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1. Community prevalence of SARS-CoV-2 in England from April to November, 2020: results from the ONS Coronavirus Infection Survey

Author

Pouwels, Koen B., Walker, A. Sarah, Crook, Derrick, Matthews, Philippa C., Peto, Tim, Pritchard, Emma, Stoesser, Nicole, Vihta, Karina-Doris, Howarth, Alison, Doherty, George, Kavanagh, James, Chau, Kevin K., Hatch, Stephanie B., Ebner, Daniel, Martins Ferreira, Lucas, Christott, Thomas, Marsden, Brian D., Dejnirattisai, Wanwisa, Mongkolsapaya, Juthathip, Hoosdally, Sarah, Cornall, Richard, Stuart, David I., Screaton, Gavin, Eyre, David, Bell, John, Cox, Stuart, Paddon, Kevin, James, Tim, House, Thomas, Newton, John N., Robotham, Julie V., Birrell, Paul, Jordan, Helena, Sheppard, Tim, Athey, Graham, Moody, Dan, Curry, Leigh, Brereton, Pamela, Hay, Jodie, Vansteenhouse, Harper, Bell, Iain, Diamond, Ian, Lambert, Alex, Benton, Pete, Rourke, Emma, Hawkes, Stacey, Henry, Sarah, Scruton, James, Stokes, Peter, Thomas, Tina, Allen, John, Black, Russell, Bovill, Heather, Braunholtz, David, Brown, Dominic, Collyer, Sarah, Crees, Megan, Daglish, Colin, Davies, Byron, Donnarumma, Hannah, Douglas-Mann, Julia, Felton, Antonio, Finselbach, Hannah, Fordham, Eleanor, Ipser, Alberta, Jenkins, Joe, Jones, Joel, Kent, Katherine, Kerai, Geeta, Lloyd, Lina, Masding, Victoria, Osborn, Ellie, Patel, Alpi, Pereira, Elizabeth, Pett, Tristan, Randall, Melissa, Reeve, Donna, Shah, Palvi, Snook, Ruth, Studley, Ruth, Sutherland, Esther, Swinn, Eliza, Thomas, Heledd, Tudor, Anna, Weston, Joshua, Leib, Shayla, Tierney, James, Farkas, Gabor, Cobb, Raf, Van Galen, Folkert, Compton, Lewis, Irving, James, Clarke, John, Mullis, Rachel, Ireland, Lorraine, Airimitoaie, Diana, Nash, Charlotte, Cox, Danielle, Fisher, Sarah, Moore, Zoe, McLean, James, Kerby, Matt, Pouwels, Koen B, Robotham, Julie V, Birrell, Paul J, Gelman, Andrew, Bowers, Nikola, Boreham, Ian, Lewis, James, Bell, John I, Newton, John N, Farrar, Jeremy, and Walker, Ann Sarah

Published
2021
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3. Antibody responses and correlates of protection in the general population after two doses of the ChAdOx1 or BNT162b2 vaccines

Author

Wei, Jia, Pouwels, Koen B., Stoesser, Nicole, Matthews, Philippa C., Diamond, Ian, Studley, Ruth, Rourke, Emma, Cook, Duncan, Bell, John I., Newton, John N., Farrar, Jeremy, Howarth, Alison, Marsden, Brian D., Hoosdally, Sarah, Jones, E. Yvonne, Stuart, David I., Crook, Derrick W., Peto, Tim E. A., Walker, A. Sarah, Eyre, David W., Thomas, Tina, Ayoubkhani, Daniel, Black, Russell, Felton, Antonio, Crees, Megan, Jones, Joel, Lloyd, Lina, Sutherland, Esther, Pritchard, Emma, Vihta, Karina-Doris, Doherty, George, Kavanagh, James, Chau, Kevin K., Hatch, Stephanie B., Ebner, Daniel, Ferreira, Lucas Martins, Christott, Thomas, Dejnirattisai, Wanwisa, Mongkolsapaya, Juthathip, Cameron, Sarah, Tamblin-Hopper, Phoebe, Wolna, Magda, Brown, Rachael, Cornall, Richard, Screaton, Gavin, Lythgoe, Katrina, Bonsall, David, Golubchik, Tanya, Fryer, Helen, Cox, Stuart, Paddon, Kevin, James, Tim, House, Thomas, Robotham, Julie, Birrell, Paul, Jordan, Helena, Sheppard, Tim, Athey, Graham, Moody, Dan, Curry, Leigh, Brereton, Pamela, Jarvis, Ian, Godsmark, Anna, Morris, George, Mallick, Bobby, Eeles, Phil, Hay, Jodie, VanSteenhouse, Harper, Lee, Jessica, White, Sean, Evans, Tim, Bloemberg, Lisa, Allison, Katie, Pandya, Anouska, Davis, Sophie, Conway, David I., MacLeod, Margaret, and Cunningham, Chris

Abstract

Antibody responses are an important part of immunity after Coronavirus Disease 2019 (COVID-19) vaccination. However, antibody trajectories and the associated duration of protection after a second vaccine dose remain unclear. In this study, we investigated anti-spike IgG antibody responses and correlates of protection after second doses of ChAdOx1 or BNT162b2 vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United Kingdom general population. In 222,493 individuals, we found significant boosting of anti-spike IgG by the second doses of both vaccines in all ages and using different dosing intervals, including the 3-week interval for BNT162b2. After second vaccination, BNT162b2 generated higher peak levels than ChAdOX1. Older individuals and males had lower peak levels with BNT162b2 but not ChAdOx1, whereas declines were similar across ages and sexes with ChAdOX1 or BNT162b2. Prior infection significantly increased antibody peak level and half-life with both vaccines. Anti-spike IgG levels were associated with protection from infection after vaccination and, to an even greater degree, after prior infection. At least 67% protection against infection was estimated to last for 2–3 months after two ChAdOx1 doses, for 5–8 months after two BNT162b2 doses in those without prior infection and for 1–2 years for those unvaccinated after natural infection. A third booster dose might be needed, prioritized to ChAdOx1 recipients and those more clinically vulnerable.

Published
2022

4. Anti-spike antibody response to natural SARS-CoV-2 infection in the general population

Author

Wei, Jia, Matthews, Philippa C., Stoesser, Nicole, Maddox, Thomas, Lorenzi, Luke, Studley, Ruth, Bell, John I., Newton, John N., Farrar, Jeremy, Diamond, Ian, Rourke, Emma, Howarth, Alison, Marsden, Brian D., Hoosdally, Sarah, Jones, E. Yvonne, Stuart, David I., Crook, Derrick W., Peto, Tim E. A., Pouwels, Koen B., Walker, A. Sarah, Eyre, David W., Thomas, Tina, Cook, Duncan, Ayoubkhani, Daniel, Black, Russell, Felton, Antonio, Crees, Megan, Jones, Joel, Lloyd, Lina, Sutherland, Esther, Pritchard, Emma, Vihta, Karina-Doris, Doherty, George, Kavanagh, James, Chau, Kevin K., Hatch, Stephanie B., Ebner, Daniel, Ferreira, Lucas Martins, Christott, Thomas, Dejnirattisai, Wanwisa, Mongkolsapaya, Juthathip, Cameron, Sarah, Tamblin-Hopper, Phoebe, Wolna, Magda, Brown, Rachael, Cornall, Richard, Screaton, Gavin, Lythgoe, Katrina, Bonsall, David, Golubchik, Tanya, Fryer, Helen, Cox, Stuart, Paddon, Kevin, James, Tim, House, Thomas, Robotham, Julie, Birrell, Paul, Jordan, Helena, Sheppard, Tim, Athey, Graham, Moody, Dan, Curry, Leigh, Brereton, Pamela, Jarvis, Ian, Godsmark, Anna, Morris, George, Mallick, Bobby, Eeles, Phil, Hay, Jodie, VanSteenhouse, Harper, Lee, Jessica, White, Sean, Evans, Tim, Bloemberg, Lisa, Allison, Katie, Pandya, Anouska, Davis, Sophie, Conway, David I., MacLeod, Margaret, and Cunningham, Chris

Abstract

Understanding the trajectory, duration, and determinants of antibody responses after SARS-CoV-2 infection can inform subsequent protection and risk of reinfection, however large-scale representative studies are limited. Here we estimated antibody response after SARS-CoV-2 infection in the general population using representative data from 7,256 United Kingdom COVID-19 infection survey participants who had positive swab SARS-CoV-2 PCR tests from 26-April-2020 to 14-June-2021. A latent class model classified 24% of participants as ‘non-responders’ not developing anti-spike antibodies, who were older, had higher SARS-CoV-2 cycle threshold values during infection (i.e. lower viral burden), and less frequently reported any symptoms. Among those who seroconverted, using Bayesian linear mixed models, the estimated anti-spike IgG peak level was 7.3-fold higher than the level previously associated with 50% protection against reinfection, with higher peak levels in older participants and those of non-white ethnicity. The estimated anti-spike IgG half-life was 184 days, being longer in females and those of white ethnicity. We estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years. These estimates could inform planning for vaccination booster strategies.

Published
2021

5. Antibody responses to SARS-CoV-2 vaccines in 45,965 adults from the general population of the United Kingdom

Author

Wei, Jia, Stoesser, Nicole, Matthews, Philippa C., Ayoubkhani, Daniel, Studley, Ruth, Bell, Iain, Bell, John I., Newton, John N., Farrar, Jeremy, Diamond, Ian, Rourke, Emma, Howarth, Alison, Marsden, Brian D., Hoosdally, Sarah, Jones, E. Yvonne, Stuart, David I., Crook, Derrick W., Peto, Tim E. A., Pouwels, Koen B., Eyre, David W., Walker, A. Sarah, Lambert, Alex, Thomas, Tina, Black, Russell, Felton, Antonio, Crees, Megan, Jones, Joel, Lloyd, Lina, Sutherland, Esther, Pritchard, Emma, Vihta, Karina-Doris, Doherty, George, Kavanagh, James, Chau, Kevin K., Hatch, Stephanie B., Ebner, Daniel, Ferreira, Lucas Martins, Christott, Thomas, Dejnirattisai, Wanwisa, Mongkolsapaya, Juthathip, Cameron, Sarah, Tamblin-Hopper, Phoebe, Wolna, Magda, Brown, Rachael, Cornall, Richard, Screaton, Gavin, Lythgoe, Katrina, Bonsall, David, Golubchik, Tanya, Fryer, Helen, Cox, Stuart, Paddon, Kevin, James, Tim, House, Thomas, Robotham, Julie, Birrell, Paul, Jordan, Helena, Sheppard, Tim, Athey, Graham, Moody, Dan, Curry, Leigh, Brereton, Pamela, Jarvis, Ian, Godsmark, Anna, Morris, George, Mallick, Bobby, Eeles, Phil, Hay, Jodie, VanSteenhouse, Harper, and Lee, Jessica

Abstract

We report that in a cohort of 45,965 adults, who were receiving either the ChAdOx1 or the BNT162b2 SARS-CoV-2 vaccines, in those who had no prior infection with SARS-CoV-2, seroconversion rates and quantitative antibody levels after a single dose were lower in older individuals, especially in those aged >60 years. Two vaccine doses achieved high responses across all ages. Antibody levels increased more slowly and to lower levels with a single dose of ChAdOx1 compared with a single dose of BNT162b2, but waned following a single dose of BNT162b2 in older individuals. In descriptive latent class models, we identified four responder subgroups, including a ‘low responder’ group that more commonly consisted of people aged >75 years, males and individuals with long-term health conditions. Given our findings, we propose that available vaccines should be prioritized for those not previously infected and that second doses should be prioritized for individuals aged >60 years. Further data are needed to better understand the extent to which quantitative antibody responses are associated with vaccine-mediated protection.

Published
2021

6. The Duration, Dynamics, and Determinants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibody Responses in Individual Healthcare Workers

Author

Lumley, Sheila F, Wei, Jia, O’Donnell, Denise, Stoesser, Nicole E, Matthews, Philippa C, Howarth, Alison, Hatch, Stephanie B, Marsden, Brian D, Cox, Stuart, James, Tim, Peck, Liam J, Ritter, Thomas G, de Toledo, Zoe, Cornall, Richard J, Jones, E Yvonne, Stuart, David I, Screaton, Gavin, Ebner, Daniel, Hoosdally, Sarah, Crook, Derrick W, Conlon, Christopher P, Pouwels, Koen B, Walker, A Sarah, Peto, Tim E A, Walker, Timothy M, Jeffery, Katie, Eyre, David W, Abbott, Molly, Abhari, Roxanna, Abuelgasim, Hibatullah, Ahmed-Firani, Tariq, Alhussni, Ahmed, Argles, Isobel, Ashworth, Rebecca, Back, Francesca, Black, Susannah, Brennan, Isabelle, Cansdale, Lottie, Chakravorty, Triya, Choudhury, Zahra, Clay, Helen, Conway-Jones, Rebecca, Curtis, Aisling, Cutteridge, Joseph, Danbury, Hannah, Davies, Hettie, Denly, Lucy, Dequaire, Julie, Dimitrov, Stoyan, Dunlop, Ella, Dunn, Polly, East, Cameron, Eastwood, Ben, Edwardes, Chantal, Evans, Meirian, Fields, Charlotte, Flaherty, Sarah, Foord, Thomas, Freer, Rosie, Fuchs, Hannah, Grassam-Rowe, Alexander, Greenan-Barrett, Lewis, Gunnell, James, Harries, Callum, Harris, Edward, Hatton, Elizabeth, Hennessy, Conor, Holland, Christian, Holloway, Ben, Howgego, Gregory, Barnham, Isaac Jarratt, Johnson, Síle, Johnson, Thomas, Johnstone, Daniela, Jurdon, Rebecca, Kelly, Gabriella, Kerneis, Sven, Khulusi, Beinn, Killen, Annabel, Kourdov, Stefan, Kumarendran, Mary, Laurenson-Schafer, Hannah, Lawrence, Ruby, Lee, Charlotte, Livingstone, Angus, Lynch, Rosie, Madsen, Tara, Manji, Ali, Marsh, James, Mason, Chris, Mccance, Angus, Mcgivern, Euan, Mckinlay, Ailsa, Mighiu, Alexandra, Millar, Lancelot, Mohamed, Yethrib, Motohashi, Kenzo, Myat, San, Nezhentsev, Andrey, O’Byrne, Katherine, Okuwoga, Temitope, Oliver, Madeleine, Pattenden, Saxon, Perera, Vimukthi, Petit, Yva, Pickles, Florence, Pikoula, Maria, Randhawa, Govind, Ravi, Krupa, Reed, Lara, Rigler, Caitlin, Robinson, Charlotte, Rothwell, Evie, Santos-Paulo, Stephanie, Savva, Constantinos, Scharmeli, Alice, Scott, Samuel, Shabir, Zamin, Sharma, Ishta, Sheehan, Remarez, Shibu, Afrah, Somanathan, Arun, Sussmes, Samuel, Sweeney, Owen, Swift, Emily, Tadikamalla, Gayatri, Tamblyn, Morwenna, Taylor, Adan, Naudé, Rebecca Te Water, Thomas, Sarah, Thompson, Connor, Till, Lottie, Toward, Ross, Virgo, Charis, Vorley, Imogen, Waite, Seren, Ward, Harry, Ward, Jocelyn, Watson, Adam, Watson, Lily, Wedlich, Matthew, Wilkins, Laura, Wilson, Jack, Wilson, Joseph, Wong, William, Young, Rebecca, Doherty, George, Kavanagh, James, Chau, Kevin K, Fowler, Philip W, Swann, Jeremy, Volk, Denis, Yang-Turner, Fan, Skelly, Donal, Karpe, Fredrik, Neville, Matt J, Ferreira, Lucas Martins, Christott, Thomas, Rodger, Gillian, Pickford, Hayleah, Cameron, Sarah, Tamblin-Hopper, Phoebe, Amini, Ali, Andersson, Monique, Anson, Karen, Aston, Lisa, Axten, David, Barot, Simran, Bellinger, Trisha, Bialek, Adrian, Bodo, Noemi, Brent, Andrew, Campbell, Mark, Cox, Vanessa, Cronin, Tammy, Davies, Timothy, Deales, Alessio, Downs, Louise, Drennan, Philip, Dudareva, Maria, Gates, Laura, Gates, Michelle, Georgiou, Dominique, Gergely, Bernadett, Holland, Louise, Jones, Nicola, Jones, Sarah, Kerr, Sharon, Lawson, Elaine, Looms, Stacy, Luciw, Michael, Martins, Diva, Mcknight, Mary, Mentzer, Alexander, Millard, Rebecca, Mitchell, Tracey, Morgan, Lisa, Morrow, Jordan, Mortimore, Emma, Mullins, Harriet, Nevard, Heather, O’Donnell, Anne-Marie, Patel, Kaisha, Peto, Leon, Philips, Jane, Ponting, Jessica, Ray, Roshni, Robles, Maria, Rughani, Sonam, Sande, Nellia, Shaw, Robert, Simons, Emma-Jane, Sims, Elizabeth, Smit, Kyla, Smith, Lucianne, Szczurkowska, Justyna, Thompson, Zoe, Turford, Rachel, Vilca, Kim, Vogt, Alexander, Warren, Fiona, Warren, Laura, Wharton, Vicki, Whitty, Alison, Woodley, Heather, Wozniak, Barbara, Young, Bernadette, Justice, Anita, Jesuthasan, Gerald, Wareing, Susan, Fadzillah, Nurul Huda Mohamad, Cann, Kathryn, Kirton, Richard, Sutton, Claire, Salvagno, Claudia, D’Amato, Gabriella, Pill, Gemma, Butcher, Lisa, Rylance-Knight, Lydia, Tabirao, Merline, Moroney, Ruth, Wright, Sarah, and Group, Oxford University Hospitals Staff Testing

Subjects
0301 basic medicine, Microbiology (medical), Adult, medicine.medical_specialty, Health Personnel, Population, Antibodies, Viral, Immunoglobulin G, Serology, 03 medical and health sciences, 0302 clinical medicine, Seroepidemiologic Studies, Internal medicine, Correspondence, Credible interval, Major Article, Seroprevalence, Medicine, Humans, 030212 general & internal medicine, education, Survival analysis, Antibody, education.field_of_study, biology, business.industry, SARS-CoV-2, COVID-19, Bayes Theorem, Waning, Titer, 030104 developmental biology, Infectious Diseases, AcademicSubjects/MED00290, Reinfection, Antibody Formation, biology.protein, Longitudinal, business
Abstract

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) antibody measurements can be used to estimate the proportion of a population exposed or infected and may be informative about the risk of future infection. Previous estimates of the duration of antibody responses vary. Methods We present 6 months of data from a longitudinal seroprevalence study of 3276 UK healthcare workers (HCWs). Serial measurements of SARS-CoV-2 anti-nucleocapsid and anti-spike IgG were obtained. Interval censored survival analysis was used to investigate the duration of detectable responses. Additionally, Bayesian mixed linear models were used to investigate anti-nucleocapsid waning. Results Anti-spike IgG levels remained stably detected after a positive result, for example, in 94% (95% credibility interval [CrI] 91–96%) of HCWs at 180 days. Anti-nucleocapsid IgG levels rose to a peak at 24 (95% CrI 19–31) days post first polymerase chain reaction (PCR)-positive test, before beginning to fall. Considering 452 anti-nucleocapsid seropositive HCWs over a median of 121 days from their maximum positive IgG titer, the mean estimated antibody half-life was 85 (95% CrI 81–90) days. Higher maximum observed anti-nucleocapsid titers were associated with longer estimated antibody half-lives. Increasing age, Asian ethnicity, and prior self-reported symptoms were independently associated with higher maximum anti-nucleocapsid levels and increasing age and a positive PCR test undertaken for symptoms with longer anti-nucleocapsid half-lives. Conclusions SARS-CoV-2 anti-nucleocapsid antibodies wane within months and fall faster in younger adults and those without symptoms. However, anti-spike IgG remains stably detected. Ongoing longitudinal studies are required to track the long-term duration of antibody levels and their association with immunity to SARS-CoV-2 reinfection.

Published
2021

7. Differential occupational risks to healthcare workers from SARS-CoV-2: A prospective observational study

Author

Eyre, David W, Lumley, Sheila F, O’Donnell, Denise, Campbell, Mark, Sims, Elizabeth, Lawson, Elaine, Warren, Fiona, James, Tim, Cox, Stuart, Howarth, Alison, Doherty, George, Hatch, Stephanie B, Kavanagh, James, Chau, Kevin K, Fowler, Philip W, Swann, Jeremy, Volk, Denis, Yang-Turner, Fan, Stoesser, Nicole E, Matthews, Philippa C, Dudareva, Maria, Davies, Timothy, Shaw, Robert H, Peto, Leon, Downs, Louise O, Vogt, Alexander, Amini, Ali, Young, Bernadette C, Drennan, Philip, Mentzer, Alexander J, Skelly, Donal, Karpe, Fredrik, Neville, Matt J, Andersson, Monique, Brent, Andrew J, Jones, Nicola, Ferreira, Lucas Martins, Christott, Thomas, Marsden, Brian D, Hoosdally, Sarah, Cornall, Richard, Crook, Derrick W, Stuart, David, Screaton, Gavin, Peto, Timothy EA, Holthof, Bruno, O’Donnell, Anne-Marie, Ebner, Daniel, Conlon, Christopher P, Jeffery, Katie, and Walker, Timothy M

Subjects
medicine.medical_specialty, business.industry, Psychological intervention, Odds ratio, Logistic regression, Intensive care unit, law.invention, law, Emergency medicine, Health care, Medicine, Observational study, business, Personal protective equipment, Contact tracing
Abstract

BackgroundPersonal protective equipment (PPE) and social distancing are designed to mitigate risk of occupational SARS-CoV-2 infection in hospitals. Why healthcare workers nevertheless remain at increased risk is uncertain.MethodsWe conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using nasopharyngeal PCR testing and immunoassays for IgG antibodies. A positive result by either modality determined a composite outcome. Risk-factors for Covid-19 were investigated using multivariable logistic regression.Results1083/9809(11.0%) staff had evidence of Covid-19 at some time and provided data on potential risk-factors. Staff with a confirmed household contact were at greatest risk (adjusted odds ratio [aOR] 4.63 [95%CI 3.30-6.50]). Higher rates of Covid-19 were seen in staff working in Covid-19-facing areas (21.2% vs. 8.2% elsewhere) (aOR 2.49 [2.00-3.12]). Controlling for Covid-19-facing status, risks were heterogenous across the hospital, with higher rates in acute medicine (1.50 [1.05-2.15]) and sporadic outbreaks in areas with few or no Covid-19 patients. Covid-19 intensive care unit (ICU) staff were relatively protected (0.46 [0.29-0.72]). Positive results were more likely in Black (1.61 [1.20-2.16]) and Asian (1.58 [1.34-1.86]) staff, independent of role or working location, and in porters and cleaners (1.93 [1.25-2.97]). Contact tracing around asymptomatic staff did not lead to enhanced case identification. 24% of staff/patients remained PCR-positive at ≥6 weeks post-diagnosis.ConclusionsIncreased Covid-19 risk was seen in acute medicine, among Black and Asian staff, and porters and cleaners. A bundle of PPE-related interventions protected staff in ICU.

Published
2020
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8. A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function.

Author

Fagan, Vincent, Johansson, Catrine, Gileadi, Carina, Monteiro, Octovia, Dunford, James Edward, Nibhani, Reshma, Philpott, Martin, Malzahn, Jessica, Wells, Graham, Farham, Ruth, Cribbs, Adam, Halidi, Nadia, Li, Fengling, Chau, Irene, Greschik, Holger, Velupillai, Srikannathasan, Allali-Hassani, Abdellah, Bennett, James M, Christott, Thomas, Giroud, Charline, Lewis, Andrew M, Huber, Kilian VM, Athanasou, Nick, Bountra, Chas, Jung, Manfred, Schüle, Roland, Vedadi, Masoud, Arrowsmith, Cheryl H, Xiong, Yan, Jin, Jian, Fedorov, Oleg, Farnie, Gillian, Brennan, Paul E, Oppermann, Udo CT, Fagan, Vincent, Johansson, Catrine, Gileadi, Carina, Monteiro, Octovia, Dunford, James Edward, Nibhani, Reshma, Philpott, Martin, Malzahn, Jessica, Wells, Graham, Farham, Ruth, Cribbs, Adam, Halidi, Nadia, Li, Fengling, Chau, Irene, Greschik, Holger, Velupillai, Srikannathasan, Allali-Hassani, Abdellah, Bennett, James M, Christott, Thomas, Giroud, Charline, Lewis, Andrew M, Huber, Kilian VM, Athanasou, Nick, Bountra, Chas, Jung, Manfred, Schüle, Roland, Vedadi, Masoud, Arrowsmith, Cheryl H, Xiong, Yan, Jin, Jian, Fedorov, Oleg, Farnie, Gillian, Brennan, Paul E, and Oppermann, Udo CT

Abstract

Modifications of histone tails, including lysine/arginine methylation, provide the basis of a 'chromatin or histone code'. Proteins that con-tain 'reader' domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyl-lysine/arginine reader domains and was identified as a putative onco-gene and transcriptional co-activator. Here we report a SPIN1 chemi-cal probe inhibitor with low nanomolar in vitro activity, exquisite selectivity on a panel of methyl reader and writer proteins, and with submicromolar cellular activity. X-ray crystallography showed that this Tudor domain chemical probe simultaneously engages Tudor domains 1 and 2 via a bidentate binding mode. Small molecule inhibition and siRNA knockdown of SPIN1, as well as chemoproteomic studies, iden-tified genes which are transcriptionally regulated by SPIN1 in squa-mous cell carcinoma and suggest that SPIN1 may have a roll in cancer related inflammation and/or cancer metastasis.

Published
2019

9. Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1)

Author

Xiong, Yan, Greschik, Holger, Johansson, Catrine, Seifert, Ludwig, Bacher, Jahannes, Park, Kwang-su, Babault, Nicolas, Martini, Michael, Fagan, Vincent, Li, Fengling, Chau, Irene, Christott, Thomas, Dilworth, David, Barsyte-Lovejoy, Dalia, Vedadi, Masoud, Arrowsmith, Cheryl H., Brennan, Paul, Fedorov, Oleg, Jung, Manfred Jung, Farnie, Gillian, Lui, Jing, Oppermann, Udo, Schüle, Roland, Jin, Jian, Xiong, Yan, Greschik, Holger, Johansson, Catrine, Seifert, Ludwig, Bacher, Jahannes, Park, Kwang-su, Babault, Nicolas, Martini, Michael, Fagan, Vincent, Li, Fengling, Chau, Irene, Christott, Thomas, Dilworth, David, Barsyte-Lovejoy, Dalia, Vedadi, Masoud, Arrowsmith, Cheryl H., Brennan, Paul, Fedorov, Oleg, Jung, Manfred Jung, Farnie, Gillian, Lui, Jing, Oppermann, Udo, Schüle, Roland, and Jin, Jian

Abstract

By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective, and cell-active SPIN1 inhibitor, compound 3 (MS31). Compound 3 potently inhibited binding of trimethyllysine-containing peptides to SPIN1, displayed high binding affinity, was highly selective for SPIN1 over other epigenetic readers and writers, directly engaged SPIN1 in cells, and was not toxic to nontumorigenic cells. The crystal structure of the SPIN1–compound 3 complex indicated that it selectively binds tudor domain II of SPIN1. We also designed a structurally similar but inactive compound 4 (MS31N) as a negative control. Our results have demonstrated for the first time that potent, selective, and cell-active fragment-like inhibitors can be generated by targeting a single tudor domain.

Published
2019

10. Structural insights into interaction mechanisms of alternative piperazine-urea YEATS domain binders in MLLT1

Author

Ni, Xiaomin, Heidenreich, David Jonas, Christott, Thomas, Bennett, James, Moustakim, Moses, Brennan, Paul E., Fedorov, Oleg, Knapp, Stefan, Chaikuad, Apirat, Ni, Xiaomin, Heidenreich, David Jonas, Christott, Thomas, Bennett, James, Moustakim, Moses, Brennan, Paul E., Fedorov, Oleg, Knapp, Stefan, and Chaikuad, Apirat

Abstract

YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family.

Published
2019

12. Differential occupational risks to healthcare workers from SARS-CoV-2 observed during a prospective observational study.

Author

Eyre DW, Lumley SF, O'Donnell D, Campbell M, Sims E, Lawson E, Warren F, James T, Cox S, Howarth A, Doherty G, Hatch SB, Kavanagh J, Chau KK, Fowler PW, Swann J, Volk D, Yang-Turner F, Stoesser N, Matthews PC, Dudareva M, Davies T, Shaw RH, Peto L, Downs LO, Vogt A, Amini A, Young BC, Drennan PG, Mentzer AJ, Skelly DT, Karpe F, Neville MJ, Andersson M, Brent AJ, Jones N, Martins Ferreira L, Christott T, Marsden BD, Hoosdally S, Cornall R, Crook DW, Stuart DI, Screaton G, Peto TE, Holthof B, O'Donnell AM, Ebner D, Conlon CP, Jeffery K, and Walker TM

Subjects
Adolescent, Adult, Age Factors, Aged, Asymptomatic Infections epidemiology, Betacoronavirus isolation & purification, COVID-19, Coronavirus Infections transmission, Coronavirus Infections virology, Female, Hospitals, Teaching statistics & numerical data, Humans, Incidence, Infectious Disease Transmission, Patient-to-Professional statistics & numerical data, Intensive Care Units statistics & numerical data, Male, Middle Aged, Pandemics, Pneumonia, Viral transmission, Pneumonia, Viral virology, Risk, SARS-CoV-2, Surveys and Questionnaires, United Kingdom epidemiology, Young Adult, Coronavirus Infections epidemiology, Health Personnel statistics & numerical data, Pneumonia, Viral epidemiology
Abstract

We conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using naso-/oro-pharyngeal PCR testing and immunoassays for IgG antibodies. 1128/10,034 (11.2%) staff had evidence of Covid-19 at some time. Using questionnaire data provided on potential risk-factors, staff with a confirmed household contact were at greatest risk (adjusted odds ratio [aOR] 4.82 [95%CI 3.45-6.72]). Higher rates of Covid-19 were seen in staff working in Covid-19-facing areas (22.6% vs. 8.6% elsewhere) (aOR 2.47 [1.99-3.08]). Controlling for Covid-19-facing status, risks were heterogenous across the hospital, with higher rates in acute medicine (1.52 [1.07-2.16]) and sporadic outbreaks in areas with few or no Covid-19 patients. Covid-19 intensive care unit staff were relatively protected (0.44 [0.28-0.69]), likely by a bundle of PPE-related measures. Positive results were more likely in Black (1.66 [1.25-2.21]) and Asian (1.51 [1.28-1.77]) staff, independent of role or working location, and in porters and cleaners (2.06 [1.34-3.15])., Competing Interests: DE Lecture fees from Gilead, outside the submitted work, SL, DO, MC, ES, EL, FW, TJ, SC, AH, GD, SH, JK, KC, PF, JS, DV, FY, NS, PM, MD, TD, RS, LP, LD, AV, AA, BY, PD, AM, DS, FK, MN, MA, AB, NJ, LM, TC, BM, SH, RC, DC, DS, GS, TP, BH, AO, DE, CC, KJ, TW No competing interests declared, (© 2020, Eyre et al.)

Published
2020
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