicola Reynolds, Amy Ash, John Danesh, Corin Yeats, Claudia Wierzbicki, Kordo Saeed, John Boyes, Michael A. Quail, Sharon J. Peacock, Nabil-Fareed Alikhan, Jon-Paul Keatley, Claudio Fronterre, Garry Scarlett, James McKenna, Thushan I de Silva, Malte L Pinckert, Kate B. Cook, Amy Gaskin, Rajiv Shah, Matthew T. G. Holden, Sophie J Prosolek, Nathaniel Storey, Ryan P George, Lindsay Coupland, Jenifer Mason, Matthew Carlile, Thomas D Stanton, Guy Mollett, Siddharth Mookerjee, Mary Ramsay, Steven Platt, Stephen W Attwood, Susanne Stonehouse, Sophie Jones, Venkat Sivaprakasam, Amy Plimmer, Mark Whitehead, Catherine Bresner, Stefanie V Lensing, Louissa R Macfarlane-Smith, Colin P. Smith, Wendy Hogsden, Charlotte Nelson, Ian Johnston, Jeffrey C. Barrett, Joshua B Singer, Samuel Robson, Zoltán Molnár, Emma L. Wise, Sian Ellard, Kim S Smith, Alice Broos, Manjinder Khakh, Kathryn A Jackson, Claire Cormie, Rachel Tucker, Ian Goodfellow, S.E. Moses, Nicola Cumley, Meera Chand, Debra Padgett, Cassandra S Malone, James V. Price, Themoula Charalampous, Ronan A Lyons, Natalie Groves, Stefan Rooke, Rebekah E Wilson, Stephen Bonner, Richard Stark, Sharon Campbell, Michelle Lister, Carlos Balcazar, Ana da Silva Filipe, Ben Warne, Thomas N. Williams, Marta Gallis, Lauren Gilbert, Rose K Davidson, Angela Helen Beckett, Ember Hilvers, Kathryn McCluggage, Eileen Gallagher, Charlotte Beaver, Nick Cortes, Alisha Davies, Yusri Taha, Leah Ensell, Emanuela Pelosi, Elias Allara, Cressida Auckland, Eleanor Drury, Richard Eccles, Adela Alcolea-Medina, William L Hamilton, Rich Livett, Rachel Blacow, Margaret Hughes, Sarah François, Melisa Louise Fenton, Liz Ratcliffe, Verity Hill, Stephanie Hutchings, Kathryn Ann Harris, Emma Betteridge, William D. Fuller, Sophia T Girgis, Louise Berry, Gemma Clark, Nicholas M Redshaw, Richard Hopes, Leonardo de Oliveira Martins, Alexander J Keeley, Beth Blane, Wendy S. Barclay, Victoria Wright, Anita Lucaci, Luke R. Green, Fenella D. Halstead, Sarah Wyllie, Iraad F. Bronner, Áine O'Toole, Ravi Gupta, Leanne Kane, Clare M. McCann, Michael R Chapman, David W Eyre, Kelly Bicknell, Aileen G. Rowan, Sara Rey, Shazaad Ahmad, Diana Rajan, S Taylor, Sarah J. O'Brien, Alessandro M Carabelli, Amelia Joseph, Max Whiteley, Riaz Jannoo, Victoria Blakey, Martin D. Curran, David J. Studholme, Harmeet K Gill, Thomas R. A. Davis, Sushmita Sridhar, Clive Graham, Julian Tang, Clare Pearson, Mark Kristiansen, Miren Iturriza-Gomara, National Institute for Health Research, and UK Research and Innovation

Subjects
Delta, Adult, Male, 2019-20 coronavirus outbreak, COVID-19 Vaccines, Vaccination Coverage, Coronavirus disease 2019 (COVID-19), Adolescent, General Science & Technology, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Vaccine Efficacy, Biology, Young Adult, Exponential growth, Ethnicity, Prevalence, Humans, Child, Aged, Family Characteristics, Multidisciplinary, High prevalence, COVID-19 Genomics UK (COG-UK) Consortium11‡, SARS-CoV-2, Age Factors, COVID-19, Middle Aged, Virology, Hospitalization, England, Socioeconomic Factors, COVID-19 Nucleic Acid Testing, Child, Preschool, Female, Self Report
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were rising during early summer 2021 in many countries as a result of the Delta variant. We assessed reverse transcription polymerase chain reaction swab positivity in the Real-time Assessment of Community Transmission–1 (REACT-1) study in England. During June and July 2021, we observed sustained exponential growth with an average doubling time of 25 days, driven by complete replacement of the Alpha variant by Delta and by high prevalence at younger, less-vaccinated ages. Prevalence among unvaccinated people [1.21% (95% credible interval 1.03%, 1.41%)] was three times that among double-vaccinated people [0.40% (95% credible interval 0.34%, 0.48%)]. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination.

Published
2021

6. The impact of viral mutations on recognition by SARS-CoV-2 specific T cells

Author

Thushan I. de Silva, Guihai Liu, Benjamin B. Lindsey, Danning Dong, Shona C. Moore, Nienyun Sharon Hsu, Dhruv Shah, Dannielle Wellington, Alexander J. Mentzer, Adrienn Angyal, Rebecca Brown, Matthew D. Parker, Zixi Ying, Xuan Yao, Lance Turtle, Susanna Dunachie, Mala K. Maini, Graham Ogg, Julian C. Knight, Yanchun Peng, Sarah L. Rowland-Jones, Tao Dong, David M. Aanensen, Khalil Abudahab, Helen Adams, Alexander Adams, Safiah Afifi, Dinesh Aggarwal, Shazaad S.Y. Ahmad, Louise Aigrain, Adela Alcolea-Medina, Nabil-Fareed Alikhan, Elias Allara, Roberto Amato, Tara Annett, Stephen Aplin, Cristina V. Ariani, Hibo Asad, Amy Ash, Paula Ashfield, Fiona Ashford, Laura Atkinson, Stephen W. Attwood, Cressida Auckland, Alp Aydin, David J. Baker, Paul Baker, Carlos E. Balcazar, Jonathan Ball, Jeffrey C. Barrett, Magdalena Barrow, Edward Barton, Matthew Bashton, Andrew R. Bassett, Rahul Batra, Chris Baxter, Nadua Bayzid, Charlotte Beaver, Angela H. Beckett, Shaun M. Beckwith, Luke Bedford, Robert Beer, Andrew Beggs, Katherine L. Bellis, Louise Berry, Beatrice Bertolusso, Angus Best, Emma Betteridge, David Bibby, Kelly Bicknell, Debbie Binns, Alec Birchley, Paul W. Bird, Chloe Bishop, Rachel Blacow, Victoria Blakey, Beth Blane, Frances Bolt, James Bonfield, Stephen Bonner, David Bonsall, Tim Boswell, Andrew Bosworth, Yann Bourgeois, Olivia Boyd, Declan T. Bradley, Cassie Breen, Catherine Bresner, Judith Breuer, Stephen Bridgett, Iraad F. Bronner, Ellena Brooks, Alice Broos, Julianne R. Brown, Giselda Bucca, Sarah L. Buchan, David Buck, Matthew Bull, Phillipa J. Burns, Shirelle Burton-Fanning, Timothy Byaruhanga, Matthew Byott, Sharon Campbell, Alessandro M. Carabelli, James S. Cargill, Matthew Carlile, Silvia F. Carvalho, Anna Casey, Anibolina Castigador, Jana Catalan, Vicki Chalker, Nicola J. Chaloner, Meera Chand, Joseph G. Chappell, Themoula Charalampous, Wendy Chatterton, Yasmin Chaudhry, Carol M. Churcher, Gemma Clark, Phillip Clarke, Benjamin J. Cogger, Kevin Cole, Jennifer Collins, Rachel Colquhoun, Thomas R. Connor, Kate F. Cook, Jason Coombes, Sally Corden, Claire Cormie, Nicholas Cortes, Marius Cotic, Seb Cotton, Simon Cottrell, Lindsay Coupland, MacGregor Cox, Alison Cox, Noel Craine, Liam Crawford, Aidan Cross, Matthew R. Crown, Dorian Crudgington, Nicola Cumley, Tanya Curran, Martin D. Curran, Ana da Silva Filipe, Gavin Dabrera, Alistair C. Darby, Rose K. Davidson, Alisha Davies, Robert M. Davies, Thomas Davis, Daniela de Angelis, Elen De Lacy, Leonardo de Oliveira Martins, Johnny Debebe, Rebecca Denton-Smith, Samir Dervisevic, Rebecca Dewar, Jayasree Dey, Joana Dias, Donald Dobie, Matthew J. Dorman, Fatima Downing, Megan Driscoll, Louis du Plessis, Nichola Duckworth, Jillian Durham, Kirstine Eastick, Lisa J. Easton, Richard Eccles, Jonathan Edgeworth, Sue Edwards, Kate El Bouzidi, Sahar Eldirdiri, Nicholas Ellaby, Scott Elliott, Gary Eltringham, Leah Ensell, Michelle J. Erkiert, Marina Escalera Zamudio, Sarah Essex, Johnathan M. Evans, Cariad Evans, William Everson, Derek J. Fairley, Karlie Fallon, Arezou Fanaie, Ben W. Farr, Christopher Fearn, Theresa Feltwell, Lynne Ferguson, Laia Fina, Flavia Flaviani, Vicki M. Fleming, Sally Forrest, Ebenezer Foster-Nyarko, Benjamin H. Foulkes, Luke Foulser, Mireille Fragakis, Dan Frampton, Sarah Francois, Christophe Fraser, Timothy M. Freeman, Helen Fryer, Marc Fuchs, William Fuller, Kavitha Gajee, Katerina Galai, Abbie Gallagher, Eileen Gallagher, Michael D. Gallagher, Marta Gallis, Amy Gaskin, Bree Gatica-Wilcox, Lily Geidelberg, Matthew Gemmell, Iliana Georgana, Ryan P. George, Laura Gifford, Lauren Gilbert, Sophia T. Girgis, Sharon Glaysher, Emily J. Goldstein, Tanya Golubchik, Andrea N. Gomes, Sónia Gonçalves, Ian G. Goodfellow, Scott Goodwin, Salman Goudarzi, Marina Gourtovaia, Clive Graham, Lee Graham, Paul R. Grant, Luke R. Green, Angie Green, Jane Greenaway, Richard Gregory, Martyn Guest, Rory N. Gunson, Ravi K. Gupta, Bernardo Gutierrez, Sam T. Haldenby, William L. Hamilton, Samantha E. Hansford, Tanzina Haque, Kathryn A. Harris, Ian Harrison, Ewan M. Harrison, Jennifer Hart, John A. Hartley, William T. Harvey, Matthew Harvey, Mohammed O. Hassan-Ibrahim, Judith Heaney, Thomas Helmer, John H. Henderson, Andrew R. Hesketh, Jessica Hey, David Heyburn, Ellen E. Higginson, Verity Hill, Jack D. Hill, Rachel A. Hilson, Ember Hilvers, Matthew T.G. Holden, Amy Hollis, Christopher W. Holmes, Nadine Holmes, Alison H. Holmes, Richard Hopes, Hailey R. Hornsby, Myra Hosmillo, Catherine Houlihan, Hannah C. Howson-Wells, Jonathan Hubb, Hannah Huckson, Warwick Hughes, Joseph Hughes, Margaret Hughes, Stephanie Hutchings, Giles Idle, Chris J. Illingworth, Robert Impey, Dianne Irish-Tavares, Miren Iturriza-Gomara, Rhys Izuagbe, Chris Jackson, Ben Jackson, Leigh M. Jackson, Kathryn A. Jackson, David K. Jackson, Aminu S. Jahun, Victoria James, Keith James, Christopher Jeanes, Aaron R. Jeffries, Sarah Jeremiah, Andrew Jermy, Michaela John, Rob Johnson, Kate Johnson, Ian Johnston, Owen Jones, Sophie Jones, Hannah Jones, Christopher R. Jones, Neil Jones, Amelia Joseph, Sarah Judges, Gemma L. Kay, Sally Kay, Jon-Paul Keatley, Alexander J. Keeley, Anita Kenyon, Leanne M. Kermack, Manjinder Khakh, Stephen P. Kidd, Maimuna Kimuli, Stuart Kirk, Christine Kitchen, Katie Kitchman, Bridget A. Knight, Cherian Koshy, Moritz U.G. Kraemer, Sara Kumziene-Summerhayes, Dominic Kwiatkowski, Angie Lackenby, Kenneth G. Laing, Temi Lampejo, Cordelia F. Langford, Deborah Lavin, Andrew I. Lawton, Jack Lee, David Lee, Stefanie V. Lensing, Steven Leonard, Lisa J. Levett, Thanh Le-Viet, Jonathan Lewis, Kevin Lewis, Jennifier Liddle, Steven Liggett, Patrick J. Lillie, Michelle M. Lister, Rich Livett, Stephanie Lo, Nicholas J. Loman, Matthew W. Loose, Stavroula F. Louka, Katie F. Loveson, Sarah Lowdon, Hannah Lowe, Helen L. Lowe, Anita O. Lucaci, Catherine Ludden, Jessica Lynch, Ronan A. Lyons, Katrina Lythgoe, Nicholas W. Machin, George MacIntyre-Cockett, Andrew Mack, Ben Macklin, Alasdair Maclean, Emily Macnaughton, Pinglawathee Madona, Mailis Maes, Laurentiu Maftei, Adhyana I.K. Mahanama, Tabitha W. Mahungu, Daniel Mair, Joshua Maksimovic, Cassandra S. Malone, Daniel Maloney, Nikos Manesis, Robin Manley, Anna Mantzouratou, Angela Marchbank, Arun Mariappan, Inigo Martincorena, Rocio T. Martinez Nunez, Alison E. Mather, Patrick Maxwell, Megan Mayhew, Tamyo Mbisa, Clare M. McCann, Shane A. McCarthy, Kathryn McCluggage, Patrick C. McClure, J.T. McCrone, Martin P. McHugh, James P. McKenna, Caoimhe McKerr, Georgina M. McManus, Claire L. McMurray, Claire McMurray, Alan McNally, Lizzie Meadows, Nathan Medd, Oliver Megram, Mirko Menegazzo, Ian Merrick, Stephen L. Michell, Michelle L. Michelsen, Mariyam Mirfenderesky, Jeremy Mirza, Julia Miskelly, Emma Moles-Garcia, Robin J. Moll, Zoltan Molnar, Irene M. Monahan, Matteo Mondani, Siddharth Mookerjee, Christopher Moore, Jonathan Moore, Nathan Moore, Catherine Moore, Helen Morcrette, Sian Morgan, Mari Morgan, Matilde Mori, Arthur Morriss, Samuel Moses, Craig Mower, Peter Muir, Afrida Mukaddas, Florence Munemo, Robert Munn, Abigail Murray, Leanne J. Murray, Darren R. Murray, Manasa Mutingwende, Richard Myers, Eleni Nastouli, Gaia Nebbia, Andrew Nelson, Charlotte Nelson, Sam Nicholls, Jenna Nichols, Roberto Nicodemi, Kyriaki Nomikou, Justin O’Grady, Sarah O'Brien, Mina Odedra, Natasha Ohemeng-Kumi, Karen Oliver, Richard J. Orton, Husam Osman, null xeine O'Toole, Nicole Pacchiarini, Debra Padgett, Andrew J. Page, Emily J. Park, Naomi R. Park, Surendra Parmar, David G. Partridge, David Pascall, Amita Patel, Bindi Patel, Steve Paterson, Brendan A.I. Payne, Sharon J. Peacock, Clare Pearson, Emanuela Pelosi, Benita Percival, Jon Perkins, Malorie Perry, Malte L. Pinckert, Steven Platt, Olga Podplomyk, Manoj Pohare, Marcus Pond, Cassie F. Pope, Radoslaw Poplawski, Jessica Powell, Jennifer Poyner, Liam Prestwood, Anna Price, James R. Price, Jacqui A. Prieto, David T. Pritchard, Sophie J. Prosolek, Georgia Pugh, Monika Pusok, Oliver G. Pybus, Hannah M. Pymont, Michael A. Quail, Joshua Quick, Clara Radulescu, Jayna Raghwani, Manon Ragonnet-Cronin, Lucille Rainbow, Diana Rajan, Shavanthi Rajatileka, Newara A. Ramadan, Andrew Rambaut, John Ramble, Paul A. Randell, Paul Randell, Liz Ratcliffe, Veena Raviprakash, Mohammad Raza, Nicholas M. Redshaw, Sara Rey, Nicola Reynolds, Alex Richter, David L. Robertson, Esther Robinson, Samuel C. Robson, Fiona Rogan, Stefan Rooke, Will Rowe, Sunando Roy, Steven Rudder, Chris Ruis, Steven Rushton, Felicity Ryan, Kordo Saeed, Buddhini Samaraweera, Christine M. Sambles, Roy Sanderson, Theo Sanderson, Fei Sang, Thea Sass, Emily Scher, Garren Scott, Carol Scott, Jasveen Sehmi, Sharif Shaaban, Divya Shah, Jessica Shaw, Ekaterina Shelest, James G. Shepherd, Liz A. Sheridan, Nicola Sheriff, Lesley Shirley, John Sillitoe, Siona Silviera, David A. Simpson, Aditi Singh, Dawn Singleton, Timofey Skvortsov, Tim J. Sloan, Graciela Sluga, Ken Smith, Kim S. Smith, Perminder Smith, Darren L. Smith, Louise Smith, Colin P. Smith, Nikki Smith, Katherine L. Smollett, Luke B. Snell, Thomas Somassa, Joel Southgate, Karla Spellman, Michael H. Spencer Chapman, Lewis G. Spurgin, Moira J. Spyer, Rachael Stanley, William Stanley, Thomas D. Stanton, Igor Starinskij, Joanne Stockton, Susanne Stonehouse, Nathaniel Storey, David J. Studholme, Malur Sudhanva, Emma Swindells, Yusri Taha, Ngee Keong Tan, Julian W. Tang, Miao Tang, Ben E.W. Taylor, Joshua F. Taylor, Sarah Taylor, Ben Temperton, Kate E. Templeton, Claire Thomas, Laura Thomson, Emma C. Thomson, Alicia Thornton, Scott A.J. Thurston, John A. Todd, Rachael Tomb, Lily Tong, Gerry Tonkin-Hill, M. Estee Torok, Jaime M. Tovar-Corona, Amy Trebes, Alexander J. Trotter, Ioulia Tsatsani, Robyn Turnbull, Katherine A. Twohig, Helen Umpleby, Anthony P. Underwood, Edith E. Vamos, Tetyana I. Vasylyeva, Sreenu Vattipally, Gabrielle Vernet, Barry B. Vipond, Erik M. Volz, Sarah Walsh, Dennis Wang, Ben Warne, Joanna Warwick-Dugdale, Elizabeth Wastnedge, Joanne Watkins, Louisa K. Watson, Sheila Waugh, Hermione J. Webster, Danni Weldon, Elaine Westwick, Thomas Whalley, Helen Wheeler, Mark Whitehead, Max Whiteley, Andrew Whitwham, Claudia Wierzbicki, Nicholas J. Willford, Lesley-Anne Williams, Rebecca Williams, Cheryl Williams, Chris Williams, Charlotte A. Williams, Rachel J. Williams, Thomas Williams, Catryn Williams, Kathleen A. Williamson, Eleri Wilson-Davies, Eric Witele, Karen T. Withell, Adam A. Witney, Paige Wolverson, Nick Wong, Trudy Workman, Victoria Wright, Derek W. Wright, Tim Wyatt, Sarah Wyllie, Li Xu-McCrae, Mehmet Yavus, Geraldine Yaze, Corin A. Yeats, Gonzalo Yebra, Wen C. Yew, Gregory R. Young, Jamie Young, Alex E. Zarebski, Peijun Zhang, J. Kenneth Baillie, Malcolm G. Semple, Peter J.M. Openshaw, Gail Carson, Beatrice Alex, Petros Andrikopoulos, Benjamin Bach, Wendy S. Barclay, Debby Bogaert, Kanta Chechi, Graham S. Cooke, Annemarie B. Docherty, Gonçalo dos Santos Correia, Marc-Emmanuel Dumas, Jake Dunning, Tom Fletcher, Christopher A. Green, William Greenhalf, Julian L. Griffin, Rishi K. Gupta, Ewen M. Harrison, Julian A. Hiscox, Antonia Ying Wai Ho, Peter W. Horby, Samreen Ijaz, Saye Khoo, Paul Klenerman, Andrew Law, Matthew R. Lewis, Sonia Liggi, Wei Shen Lim, Lynn Maslen, Laura Merson, Alison M. Meynert, Mahdad Noursadeghi, Michael Olanipekun, Anthonia Osagie, Massimo Palmarini, Carlo Palmieri, William A. Paxton, Georgios Pollakis, Nicholas Price, Clark D. Russell, Vanessa Sancho-Shimizu, Caroline J. Sands, Janet T. Scott, Louise Sigfrid, Tom Solomon, Shiranee Sriskandan, David Stuart, Charlotte Summers, Olivia V. Swann, Zoltan Takats, Panteleimon Takis, Richard S. Tedder, A.A. Roger Thompson, Ryan S. Thwaites, Maria Zambon, Hayley Hardwick, Chloe Donohue, Fiona Griffiths, Wilna Oosthuyzen, Cara Donegan, Rebecca G. Spencer, Jo Dalton, Michelle Girvan, Egle Saviciute, Stephanie Roberts, Janet Harrison, Laura Marsh, Marie Connor, Sophie Halpin, Clare Jackson, Carrol Gamble, Daniel Plotkin, James Lee, Gary Leeming, Murray Wham, Sara Clohisey, Ross Hendry, James Scott-Brown, Victoria Shaw, Sarah E. McDonald, Seán Keating, Katie A. Ahmed, Jane A. Armstrong, Milton Ashworth, Innocent G. Asiimwe, Siddharth Bakshi, Samantha L. Barlow, Laura Booth, Benjamin Brennan, Katie Bullock, Benjamin W.A. Catterall, Jordan J. Clark, Emily A. Clarke, Sarah Cole, Louise Cooper, Helen Cox, Christopher Davis, Oslem Dincarslan, Chris Dunn, Philip Dyer, Angela Elliott, Anthony Evans, Lorna Finch, Lewis W.S. Fisher, Terry Foster, Isabel Garcia-Dorival, Philip Gunning, Catherine Hartley, Rebecca L. Jensen, Christopher B. Jones, Trevor R. Jones, Shadia Khandaker, Katharine King, Robyn T. Kiy, Chrysa Koukorava, Annette Lake, Suzannah Lant, Diane Latawiec, Lara Lavelle-Langham, Daniella Lefteri, Lauren Lett, Lucia A. Livoti, Maria Mancini, Sarah McDonald, Laurence McEvoy, John McLauchlan, Soeren Metelmann, Nahida S. Miah, Joanna Middleton, Joyce Mitchell, Ellen G. Murphy, Rebekah Penrice-Randal, Jack Pilgrim, Tessa Prince, Will Reynolds, P. Matthew Ridley, Debby Sales, Victoria E. Shaw, Rebecca K. Shears, Benjamin Small, Krishanthi S. Subramaniam, Agnieska Szemiel, Aislynn Taggart, Jolanta Tanianis-Hughes, Jordan Thomas, Erwan Trochu, Libby van Tonder, Eve Wilcock, J. Eunice Zhang, Lisa Flaherty, Nicole Maziere, Emily Cass, Alejandra Doce Carracedo, Nicola Carlucci, Anthony Holmes, Hannah Massey, Lee Murphy, Nicola Wrobel, Sarah McCafferty, Kirstie Morrice, Alan MacLean, Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Erin L. Aldera, Ana Alegria, Sam Allen, Brian Angus, Abdul Ashish, Dougal Atkinson, Shahedal Bari, Gavin Barlow, Stella Barnass, Nicholas Barrett, Christopher Bassford, Sneha Basude, David Baxter, Michael Beadsworth, Jolanta Bernatoniene, John Berridge, Colin Berry, Nicola Best, Pieter Bothma, David Chadwick, Robin Brittain-Long, Naomi Bulteel, Tom Burden, Andrew Burtenshaw, Vikki Caruth, Duncan Chambler, Nigel Chee, Jenny Child, Srikanth Chukkambotla, Tom Clark, Paul Collini, Catherine Cosgrove, Jason Cupitt, Maria-Teresa Cutino-Moguel, Paul Dark, Chris Dawson, Phil Donnison, Sam Douthwaite, Andrew Drummond, Ingrid DuRand, Ahilanadan Dushianthan, Tristan Dyer, Chi Eziefula, Chrisopher Fegan, Adam Finn, Duncan Fullerton, Sanjeev Garg, Atul Garg, Effrossyni Gkrania-Klotsas, Jo Godden, Arthur Goldsmith, Elaine Hardy, Stuart Hartshorn, Daniel Harvey, Peter Havalda, Daniel B. Hawcutt, Maria Hobrok, Luke Hodgson, Anil Hormis, Michael Jacobs, Susan Jain, Paul Jennings, Agilan Kaliappan, Vidya Kasipandian, Stephen Kegg, Michael Kelsey, Jason Kendall, Caroline Kerrison, Ian Kerslake, Oliver Koch, Gouri Koduri, George Koshy, Shondipon Laha, Steven Laird, Susan Larkin, Tamas Leiner, Patrick Lillie, James Limb, Vanessa Linnett, Jeff Little, Mark Lyttle, Michael MacMahon, Emily MacNaughton, Ravish Mankregod, Huw Masson, Elijah Matovu, Katherine McCullough, Ruth McEwen, Manjula Meda, Gary Mills, Jane Minton, Kavya Mohandas, Quen Mok, James Moon, Elinoor Moore, Patrick Morgan, Craig Morris, Katherine Mortimore, Mbiye Mpenge, Rohinton Mulla, Michael Murphy, Megan Nagel, Thapas Nagarajan, Mark Nelson, Lillian Norris, Matthew K. O'Shea, Igor Otahal, Marlies Ostermann, Mark Pais, Selva Panchatsharam, Danai Papakonstantinou, Hassan Paraiso, Brij Patel, Natalie Pattison, Justin Pepperell, Mark Peters, Mandeep Phull, Stefania Pintus, Jagtur Singh Pooni, Tim Planche, Frank Post, David Price, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Tim Reynolds, Neil Richardson, Mark Roberts, Devender Roberts, Alistair Rose, Guy Rousseau, Bobby Ruge, Brendan Ryan, Taranprit Saluja, Matthias L. Schmid, Aarti Shah, Prad Shanmuga, Anil Sharma, Anna Shawcross, Jeremy Sizer, Manu Shankar-Hari, Richard Smith, Catherine Snelson, Nick Spittle, Nikki Staines, Tom Stambach, Richard Stewart, Pradeep Subudhi, Tamas Szakmany, Kate Tatham, Jo Thomas, Chris Thompson, Robert Thompson, Ascanio Tridente, Darell Tupper-Carey, Mary Twagira, Nick Vallotton, Rama Vancheeswaran, Lisa Vincent-Smith, Shico Visuvanathan, Alan Vuylsteke, Sam Waddy, Rachel Wake, Andrew Walden, Ingeborg Welters, Tony Whitehouse, Paul Whittaker, Ashley Whittington, Padmasayee Papineni, Meme Wijesinghe, Martin Williams, Lawrence Wilson, Stephen Winchester, Martin Wiselka, Adam Wolverson, Daniel G. Wootton, Andrew Workman, Bryan Yates, Peter Young, UK Research and Innovation, Division of Computational and Systems Medicine, Imperial College London, London, SW7 2AZ, UK, Imperial College London - National Heart and Lung Institute, Centre National de la Recherche Scientifique (CNRS), and Apollo - University of Cambridge Repository

Subjects
Molecular biology, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Science, Immunology, Biology, Epitope, Article, A900, 03 medical and health sciences, 0302 clinical medicine, Data sequences, Immune system, COVID-19 Genomics UK (COG-UK) Consortium, Virology, Cytotoxic T cell, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Immune response, Receptor, ISARIC4C Investigators, 030304 developmental biology, 0303 health sciences, Multidisciplinary, C100, A300, C900, 3. Good health, Phylogenetics, 030220 oncology & carcinogenesis, Humoral immunity, [SDV.IMM]Life Sciences [q-bio]/Immunology, CD8
Abstract

We identify amino acid variants within dominant SARS-CoV-2 T-cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T-cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T-cell responsiveness was seen due to Q213K in the A*01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215, due to P13L, P13S and P13T in the B*27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17, and due to T362I and P365S in the A*03:01/A*11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T-cell lines unable to recognise variant epitopes have diverse T-cell receptor repertoires. These data demonstrate the potential for T-cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T-cell as well as humoral immunity., Graphical Abstract

Published
2021
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7. Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7

Author

Bo Meng, Steven A. Kemp, Guido Papa, Rawlings Datir, Isabella A.T.M. Ferreira, Sara Marelli, William T. Harvey, Spyros Lytras, Ahmed Mohamed, Giulia Gallo, Nazia Thakur, Dami A. Collier, Petra Mlcochova, Lidia M. Duncan, Alessandro M. Carabelli, Julia C. Kenyon, Andrew M. Lever, Anna De Marco, Christian Saliba, Katja Culap, Elisabetta Cameroni, Nicholas J. Matheson, Luca Piccoli, Davide Corti, Leo C. James, David L. Robertson, Dalan Bailey, Ravindra K. Gupta, Samuel C. Robson, Nicholas J. Loman, Thomas R. Connor, Tanya Golubchik, Rocio T. Martinez Nunez, Catherine Ludden, Sally Corden, Ian Johnston, David Bonsall, Colin P. Smith, Ali R. Awan, Giselda Bucca, M. Estee Torok, Kordo Saeed, Jacqui A. Prieto, David K. Jackson, William L. Hamilton, Luke B. Snell, Catherine Moore, Ewan M. Harrison, Sonia Goncalves, Derek J. Fairley, Matthew W. Loose, Joanne Watkins, Rich Livett, Samuel Moses, Roberto Amato, Sam Nicholls, Matthew Bull, Darren L. Smith, Jeff Barrett, David M. Aanensen, Martin D. Curran, Surendra Parmar, Dinesh Aggarwal, James G. Shepherd, Matthew D. Parker, Sharon Glaysher, Matthew Bashton, Anthony P. Underwood, Nicole Pacchiarini, Katie F. Loveson, Kate E. Templeton, Cordelia F. Langford, John Sillitoe, Thushan I. de Silva, Dennis Wang, Dominic Kwiatkowski, Andrew Rambaut, Justin O’Grady, Simon Cottrell, Matthew T.G. Holden, Emma C. Thomson, Husam Osman, Monique Andersson, Anoop J. Chauhan, Mohammed O. Hassan-Ibrahim, Mara Lawniczak, Alex Alderton, Meera Chand, Chrystala Constantinidou, Meera Unnikrishnan, Alistair C. Darby, Julian A. Hiscox, Steve Paterson, Inigo Martincorena, Erik M. Volz, Andrew J. Page, Oliver G. Pybus, Andrew R. Bassett, Cristina V. Ariani, Michael H. Spencer Chapman, Kathy K. Li, Rajiv N. Shah, Natasha G. Jesudason, Yusri Taha, Martin P. McHugh, Rebecca Dewar, Aminu S. Jahun, Claire McMurray, Sarojini Pandey, James P. McKenna, Andrew Nelson, Gregory R. Young, Clare M. McCann, Scott Elliott, Hannah Lowe, Ben Temperton, Sunando Roy, Anna Price, Sara Rey, Matthew Wyles, Stefan Rooke, Sharif Shaaban, Mariateresa de Cesare, Laura Letchford, Siona Silveira, Emanuela Pelosi, Eleri Wilson-Davies, Myra Hosmillo, Áine O’Toole, Andrew R. Hesketh, Richard Stark, Louis du Plessis, Chris Ruis, Helen Adams, Yann Bourgeois, Stephen L. Michell, Dimitris Grammatopoulos, Jonathan Edgeworth, Judith Breuer, John A. Todd, Christophe Fraser, David Buck, Michaela John, Gemma L. Kay, Steve Palmer, Sharon J. Peacock, David Heyburn, Danni Weldon, Esther Robinson, Alan McNally, Peter Muir, Ian B. Vipond, John Boyes, Venkat Sivaprakasam, Tranprit Salluja, Samir Dervisevic, Emma J. Meader, Naomi R. Park, Karen Oliver, Aaron R. Jeffries, Sascha Ott, Ana da Silva Filipe, David A. Simpson, Chris Williams, Jane A.H. Masoli, Bridget A. Knight, Christopher R. Jones, Cherian Koshy, Amy Ash, Anna Casey, Andrew Bosworth, Liz Ratcliffe, Li Xu-McCrae, Hannah M. Pymont, Stephanie Hutchings, Lisa Berry, Katie Jones, Fenella Halstead, Thomas Davis, Christopher Holmes, Miren Iturriza-Gomara, Anita O. Lucaci, Paul Anthony Randell, Alison Cox, Pinglawathee Madona, Kathryn Ann Harris, Julianne Rose Brown, Tabitha W. Mahungu, Dianne Irish-Tavares, Tanzina Haque, Jennifer Hart, Eric Witele, Melisa Louise Fenton, Steven Liggett, Clive Graham, Emma Swindells, Jennifer Collins, Gary Eltringham, Sharon Campbell, Patrick C. McClure, Gemma Clark, Tim J. Sloan, Carl Jones, Jessica Lynch, Ben Warne, Steven Leonard, Jillian Durham, Thomas Williams, Sam T. Haldenby, Nathaniel Storey, Nabil-Fareed Alikhan, Nadine Holmes, Christopher Moore, Matthew Carlile, Malorie Perry, Noel Craine, Ronan A. Lyons, Angela H. Beckett, Salman Goudarzi, Christopher Fearn, Kate Cook, Hannah Dent, Hannah Paul, Robert Davies, Beth Blane, Sophia T. Girgis, Mathew A. Beale, Katherine L. Bellis, Matthew J. Dorman, Eleanor Drury, Leanne Kane, Sally Kay, Samantha McGuigan, Rachel Nelson, Liam Prestwood, Shavanthi Rajatileka, Rahul Batra, Rachel J. Williams, Mark Kristiansen, Angie Green, Anita Justice, Adhyana I.K. Mahanama, Buddhini Samaraweera, Nazreen F. Hadjirin, Joshua Quick, Radoslaw Poplawski, Leanne M. Kermack, Nicola Reynolds, Grant Hall, Yasmin Chaudhry, Malte L. Pinckert, Iliana Georgana, Robin J. Moll, Alicia Thornton, Richard Myers, Joanne Stockton, Charlotte A. Williams, Wen C. Yew, Alexander J. Trotter, Amy Trebes, George MacIntyre-Cockett, Alec Birchley, Alexander Adams, Amy Plimmer, Bree Gatica-Wilcox, Caoimhe McKerr, Ember Hilvers, Hannah Jones, Hibo Asad, Jason Coombes, Johnathan M. Evans, Laia Fina, Lauren Gilbert, Lee Graham, Michelle Cronin, Sara Kumziene-Summerhayes, Sarah Taylor, Sophie Jones, Danielle C. Groves, Peijun Zhang, Marta Gallis, Stavroula F. Louka, Igor Starinskij, Chris Jackson, Marina Gourtovaia, Gerry Tonkin-Hill, Kevin Lewis, Jaime M. Tovar-Corona, Keith James, Laura Baxter, Mohammad T. Alam, Richard J. Orton, Joseph Hughes, Sreenu Vattipally, Manon Ragonnet-Cronin, Fabricia F. Nascimento, David Jorgensen, Olivia Boyd, Lily Geidelberg, Alex E. Zarebski, Jayna Raghwani, Moritz U.G. Kraemer, Joel Southgate, Benjamin B. Lindsey, Timothy M. Freeman, Jon-Paul Keatley, Joshua B. Singer, Leonardo de Oliveira Martins, Corin A. Yeats, Khalil Abudahab, Ben E.W. Taylor, Mirko Menegazzo, John Danesh, Wendy Hogsden, Sahar Eldirdiri, Anita Kenyon, Jenifer Mason, Trevor I. Robinson, Alison Holmes, James Price, John A. Hartley, Tanya Curran, Alison E. Mather, Giri Shankar, Rachel Jones, Robin Howe, Sian Morgan, Elizabeth Wastenge, Michael R. Chapman, Siddharth Mookerjee, Rachael Stanley, Wendy Smith, Timothy Peto, David Eyre, Derrick Crook, Gabrielle Vernet, Christine Kitchen, Huw Gulliver, Ian Merrick, Martyn Guest, Robert Munn, Declan T. Bradley, Tim Wyatt, Charlotte Beaver, Luke Foulser, Sophie Palmer, Carol M. Churcher, Ellena Brooks, Kim S. Smith, Katerina Galai, Georgina M. McManus, Frances Bolt, Francesc Coll, Lizzie Meadows, Stephen W. Attwood, Alisha Davies, Elen De Lacy, Fatima Downing, Sue Edwards, Garry P. Scarlett, Sarah Jeremiah, Nikki Smith, Danielle Leek, Sushmita Sridhar, Sally Forrest, Claire Cormie, Harmeet K. Gill, Joana Dias, Ellen E. Higginson, Mailis Maes, Jamie Young, Michelle Wantoch, Dorota Jamrozy, Stephanie Lo, Minal Patel, Verity Hill, Claire M. Bewshea, Sian Ellard, Cressida Auckland, Ian Harrison, Chloe Bishop, Vicki Chalker, Alex Richter, Andrew Beggs, Angus Best, Benita Percival, Jeremy Mirza, Oliver Megram, Megan Mayhew, Liam Crawford, Fiona Ashcroft, Emma Moles-Garcia, Nicola Cumley, Richard Hopes, Patawee Asamaphan, Marc O. Niebel, Rory N. Gunson, Amanda Bradley, Alasdair Maclean, Guy Mollett, Rachel Blacow, Paul Bird, Thomas Helmer, Karlie Fallon, Julian Tang, Antony D. Hale, Louissa R. Macfarlane-Smith, Katherine L. Harper, Holli Carden, Nicholas W. Machin, Kathryn A. Jackson, Shazaad S.Y. Ahmad, Ryan P. George, Lance Turtle, Elaine O’Toole, Joanne Watts, Cassie Breen, Angela Cowell, Adela Alcolea-Medina, Themoula Charalampous, Amita Patel, Lisa J. Levett, Judith Heaney, Aileen Rowan, Graham P. Taylor, Divya Shah, Laura Atkinson, Jack C.D. Lee, Adam P. Westhorpe, Riaz Jannoo, Helen L. Lowe, Angeliki Karamani, Leah Ensell, Wendy Chatterton, Monika Pusok, Ashok Dadrah, Amanda Symmonds, Graciela Sluga, Zoltan Molnar, Paul Baker, Stephen Bonner, Sarah Essex, Edward Barton, Debra Padgett, Garren Scott, Jane Greenaway, Brendan A.I. Payne, Shirelle Burton-Fanning, Sheila Waugh, Veena Raviprakash, Nicola Sheriff, Victoria Blakey, Lesley-Anne Williams, Jonathan Moore, Susanne Stonehouse, Louise Smith, Rose K. Davidson, Luke Bedford, Lindsay Coupland, Victoria Wright, Joseph G. Chappell, Theocharis Tsoleridis, Jonathan Ball, Manjinder Khakh, Vicki M. Fleming, Michelle M. Lister, Hannah C. Howson-Wells, Louise Berry, Tim Boswell, Amelia Joseph, Iona Willingham, Nichola Duckworth, Sarah Walsh, Emma Wise, Nathan Moore, Matilde Mori, Nick Cortes, Stephen Kidd, Rebecca Williams, Laura Gifford, Kelly Bicknell, Sarah Wyllie, Allyson Lloyd, Robert Impey, Cassandra S. Malone, Benjamin J. Cogger, Nick Levene, Lynn Monaghan, Alexander J. Keeley, David G. Partridge, Mohammad Raza, Cariad Evans, Kate Johnson, Emma Betteridge, Ben W. Farr, Scott Goodwin, Michael A. Quail, Carol Scott, Lesley Shirley, Scott A.J. Thurston, Diana Rajan, Iraad F. Bronner, Louise Aigrain, Nicholas M. Redshaw, Stefanie V. Lensing, Shane McCarthy, Alex Makunin, Carlos E. Balcazar, Michael D. Gallagher, Kathleen A. Williamson, Thomas D. Stanton, Michelle L. Michelsen, Joanna Warwick-Dugdale, Robin Manley, Audrey Farbos, James W. Harrison, Christine M. Sambles, David J. Studholme, Angie Lackenby, Tamyo Mbisa, Steven Platt, Shahjahan Miah, David Bibby, Carmen Manso, Jonathan Hubb, Gavin Dabrera, Mary Ramsay, Daniel Bradshaw, Ulf Schaefer, Natalie Groves, Eileen Gallagher, David Lee, David Williams, Nicholas Ellaby, Hassan Hartman, Nikos Manesis, Vineet Patel, Juan Ledesma, Katherine A. Twohig, Elias Allara, Clare Pearson, Jeffrey K.J. Cheng, Hannah E. Bridgewater, Lucy R. Frost, Grace Taylor-Joyce, Paul E. Brown, Lily Tong, Alice Broos, Daniel Mair, Jenna Nichols, Stephen N. Carmichael, Katherine L. Smollett, Kyriaki Nomikou, Elihu Aranday-Cortes, Natasha Johnson, Seema Nickbakhsh, Edith E. Vamos, Margaret Hughes, Lucille Rainbow, Richard Eccles, Charlotte Nelson, Mark Whitehead, Richard Gregory, Matthew Gemmell, Claudia Wierzbicki, Hermione J. Webster, Chloe L. Fisher, Adrian W. Signell, Gilberto Betancor, Harry D. Wilson, Gaia Nebbia, Flavia Flaviani, Alberto C. Cerda, Tammy V. Merrill, Rebekah E. Wilson, Marius Cotic, Nadua Bayzid, Thomas Thompson, Erwan Acheson, Steven Rushton, Sarah O’Brien, David J. Baker, Steven Rudder, Alp Aydin, Fei Sang, Johnny Debebe, Sarah Francois, Tetyana I. Vasylyeva, Marina Escalera Zamudio, Bernardo Gutierrez, Angela Marchbank, Joshua Maksimovic, Karla Spellman, Kathryn McCluggage, Mari Morgan, Robert Beer, Safiah Afifi, Trudy Workman, William Fuller, Catherine Bresner, Adrienn Angyal, Luke R. Green, Paul J. Parsons, Rachel M. Tucker, Rebecca Brown, Max Whiteley, James Bonfield, Christoph Puethe, Andrew Whitwham, Jennifier Liddle, Will Rowe, Igor Siveroni, Thanh Le-Viet, Amy Gaskin, Rob Johnson, Irina Abnizova, Mozam Ali, Laura Allen, Ralph Anderson, Cristina Ariani, Siobhan Austin-Guest, Sendu Bala, Jeffrey Barrett, Andrew Bassett, Kristina Battleday, James Beal, Mathew Beale, Sam Bellany, Tristram Bellerby, Katie Bellis, Duncan Berger, Matt Berriman, Paul Bevan, Simon Binley, Jason Bishop, Kirsty Blackburn, Nick Boughton, Sam Bowker, Timothy Brendler-Spaeth, Iraad Bronner, Tanya Brooklyn, Sarah Kay Buddenborg, Robert Bush, Catarina Caetano, Alex Cagan, Nicola Carter, Joanna Cartwright, Tiago Carvalho Monteiro, Liz Chapman, Tracey-Jane Chillingworth, Peter Clapham, Richard Clark, Adrian Clarke, Catriona Clarke, Daryl Cole, Elizabeth Cook, Maria Coppola, Linda Cornell, Clare Cornwell, Craig Corton, Abby Crackett, Alison Cranage, Harriet Craven, Sarah Craw, Mark Crawford, Tim Cutts, Monika Dabrowska, Matt Davies, Joseph Dawson, Callum Day, Aiden Densem, Thomas Dibling, Cat Dockree, David Dodd, Sunil Dogga, Matthew Dorman, Gordon Dougan, Martin Dougherty, Alexander Dove, Lucy Drummond, Monika Dudek, Laura Durrant, Elizabeth Easthope, Sabine Eckert, Pete Ellis, Ben Farr, Michael Fenton, Marcella Ferrero, Neil Flack, Howerd Fordham, Grace Forsythe, Matt Francis, Audrey Fraser, Adam Freeman, Anastasia Galvin, Maria Garcia-Casado, Alex Gedny, Sophia Girgis, James Glover, Oliver Gould, Andy Gray, Emma Gray, Coline Griffiths, Yong Gu, Florence Guerin, Will Hamilton, Hannah Hanks, Ewan Harrison, Alexandria Harrott, Edward Harry, Julia Harvison, Paul Heath, Anastasia Hernandez-Koutoucheva, Rhiannon Hobbs, Dave Holland, Sarah Holmes, Gary Hornett, Nicholas Hough, Liz Huckle, Lena Hughes-Hallet, Adam Hunter, Stephen Inglis, Sameena Iqbal, Adam Jackson, David Jackson, Carlos Jimenez Verdejo, Matthew Jones, Kalyan Kallepally, Keely Kay, Jon Keatley, Alan Keith, Alison King, Lucy Kitchin, Matt Kleanthous, Martina Klimekova, Petra Korlevic, Ksenia Krasheninnkova, Greg Lane, Cordelia Langford, Adam Laverack, Katharine Law, Stefanie Lensing, Amanah Lewis-Wade, Jennifer Liddle, Quan Lin, Sarah Lindsay, Sally Linsdell, Rhona Long, Jamie Lovell, Jon Lovell, James Mack, Mark Maddison, Aleksei Makunin, Irfan Mamun, Jenny Mansfield, Neil Marriott, Matt Martin, Matthew Mayho, Jo McClintock, Sandra McHugh, Liz MapcMinn, Carl Meadows, Emily Mobley, Robin Moll, Maria Morra, Leanne Morrow, Kathryn Murie, Sian Nash, Claire Nathwani, Plamena Naydenova, Alexandra Neaverson, Ed Nerou, Jon Nicholson, Tabea Nimz, Guillaume G. Noell, Sarah O’Meara, Valeriu Ohan, Charles Olney, Doug Ormond, Agnes Oszlanczi, Yoke Fei Pang, Barbora Pardubska, Naomi Park, Aaron Parmar, Gaurang Patel, Maggie Payne, Sharon Peacock, Arabella Petersen, Deborah Plowman, Tom Preston, Michael Quail, Richard Rance, Suzannah Rawlings, Nicholas Redshaw, Joe Reynolds, Mark Reynolds, Simon Rice, Matt Richardson, Connor Roberts, Katrina Robinson, Melanie Robinson, David Robinson, Hazel Rogers, Eduardo Martin Rojo, Daljit Roopra, Mark Rose, Luke Rudd, Ramin Sadri, Nicholas Salmon, David Saul, Frank Schwach, Phil Seekings, Alison Simms, Matt Sinnott, Shanthi Sivadasan, Bart Siwek, Dale Sizer, Kenneth Skeldon, Jason Skelton, Joanna Slater-Tunstill, Lisa Sloper, Nathalie Smerdon, Chris Smith, Christen Smith, James Smith, Katie Smith, Michelle Smith, Sean Smith, Tina Smith, Leighton Sneade, Carmen Diaz Soria, Catarina Sousa, Emily Souster, Andrew Sparkes, Michael Spencer-Chapman, Janet Squares, Robert Stanley, Claire Steed, Tim Stickland, Ian Still, Mike Stratton, Michelle Strickland, Allen Swann, Agnieszka Swiatkowska, Neil Sycamore, Emma Swift, Edward Symons, Suzanne Szluha, Emma Taluy, Nunu Tao, Katy Taylor, Sam Taylor, Stacey Thompson, Mark Thompson, Mark Thomson, Nicholas Thomson, Scott Thurston, Dee Toombs, Benjamin Topping, Jaime Tovar-Corona, Daniel Ungureanu, James Uphill, Jana Urbanova, Philip Jansen Van, Valerie Vancollie, Paul Voak, Danielle Walker, Matthew Walker, Matt Waller, Gary Ward, Charlie Weatherhogg, Niki Webb, Alan Wells, Eloise Wells, Luke Westwood, Theo Whipp, Thomas Whiteley, Georgia Whitton, Sara Widaa, Mia Williams, Mark Wilson, Sean Wright, and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Resistance, MC UU 1201412, Plasma protein binding, Antibodies, Viral, medicine.disease_cause, MR/R024758/1, 0302 clinical medicine, Recurrence, Chlorocebus aethiops, deletion, Biology (General), Receptor, Phylogeny, Infectivity, Mutation, biology, infectivity, MC_UU_12014/12, C500, C700, UKRI, MRC, Antibody Escape, Spike Glycoprotein, Coronavirus, antibody escape, Antibody, Protein Binding, QH301-705.5, Sars-cov-2, Alpha (ethology), Article, General Biochemistry, Genetics and Molecular Biology, Virus, Cell Line, resistance, Deletion, 03 medical and health sciences, spike mutation, medicine, Alpha Variant, Animals, Humans, neutralizing antibodies, B.1.1.7, Vero Cells, Pandemics, Immune Evasion, SARS-CoV-2, Biochemistry, Genetics and Molecular Biology(all), COVID-19, MR/P008801/1, Antibodies, Neutralizing, Virology, body regions, HEK293 Cells, 030104 developmental biology, Alpha variant, Spike Mutation, biology.protein, Vero cell, Neutralizing Antibodies, 030217 neurology & neurosurgery
Abstract

We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted., Graphical abstract, Meng et al. report that the SARS-CoV-2 spike ΔH69/V70 has arisen multiple times. The deletion increases entry efficiency associated with increased cleaved spike in virions and can compensate for loss of infectivity. The B.1.1.7 spike requires ΔH69/V70 for efficient cell entry and cell-cell fusion activity.

Published
2021
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8. Comparative effects of viral-transport-medium heat inactivation upon downstream SARS-CoV-2 detection in patient samples

Author

Andrew V. Benest, Gemma Clarke, Vicki M. Fleming, Sarah Walsh, Hannah C. Howson-Wells, Rebecca Tarbox, Jamie L. Thompson, Manjinder Khakh, Alice Cardall, Nichola Duckworth, Tim J. Sloan, Jaineeta Richardson, Michelle Lister, Chris Denning, C. Patrick McClure, Angela Downie Ruiz Velasco, and Claire Seedhouse

Subjects
Microbiology (medical), Hot Temperature, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), viral transport media, RT-qPCR testing, Microbiology, Genome, Sensitivity and Specificity, Virus, Specimen Handling, Disease, Diagnosis and Diagnostics, Medicine, Humans, business.industry, SARS-CoV-2, RNA, COVID-19, General Medicine, Virology, Culture Media, Reverse transcription polymerase chain reaction, Heat inactivation, COVID-19 Nucleic Acid Testing, RNA, Viral, Virus Inactivation, RNA extraction, Reagent Kits, Diagnostic, Primer (molecular biology), business
Abstract

Introduction. The COVID-19 pandemic, which began in 2020 is testing economic resilience and surge capacity of healthcare providers worldwide. At the time of writing, positive detection of the SARS-CoV-2 virus remains the only method for diagnosing COVID-19 infection. Rapid upscaling of national SARS-CoV-2 genome testing presented challenges: (1) Unpredictable supply chains of reagents and kits for virus inactivation, RNA extraction and PCR-detection of viral genomes. (2) Rapid time to result of Hypothesis. Extraction-free sample processing would impact commercially available SARS-CoV-2 genome detection methods. Aim. We evaluated whether alternative commercially available kits provided sensitivity and accuracy of SARS-CoV-2 genome detection comparable to those used by regional National Healthcare Services (NHS). Methodology. We tested several detection methods and tested whether detection was altered by heat inactivation, an approach for rapid one-step viral inactivation and RNA extraction without chemicals or kits. Results. Using purified RNA, we found the CerTest VIASURE kit to be comparable to the Altona RealStar system currently in use, and further showed that both diagnostic kits performed similarly in the BioRad CFX96 and Roche LightCycler 480 II machines. Additionally, both kits were comparable to a third alternative using a combination of Quantabio qScript one-step Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) mix and Centre for Disease Control and Prevention (CDC)-accredited N1 and N2 primer/probes when looking specifically at borderline samples. Importantly, when using the kits in an extraction-free protocol, following heat inactivation, we saw differing results, with the combined Quantabio-CDC assay showing superior accuracy and sensitivity. In particular, detection using the CDC N2 probe following the extraction-free protocol was highly correlated to results generated with the same probe following RNA extraction and reported clinically (n=127; R2=0.9259). Conclusion. Our results demonstrate that sample treatment can greatly affect the downstream performance of SARS-CoV-2 diagnostic kits, with varying impact depending on the kit. We also showed that one-step heat-inactivation methods could reduce time from swab receipt to outcome of test result. Combined, these findings present alternatives to the protocols in use and can serve to alleviate any arising supply-chain issues at different points in the workflow, whilst accelerating testing, and reducing cost and environmental impact.

Published
2021

9. Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity

Author

Erik Volz, Verity Hill, John T. McCrone, Anna Price, David Jorgensen, Áine O’Toole, Joel Southgate, Robert Johnson, Ben Jackson, Fabricia F. Nascimento, Sara M. Rey, Samuel M. Nicholls, Rachel M. Colquhoun, Ana da Silva Filipe, James Shepherd, David J. Pascall, Rajiv Shah, Natasha Jesudason, Kathy Li, Ruth Jarrett, Nicole Pacchiarini, Matthew Bull, Lily Geidelberg, Igor Siveroni, Ian Goodfellow, Nicholas J. Loman, Oliver G. Pybus, David L. Robertson, Emma C. Thomson, Andrew Rambaut, Thomas R. Connor, Cherian Koshy, Emma Wise, Nick Cortes, Jessica Lynch, Stephen Kidd, Matilde Mori, Derek J. Fairley, Tanya Curran, James P. McKenna, Helen Adams, Christophe Fraser, Tanya Golubchik, David Bonsall, Catrin Moore, Sarah L. Caddy, Fahad A. Khokhar, Michelle Wantoch, Nicola Reynolds, Ben Warne, Joshua Maksimovic, Karla Spellman, Kathryn McCluggage, Michaela John, Robert Beer, Safiah Afifi, Sian Morgan, Angela Marchbank, Christine Kitchen, Huw Gulliver, Ian Merrick, Martyn Guest, Robert Munn, Trudy Workman, William Fuller, Catherine Bresner, Luke B. Snell, Themoula Charalampous, Gaia Nebbia, Rahul Batra, Jonathan Edgeworth, Samuel C. Robson, Angela Beckett, Katie F. Loveson, David M. Aanensen, Anthony P. Underwood, Corin A. Yeats, Khalil Abudahab, Ben E.W. Taylor, Mirko Menegazzo, Gemma Clark, Wendy Smith, Manjinder Khakh, Vicki M. Fleming, Michelle M. Lister, Hannah C. Howson-Wells, Louise Berry, Tim Boswell, Amelia Joseph, Iona Willingham, Paul Bird, Thomas Helmer, Karlie Fallon, Christopher Holmes, Julian Tang, Veena Raviprakash, Sharon Campbell, Nicola Sheriff, Matthew W. Loose, Nadine Holmes, Christopher Moore, Matthew Carlile, Victoria Wright, Fei Sang, Johnny Debebe, Francesc Coll, Adrian W. Signell, Gilberto Betancor, Harry D. Wilson, Theresa Feltwell, Charlotte J. Houldcroft, Sahar Eldirdiri, Anita Kenyon, Thomas Davis, Oliver Pybus, Louis du Plessis, Alex Zarebski, Jayna Raghwani, Moritz Kraemer, Sarah Francois, Stephen Attwood, Tetyana Vasylyeva, M. Estee Torok, William L. Hamilton, Ian G. Goodfellow, Grant Hall, Aminu S. Jahun, Yasmin Chaudhry, Myra Hosmillo, Malte L. Pinckert, Iliana Georgana, Anna Yakovleva, Luke W. Meredith, Samuel Moses, Hannah Lowe, Felicity Ryan, Chloe L. Fisher, Ali R. Awan, John Boyes, Judith Breuer, Kathryn Ann Harris, Julianne Rose Brown, Divya Shah, Laura Atkinson, Jack C.D. Lee, Adela Alcolea-Medina, Nathan Moore, Nicholas Cortes, Rebecca Williams, Michael R. Chapman, Lisa J. Levett, Judith Heaney, Darren L. Smith, Matthew Bashton, Gregory R. Young, John Allan, Joshua Loh, Paul A. Randell, Alison Cox, Pinglawathee Madona, Alison Holmes, Frances Bolt, James Price, Siddharth Mookerjee, Aileen Rowan, Graham P. Taylor, Manon Ragonnet-Cronin, Rob Johnson, Olivia Boyd, Erik M. Volz, Kirstyn Brunker, Katherine L. Smollett, Joshua Quick, Claire McMurray, Joanne Stockton, Sam Nicholls, Will Rowe, Radoslaw Poplawski, Rocio T. Martinez-Nunez, Jenifer Mason, Trevor I. Robinson, Elaine O'Toole, Joanne Watts, Cassie Breen, Angela Cowell, Catherine Ludden, Graciela Sluga, Nicholas W. Machin, Shazaad S.Y. Ahmad, Ryan P. George, Fenella Halstead, Venkat Sivaprakasam, James G. Shepherd, Patawee Asamaphan, Marc O. Niebel, Kathy K. Li, Rajiv N. Shah, Natasha G. Jesudason, Yasmin A. Parr, Lily Tong, Alice Broos, Daniel Mair, Jenna Nichols, Stephen N. Carmichael, Kyriaki Nomikou, Elihu Aranday-Cortes, Natasha Johnson, Igor Starinskij, Richard J. Orton, Joseph Hughes, Sreenu Vattipally, Joshua B. Singer, Antony D. Hale, Louissa R. Macfarlane-Smith, Katherine L. Harper, Yusri Taha, Brendan A.I. Payne, Shirelle Burton-Fanning, Sheila Waugh, Jennifer Collins, Gary Eltringham, Kate E. Templeton, Martin P. McHugh, Rebecca Dewar, Elizabeth Wastenge, Samir Dervisevic, Rachael Stanley, Reenesh Prakash, Claire Stuart, Ngozi Elumogo, Dheeraj K. Sethi, Emma J. Meader, Lindsay J. Coupland, Will Potter, Clive Graham, Edward Barton, Debra Padgett, Garren Scott, Emma Swindells, Jane Greenaway, Andrew Nelson, Wen C. Yew, Paola C. Resende Silva, Monique Andersson, Robert Shaw, Timothy Peto, Anita Justice, David Eyre, Derrick Crooke, Sarah Hoosdally, Tim J. Sloan, Nichola Duckworth, Sarah Walsh, Anoop J. Chauhan, Sharon Glaysher, Kelly Bicknell, Sarah Wyllie, Ethan Butcher, Scott Elliott, Allyson Lloyd, Robert Impey, Nick Levene, Lynn Monaghan, Declan T. Bradley, Elias Allara, Clare Pearson, Peter Muir, Ian B. Vipond, Richard Hopes, Hannah M. Pymont, Stephanie Hutchings, Martin D. Curran, Surendra Parmar, Angie Lackenby, Tamyo Mbisa, Steven Platt, Shahjahan Miah, David Bibby, Carmen Manso, Jonathan Hubb, Meera Chand, Gavin Dabrera, Mary Ramsay, Daniel Bradshaw, Alicia Thornton, Richard Myers, Ulf Schaefer, Natalie Groves, Eileen Gallagher, David Lee, David Williams, Nicholas Ellaby, Ian Harrison, Hassan Hartman, Nikos Manesis, Vineet Patel, Chloe Bishop, Vicki Chalker, Husam Osman, Andrew Bosworth, Esther Robinson, Matthew T.G. Holden, Sharif Shaaban, Alec Birchley, Alexander Adams, Alisha Davies, Amy Gaskin, Amy Plimmer, Bree Gatica-Wilcox, Caoimhe McKerr, Catherine Moore, Chris Williams, David Heyburn, Elen De Lacy, Ember Hilvers, Fatima Downing, Giri Shankar, Hannah Jones, Hibo Asad, Jason Coombes, Joanne Watkins, Johnathan M. Evans, Laia Fina, Laura Gifford, Lauren Gilbert, Lee Graham, Malorie Perry, Mari Morgan, Michelle Cronin, Noel Craine, Rachel Jones, Robin Howe, Sally Corden, Sara Rey, Sara Kumziene-Summerhayes, Sarah Taylor, Simon Cottrell, Sophie Jones, Sue Edwards, Justin O’Grady, Andrew J. Page, John Wain, Mark A. Webber, Alison E. Mather, David J. Baker, Steven Rudder, Muhammad Yasir, Nicholas M. Thomson, Alp Aydin, Ana P. Tedim, Gemma L. Kay, Alexander J. Trotter, Rachel A.J. Gilroy, Nabil-Fareed Alikhan, Leonardo de Oliveira Martins, Thanh Le-Viet, Lizzie Meadows, Anastasia Kolyva, Maria Diaz, Andrew Bell, Ana Victoria Gutierrez, Ian G. Charles, Evelien M. Adriaenssens, Robert A. Kingsley, Anna Casey, David A. Simpson, Zoltan Molnar, Thomas Thompson, Erwan Acheson, Jane A.H. Masoli, Bridget A. Knight, Andrew Hattersley, Sian Ellard, Cressida Auckland, Tabitha W. Mahungu, Dianne Irish-Tavares, Tanzina Haque, Yann Bourgeois, Garry P. Scarlett, David G. Partridge, Mohammad Raza, Cariad Evans, Kate Johnson, Steven Liggett, Paul Baker, Sarah Essex, Ronan A. Lyons, Laura G. Caller, Sergi Castellano, Rachel J. Williams, Mark Kristiansen, Sunando Roy, Charlotte A. Williams, Patricia L. Dyal, Helena J. Tutill, Yasmin N. Panchbhaya, Leysa M. Forrest, Paola Niola, Jacqueline Findlay, Tony T. Brooks, Artemis Gavriil, Lamia Mestek-Boukhibar, Sam Weeks, Sarojini Pandey, Lisa Berry, Katie Jones, Alex Richter, Andrew Beggs, Colin P. Smith, Giselda Bucca, Andrew R. Hesketh, Ewan M. Harrison, Sharon J. Peacock, Sophie Palmer, Carol M. Churcher, Katherine L. Bellis, Sophia T. Girgis, Plamena Naydenova, Beth Blane, Sushmita Sridhar, Chris Ruis, Sally Forrest, Claire Cormie, Harmeet K. Gill, Joana Dias, Ellen E. Higginson, Mailis Maes, Jamie Young, Leanne M. Kermack, Nazreen F. Hadjirin, Dinesh Aggarwal, Luke Griffith, Tracey Swingler, Rose K. Davidson, Thomas Williams, Carlos E. Balcazar, Michael D. Gallagher, Áine O'Toole, Stefan Rooke, Rachel Colquhoun, Jordan Ashworth, J.T. McCrone, Emily Scher, Xiaoyu Yu, Kathleen A. Williamson, Thomas D. Stanton, Stephen L. Michell, Claire M. Bewshea, Ben Temperton, Michelle L. Michelsen, Joanna Warwick-Dugdale, Robin Manley, Audrey Farbos, James W. Harrison, Christine M. Sambles, David J. Studholme, Aaron R. Jeffries, Alistair C. Darby, Julian A. Hiscox, Steve Paterson, Miren Iturriza-Gomara, Kathryn A. Jackson, Anita O. Lucaci, Edith E. Vamos, Margaret Hughes, Lucille Rainbow, Richard Eccles, Charlotte Nelson, Mark Whitehead, Lance Turtle, Sam T. Haldenby, Richard Gregory, Matthew Gemmell, Dominic Kwiatkowski, Thushan I. de Silva, Nikki Smith, Adrienn Angyal, Benjamin B. Lindsey, Danielle C. Groves, Luke R. Green, Dennis Wang, Timothy M. Freeman, Matthew D. Parker, Alexander J. Keeley, Paul J. Parsons, Rachel M. Tucker, Rebecca Brown, Matthew Wyles, Chrystala Constantinidou, Meera Unnikrishnan, Sascha Ott, Jeffrey K.J. Cheng, Hannah E. Bridgewater, Lucy R. Frost, Grace Taylor-Joyce, Richard Stark, Laura Baxter, Mohammad T. Alam, Paul E. Brown, Patrick C. McClure, Joseph G. Chappell, Theocharis Tsoleridis, Jonathan Ball, Dimitris Grammatopoulos, David Buck, John A. Todd, Angie Green, Amy Trebes, George MacIntyre-Cockett, Mariateresa de Cesare, Cordelia Langford, Alex Alderton, Roberto Amato, Sonia Goncalves, David K. Jackson, Ian Johnston, John Sillitoe, Steve Palmer, Mara Lawniczak, Matt Berriman, John Danesh, Rich Livett, Lesley Shirley, Ben Farr, Mike Quail, Scott Thurston, Naomi Park, Emma Betteridge, Danni Weldon, Scott Goodwin, Rachel Nelson, Charlotte Beaver, Laura Letchford, David A. Jackson, Luke Foulser, Liz McMinn, Liam Prestwood, Sally Kay, Leanne Kane, Matthew J. Dorman, Inigo Martincorena, Christoph Puethe, Jon-Paul Keatley, Gerry Tonkin-Hill, Christen Smith, Dorota Jamrozy, Mathew A. Beale, Minal Patel, Cristina Ariani, Michael Spencer-Chapman, Eleanor Drury, Stephanie Lo, Shavanthi Rajatileka, Carol Scott, Keith James, Sarah K. Buddenborg, Duncan J. Berger, Gaurang Patel, Maria V. Garcia-Casado, Thomas Dibling, Samantha McGuigan, Hazel A. Rogers, Adam D. Hunter, Emily Souster, Alexandra S. Neaverson, Medical Research Council (MRC), Pascall, David [0000-0002-7543-0860], and Apollo - University of Cambridge Repository

Subjects
Genome, Genetic analysis, 0302 clinical medicine, Clade, 11 Medical and Health Sciences, Genetics, 0303 health sciences, education.field_of_study, Phylogenetic tree, Virulence, C500, COG-UK Consortium, C700, Transmissibility (vibration), 3. Good health, founder effect, Spike Glycoprotein, Coronavirus, epidemiology, Viral load, Population, Glycine, B100, Genomics, Genome, Viral, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, evolution, Humans, education, 030304 developmental biology, Aspartic Acid, Whole Genome Sequencing, Biochemistry, Genetics and Molecular Biology(all), SARS-CoV-2, COVID-19, spike, The COVID-19 Genomics UK Consortium, A300, 06 Biological Sciences, United Kingdom, Amino Acid Substitution, Evolutionary biology, Mutation, Biological dispersal, 030217 neurology & neurosurgery, Founder effect, Developmental Biology
Abstract

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant., Graphical Abstract, Highlights • Increasing frequency of SARS-CoV-2 D614G is consistent with a selective advantage • Phylodynamic analyses do not show significantly different growth of D614G clusters • There is no association of D614G replacement with greater severity of infection • The D614G replacement is associated with higher viral loads and younger patient age, Analysis of the spread and frequency of SARS-CoV-2 D614G in the United Kingdom suggests a selective advantage for this strain that is associated with higher viral loads in younger patients but not higher COVID-19 clinical severity or mortality.

Published
2021
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10. Comparative effects of viral transport medium heat inactivation upon downstream SARS-CoV-2 detection in patient samples

Author

Chris Denning, Sarah Walsh, Nichola Duckworth, C. Patrick McClure, Tim J. Sloan, Rebecca Tarbox, Andrew V. Benest, Alice Cardall, Angela Downie Ruiz Velasco, Vicki M. Fleming, Gemma Clarke, Claire Seedhouse, Michelle Lister, Jamie L. Thompson, Manjinder Khakh, Jaineeta Richardson, and Hannah C. Howson-Wells

Subjects
Downstream (manufacturing), Surge Capacity, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pandemic, Viral Transport medium, RNA extraction, Biology, Virology, Genome, Virus
Abstract

The COVID-19 pandemic, which began in 2020 is testing economic resilience and surge capacity of healthcare providers worldwide. At time of writing, positive detection of the SARS-CoV-2 virus remains the only method for diagnosing COVID-19 infection. Rapid upscaling of national SARS-CoV-2 genome testing presented challenges: 1) Unpredictable supply chains of reagents and kits for virus inactivation, RNA extraction and PCR-detection of viral genomes 2) Rapid time to result of 2=0.9259). Our results demonstrate that sample treatment can greatly affect the downstream performance of SARS-CoV-2 diagnostic kits, with varying impact depending on the kit. We also showed that one-step heat inactivation methods could reduce time from swab receipt to outcome of test result. Combined, these findings present alternatives to the protocols in use and can serve to alleviate any arising supply chain issues at different points in the workflow, whilst accelerating testing, and reducing cost and environmental impact.

Published
2020
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11. Metagenomics Reveals Impact of Urbanisation in Central India on the Human Gut Microbiome and its Antimicrobial Resistance Profiles

Author

Shrejal Bhotmange, Mark H. Wilcox, Pratishtha Jain, Lorraine A. Draper, Adam M. Blanchard, Rajpal S. Kashyap, Tim J. Sloan, Ashish R. Satav, Colin Hill, Tanya Monaghan, Rima Biswas, Shrikant Ambalkar, Sonali Manke, Stephen R. Stockdale, Jinal Gandhi, Richard D. Emes, and Rupam R. Nashine

Subjects
Human gut, Antibiotic resistance, Metagenomics, Zoology, Microbiome, Biology
Abstract

Background The impact of the rapid urbanisation of low- and middle-income countries on the human gut microbiome remains grossly understudied. Whilst the effect of urbanisation on the bacterial populations of the human gut microbiome have been documented, little is known about the influence of diet and antibiotics on the bacteriome, its virome, and antibiotic resistome. Here, we use shotgun metagenomics to comprehensively characterise the bacterial and viral fractions of the human gut microbiome, and their encoded functions, from two divergent Central Indian populations (rural agriculturalists from Melghat and an urban population in Nagpur). Additionally, we investigate cohorts with and without diarrhoea, and the potential burden of Clostridioides difficile, associated with widespread unregulated use of antibiotics in India. Results We observed distinct rural-urban differences in the gut microbiome, including viral diversity and composition, with geography exhibiting a greater influence than diarrhoeal status. Urban microbiomes were enriched in metabolic pathways responsible for degradation of drugs and organic compounds, which were predicted to relate to replacement of rural-enriched Prevotella spp. and fermentative Clostridiales with Enterobacteriaceae and Bacteroides spp. By linking phages present in the microbiome to their bacterial hosts through CRISPR spacers, a shift from Prevotella- and Eubacterium-infecting phages to Bacteroides- and Parabacteroides-infecting phages was observed in rural and urban populations, respectively. Additionally, the auxiliary metabolic potential of rural-associated phage populations was enriched for carbon and amino acid energy harvesting potential, compared to urban-associated phages. A core set of antimicrobial resistance genes was identified in both populations, particularly those conferring resistance to macrolides, tetracyclines and 1stgeneration cephalosporins, with the majority also showing evidence of resistance to fluoroquinolones, aminoglycosides and sulphonamides. In a subgroup of urban subjects with diarrhoea and high antibiotic exposure, most of whom tested positive for C. difficile toxin, evidence of resistance to fosfomycin, glycopeptides, daptomycin, 3rd generation cephalosporins and carbapenems was widespread. Conclusions We report distinct differences in antimicrobial resistance gene profiles as well as a marked variation in the burden of C. difficile disease between rural and urban populations. The key drivers of variation in urban and rural Indian microbiomes are geography, diet, industrial and healthcare exposures.

Published
2019
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12. Timing Is Everything: Impact of Naturally Occurring Staphylococcus aureus AgrC Cytoplasmic Domain Adaptive Mutations on Autoinduction

Author

Ewan Murray, Boyan B. Bonev, Ruth C. Massey, Paul Williams, Maho Yokoyama, Tim J. Sloan, and Weng C. Chan

Subjects
Staphylococcus aureus, 0303 health sciences, 030306 microbiology, Mutant, Autophosphorylation, Leukocidin, quorum sensing, Virulence, Biology, Microbiology, molecular dynamics, Virulence factor, Cell biology, virulence, AgrC, 03 medical and health sciences, Response regulator, Quorum sensing, accessory gene regulator (agr), Binding site, autoinducing peptide (AIP), Molecular Biology, exotoxins, sensor kinase, 030304 developmental biology
Abstract

Mutations in the polymorphic Staphylococcus aureusagr locus responsible for quorum sensing (QS)-dependent virulence gene regulation occur frequently during host adaptation. In two genomically closely related S. aureus clinical isolates exhibiting marked differences in Panton-Valentine leukocidin production, a mutation conferring an N267I substitution was identified in the cytoplasmic domain of the QS sensor kinase, AgrC. This natural mutation delayed the onset and accumulation of autoinducing peptide (AIP) and showed reduced responsiveness to exogenous AIPs. Other S. aureus strains harboring naturally occurring AgrC cytoplasmic domain mutations were identified, including T247I, I311T, A343T, L245S, and F264C. These mutations were associated with reduced cytotoxicity, delayed/reduced AIP production, and impaired sensitivity to exogenous AIP. Molecular dynamics simulations were used to model the AgrC cytoplasmic domain conformational changes arising. Although mutations were localized in different parts of the C-terminal domain, their impact on molecular structure was manifested by twisting of the leading helical hairpin α1-α2, accompanied by repositioning of the H-box and G-box, along with closure of the flexible loop connecting the two and occlusion of the ATP-binding site. Such conformational rearrangements of key functional subdomains in these mutants highlight the cooperative response of molecular structure involving dimerization and ATP binding and phosphorylation, as well as the binding site for the downstream response element AgrA. These appear to increase the threshold for agr activation via AIP-dependent autoinduction, thus reducing virulence and maintaining S. aureus in an agr-downregulated “colonization” mode. IMPORTANCE Virulence factor expression in Staphylococcus aureus is regulated via autoinducing peptide (AIP)-dependent activation of the sensor kinase AgrC, which forms an integral part of the agr quorum sensing system. In response to bound AIP, the cytoplasmic domain of AgrC (AgrC-cyt) undergoes conformational changes resulting in dimerization, autophosphorylation, and phosphotransfer to the response regulator AgrA. Naturally occurring mutations in AgrC-cyt are consistent with repositioning of key functional domains, impairing dimerization and restricting access to the ATP-binding pocket. Strains harboring specific AgrC-cyt mutations exhibit reduced AIP autoinduction efficiency and a timing-dependent attenuation of cytotoxicity which may confer a survival advantage during established infection by promoting colonization while restricting unnecessary overproduction of exotoxins.

Published
2019
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13. Timing Is Everything: Impact of Naturally Occurring

Author

Tim J, Sloan, Ewan, Murray, Maho, Yokoyama, Ruth C, Massey, Weng C, Chan, Boyan B, Bonev, and Paul, Williams

Subjects
Models, Molecular, Cytoplasm, Staphylococcus aureus, Time Factors, Molecular Dynamics Simulation, Peptides, Cyclic, Protein Structure, Secondary, AgrC, Adenosine Triphosphate, Bacterial Proteins, Protein Domains, Phosphorylation, autoinducing peptide (AIP), sensor kinase, Binding Sites, quorum sensing, molecular dynamics, virulence, Amino Acid Substitution, Trans-Activators, accessory gene regulator (agr), Protein Multimerization, Protein Kinases, exotoxins, Protein Binding, Research Article
Abstract

Virulence factor expression in Staphylococcus aureus is regulated via autoinducing peptide (AIP)-dependent activation of the sensor kinase AgrC, which forms an integral part of the agr quorum sensing system. In response to bound AIP, the cytoplasmic domain of AgrC (AgrC-cyt) undergoes conformational changes resulting in dimerization, autophosphorylation, and phosphotransfer to the response regulator AgrA. Naturally occurring mutations in AgrC-cyt are consistent with repositioning of key functional domains, impairing dimerization and restricting access to the ATP-binding pocket. Strains harboring specific AgrC-cyt mutations exhibit reduced AIP autoinduction efficiency and a timing-dependent attenuation of cytotoxicity which may confer a survival advantage during established infection by promoting colonization while restricting unnecessary overproduction of exotoxins., Mutations in the polymorphic Staphylococcus aureus agr locus responsible for quorum sensing (QS)-dependent virulence gene regulation occur frequently during host adaptation. In two genomically closely related S. aureus clinical isolates exhibiting marked differences in Panton-Valentine leukocidin production, a mutation conferring an N267I substitution was identified in the cytoplasmic domain of the QS sensor kinase, AgrC. This natural mutation delayed the onset and accumulation of autoinducing peptide (AIP) and showed reduced responsiveness to exogenous AIPs. Other S. aureus strains harboring naturally occurring AgrC cytoplasmic domain mutations were identified, including T247I, I311T, A343T, L245S, and F264C. These mutations were associated with reduced cytotoxicity, delayed/reduced AIP production, and impaired sensitivity to exogenous AIP. Molecular dynamics simulations were used to model the AgrC cytoplasmic domain conformational changes arising. Although mutations were localized in different parts of the C-terminal domain, their impact on molecular structure was manifested by twisting of the leading helical hairpin α1-α2, accompanied by repositioning of the H-box and G-box, along with closure of the flexible loop connecting the two and occlusion of the ATP-binding site. Such conformational rearrangements of key functional subdomains in these mutants highlight the cooperative response of molecular structure involving dimerization and ATP binding and phosphorylation, as well as the binding site for the downstream response element AgrA. These appear to increase the threshold for agr activation via AIP-dependent autoinduction, thus reducing virulence and maintaining S. aureus in an agr-downregulated “colonization” mode. IMPORTANCE Virulence factor expression in Staphylococcus aureus is regulated via autoinducing peptide (AIP)-dependent activation of the sensor kinase AgrC, which forms an integral part of the agr quorum sensing system. In response to bound AIP, the cytoplasmic domain of AgrC (AgrC-cyt) undergoes conformational changes resulting in dimerization, autophosphorylation, and phosphotransfer to the response regulator AgrA. Naturally occurring mutations in AgrC-cyt are consistent with repositioning of key functional domains, impairing dimerization and restricting access to the ATP-binding pocket. Strains harboring specific AgrC-cyt mutations exhibit reduced AIP autoinduction efficiency and a timing-dependent attenuation of cytotoxicity which may confer a survival advantage during established infection by promoting colonization while restricting unnecessary overproduction of exotoxins.

Published
2019

14. Understanding the ecology and evolution of polymicrobial wound infections

Author

Tim J. Sloan, Paul Williams, Steve Diggle, and Ana L Da Silva

Subjects
Genetic diversity, education.field_of_study, Innate immune system, biology, Population, Virulence, biology.organism_classification, Phenotype, Microbiology, Colonisation, Antibiotic resistance, General Materials Science, education, Bacteria
Abstract

Chronic wounds (CW) are a common complication of diabetic ulcers (DUs), which are a major burden to health care systems worldwide and can result in lower limb amputation due to the intractability of the infection. In DUs there is a high probability of the infecting bacteria evolving considerable phenotypic and genetic diversity, as has previously been shown for chronic lung infections. However, it is not known whether this is also the case for chronic DUs, and whether diversity impacts on virulence and antibiotic resistance. To study this, bacterial populations were isolated from different samples from patients with DUs. Phenotypic diversity was investigated in P. aeruginosa populations through the analysis of phenotypes traditionally associated with pathogenicity, and through a whole genome study. Phenotypic variation in P. aeruginosa isolates taken from different patients was observed, but little variation within the same CW (with exception of one patient with a leg ulcer). Antibiotic resistance was found to increase during the course of infection, and it became apparent that P. aeruginosa colonisation in DUs is via a single strain per ulcer, and potentially per patient, even though some sample-specific phenotypic profiles were found to arise from a homogenous population. For this case, a detailed genomic analysis between bone and blood isolates was done, including a comparison of their transcriptomes using RNAseq. The results suggest that the loss of flagellum facilitated evasion of the innate immune system, which allowed bacteria to go undetected and spread systemically causing the rapid decline in the patient’s health.

Published
2019
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15. Metagenomics reveals impact of geography and acute diarrheal disease on the Central Indian human gut microbiome

Author

Sonali Manke, Colin Hill, Ashish R. Satav, Rima Biswas, Tanya Monaghan, Pratishtha Jain, Rupam R. Nashine, Adam M. Blanchard, Tim J. Sloan, Shrejal Bhotmange, Rajpal S. Kashyap, Jinal Gandhi, Lorraine A. Draper, Shrikant Ambalkar, Mark H. Wilcox, Richard D. Emes, and Stephen R. Stockdale

Subjects
Adult, Diarrhea, Male, Rural Population, 0301 basic medicine, Microbiology (medical), Urban Population, Central India, India, Biology, Microbiology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Antibiotic resistance, Human gut, antibiotic resistome, Humans, Microbiome, lcsh:RC799-869, Enterocolitis, Pseudomembranous, Aged, Gut microbiome, virome, Bacteria, Diarrheal diseases, Clostridioides difficile, Gastroenterology, Middle Aged, Anti-Bacterial Agents, Cephalosporins, Gastrointestinal Microbiome, 030104 developmental biology, Infectious Diseases, Carbapenems, Metagenomics, lcsh:Diseases of the digestive system. Gastroenterology, Female, 030211 gastroenterology & hepatology, Diarrheal disease, Clostridioides, Research Article, Research Paper
Abstract

© 2020, © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. Background: The Central Indian gut microbiome remains grossly understudied. Herein, we sought to investigate the burden of antimicrobial resistance and diarrheal diseases, particularly Clostridioides difficile, in rural-agricultural and urban populations in Central India, where there is widespread unregulated antibiotic use. We utilized shotgun metagenomics to comprehensively characterize the bacterial and viral fractions of the gut microbiome and their encoded functions in 105 participants. Results: We observed distinct rural-urban differences in bacterial and viral populations, with geography exhibiting a greater influence than diarrheal status. Clostridioides difficile disease was more commonly observed in urban subjects, and their microbiomes were enriched in metabolic pathways relating to the metabolism of industrial compounds and genes encoding resistance to 3rd generation cephalosporins and carbapenems. By linking phages present in the microbiome to their bacterial hosts through CRISPR spacers, phage variation could be directly related to shifts in bacterial populations, with the auxiliary metabolic potential of rural-associated phages enriched for carbon and amino acid energy metabolism. Conclusions: We report distinct differences in antimicrobial resistance gene profiles, enrichment of metabolic pathways and phage composition between rural and urban populations, as well as a higher burden of Clostridioides difficile disease in the urban population. Our results reveal that geography is the key driver of variation in urban and rural Indian microbiomes, with acute diarrheal disease, including C. difficile disease exerting a lesser impact. Future studies will be required to understand the potential role of dietary, cultural, and genetic factors in contributing to microbiome differences between rural and urban populations.

Published
2020
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16. Examining diabetic heel ulcers through an ecological lens: microbial community dynamics associated with healing and infection

Author

James Turton, Michelle Lister, Mathew Diggle, R. Elizabeth Sockett, Frances L. Game, Alison Musgrove, Jess Tyson, Vicki M. Fleming, William Jeffcoate, Matthew Loose, and Tim J. Sloan

Subjects
0301 basic medicine, Microbiology (medical), Longitudinal sample, Male, medicine.medical_specialty, Heel, 030106 microbiology, Infections, Microbiology, 03 medical and health sciences, Diabetes mellitus, Internal medicine, RNA, Ribosomal, 16S, Epidemiology, medicine, Multiple time, Cluster Analysis, Humans, Microbiome, Heel ulcers, Aged, Analysis of Variance, Wound Healing, business.industry, Microbiota, General Medicine, Sequence Analysis, DNA, Middle Aged, medicine.disease, Diabetic foot, Diabetic Foot, Markov Chains, Anti-Bacterial Agents, Casts, Surgical, 030104 developmental biology, medicine.anatomical_structure, Female, business
Abstract

Purpose. While some micro-organisms, such as Staphylococcus aureus , are clearly implicated in causing tissue damage in diabetic foot ulcers (DFUs), our knowledge of the contribution of the entire microbiome to clinical outcomes is limited. We profiled the microbiome of a longitudinal sample series of 28 people with diabetes and DFUs of the heel in an attempt to better characterize the relationship between healing, infection and the microbiome. Methodology. In total, 237 samples were analysed from 28 DFUs, collected at fortnightly intervals for 6 months or until healing. Microbiome profiles were generated by 16S rRNA gene sequence analysis, supplemented by targeted nanopore sequencing. Result/Key findings. DFUs which failed to heal during the study period (20/28, 71.4 %) were more likely to be persistently colonized with a heterogeneous community of micro-organisms including anaerobes and Enterobacteriaceae (log-likelihood ratio 9.56, P=0.008). During clinically apparent infection, a reduction in the diversity of micro-organisms in a DFU was often observed due to expansion of one or two taxa, with recovery in diversity at resolution. Modelling of the predicted species interactions in a single DFU with high diversity indicated that networks of metabolic interactions may exist that contribute to the formation of stable communities. Conclusion. Longitudinal profiling is an essential tool for improving our understanding of the microbiology of chronic wounds, as community dynamics associated with clinical events can only be identified by examining changes over multiple time points. The development of complex communities, particularly involving Enterobacteriaceae and strict anaerobes, may be contributing to poor outcomes in DFUs and requires further investigation.

Published
2019

17. PTU-047 High prevalence of clostridium difficile ribotype 078 in IBD outpatients

Author

Tim J. Sloan, Jill Garratt, Yashwant R. Mahida, David W Eyre, D. Pickering, Yirga Falcone, Melanie Lingaya, Tanya Monaghan, Mark H. Wilcox, Jane Freeman, Helen Foreman, and N R Lewis

Subjects
medicine.medical_specialty, education.field_of_study, business.industry, Population, Prevalence, Context (language use), Clostridium difficile, medicine.disease, Carriage, Internal medicine, Cohort, Medicine, Sample collection, Colitis, business, education
Abstract

Background and Objectives Point prevalence studies have reported higher carriage rates of C. difficile in IBD patients compared with the general population, but longitudinal prospective data are lacking. The objectives of this observational study were to investigate and molecularly characterise isolates of C. difficile, collected prospectively on a monthly basis over a one-year period among IBD outpatients and healthy controls (HC). Methods At enrolment, recruited participants had established diagnoses of UC (n=16) and Crohn’s disease (n=6) and reported no recent hospitalisation or exposure to antibiotics. PCR ribotype and toxin status (cytotoxigenic culture) were determined for all +ive stool cultures. All participants underwent a monthly telephone interview to identify potential risk factors for C. difficile acquisition (changes in medications, exposure to antibiotics, clinic attendances, hospitalisation) and to assess for disease activity (Harvey-Bradshaw Index and Simple Clinical Activity Colitis Index). Results Two patients underwent physician-initiated laboratory testing of C. difficile during the sample collection phase, although no participants developed or were treated for C. difficile infection. C. difficile was cultured from 29/223 samples (13%) representing 16/22 patients and 1 of 5 HC with concurrent antibiotic exposure in 6/29 visits (20%). Of the toxin +ive isolates (n=25; 078, 005, 302 and 015), 72% (n=21) were PCR ribotype 078. Toxigenic negative ribotypes included 023, 026 and 656. Of those toxin +ive isolates, 9 samples (36%) were associated with relapsing IBD of which 7/9 were ribotype 078. Multiple stool specimens also tested +ive for different ribotypes in 3 patients with UC, all of whom were taking regular immunosuppressants. WGS studies of the 078 isolates revealed marked genetic similarity, with only 3 of the 21 isolates varying by 1 or more nucleotides when compared to the 078 reference genome, suggesting there may have been a common source for cross-transmission. Conclusions The high prevalence of PCR ribotype 078 in this IBD outpatient cohort is consistent with the recent emergence of this strain in the community. These results reinforce the importance of testing all in-and outpatients with an apparent flare or relapsing IBD for carriage of toxigenic C. difficile to inform optimal management strategies. Future research is needed to understand the predominance of 078 isolates in IBD, particularly in the context of clinical relapse.

Published
2018
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18. Do diverticula provide a unique niche for microbiota which can lead to activation of the innate immune system?

Author

Robin C. Spiller and Tim J. Sloan

Subjects
0301 basic medicine, medicine.medical_specialty, Population, Disease, Asymptomatic, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, Humans, education, education.field_of_study, business.industry, Microbiota, Gastroenterology, Diverticulitis, medicine.disease, Inflammatory Bowel Diseases, Obesity, Immunity, Innate, Surgery, Diverticulosis, Diverticulum, 030104 developmental biology, Immune System, Diverticular disease, Number needed to treat, 030211 gastroenterology & hepatology, medicine.symptom, business
Abstract

As individuals living a Western lifestyle age, the prevalence of diverticulosis steadily rises reaching around 50% over the age of 75 years.1 While for most this is a harmless ageing change reflecting weakening of colonic connective tissue, around 30% suffer recurrent abdominal pain, often with diarrhoea,2 and 1–4% will be hospitalised with diverticulitis.3 As our population steadily ages this represents a substantial health burden, however, we know surprisingly little about the underlying mechanisms of this disease. Heritability of symptomatic diverticular disease is around 40%,4 however, studies of immigrants from low-risk areas to high-risk countries show that environmental factors are equally important.3 Once hospitalised with diverticulitis the risk of further hospitalisation is around 1% per year but the majority continue to suffer pain or bowel disturbance, at least for the 1st year after discharge.5 Diverticulitis is associated with inflammation, tissue destruction and remodelling which includes striking muscular hypertrophy and morphological abnormalities of the enteric nerves thought to be responsible for symptoms.6 However the mechanisms whereby diverticulosis leads to diverticulitis remains unclear though dietary factors such as meat eating, obesity and low fibre intake play a role. One way these could act is by altering the microbiota.7 This might also account for reports that antibiotics8 probiotics9 or the anti-inflammatory agent mesalazine10 can reduce symptoms, though in most cases the number needed to treat is high. The current paper11 represents a start in our attempts to understand this phenomenon. The authors hypothesised that the presence of diverticula creates a unique environment which leads to important changes in microbiota with potential effects on the gut immune system and hence symptoms. Controls (n=14) and 16 patients with asymptomatic diverticulosis (termed ‘diverticulosis’) were compared with 8 patients with …

Published
2016

19. Molecular Characterization and Panton-Valentine Leucocidin Typing of Community-Acquired Methicillin-Sensitive Staphylococcus aureus Clinical Isolates

Author

Angela M. Kearns, Tim J. Sloan, Richard James, and Kome Otokunefor

Subjects
Adult, Male, Microbiology (medical), Staphylococcus aureus, Adolescent, Virulence Factors, Epidemiology, Prophages, Staphylococcus Phages, Bacterial Toxins, Exotoxins, Microbial Sensitivity Tests, Biology, Staphylococcal infections, medicine.disease_cause, Microbiology, Methicillin, Young Adult, Leukocidins, medicine, Humans, Typing, Child, skin and connective tissue diseases, Prophage, Aged, Molecular Epidemiology, Molecular epidemiology, Haplotype, Infant, Newborn, Infant, Middle Aged, Staphylococcal Infections, respiratory system, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, medicine.disease, Community-Acquired Infections, Molecular Typing, Haplotypes, Child, Preschool, bacteria, Multilocus sequence typing, Female
Abstract

Limited comprehensive molecular typing data exist currently for Panton-Valentine leucocidin (PVL)-positive, methicillin-sensitive Staphylococcus aureus (PVL-MSSA) clinical isolates. Characterization of PVL-MSSA isolates by multilocus sequence typing (MLST) and spa typing in this study showed a genetic similarity to PVL-positive, methicillin-resistant S. aureus (PVL-MRSA) strains, although three novel spa types and a novel MLST (ST1518) were detected. Furthermore, the detection of PVL phages and haplotypes in PVL-MSSA identical to those previously found in PVL-MRSA isolates highlights the role these strains may play as precursors of emerging lineages of clinical significance.

Published
2012
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20. Explanatory and Diagnostic Labels and Perceived Prognosis in Chronic Low Back Pain

Author

Tim J. Sloan and David A. Walsh

Subjects
Adult, Male, Coping (psychology), medicine.medical_specialty, Attitude of Health Personnel, MEDLINE, Diagnostic Techniques, Neurological, Diagnostic Self Evaluation, medicine, Humans, Orthopedics and Sports Medicine, Physical Examination, Aged, Physician-Patient Relations, business.industry, Middle Aged, Prognosis, Low back pain, Chronic low back pain, Content analysis, Radiological weapon, Chronic Disease, Orthopedic surgery, Physical therapy, Female, Neurology (clinical), medicine.symptom, business, Attitude to Health, Low Back Pain
Abstract

STUDY DESIGN Content analysis of patient interviews, clinic letters, and radiology reports for patients with chronic low back pain of greater than 12 months duration. OBJECTIVE To explore the language used by patients and healthcare professionals to describe low back pain and any potential effect on patient perceived prognosis. SUMMARY OF BACKGROUND DATA Diagnostic explanations by healthcare professionals may influence patient coping and uptake of therapy by patients with chronic low back pain. Although the correlation between radiologic changes and chronic low back pain is weak, these investigations are often used by clinicians as an explanation of the underlying cause for the pain. METHODS Patients were asked about their understanding of the mechanisms underlying their pain, flares, and future outcome. Notes from these interviews were transcribed, along with correspondence from primary care physicians, orthopedic surgeons and pain physicians, and lumbar spine radiology reports for these patients. Content analysis was performed to identify and group key terms. RESULTS Two major categories representing the predominant themes emerging from the content analysis were "Degeneration" and "Mechanical." Degenerative terms such as "wear and tear" and "disc space loss" indicated a progressive loss of structural integrity. Examples of phrases used by patients included "deterioration […] spine is crumbling" and "collapsing […] discs wearing out." The use of degenerative terms by patients was associated with a poor perceived prognosis (P < 0.01). Degenerative and mechanical terms were more commonly used by patients when they were documented in correspondence from secondary care specialists (P = 0.03 and 0.01, respectively). CONCLUSION A common language is shared between professionals and patients that may encourage unhelpful beliefs. The use of degenerative terms such as wear and tear by patients is associated with a poor perceived prognosis. The explanation of radiological findings to patients presents an opportunity to challenge unhelpful beliefs, thus facilitating uptake of active treatment strategies.

Published
2010
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21. Beliefs About the Causes and Consequences of Pain in Patients With Chronic Inflammatory or Noninflammatory Low Back Pain and in Pain-Free Individuals

Author

Weiya Zhang, Rajiva Gupta, David A. Walsh, and Tim J. Sloan

Subjects
Adult, Male, Health Knowledge, Attitudes, Practice, medicine.medical_specialty, Physical disability, Cross-sectional study, Disability Evaluation, Surveys and Questionnaires, Adaptation, Psychological, medicine, Humans, Orthopedics and Sports Medicine, Depression (differential diagnoses), Aged, Pain Measurement, Inflammation, Chi-Square Distribution, business.industry, Chronic pain, Middle Aged, medicine.disease, Low back pain, Cross-Sectional Studies, Logistic Models, Case-Control Studies, Chronic Disease, Linear Models, Physical therapy, Anxiety, Female, Pain catastrophizing, Neurology (clinical), medicine.symptom, business, Low Back Pain, Chi-squared distribution, Prejudice, Stress, Psychological
Abstract

STUDY DESIGN Case control study including 2 groups of patients with low back pain (LBP, inflammatory and noninflammatory) and a pain-free community control group. OBJECTIVE We explored whether pain beliefs differ between patients with chronic LBP attributed to inflammatory or noninflammatory medical diagnoses, and between patients with chronic LBP and pain-free controls. SUMMARY OF BACKGROUND DATA Beliefs strongly influence patients' engagement in and response to treatments for chronic LBP. It is unclear, however, whether unhelpful beliefs held by patients with chronic LBP are predominantly associated with diagnosis, or with other aspects of the patient's pain experience. METHODS Patients and controls completed the pain beliefs questionnaire addressing beliefs about the causes and consequences of pain. Patients also completed questionnaires addressing catastrophizing (Coping Strategies Questionnaire), physical disability and bodily pain (SF-36 Health Survey), and psychological distress (Spielberger State-Trait Anxiety Inventory Short Form and Cognitive Depression Index). Variance analysis and chi2 test were used as appropriate, adjusting for effects of covariates and multiple comparisons. Linear regression and logistic regression were used to adjust for confounding factors. RESULTS Patients with noninflammatory LBP more strongly endorsed organic pain beliefs (e.g., that pain necessarily indicates damage), and catastrophizing (e.g., that the pain is never going to get better), than did patients with inflammatory LBP (P < 0.01). Patients with inflammatory LBP, in turn, more strongly endorsed organic pain beliefs than did pain-free controls (P < 0.05). Endorsement of organic pain beliefs was associated with catastrophizing. CONCLUSION Organic pain beliefs are associated with increased catastrophizing in patients with chronic LBP, and addressing these beliefs may help patients to manage their pain and disability. Meanings attributed to inflammatory and noninflammatory diagnostic labels may contribute to the different pain beliefs held by different patient groups.

Published
2008
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22. OC-088 Associations Between Microbiota, Colonic Volume and Transit During A Low Fodmap Diet

Author

C Mulvenna, M Lomer, Shanthi Krishnasamy, Giles Major, Robin C. Spiller, Susan E. Pritchard, P Gowland, Tim J. Sloan, and Jonna Jalanka

Subjects
0303 health sciences, medicine.medical_specialty, biology, Ruminococcus, Gastroenterology, Transit time, Exploratory analysis, biology.organism_classification, 3. Good health, law.invention, Breath hydrogen, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Low fodmap diet, medicine, Registered dietitian, Ingestion, 030211 gastroenterology & hepatology, Food science, 030304 developmental biology
Abstract

Introduction Ingestion of poorly digested carbohydrates can induce functional gastrointestinal symptoms, which may be relieved by a diet low in fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs). How dietary changes alter intestinal microbiota and gut function remains unclear. This abstract reports changes in microbiota seen in a randomised controlled trial presented at DDW 20141 and associations with colonic volume (CV), transit and dietary oligofructose. Methods All subjects (healthy adults) followed a low FODMAP diet for 7 days, supervised by a registered dietitian. They supplemented their diet with oligofructose (OF) or maltodextrin (MD) 7 g twice daily. CV and transit were assessed by magnetic resonance imaging pre- and post-intervention, as were fasting breath hydrogen(H2) and methane(CH4). Stool samples were collected before and after intervention for exploratory analysis of microbiota by 16 S Miseq sequencing. Results 37 subjects (19 OF: 18 MD) completed the trial. All reported results were significant at corrected level p = 0.05 unless stated. At baseline the combined abundance of 3 bacterial genera - Bifidobacteria, Ruminococcus and Oscillospira - correlated positively with CV (r = 0.49) and transit time (r = 0.29, p Conclusion Increase in Bifidobacteria and H2 confirm previous reports after OF or the low FODMAP diet. The increase in certain bacterial taxa after MD may result from polysaccharides included in the low FODMAP diet. Larger volumes were associated with specific bacteria but the mechanism is unclear. Future research should include assessment of volumes, transit and microbiota to provide new insights into the complex relationship between microbiology, physiology and therapy. Reference 1 Major, et al. OC-114, DDF 2014. Disclosure of Interest None Declared

Published
2016
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24. Effect of a pathway bundle on length of stay

Author

K Chatterjee, D Ewins, Tim J. Sloan, J Sloan, M Waters, N Laundy, and G Holland

Subjects
Male, medicine.medical_specialty, Critical Care and Intensive Care Medicine, Hospitals, General, Medical care, Patient Admission, medicine, Humans, Clinical care, General hospital, Medical Audit, Emergency admission, business.industry, General Medicine, Emergency department, Length of Stay, Middle Aged, Hospitals, District, England, Bundle, Emergency medicine, Emergency Medicine, Critical Pathways, Female, business, Emergency Service, Hospital, Patient stay
Abstract

Pathways to guide clinical care are well accepted and used in many emergency departments. We wanted to introduce a number ("bundle") over a short space of time and involve the whole patient stay in the pathway. It was hypothesised that a more efficient process would result with an overall reduction in length of stay (LoS).A "bundle" of 14 evidence-based pathways of care was introduced into a medium-sized district general hospital (DGH) in late 2006/early 2007. These pathways covered emergency department care and acute medical care for a period of up to 48 h. A total of 8184 acute emergency admission episodes were audited, 3852 in the 8 months before introduction of the new pathways and 4332 in the 8 months after their introduction.The overall effect of introducing the pathway bundle had a trend towards reduction in LoS by 0.2 days (95% CI -0.2 to 0.5), but this was not statistically significant (p0.1). However, in those patients with/=2 diagnoses, the introduction of the pathway bundle had an independent effect in reducing LoS by 0.4 days (95% CI 0.04 to 0.7, p0.01). In patients with/=2 diagnoses (63.0% of all pre-pathway cases and 63.4% of all post-pathway cases), the reduction in LoS equates to a saving of 2154 (CI 215 to 3769) bed days per annum or 5.9 (CI 0.6 to 10.3) beds saved each day. This reduced LoS represents an improvement of 2.5% (CI 0.25% to 4.38%) in medical bed usage. As this benefit occurs in the uncomplicated group of patients without multiple co-morbidities, such pathways would have the most effect in the type of patients who may be looked after by an emergency or acute physician. They are much less likely to be effective in those who require specialist intervention due to a more complicated presentation and possibly those with multiple co-morbidities.The introduction of a bundle of evidence-based care pathways can modestly reduce LoS for certain types of acute medical patients in a DGH setting.

Published
2009

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