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5. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

Author

Aboagye, Jeremy, Adams, Kelly, Ali, Aabidah, Allen, Elizabeth, Allison, Jennifer L., Anslow, Rachel, Arbe-Barnes, Edward H., Babbage, Gavin, Baillie, Kenneth, Baker, Megan, Baker, Natalie, Baker, Philip, Baleanu, Ioana, Ballaminut, Juliana, Barnes, Eleanor, Barrett, Jordan, Bates, Louise, Batten, Alexander, Beadon, Kirsten, Beckley, Rebecca, Berrie, Eleanor, Berry, Lisa, Beveridge, Amy, Bewley, Kevin R., Bijker, Else Margreet, Bingham, Tracey, Blackwell, Luke, Blundell, Caitlin L., Bolam, Emma, Boland, Elena, Borthwick, Nicola, Bower, Thomas, Boyd, Amy, Brenner, Tanja, Bright, Philip D., Brown-O'Sullivan, Charlie, Brunt, Emily, Burbage, Jamie, Burge, Sharon, Buttigieg, Karen R., Byard, Nicholas, Cabera Puig, Ingrid, Calvert, Anna, Camara, Susana, Cao, Michelangelo, Cappuccini, Federica, Carr, Melanie, Carroll, Miles W., Carter, Victoria, Cathie, Katrina, Challis, Ruth J., Charlton, Sue, Chelysheva, Irina, Cho, Jee-Sun, Cicconi, Paola, Cifuentes, Liliana, Clark, Helen, Clark, Elizabeth, Cole, Tom, Colin-Jones, Rachel, Conlon, Christopher P., Cook, Aislinn, Coombes, Naomi S., Cooper, Rachel, Cosgrove, Catherine A., Coy, Karen, Crocker, Wendy E.M., Cunningham, Christina J., Damratoski, Brad E., Dando, Lynne, Datoo, Mehreen S., Davies, Hannah, De Graaf, Hans, Demissie, Tesfaye, Di Maso, Claudio, Dietrich, Isabelle, Dong, Tao, Donnellan, Francesca R., Douglas, Naomi, Downing, Charlotte, Drake, Jonathan, Drake-Brockman, Rachael, Drury, Ruth Elizabeth, Dunachie, Susanna Jane, Edwards, Nick J., Edwards, Frances D.L., Edwards, Chris J., Elias, Sean C., Elmore, Michael J., Emary, Katherine R.W., English, Marcus Rex, Fagerbrink, Susanne, Felle, Sally, Feng, Shuo, Field, Samantha, Fixmer, Carine, Fletcher, Clare, Ford, Karen J., Fowler, Jamie, Fox, Polly, Francis, Emma, Frater, John, Furze, Julie, Fuskova, Michelle, Galiza, Eva, Gbesemete, Diane, Gilbride, Ciaran, Godwin, Kerry, Gorini, Giacomo, Goulston, Lyndsey, Grabau, Caroline, Gracie, Lara, Gray, Zoe, Guthrie, Lucy Belle, Hackett, Mark, Halwe, Sandro, Hamilton, Elizabeth, Hamlyn, Joseph, Hanumunthadu, Brama, Harding, Irasha, Harris, Stephanie A., Harris, Andrew, Harrison, Daisy, Harrison, Clare, Hart, Thomas C., Haskell, Louise, Hawkins, Sophia, Head, Ian, Henry, John Aaron, Hill, Jennifer, Hodgson, Susanne H.C., Hou, Mimi M., Howe, Elizabeth, Howell, Nicola, Hutlin, Cecilia, Ikram, Sabina, Isitt, Catherine, Iveson, Poppy, Jackson, Susan, Jackson, Frederic, James, Sir William, Jenkins, Megan, Jones, Elizabeth, Jones, Kathryn, Jones, Christine E., Jones, Bryony, Kailath, Reshma, Karampatsas, Konstantinos, Keen, Jade, Kelly, Sarah, Kelly, Dearbhla, Kerr, David, Kerridge, Simon, Khan, Liaquat, Khan, Uzma, Killen, Annabel, Kinch, Jasmin, King, Thomas B., King, Lloyd, King, Jade, Kingham-Page, Lucy, Klenerman, Paul, Knapper, Francesca, Knight, Julian C., Knott, Daniel, Koleva, Stanislava, Kupke, Alexandra, Larkworthy, Colin W., Larwood, Jessica P.J., Laskey, Anna, Lawrie, Alison M., Lee, Arlene, Ngan Lee, Kim Yee, Lees, Emily A, Legge, Helen, Lelliott, Alice, Lemm, Nana-Marie, Lias, Amelia M., Linder, Aline, Lipworth, Samuel, Liu, Xinxue, Liu, Shuchang, Lopez Ramon, Raquel, Lwin, May, Mabesa, Francesca, Madhavan, Meera, Mallett, Garry, Mansatta, Kushal, Marcal, Ines, Marinou, Spyridoula, Marlow, Emma, Marshall, Julia L., Martin, Jane, McEwan, Joanne, McInroy, Lorna, Meddaugh, Gretchen, Mentzer, Alexander J., Mirtorabi, Neginsadat, Moore, Maria, Moran, Edward, Morey, Ella, Morgan, Victoria, Morris, Susan Jane, Morrison, Hazel, Morshead, Gertraud, Morter, Richard, Mujadidi, Yama F., Muller, Jilly, Munera-Huertas, Tatiana, Munro, Claire, Munro, Alasdair, Murphy, Sarah, Munster, Vincent J., Mweu, Philomena, Noé, Andrés, Nugent, Fay L., Nuthall, Elizabeth, O'Brien, Katie, O'Connor, Daniel, Oguti, Blanché, Oliver, Jennifer L., Oliveira, Catarina, O'Reilly, Peter John, Osborn, Mairead, Osborne, Piper, Owen, Cathy, Owens, Daniel, Owino, Nelly, Pacurar, Mihaela, Parker, Kaye, Parracho, Helena, Patrick-Smith, Maia, Payne, Victoria, Pearce, Jennifer, Peng, Yanchun, Peralta Alvarez, Marco Polo, Perring, James, Pfafferott, Katja, Pipini, Dimitra, Plested, Emma, Pluess-Hall, Helen, Pollock, Katrina, Poulton, Ian, Presland, Laura, Provstgaard-Morys, Samuel, Pulido, David, Radia, Kajal, Ramos Lopez, Fernando, Rand, Jade, Ratcliffe, Helen, Rawlinson, Thomas, Rhead, Sarah, Riddell, Amy, Ritchie, Adam John, Roberts, Hannah, Robson, Joanna, Roche, Sophie, Rohde, Cornelius, Rollier, Christine S., Romani, Rossana, Rudiansyah, Indra, Saich, Stephen, Sajjad, Sara, Salvador, Stephannie, Sanchez Riera, Lidia, Sanders, Helen, Sanders, Katherine, Sapaun, Shari, Sayce, Chloe, Schofield, Ella, Screaton, Gavin, Selby, Beatrice, Semple, Calum, Sharpe, Hannah R., Shaik, Imam, Shea, Adam, Shelton, Holly, Silk, Sarah, Silva-Reyes, Laura, Skelly, Donal T., Smee, Heather, Smith, Catherine C., Smith, David J., Song, Rinn, Spencer, Alexandra J., Stafford, Elizabeth, Steele, Amy, Stefanova, Elena, Stockdale, Lisa, Szigeti, Anna, Tahiri-Alaoui, Abdessamad, Tait, Moira, Talbot, Helen, Tanner, Rachel, Taylor, Iona Jennifer, Taylor, Victoria, Te Water Naude, Rebecca, Thakur, Nazia, Themistocleous, Yrene, Themistocleous, Andreas, Thomas, Merin, Thomas, Tonia M., Thompson, Amber, Thomson-Hill, Samantha, Tomlins, Jennifer, Tonks, Susan, Towner, James, Tran, Nguyen, Tree, Julia A., Truby, Adam, Turkentine, Kate, Turner, Cheryl, Turner, Nicola, Turner, Sally, Tuthill, Toby, Ulaszewska, Marta, Varughese, Rachel, Van Doremalen, Neeltje, Veighey, Kristin, Verheul, Marije K., Vichos, Iason, Vitale, Elia, Walker, Laura, Watson, Marion E.E., Welham, Benjamin, Wheat, Julie, White, Caroline, White, Rachel, Worth, Andrew T., Wright, Danny, Wright, Suzie, Yao, Xin Li, Yau, Yasmine, Folegatti, Pedro M, Ewer, Katie J, Aley, Parvinder K, Angus, Brian, Becker, Stephan, Belij-Rammerstorfer, Sandra, Bellamy, Duncan, Bibi, Sagida, Bittaye, Mustapha, Clutterbuck, Elizabeth A, Dold, Christina, Faust, Saul N, Finn, Adam, Flaxman, Amy L, Hallis, Bassam, Heath, Paul, Jenkin, Daniel, Lazarus, Rajeka, Makinson, Rebecca, Minassian, Angela M, Pollock, Katrina M, Ramasamy, Maheshi, Robinson, Hannah, Snape, Matthew, Tarrant, Richard, Voysey, Merryn, Green, Catherine, Douglas, Alexander D, Hill, Adrian V S, Lambe, Teresa, Gilbert, Sarah C, and Pollard, Andrew J

Published
2020
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6. Safety and High Level Efficacy of the Combination Malaria Vaccine Regimen of RTS,S/AS01 B With Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara Vectored Vaccines Expressing ME-TRAP

Author

Rampling, Tommy, Ewer, Katie J., Bowyer, Georgina, Bliss, Carly M., Edwards, Nick J., Wright, Danny, Payne, Ruth O., Venkatraman, Navin, de Barra, Eoghan, Snudden, Claudia M., Poulton, Ian D., de Graaf, Hans, Sukhtankar, Priya, Roberts, Rachel, Ivinson, Karen, Weltzin, Rich, Rajkumar, Bebi-Yassin, Wille-Reece, Ulrike, Lee, Cynthia K., Ockenhouse, Christian F., Sinden, Robert E., Gerry, Stephen, Lawrie, Alison M., Vekemans, Johan, Morelle, Danielle, Lievens, Marc, Ballou, Ripley W., Cooke, Graham S., Faust, Saul N., Gilbert, Sarah, and Hill, Adrian V. S.

Published
2016

7. Demonstration of the Blood-Stage Plasmodium falciparum Controlled Human Malaria Infection Model to Assess Efficacy of the P. falciparum Apical Membrane Antigen 1 Vaccine, FMP2.1/AS01

Author

Payne, Ruth O., Milne, Kathryn H., Elias, Sean C., Edwards, Nick J., Douglas, Alexander D., Brown, Rebecca E., Silk, Sarah E., Biswas, Sumi, Miura, Kazutoyo, Roberts, Rachel, Rampling, Thomas W., Venkatraman, Navin, Hodgson, Susanne H., Labbé, Geneviève M., Halstead, Fenella D., Poulton, Ian D., Nugent, Fay L., de Graaf, Hans, Sukhtankar, Priya, Williams, Nicola C., Ockenhouse, Christian F., Kathcart, April K., Qabar, Aziz N., Waters, Norman C., Soisson, Lorraine A., Birkett, Ashley J., Cooke, Graham S., Faust, Saul N., Woods, Colleen, Ivinson, Karen, McCarthy, James S., Diggs, Carter L., Vekemans, Johan, Long, Carole A., Hill, Adrian V. S., Lawrie, Alison M., Dutta, Sheetij, and Draper, Simon J.

Published
2016

10. Safety and efficacy of novel malaria vaccine regimens of RTS,S/AS01B alone, or with concomitant ChAd63-MVA-vectored vaccines expressing ME-TRAP

Author

Rampling, Tommy, Ewer, Katie J., Bowyer, Georgina, Edwards, Nick J., Wright, Danny, Sridhar, Saranya, Payne, Ruth, Powlson, Jonathan, Bliss, Carly, Venkatraman, Navin, Poulton, Ian D., de Graaf, Hans, Gbesemete, Diane, Grobbelaar, Amy, Davies, Huw, Roberts, Rachel, Angus, Brian, Ivinson, Karen, Weltzin, Rich, Rajkumar, Bebi-Yassin, Wille-Reece, Ulrike, Lee, Cynthia, Ockenhouse, Chris, Sinden, Robert E., Gerry, Stephen C., Lawrie, Alison M., Vekemans, Johan, Morelle, Danielle, Lievens, Marc, Ballou, Ripley W., Lewis, David J. M., Cooke, Graham S., Faust, Saul N., Gilbert, Sarah, and Hill, Adrian V. S

Published
2018
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13. Distinct early cellular kinetics in participants protected against colonization upon Bordetella pertussis challenge.

Author

Diks, Annieck M., de Graaf, Hans, Teodosio, Cristina, Groenland, Rick J., de Mooij, Bas, Ibrahim, Muktar, Hill, Alison R., Read, Robert C., van Dongen, Jacques J. M., and Berkowska, Magdalena A.

Abstract

BACKGROUND. To date, only limited data are available on the mechanisms of protection against colonization with Bordetella pertussis in humans. METHODS. In this study, the cellular responses to B. pertussis challenge were monitored longitudinally using highdimensional EuroFlow-based flow cytometry, allowing quantitative detection of more than 250 different immune cell subsets in the blood of 15 healthy donors. RESULTS. Participants who were protected against colonization showed different early cellular responses compared with colonized participants. Especially prominent for colonization-protected participants were the early expansion of CD36- nonclassical monocytes on day 1 (D1), natural killer cells (D3), follicular T helper cells (D1-D3), and plasma cells (D3). Plasma cell expansion on D3 correlated negatively with the CFU load on D7 and D9 after challenge. Increased plasma cell maturation on D11-D14 was found in participants with seroconversion. CONCLUSION. These early cellular immune responses following experimental infection can now be further characterized and potentially linked to an efficient mucosal immune response, preventing colonization. Ultimately, their presence may be used to evaluate whether new B. pertussis vaccine candidates are protective against B. pertussis colonization, e.g., by bacterial challenge after vaccination. [ABSTRACT FROM AUTHOR]

Published
2023
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14. Poor CD4+ T Cell Immunogenicity Limits Humoral Immunity to P. falciparum Transmission-Blocking Candidate Pfs25 in Humans

Author

Zaric, Marija, primary, Marini, Arianna, additional, Nielsen, Carolyn M., additional, Gupta, Gaurav, additional, Mekhaiel, David, additional, Pham, Thao P., additional, Elias, Sean C., additional, Taylor, Iona J., additional, de Graaf, Hans, additional, Payne, Ruth O., additional, Li, Yuanyuan, additional, Silk, Sarah E., additional, Williams, Chris, additional, Hill, Adrian V. S., additional, Long, Carole A., additional, Miura, Kazutoyo, additional, and Biswas, Sumi, additional

Published
2021
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15. Safety and Immunogenicity of ChAd63/MVA Pfs25-IMX313 in a Phase I First-in-Human Trial

Author

de Graaf, Hans, primary, Payne, Ruth O., additional, Taylor, Iona, additional, Miura, Kazutoyo, additional, Long, Carol A., additional, Elias, Sean C., additional, Zaric, Marija, additional, Minassian, Angela M., additional, Silk, Sarah E., additional, Li, Lee, additional, Poulton, Ian D., additional, Baker, Megan, additional, Draper, Simon J., additional, Gbesemete, Diane, additional, Brendish, Nathan J., additional, Martins, Filipa, additional, Marini, Arianna, additional, Mekhaiel, David, additional, Edwards, Nick J., additional, Roberts, Rachel, additional, Vekemans, Johan, additional, Moyle, Sarah, additional, Faust, Saul N., additional, Berrie, Eleanor, additional, Lawrie, Alison M., additional, Hill, Fergal, additional, Hill, Adrian V. S., additional, and Biswas, Sumi, additional

Published
2021
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16. A recombinant commensal bacteria elicits heterologous antigen-specific immune responses during pharyngeal carriage

Author

Laver, Jay R., primary, Gbesemete, Diane, additional, Dale, Adam P., additional, Pounce, Zoe C., additional, Webb, Carl N., additional, Roche, Eleanor F., additional, Guy, Jonathan M., additional, Berreen, Graham, additional, Belogiannis, Konstantinos, additional, Hill, Alison R., additional, Ibrahim, Muktar M., additional, Ahmed, Muhammad, additional, Cleary, David W., additional, Pandey, Anish K., additional, Humphries, Holly E., additional, Allen, Lauren, additional, de Graaf, Hans, additional, Maiden, Martin C., additional, Faust, Saul N., additional, Gorringe, Andrew R., additional, and Read, Robert C., additional

Published
2021
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19. Immunocompromised Children and Young People Are at No Increased Risk of Severe COVID-19

Author

Chappell, H., primary, Patel, Ravin, additional, Driessens, Corine, additional, Tarr, Alexander, additional, Irving, W.L., additional, Tighe, Paddy, additional, Jackson, H.J., additional, Harvey-Cowlishaw, Tyler, additional, Mills, Lynne, additional, Shaunak, Meera, additional, Gbesemete, Diane, additional, Leahy, Alice, additional, Lucas, Jane, additional, Faust, Saul N., additional, and de Graaf, Hans, additional

Published
2021
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20. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

Author

Folegatti, Pedro M, primary, Ewer, Katie J, additional, Aley, Parvinder K, additional, Angus, Brian, additional, Becker, Stephan, additional, Belij-Rammerstorfer, Sandra, additional, Bellamy, Duncan, additional, Bibi, Sagida, additional, Bittaye, Mustapha, additional, Clutterbuck, Elizabeth A, additional, Dold, Christina, additional, Faust, Saul N, additional, Finn, Adam, additional, Flaxman, Amy L, additional, Hallis, Bassam, additional, Heath, Paul, additional, Jenkin, Daniel, additional, Lazarus, Rajeka, additional, Makinson, Rebecca, additional, Minassian, Angela M, additional, Pollock, Katrina M, additional, Ramasamy, Maheshi, additional, Robinson, Hannah, additional, Snape, Matthew, additional, Tarrant, Richard, additional, Voysey, Merryn, additional, Green, Catherine, additional, Douglas, Alexander D, additional, Hill, Adrian V S, additional, Lambe, Teresa, additional, Gilbert, Sarah C, additional, Pollard, Andrew J, additional, Aboagye, Jeremy, additional, Adams, Kelly, additional, Ali, Aabidah, additional, Allen, Elizabeth, additional, Allison, Jennifer L., additional, Anslow, Rachel, additional, Arbe-Barnes, Edward H., additional, Babbage, Gavin, additional, Baillie, Kenneth, additional, Baker, Megan, additional, Baker, Natalie, additional, Baker, Philip, additional, Baleanu, Ioana, additional, Ballaminut, Juliana, additional, Barnes, Eleanor, additional, Barrett, Jordan, additional, Bates, Louise, additional, Batten, Alexander, additional, Beadon, Kirsten, additional, Beckley, Rebecca, additional, Berrie, Eleanor, additional, Berry, Lisa, additional, Beveridge, Amy, additional, Bewley, Kevin R., additional, Bijker, Else Margreet, additional, Bingham, Tracey, additional, Blackwell, Luke, additional, Blundell, Caitlin L., additional, Bolam, Emma, additional, Boland, Elena, additional, Borthwick, Nicola, additional, Bower, Thomas, additional, Boyd, Amy, additional, Brenner, Tanja, additional, Bright, Philip D., additional, Brown-O'Sullivan, Charlie, additional, Brunt, Emily, additional, Burbage, Jamie, additional, Burge, Sharon, additional, Buttigieg, Karen R., additional, Byard, Nicholas, additional, Cabera Puig, Ingrid, additional, Calvert, Anna, additional, Camara, Susana, additional, Cao, Michelangelo, additional, Cappuccini, Federica, additional, Carr, Melanie, additional, Carroll, Miles W., additional, Carter, Victoria, additional, Cathie, Katrina, additional, Challis, Ruth J., additional, Charlton, Sue, additional, Chelysheva, Irina, additional, Cho, Jee-Sun, additional, Cicconi, Paola, additional, Cifuentes, Liliana, additional, Clark, Helen, additional, Clark, Elizabeth, additional, Cole, Tom, additional, Colin-Jones, Rachel, additional, Conlon, Christopher P., additional, Cook, Aislinn, additional, Coombes, Naomi S., additional, Cooper, Rachel, additional, Cosgrove, Catherine A., additional, Coy, Karen, additional, Crocker, Wendy E.M., additional, Cunningham, Christina J., additional, Damratoski, Brad E., additional, Dando, Lynne, additional, Datoo, Mehreen S., additional, Davies, Hannah, additional, De Graaf, Hans, additional, Demissie, Tesfaye, additional, Di Maso, Claudio, additional, Dietrich, Isabelle, additional, Dong, Tao, additional, Donnellan, Francesca R., additional, Douglas, Naomi, additional, Downing, Charlotte, additional, Drake, Jonathan, additional, Drake-Brockman, Rachael, additional, Drury, Ruth Elizabeth, additional, Dunachie, Susanna Jane, additional, Edwards, Nick J., additional, Edwards, Frances D.L., additional, Edwards, Chris J., additional, Elias, Sean C., additional, Elmore, Michael J., additional, Emary, Katherine R.W., additional, English, Marcus Rex, additional, Fagerbrink, Susanne, additional, Felle, Sally, additional, Feng, Shuo, additional, Field, Samantha, additional, Fixmer, Carine, additional, Fletcher, Clare, additional, Ford, Karen J., additional, Fowler, Jamie, additional, Fox, Polly, additional, Francis, Emma, additional, Frater, John, additional, Furze, Julie, additional, Fuskova, Michelle, additional, Galiza, Eva, additional, Gbesemete, Diane, additional, Gilbride, Ciaran, additional, Godwin, Kerry, additional, Gorini, Giacomo, additional, Goulston, Lyndsey, additional, Grabau, Caroline, additional, Gracie, Lara, additional, Gray, Zoe, additional, Guthrie, Lucy Belle, additional, Hackett, Mark, additional, Halwe, Sandro, additional, Hamilton, Elizabeth, additional, Hamlyn, Joseph, additional, Hanumunthadu, Brama, additional, Harding, Irasha, additional, Harris, Stephanie A., additional, Harris, Andrew, additional, Harrison, Daisy, additional, Harrison, Clare, additional, Hart, Thomas C., additional, Haskell, Louise, additional, Hawkins, Sophia, additional, Head, Ian, additional, Henry, John Aaron, additional, Hill, Jennifer, additional, Hodgson, Susanne H.C., additional, Hou, Mimi M., additional, Howe, Elizabeth, additional, Howell, Nicola, additional, Hutlin, Cecilia, additional, Ikram, Sabina, additional, Isitt, Catherine, additional, Iveson, Poppy, additional, Jackson, Susan, additional, Jackson, Frederic, additional, James, Sir William, additional, Jenkins, Megan, additional, Jones, Elizabeth, additional, Jones, Kathryn, additional, Jones, Christine E., additional, Jones, Bryony, additional, Kailath, Reshma, additional, Karampatsas, Konstantinos, additional, Keen, Jade, additional, Kelly, Sarah, additional, Kelly, Dearbhla, additional, Kerr, David, additional, Kerridge, Simon, additional, Khan, Liaquat, additional, Khan, Uzma, additional, Killen, Annabel, additional, Kinch, Jasmin, additional, King, Thomas B., additional, King, Lloyd, additional, King, Jade, additional, Kingham-Page, Lucy, additional, Klenerman, Paul, additional, Knapper, Francesca, additional, Knight, Julian C., additional, Knott, Daniel, additional, Koleva, Stanislava, additional, Kupke, Alexandra, additional, Larkworthy, Colin W., additional, Larwood, Jessica P.J., additional, Laskey, Anna, additional, Lawrie, Alison M., additional, Lee, Arlene, additional, Ngan Lee, Kim Yee, additional, Lees, Emily A, additional, Legge, Helen, additional, Lelliott, Alice, additional, Lemm, Nana-Marie, additional, Lias, Amelia M., additional, Linder, Aline, additional, Lipworth, Samuel, additional, Liu, Xinxue, additional, Liu, Shuchang, additional, Lopez Ramon, Raquel, additional, Lwin, May, additional, Mabesa, Francesca, additional, Madhavan, Meera, additional, Mallett, Garry, additional, Mansatta, Kushal, additional, Marcal, Ines, additional, Marinou, Spyridoula, additional, Marlow, Emma, additional, Marshall, Julia L., additional, Martin, Jane, additional, McEwan, Joanne, additional, McInroy, Lorna, additional, Meddaugh, Gretchen, additional, Mentzer, Alexander J., additional, Mirtorabi, Neginsadat, additional, Moore, Maria, additional, Moran, Edward, additional, Morey, Ella, additional, Morgan, Victoria, additional, Morris, Susan Jane, additional, Morrison, Hazel, additional, Morshead, Gertraud, additional, Morter, Richard, additional, Mujadidi, Yama F., additional, Muller, Jilly, additional, Munera-Huertas, Tatiana, additional, Munro, Claire, additional, Munro, Alasdair, additional, Murphy, Sarah, additional, Munster, Vincent J., additional, Mweu, Philomena, additional, Noé, Andrés, additional, Nugent, Fay L., additional, Nuthall, Elizabeth, additional, O'Brien, Katie, additional, O'Connor, Daniel, additional, Oguti, Blanché, additional, Oliver, Jennifer L., additional, Oliveira, Catarina, additional, O'Reilly, Peter John, additional, Osborn, Mairead, additional, Osborne, Piper, additional, Owen, Cathy, additional, Owens, Daniel, additional, Owino, Nelly, additional, Pacurar, Mihaela, additional, Parker, Kaye, additional, Parracho, Helena, additional, Patrick-Smith, Maia, additional, Payne, Victoria, additional, Pearce, Jennifer, additional, Peng, Yanchun, additional, Peralta Alvarez, Marco Polo, additional, Perring, James, additional, Pfafferott, Katja, additional, Pipini, Dimitra, additional, Plested, Emma, additional, Pluess-Hall, Helen, additional, Pollock, Katrina, additional, Poulton, Ian, additional, Presland, Laura, additional, Provstgaard-Morys, Samuel, additional, Pulido, David, additional, Radia, Kajal, additional, Ramos Lopez, Fernando, additional, Rand, Jade, additional, Ratcliffe, Helen, additional, Rawlinson, Thomas, additional, Rhead, Sarah, additional, Riddell, Amy, additional, Ritchie, Adam John, additional, Roberts, Hannah, additional, Robson, Joanna, additional, Roche, Sophie, additional, Rohde, Cornelius, additional, Rollier, Christine S., additional, Romani, Rossana, additional, Rudiansyah, Indra, additional, Saich, Stephen, additional, Sajjad, Sara, additional, Salvador, Stephannie, additional, Sanchez Riera, Lidia, additional, Sanders, Helen, additional, Sanders, Katherine, additional, Sapaun, Shari, additional, Sayce, Chloe, additional, Schofield, Ella, additional, Screaton, Gavin, additional, Selby, Beatrice, additional, Semple, Calum, additional, Sharpe, Hannah R., additional, Shaik, Imam, additional, Shea, Adam, additional, Shelton, Holly, additional, Silk, Sarah, additional, Silva-Reyes, Laura, additional, Skelly, Donal T., additional, Smee, Heather, additional, Smith, Catherine C., additional, Smith, David J., additional, Song, Rinn, additional, Spencer, Alexandra J., additional, Stafford, Elizabeth, additional, Steele, Amy, additional, Stefanova, Elena, additional, Stockdale, Lisa, additional, Szigeti, Anna, additional, Tahiri-Alaoui, Abdessamad, additional, Tait, Moira, additional, Talbot, Helen, additional, Tanner, Rachel, additional, Taylor, Iona Jennifer, additional, Taylor, Victoria, additional, Te Water Naude, Rebecca, additional, Thakur, Nazia, additional, Themistocleous, Yrene, additional, Themistocleous, Andreas, additional, Thomas, Merin, additional, Thomas, Tonia M., additional, Thompson, Amber, additional, Thomson-Hill, Samantha, additional, Tomlins, Jennifer, additional, Tonks, Susan, additional, Towner, James, additional, Tran, Nguyen, additional, Tree, Julia A., additional, Truby, Adam, additional, Turkentine, Kate, additional, Turner, Cheryl, additional, Turner, Nicola, additional, Turner, Sally, additional, Tuthill, Toby, additional, Ulaszewska, Marta, additional, Varughese, Rachel, additional, Van Doremalen, Neeltje, additional, Veighey, Kristin, additional, Verheul, Marije K., additional, Vichos, Iason, additional, Vitale, Elia, additional, Walker, Laura, additional, Watson, Marion E.E., additional, Welham, Benjamin, additional, Wheat, Julie, additional, White, Caroline, additional, White, Rachel, additional, Worth, Andrew T., additional, Wright, Danny, additional, Wright, Suzie, additional, Yao, Xin Li, additional, and Yau, Yasmine, additional

Published
2020
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22. Pharyngeal carriage of inoculated recombinant commensal bacteria generates antigen-specific immunological memory

Author

Laver, Jay R, primary, Gbesemete, Diane, additional, Dale, Adam P, additional, Pounce, Zoe C, additional, Webb, Carl N, additional, Roche, Eleanor F, additional, Berreen, Graham, additional, Belogiannis, Konstantinos, additional, Hill, Alison R, additional, Ibrahim, Muktar M, additional, Cleary, David W, additional, Pandey, Anish K, additional, Humphries, Holly E, additional, Allen, Lauren, additional, de Graaf, Hans, additional, Maiden, Martin C, additional, Faust, Saul N, additional, Gorringe, Andrew R, additional, and Read, Robert C, additional

Published
2020
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25. Muscle Biopsy Findings in Combination With Myositis‐Specific Autoantibodies Aid Prediction of Outcomes in Juvenile Dermatomyositis

Author

Deakin, Claire T., Yasin, Shireena A., Simou, Stefania, Arnold, Katie A., Tansley, Sarah L., Betteridge, Zoe E., McHugh, Neil J., Varsani, Hemlata, Holton, Janice L., Jacques, Thomas S., Pilkington, Clarissa A., Nistala, Kiran, Wedderburn, Lucy R., Armon, Kate, Ellis‐Gage, Joe, Roper, Holly, Briggs, Vanja, Watts, Joanna, McCann, Liza, Roberts, Ian, Baildam, Eileen, Hanna, Louise, Lloyd, Olivia, Wadeson, Susan, Riley, Phil, McGovern, Ann, Ryder, Clive, Scott, Janis, Thomas, Beverley, Southwood, Taunton, Al‐Abadi, Eslam, Wyatt, Sue, Jackson, Gillian, Amin, Tania, Wood, Mark, VanRooyen, Vanessa, Burton, Deborah, Davidson, Joyce, Gardner‐Medwin, Janet, Martin, Neil, Ferguson, Sue, Waxman, Liz, Browne, Michael, Friswell, Mark, Swift, Alison, Jandial, Sharmila, Stevenson, Vicky, Wade, Debbie, Sen, Ethan, Smith, Eve, Qiao, Lisa, Watson, Stuart, Duong, Claire, Venning, Helen, Satyapal, Rangaraj, Stretton, Elizabeth, Jordan, Mary, Mosley, Ellen, Frost, Anna, Crate, Lindsay, Warrier, Kishore, Stafford, Stefanie, Hasson, Nathan, Maillard, Sue, Halkon, Elizabeth, Brown, Virginia, Juggins, Audrey, Smith, Sally, Lunt, Sian, Enayat, Elli, Kassoumeri, Laura, Beard, Laura, Glackin, Yvonne, Almeida, Beverley, Marques, Raquel, Dowle, Stefanie, Papadopoulou, Charis, Murray, Kevin, Ioannou, John, Suffield, Linda, Al‐Obaidi, Muthana, Lee, Helen, Leach, Sam, Smith, Helen, McMahon, Anne‐Marie, Chisem, Heather, Kingshott, Ruth, Wilkinson, Nick, Inness, Emma, Kendall, Eunice, Mayers, David, Etherton, Ruth, Bailey, Kathryn, Clinch, Jacqui, Fineman, Natalie, Pluess‐Hall, Helen, Vallance, Lindsay, Akeroyd, Louise, Leahy, Alice, Collier, Amy, Cutts, Rebecca, De Graaf, Hans, Davidson, Brian, Hartfree, Sarah, and Pratt, Danny

Subjects
Male, Interferon-Induced Helicase, IFIH1, Severity of Illness Index, Dermatomyositis, Quadriceps Muscle, Cohort Studies, Adrenal Cortex Hormones, Risk Factors, Odds Ratio, Threonine-tRNA Ligase, Humans, Longitudinal Studies, Child, Muscle, Skeletal, Autoantibodies, Myositis, Protective Factors, Prognosis, Pediatric Rheumatology, United Kingdom, DNA-Binding Proteins, Methotrexate, Child, Preschool, Female, Signal Recognition Particle, DNA Topoisomerases, Immunosuppressive Agents, Transcription Factors
Abstract

Objective Juvenile dermatomyositis (DM) is a rare and severe autoimmune condition characterized by rash and proximal muscle weakness. While some patients respond to standard treatment, others do not. This study was carried out to investigate whether histopathologic findings and myositis‐specific autoantibodies (MSAs) have prognostic significance in juvenile DM. Methods Muscle biopsy samples (n = 101) from patients in the UK Juvenile Dermatomyositis Cohort and Biomarker Study were stained, analyzed, and scored for severity of histopathologic features. In addition, autoantibodies were measured in the serum or plasma of patients (n = 90) and longitudinal clinical data were collected (median duration of follow‐up 4.9 years). Long‐term treatment status (on or off medication over time) was modeled using generalized estimating equations. Results Muscle biopsy scores differed according to MSA subgroup. When the effects of MSA subgroup were accounted for, increased severity of muscle histopathologic features was predictive of an increased risk of remaining on treatment over time: for the global pathology score (histopathologist's visual analog scale [hVAS] score), 1.48‐fold higher odds (95% confidence interval [95% CI] 1.12–1.96; P = 0.0058), and for the total biopsy score (determined with the standardized score tool), 1.10‐fold higher odds (95% CI 1.01–1.21; P = 0.038). A protective effect was identified in patients with anti–Mi‐2 autoantibodies, in whom the odds of remaining on treatment were 7.06‐fold lower (95% CI 1.41–35.36; P = 0.018) despite muscle biopsy scores indicating more severe disease. In patients with anti–nuclear matrix protein 2 autoantibodies, anti–transcription intermediary factor 1γ autoantibodies, or no detectable autoantibody, increased histopathologic severity alone, without adjustment for the effect of MSA subtype, was predictive of the risk of remaining on treatment: for the hVAS global pathology score, 1.61‐fold higher odds (95% CI 1.16–2.22; P = 0.004), and for the total biopsy score, 1.13‐fold higher odds (95% CI 1.03–1.24; P = 0.013). Conclusion Histopathologic severity, in combination with MSA subtype, is predictive of the risk of remaining on treatment in patients with juvenile DM and may be useful for discussing probable treatment length with parents and patients. Understanding these associations may identify patients at greater risk of severe disease.

Published
2016

26. Severe Enterovirus Infections in Hospitalized Children in the South of England

Author

de Graaf, Hans, Pelosi, Emanuela, Cooper, Andrea, Pappachan, John, Sykes, Kim, MacIntosh, Iain, Gbesemete, Diane, Clark, Tristan W., Patel, Sanjay V., Faust, Saul N., and Tebruegge, Marc

Subjects
Adolescent, enterovirus, encephalitis, Infant, Newborn, meningitis, Infant, Original Studies, Enterovirus B, Human, sepsis, Survival Rate, Extracorporeal Membrane Oxygenation, England, Central Nervous System Diseases, Child, Preschool, Enterovirus Infections, Humans, myocarditis, Child, Child, Hospitalized, Retrospective Studies
Abstract

Background: Most enterovirus surveillance studies lack detailed clinical data, which limits their clinical usefulness. This study aimed to describe the clinical spectrum and outcome of severe enterovirus infections in children, and to determine whether there are associations between causative enterovirus genotypes and clinical phenotypes. Methods: Retrospective analysis of microbiological and clinical data from a tertiary children’s hospital in the South of England over a 17-month period (2012–2013). Results: In total, 30 patients were identified, comprising sepsis (n = 9), myocarditis (n = 8), meningitis (n = 8) and encephalitis (n = 5). Cases with sepsis or myocarditis were significantly younger than those with central nervous system disease (median age 21 and 15 days vs. 79 days; P = 0.0244 and P = 0.0310, respectively). There was considerable diversity in the causative genotypes in each of the clinical phenotypes, with some predominance of echoviruses in the meningitis group, and coxsackie B viruses in the myocarditis group. Thirteen cases required mechanical ventilation, 11 cases inotropic support, 3 cases dialysis and 3 cases extracorporal membrane oxygenation. The overall mortality was 10% (sepsis group, n = 1; myocarditis group, n = 2). Of the survivors, 5 (19%) had long-term sequelae (myocardial dysfunction, n = 2; neurological sequelae, n = 3). Patients with encephalitis had the longest hospital stay (median: 16 days), compared with 9, 6 and 3 days in patients with myocarditis, sepsis and meningitis, respectively (P = 0.005). Conclusions: Enterovirus infections, particularly enteroviral myocarditis and encephalitis, can cause significant morbidity and mortality. The results show that there are currently no strong associations between clinical phenotypes and particular causative enterovirus genotypes in the South of England.

Published
2016

27. Poor CD4+ T Cell Immunogenicity Limits Humoral Immunity to P. falciparum Transmission-Blocking Candidate Pfs25 in Humans.

Author

Zaric, Marija, Marini, Arianna, Nielsen, Carolyn M., Gupta, Gaurav, Mekhaiel, David, Pham, Thao P., Elias, Sean C., Taylor, Iona J., de Graaf, Hans, Payne, Ruth O., Li, Yuanyuan, Silk, Sarah E., Williams, Chris, Hill, Adrian V. S., Long, Carole A., Miura, Kazutoyo, and Biswas, Sumi

Subjects
ANTIGENS, T cells, HUMORAL immunity, VACCINE trials, T helper cells, CELLULAR recognition, PSYCHONEUROIMMUNOLOGY
Abstract

Plasmodium falciparum transmission-blocking vaccines (TBVs) targeting the Pfs25 antigen have shown promise in mice but the same efficacy has never been achieved in humans. We have previously published pre-clinical data related to a TBV candidate Pfs25-IMX313 encoded in viral vectors which was very promising and hence progressed to human clinical trials. The results from the clinical trial of this vaccine were very modest. Here we unravel why, contrary to mice, this vaccine has failed to induce robust antibody (Ab) titres in humans to elicit transmission-blocking activity. We examined Pfs25-specific B cell and T follicular helper (Tfh) cell responses in mice and humans after vaccination with Pfs25-IMX313 encoded by replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA) delivered in the heterologous prime-boost regimen via intramuscular route. We found that after vaccination, the Pfs25-IMX313 was immunologically suboptimal in humans compared to mice in terms of serum Ab production and antigen-specific B, CD4+ and Tfh cell responses. We identified that the key determinant for the poor anti-Pfs25 Ab formation in humans was the lack of CD4+ T cell recognition of Pfs25-IMX313 derived peptide epitopes. This is supported by correlations established between the ratio of proliferated antigen-specific CD4+/Tfh-like T cells, CXCL13 sera levels, and the corresponding numbers of circulating Pfs25-specific memory B cells, that consequently reflected on antigen-specific IgG sera levels. These correlations can inform the design of next-generation Pfs25-based vaccines for robust and durable blocking of malaria transmission. [ABSTRACT FROM AUTHOR]

Published
2021
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29. Controlled Human Infection With Bordetella pertussis Induces Asymptomatic, Immunizing Colonization

Author

de Graaf, Hans, primary, Ibrahim, Muktar, primary, Hill, Alison R, primary, Gbesemete, Diane, primary, Vaughan, Andrew T, primary, Gorringe, Andrew, primary, Preston, Andrew, primary, Buisman, Annemarie M, primary, Faust, Saul N, primary, Kester, Kent E, primary, Berbers, Guy A M, primary, Diavatopoulos, Dimitri A, primary, and Read, Robert C, primary

Published
2019
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34. Safety and high level efficiency of the combination malaria vaccine regimen of RTS,S/AS01B with ChAd-MVA vectored vaccines expressing ME-TRAP

Author

Rampling, Tommy, Ewer, Katie J., Bowyer, Georgina, Bliss, Carly M., Edwards, Nick J., Wright, Danny, Payne, Ruth, Venkatraman, Navin, de Barra, Eoghan, Snudden, Claudia M., Poulton, Ian D., De Graaf, Hans, Sukhtankar, Priya, Roberts, Rachel, Ivinson, Karen, Weltzin, Rich, Rajkumar, Bebi-Yassin, Wille-Reece, Ulrike, Lee, Cynthia, Ockenhouse, Chris, Sinden, Robert E., Gerry, Stephen, Lawris, Alison M., Vekemans, Johan, Morelle, Danielle, Lievens, Marc, Ballou, Ripley W., Cooke, Graham S., Faust, Saul N., Gilbert, Sarah, and Hill, Adrian V.S.

Published
2016

36. Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

Author

Payne, Ruth O., primary, Silk, Sarah E., additional, Elias, Sean C., additional, Miura, Kazutoyo, additional, Diouf, Ababacar, additional, Galaway, Francis, additional, de Graaf, Hans, additional, Brendish, Nathan J., additional, Poulton, Ian D., additional, Griffiths, Oliver J., additional, Edwards, Nick J., additional, Jin, Jing, additional, Labbé, Geneviève M., additional, Alanine, Daniel G.W., additional, Siani, Loredana, additional, Di Marco, Stefania, additional, Roberts, Rachel, additional, Green, Nicky, additional, Berrie, Eleanor, additional, Ishizuka, Andrew S., additional, Nielsen, Carolyn M., additional, Bardelli, Martino, additional, Partey, Frederica D., additional, Ofori, Michael F., additional, Barfod, Lea, additional, Wambua, Juliana, additional, Murungi, Linda M., additional, Osier, Faith H., additional, Biswas, Sumi, additional, McCarthy, James S., additional, Minassian, Angela M., additional, Ashfield, Rebecca, additional, Viebig, Nicola K., additional, Nugent, Fay L., additional, Douglas, Alexander D., additional, Vekemans, Johan, additional, Wright, Gavin J., additional, Faust, Saul N., additional, Hill, Adrian V.S., additional, Long, Carole A., additional, Lawrie, Alison M., additional, and Draper, Simon J., additional

Published
2017
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38. Duration of intravenous antibiotic therapy for children with acute osteomyelitis or septic arthritis: a feasibility study

Author

de Graaf, Hans, primary, Sukhtankar, Priya, additional, Arch, Barbara, additional, Ahmad, Nusreen, additional, Lees, Amanda, additional, Bennett, Abigail, additional, Spowart, Catherine, additional, Hickey, Helen, additional, Jeanes, Annmarie, additional, Armon, Kate, additional, Riordan, Andrew, additional, Herberg, Jethro, additional, Hackett, Scott, additional, Gamble, Carrol, additional, Shingadia, Delane, additional, Pallett, Ann, additional, Clarke, Stuart C, additional, Henman, Philip, additional, Emonts, Marieke, additional, Sharland, Mike, additional, Finn, Adam, additional, Pollard, Andrew J, additional, Powell, Colin, additional, Marsh, Peter, additional, Ballinger, Claire, additional, Williamson, Paula R, additional, Clarke, Nicholas MP, additional, and Faust, Saul N, additional

Published
2017
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39. Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

Author

Payne, Ruth O, Silk, Sarah E, Elias, Sean C, Miura, Kazutoyo, Diouf, Ababacar, Galaway, Francis, de Graaf, Hans, Brendish, Nathan J, Poulton, Ian D, Griffiths, Oliver J, Edwards, Nick J, Jin, Jing, Labbé, Geneviève M, Alanine, Daniel Gw, Siani, Loredana, Di Marco, Stefania, Roberts, Rachel, Green, Nicky, Berrie, Eleanor, Ishizuka, Andrew S, Nielsen, Carolyn M, Bardelli, Martino, Partey, Frederica D, Ofori, Michael F, Barfod, Lea, Wambua, Juliana, Murungi, Linda M, Osier, Faith H, Biswas, Sumi, McCarthy, James S, Minassian, Angela M, Ashfield, Rebecca, Viebig, Nicola K, Nugent, Fay L, Douglas, Alexander D, Vekemans, Johan, Wright, Gavin J, Faust, Saul N, Hill, Adrian Vs, Long, Carole A, Lawrie, Alison M, Draper, Simon J, Payne, Ruth O, Silk, Sarah E, Elias, Sean C, Miura, Kazutoyo, Diouf, Ababacar, Galaway, Francis, de Graaf, Hans, Brendish, Nathan J, Poulton, Ian D, Griffiths, Oliver J, Edwards, Nick J, Jin, Jing, Labbé, Geneviève M, Alanine, Daniel Gw, Siani, Loredana, Di Marco, Stefania, Roberts, Rachel, Green, Nicky, Berrie, Eleanor, Ishizuka, Andrew S, Nielsen, Carolyn M, Bardelli, Martino, Partey, Frederica D, Ofori, Michael F, Barfod, Lea, Wambua, Juliana, Murungi, Linda M, Osier, Faith H, Biswas, Sumi, McCarthy, James S, Minassian, Angela M, Ashfield, Rebecca, Viebig, Nicola K, Nugent, Fay L, Douglas, Alexander D, Vekemans, Johan, Wright, Gavin J, Faust, Saul N, Hill, Adrian Vs, Long, Carole A, Lawrie, Alison M, and Draper, Simon J

Abstract

The development of a highly effective vaccine remains a key strategic goal to aid the control and eventual eradication of Plasmodium falciparum malaria. In recent years, the reticulocyte-binding protein homolog 5 (RH5) has emerged as the most promising blood-stage P. falciparum candidate antigen to date, capable of conferring protection against stringent challenge in Aotus monkeys. We report on the first clinical trial to our knowledge to assess the RH5 antigen - a dose-escalation phase Ia study in 24 healthy, malaria-naive adult volunteers. We utilized established viral vectors, the replication-deficient chimpanzee adenovirus serotype 63 (ChAd63), and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA), encoding RH5 from the 3D7 clone of P. falciparum. Vaccines were administered i.m. in a heterologous prime-boost regimen using an 8-week interval and were well tolerated. Vaccine-induced anti-RH5 serum antibodies exhibited cross-strain functional growth inhibition activity (GIA) in vitro, targeted linear and conformational epitopes within RH5, and inhibited key interactions within the RH5 invasion complex. This is the first time to our knowledge that substantial RH5-specific responses have been induced by immunization in humans, with levels greatly exceeding the serum antibody responses observed in African adults following years of natural malaria exposure. These data support the progression of RH5-based vaccines to human efficacy testing.

Published
2017

40. Safety and High Level Efficacy of the Combination Malaria Vaccine Regimen of RTS,S/AS01BWith Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara Vectored Vaccines Expressing ME-TRAP

Author

Rampling, Tommy, primary, Ewer, Katie J., additional, Bowyer, Georgina, additional, Bliss, Carly M., additional, Edwards, Nick J., additional, Wright, Danny, additional, Payne, Ruth O., additional, Venkatraman, Navin, additional, de Barra, Eoghan, additional, Snudden, Claudia M., additional, Poulton, Ian D., additional, de Graaf, Hans, additional, Sukhtankar, Priya, additional, Roberts, Rachel, additional, Ivinson, Karen, additional, Weltzin, Rich, additional, Rajkumar, Bebi-Yassin, additional, Wille-Reece, Ulrike, additional, Lee, Cynthia K., additional, Ockenhouse, Christian F., additional, Sinden, Robert E., additional, Gerry, Stephen, additional, Lawrie, Alison M., additional, Vekemans, Johan, additional, Morelle, Danielle, additional, Lievens, Marc, additional, Ballou, Ripley W., additional, Cooke, Graham S., additional, Faust, Saul N., additional, Gilbert, Sarah, additional, and Hill, Adrian V. S., additional

Published
2016
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41. Demonstration of the Blood-StagePlasmodium falciparumControlled Human Malaria Infection Model to Assess Efficacy of theP. falciparumApical Membrane Antigen 1 Vaccine, FMP2.1/AS01

Author

Payne, Ruth O., primary, Milne, Kathryn H., additional, Elias, Sean C., additional, Edwards, Nick J., additional, Douglas, Alexander D., additional, Brown, Rebecca E., additional, Silk, Sarah E., additional, Biswas, Sumi, additional, Miura, Kazutoyo, additional, Roberts, Rachel, additional, Rampling, Thomas W., additional, Venkatraman, Navin, additional, Hodgson, Susanne H., additional, Labbé, Geneviève M., additional, Halstead, Fenella D., additional, Poulton, Ian D., additional, Nugent, Fay L., additional, de Graaf, Hans, additional, Sukhtankar, Priya, additional, Williams, Nicola C., additional, Ockenhouse, Christian F., additional, Kathcart, April K., additional, Qabar, Aziz N., additional, Waters, Norman C., additional, Soisson, Lorraine A., additional, Birkett, Ashley J., additional, Cooke, Graham S., additional, Faust, Saul N., additional, Woods, Colleen, additional, Ivinson, Karen, additional, McCarthy, James S., additional, Diggs, Carter L., additional, Vekemans, Johan, additional, Long, Carole A., additional, Hill, Adrian V. S., additional, Lawrie, Alison M., additional, Dutta, Sheetij, additional, and Draper, Simon J., additional

Published
2016
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42. Investigating Bordetella pertussis colonisation and immunity: protocol for an inpatient controlled human infection model.

Author

de Graaf, Hans, Gbesemete, Diane, Gorringe, Andrew R., Diavatopoulos, Dimitri A., Kester, Kent E., Faust, Saul N., and Read, Robert C.

Abstract

Introduction We summarise an ethically approved protocol for the development of an experimental human challenge colonisation model. Globally Bordetella pertussis is one of the leading causes of vaccine-preventable death. Many countries have replaced whole cell vaccines with acellular vaccines over the last 20 years during which pertussis appears to be resurgent in a number of countries in the developed world that boast high immunisation coverage. The acellular vaccine provides relatively shortlived immunity and, in contrast to whole cell vaccines, may be less effective against colonisation and subsequent transmission. To improve vaccine strategies, a greater understanding of human B. pertussis colonisation is required. This article summarises a protocol and does not contain any results. Methods and analysis A controlled human colonisation model will be developed over two phases. In phase A, a low dose of the inoculum will be given intranasally to healthy participants. This dose will be escalated or deescalated until colonisation is achieved in approximately 70% (95% CI 47% to 93%) of the exposed volunteers without causing disease. The colonisation period, shedding and exploratory immunology will be assessed during a 17-day inpatient stay and follow-up over 1 year. The dose of inoculum that achieves 70% colonisation will then be confirmed in phase B, comparing healthy participants exposed to B. pertussis with a control group receiving a sham inoculum. Ethics and dissemination This study has been approved by the ethical committee reference: 17/SC/0006, 24 February 2017. Findings will be published in peerreviewed open access journals as soon as possible. [ABSTRACT FROM AUTHOR]

Published
2017
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45. Safety and High Level Efficacy of the Combination Malaria Vaccine Regimen of RTS,S/AS01B With Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara Vectored Vaccines Expressing ME-TRAP.

Author

Rampling, Tommy, Ewer, Katie J., Bowyer, Georgina, Bliss, Carly M., Edwards, Nick J., Wright, Danny, Payne, Ruth O., Venkatraman, Navin, de Barra, Eoghan, Snudden, Claudia M., Poulton, Ian D., de Graaf, Hans, Sukhtankar, Priya, Roberts, Rachel, Ivinson, Karen, Weltzin, Rich, Rajkumar, Bebi-Yassin, Wille-Reece, Ulrike, Lee, Cynthia K., and Ockenhouse, Christian F.

Subjects
MALARIA vaccines, ADENOVIRUSES, CHIMPANZEES, VACCINATION, ADVERSE health care events
Abstract

Background: The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing. In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining 2 distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to circumsporozoite protein (RTS,S/AS01B) and the other inducing potent T-cell responses to thrombospondin-related adhesion protein (TRAP) by using a viral vector.Method: Thirty-seven healthy malaria-naive adults were vaccinated with either a chimpanzee adenovirus 63 and modified vaccinia virus Ankara-vectored vaccine expressing a multiepitope string fused to TRAP and 3 doses of RTS,S/AS01B (group 1; n = 20) or 3 doses of RTS,S/AS01B alone (group 2; n = 17). CHMI was delivered by mosquito bites to 33 vaccinated subjects at week 12 after the first vaccination and to 6 unvaccinated controls.Results: No suspected unexpected serious adverse reactions or severe adverse events related to vaccination were reported. Protective vaccine efficacy was observed in 14 of 17 subjects (82.4%) in group 1 and 12 of 16 subjects (75%) in group 2. All control subjects received a diagnosis of blood-stage malaria parasite infection. Both vaccination regimens were immunogenic. Fourteen protected subjects underwent repeat CHMI 6 months after initial CHMI; 7 of 8 (87.5%) in group 1 and 5 of 6 (83.3%) in group 2 remained protected.Conclusions: The high level of sterile efficacy observed in this trial is encouraging for further evaluation of combination approaches using these vaccine types.Clinical Trials Registration: NCT01883609. [ABSTRACT FROM AUTHOR]

Published
2016
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46. Academic-healthcare partnership in phase I studies.

Author

Brendish, Nathan J., Gbesemete, Diane F., de Graaf, Hans, Edwards, Christopher J., and Faust, Saul N.

Subjects
DRUGS, INTERPROFESSIONAL relations, MEDICAL care, STUDY & teaching of medicine, PATIENT safety, RANDOMIZED controlled trials
Abstract

A letter to the editor is presented regarding the accreditation scheme launched by the British Medicines and Healthcare products Regulatory Agency (MHRA) to improve phase I safety standards in Great Britain.

Published
2015

47. Poor CD4 + T Cell Immunogenicity Limits Humoral Immunity to P. falciparum Transmission-Blocking Candidate Pfs25 in Humans.

Author

Zaric M, Marini A, Nielsen CM, Gupta G, Mekhaiel D, Pham TP, Elias SC, Taylor IJ, de Graaf H, Payne RO, Li Y, Silk SE, Williams C, Hill AVS, Long CA, Miura K, and Biswas S

Subjects
Adolescent, Adult, Animals, B-Lymphocytes drug effects, B-Lymphocytes immunology, B-Lymphocytes parasitology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes parasitology, Cells, Cultured, Disease Models, Animal, Epitopes, Female, Humans, Malaria Vaccines immunology, Malaria, Falciparum immunology, Malaria, Falciparum parasitology, Malaria, Falciparum transmission, Male, Mice, Mice, Inbred BALB C, Middle Aged, Plasmodium falciparum pathogenicity, Protozoan Proteins immunology, Recombinant Proteins immunology, Species Specificity, Vaccination, Young Adult, Antibodies, Protozoan blood, CD4-Positive T-Lymphocytes drug effects, Immunity, Humoral drug effects, Immunogenicity, Vaccine, Malaria Vaccines administration & dosage, Malaria, Falciparum prevention & control, Plasmodium falciparum immunology, Protozoan Proteins administration & dosage, Recombinant Proteins administration & dosage
Abstract

Plasmodium falciparum transmission-blocking vaccines (TBVs) targeting the Pfs25 antigen have shown promise in mice but the same efficacy has never been achieved in humans. We have previously published pre-clinical data related to a TBV candidate Pfs25-IMX313 encoded in viral vectors which was very promising and hence progressed to human clinical trials. The results from the clinical trial of this vaccine were very modest. Here we unravel why, contrary to mice, this vaccine has failed to induce robust antibody (Ab) titres in humans to elicit transmission-blocking activity. We examined Pfs25-specific B cell and T follicular helper (Tfh) cell responses in mice and humans after vaccination with Pfs25-IMX313 encoded by replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA) delivered in the heterologous prime-boost regimen via intramuscular route. We found that after vaccination, the Pfs25-IMX313 was immunologically suboptimal in humans compared to mice in terms of serum Ab production and antigen-specific B, CD4 + and Tfh cell responses. We identified that the key determinant for the poor anti-Pfs25 Ab formation in humans was the lack of CD4 + T cell recognition of Pfs25-IMX313 derived peptide epitopes. This is supported by correlations established between the ratio of proliferated antigen-specific CD4 + /Tfh-like T cells, CXCL13 sera levels, and the corresponding numbers of circulating Pfs25-specific memory B cells, that consequently reflected on antigen-specific IgG sera levels. These correlations can inform the design of next-generation Pfs25-based vaccines for robust and durable blocking of malaria transmission., Competing Interests: AH is named inventor on patent applications covering malaria vaccines and immunization regimens. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zaric, Marini, Nielsen, Gupta, Mekhaiel, Pham, Elias, Taylor, de Graaf, Payne, Li, Silk, Williams, Hill, Long, Miura and Biswas.)

Published
2021
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48. Controlled Human Infection With Bordetella pertussis Induces Asymptomatic, Immunizing Colonization.

Author

de Graaf H, Ibrahim M, Hill AR, Gbesemete D, Vaughan AT, Gorringe A, Preston A, Buisman AM, Faust SN, Kester KE, Berbers GAM, Diavatopoulos DA, and Read RC

Subjects
Adolescent, Adult, Azithromycin therapeutic use, Humans, Middle Aged, Nasopharynx, Pertussis Vaccine, Young Adult, Bordetella pertussis, Whooping Cough prevention & control
Abstract

Background: Bordetella pertussis is among the leading causes of vaccine-preventable deaths and morbidity globally. Human asymptomatic carriage as a reservoir for community transmission of infections might be a target of future vaccine strategies, but has not been demonstrated. Our objective was to demonstrate that asymptomatic nasopharyngeal carriage of Bordetella pertussis is inducible in humans and to define the microbiological and immunological features of presymptomatic infection., Methods: Healthy subjects aged 18-45 years with an antipertussis toxin immunoglobin G (IgG) concentration of <20 international units/ml were inoculated intranasally with nonattenuated, wild-type Bordetella pertussis strain B1917. Safety, colonization, and shedding were monitored over 17 days in an inpatient facility. Colonization was assessed by culture and quantitative polymerase chain reaction. Azithromycin was administered from Day 14. The inoculum dose was escalated, aiming to colonize at least 70% of participants. Immunological responses were measured., Results: There were 34 participants challenged, in groups of 4 or 5. The dose was gradually escalated from 103 colony-forming units (0% colonized) to 105 colony-forming units (80% colonized). Minor symptoms were reported in a minority of participants. Azithromycin eradicated colonization in 48 hours in 88% of colonized individuals. Antipertussis toxin IgG seroconversion occurred in 9 out of 19 colonized participants and in none of the participants who were not colonized. Nasal wash was a more sensitive method to detect colonization than pernasal swabs. No shedding of Bordetella pertussis was detected in systematically collected environmental samples., Conclusions: Bordetella pertussis colonization can be deliberately induced and leads to a systemic immune response without causing pertussis symptoms., Clinical Trials Registration: NCT03751514., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Published
2020
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49. Protocol for a controlled human infection with genetically modified Neisseria lactamica expressing the meningococcal vaccine antigen NadA: a potent new technique for experimental medicine.

Author

Gbesemete D, Laver JR, de Graaf H, Ibrahim M, Vaughan A, Faust S, Gorringe A, and Read RC

Subjects
Adolescent, Adult, Biomedical Research, Humans, Middle Aged, Prospective Studies, Young Adult, Adhesins, Bacterial biosynthesis, Adhesins, Bacterial immunology, Antigens immunology, Meningococcal Vaccines immunology, Microorganisms, Genetically-Modified, Neisseria lactamica genetics, Neisseria lactamica metabolism, Neisseria meningitidis immunology, Research Design
Abstract

Introduction: Neisseria lactamica is a commensal organism found in the human nasopharynx and is closely related to the pathogen N. meningitidis (meningococcus). Carriage of N. lactamica is associated with reduced meningococcal carriage and disease. We summarise an ethically approved protocol for an experimental human challenge study using a genetically modified strain of N. lactamica that expresses the meningococcal antigen NadA. We aim to develop a model to study the role of specific bacterial antigens in nasopharyngeal carriage and immunity, to evaluate vaccines for their efficacy in preventing colonisation and to provide a proof of principle for the development of bacterial medicines., Methods and Analysis: Healthy adult volunteers aged 18-45 years will receive an intranasal inoculation of either the NadA containing strain of N. lactamica or a genetically modified, but wild-type equivalent control strain. These challenge volunteers will be admitted for 4.5 days observation following inoculation and will then be discharged with strict infection control rules. Bedroom contacts of the challenge volunteers will also be enrolled as contact volunteers. Safety, colonisation, shedding, transmission and immunogenicity will be assessed over 90 days after which carriage will be terminated with antibiotic eradication therapy., Ethics and Dissemination: This study has been approved by the Department for Environment, Food and Rural Affairs and South Central Oxford A Research Ethics Committee (reference: 18/SC/0133). Findings will be published in peer-reviewed open-access journals as soon as possible., Trial Registration Number: NCT03630250; Pre-results., Competing Interests: Competing interests: JRL and RCR declare a potential conflict of interest: The patent WO2017103593-A1 ’New modified Neisseria lactamica transformed with recombinant DNA encoding heterologous protein, used for e.g. prophylactic treatment of pathogenic infection, preferably meningococcal infection', is assigned to the University of Southampton, with JRL and RCR as inventors., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Published
2019
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