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1. Angiogenesis-associated pathways play critical roles in neonatal sepsis outcomes

Author: Mario Fidanza, Julie Hibbert, Erica Acton, Danny Harbeson, Elizna Schoeman, Patrycja Skut, Tabitha Woodman, Adrien Eynaud, Lucy Hartnell, Byron Brook, Bing Cai, Mandy Lo, Reza Falsafi, Robert E. W. Hancock, Msandeni Chiume-Kayuni, Norman Lufesi, Constantin R. Popescu, Pascal M. Lavoie, Tobias Strunk, Andrew J. Currie, Tobias R. Kollmann, Nelly Amenyogbe, and Amy H. Lee
Subjects: Medicine, Science
Abstract: Abstract Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here provide the mechanistic evidence in support of the relevance for these observations. Angiopoetin-1 (Ang-1), which promotes vascular integrity, was decreased in blood plasma of human and murine septic newborns. In preclinical models, administration of Ang-1 provided prophylactic protection from septic death. Arachidonic acid metabolism appears to be functionally connected to Ang-1 via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Strengthening this intersection via oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death while also increasing plasma Ang-1 levels among septic newborns. Our data highlight that targeting angiogenesis-associated pathways with interventions that increase Ang-1 activity directly or indirectly through ROS/eNOS provide promising avenues to prevent and/or treat severe neonatal sepsis.
Published: 2024
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2. Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trialResearch in context

Author: Laure F. Pittet, Nicole L. Messina, Ellie McDonald, Francesca Orsini, Simone Barry, Marc Bonten, John Campbell, Julio Croda, Mariana G. Croda, Margareth Dalcolmo, Kaya Gardiner, Amanda Gwee, Bruno Jardim, Marcus V.G. Lacerda, Michaela Lucas, David J. Lynn, Laurens Manning, Kirsten P. Perrett, Jeffrey J. Post, Cristina Prat-Aymerich, Peter C. Richmond, Jorge L. Rocha, Jesus Rodriguez-Baño, Adilia Warris, Nicholas J. Wood, Andrew Davidson, Nigel Curtis, Tenaya Jamieson, Nicole Messina, Thilanka Morawakage, Susan Perlen, Kirsten Perrett, Laure Pittet, Amber Sastry, Jia Wei Teo, Katherine Lee, Cecilia Moore, Suzanna Vidmar, Rashida Ali, Ross Dunn, Peta Edler, Grace Gell, Casey Goodall, Richard Hall, Ann Krastev, Nathan La, Nick McPhate, Thao Nguyen, Jack Ren, Luke Stevens, Ahmed Alamrousi, Rhian Bonnici, Thanh Dang, Susie Germano, Jenny Hua, Rebecca McElroy, Monica Razmovska, Scott Reddiex, Xiaofang Wang, Jeremy Anderson, Kristy Azzopardi, Vicki Bennett-Wood, Anna Czajko, Nadia Mazarakis, Conor McCafferty, Frances Oppedisano, Belinda Ortika, Casey Pell, Leena Spry, Ryan Toh, Sunitha Velagapudi, Amanda Vlahos, Ashleigh Wee-Hee, Pedro Ramos, Karina De La Cruz, Dinusha Gamage, Anushka Karunanayake, Isabella Mezzetti, Benjamin Ong, Ronita Singh, Enoshini Sooriyarachchi, Suellen Nicholson, Natalie Cain, Rianne Brizuela, Han Huang, Veronica Abruzzo, Morgan Bealing, Patricia Bimboese, Kirsty Bowes, Emma Burrell, Joyce Chan, Jac Cushnahan, Hannah Elborough, Olivia Elkington, Kieran Fahey, Monique Fernandez, Catherine Flynn, Sarah Fowler, Marie Gentile Andrit, Bojana Gladanac, Catherine Hammond, Norine Ma, Sam Macalister, Emmah Milojevic, Jesutofunmi Mojeed, Jill Nguyen, Liz O'Donnell, Nadia Olivier, Isabelle Ooi, Stephanie Reynolds, Lisa Shen, Barb Sherry, Judith Spotswood, Jamie Wedderburn, Angela Younes, Donna Legge, Jason Bell, Jo Cheah, Annie Cobbledick, Kee Lim, Sonja Elia, Lynne Addlem, Anna Bourke, Clare Brophy, Nadine Henare, Narelle Jenkins, Francesca Machingaifa, Skye Miller, Kirsten Mitchell, Sigrid Pitkin, Kate Wall, Paola Villanueva, Nigel Crawford, Wendy Norton, Niki Tan, Thilakavathi Chengodu, Diane Dawson, Victoria Gordon, Tony Korman, Jess O'Bryan, Sophie Agius, Samantha Bannister, Jess Bucholc, Alison Burns, Beatriz Camesella, John Carlin, Marianna Ciaverella, Maxwell Curtis, Stephanie Firth, Christina Guo, Matthew Hannan, Erin Hill, Sri Joshi, Katherine Lieschke, Megan Mathers, Sasha Odoi, Ashleigh Rak, Chris Richards, Leah Steve, Carolyn Stewart, Eva Sudbury, Helen Thomson, Emma Watts, Fiona Williams, Angela Young, Penny Glenn, Andrew Kaynes, Amandine Philippart De Floy, Sandy Buchanan, Thijs Sondag, Ivy Xie, Harriet Edmund, Bridie Byrne, Tom Keeble, Belle Ngien, Fran Noonan, Michelle Wearing-Smith, Alison Clarke, Pemma Davies, Oliver Eastwood, Alric Ellinghaus, Rachid Ghieh, Zahra Hilton, Emma Jennings, Athina Kakkos, Iris Liang, Katie Nicol, Sally O'Callaghan, Helen Osman, Gowri Rajaram, Sophia Ratcliffe, Victoria Rayner, Ashleigh Salmon, Angela Scheppokat, Aimee Stevens, Rebekah Street, Nicholas Toogood, Nicholas Wood, Twinkle Bahaduri, Therese Baulman, Jennifer Byrne, Candace Carter, Mary Corbett, Aiken Dao, Maria Desylva, Andrew Dunn, Evangeline Gardiner, Rosemary Joyce, Rama Kandasamy, Craig Munns, Lisa Pelayo, Ketaki Sharma, Katrina Sterling, Caitlin Uren, Clinton Colaco, Mark Douglas, Kate Hamilton, Adam Bartlett, Brendan McMullan, Pamela Palasanthiran, Phoebe Williams, Justin Beardsley, Nikki Bergant, Renier Lagunday, Kristen Overton, Jeffrey Post, Yasmeen Al-Hindawi, Sarah Barney, Anthony Byrne, Lee Mead, Marshall Plit, David Lynn, Saoirse Benson, Stephen Blake, Rochelle Botten, Tee Yee Chern, Georgina Eden, Liddy Griffith, Jane James, Miriam Lynn, Angela Markow, Domenic Sacca, Natalie Stevens, Steve Wesselingh, Catriona Doran, Alice Sawka, Sue Evans, Louise Goodchild, Christine Heath, Meredith Krieg, Helen Marshall, Mark McMillan, Mary Walker, Peter Richmond, Nelly Amenyogbe, Christina Anthony, Annabelle Arnold, Beth Arrowsmith, Rym Ben-Othman, Sharon Clark, Jemma Dunnill, Nat Eiffler, Krist Ewe, Carolyn Finucane, Lorraine Flynn, Camille Gibson, Lucy Hartnell, Elysia Hollams, Heidi Hutton, Lance Jarvis, Jane Jones, Jan Jones, Karen Jones, Jennifer Kent, Tobias Kollmann, Debbie Lalich, Wenna Lee, Rachel Lim, Sonia McAlister, Fiona McDonald, Andrea Meehan, Asma Minhaj, Lisa Montgomery, Melissa O'Donnell, Jaslyn Ong, Joanne Ong, Kimberley Parkin, Glady Perez, Catherine Power, Shadie Rezazadeh, Holly Richmond, Sally Rogers, Nikki Schultz, Margaret Shave, Patrycja Skut, Lisa Stiglmayer, Alexandra Truelove, Ushma Wadia, Rachael Wallace, Justin Waring, Michelle England, Erin Latkovic, Susan Herrmann, Marcus Lacerda, Paulo Henrique Andrade, Fabiane Bianca Barbosa, Dayanne Barros, Larissa Brasil, Ana Greyce Capella, Ramon Castro, Erlane Costa, Dilcimar de Souza, Maianne Dias, José Dias, Klenilson Ferreira, Paula Figueiredo, Thamires Freitas, Ana Carolina Furtado, Larissa Gama, Vanessa Godinho, Cintia Gouy, Daniele Hinojosa, Tyane Jardim, Joel Junior, Augustto Lima, Bernardo Maia, Adriana Marins, Kelry Mazurega, Tercilene Medeiros, Rosangela Melo, Marinete Moraes, Elizandra Nascimento, Juliana Neves, Maria Gabriela Oliveira, Thais Oliveira, Ingrid Oliveira, Arthur Otsuka, Rayssa Paes, Handerson Pereira, Gabrielle Pereira, Christiane Prado, Evelyn Queiroz, Laleyska Rodrigues, Bebeto Rodrigues, Vanderson Sampaio, Anna Gabriela Santos, Daniel Santos, Tilza Santos, Evelyn Santos, Ariandra Sartim, Ana Beatriz Silva, Juliana Silva, Emanuelle Silva, Mariana Simão, Caroline Soares, Antonny Sousa, Alexandre Trindade, Fernando Val, Adria Vasconcelos, Heline Vasconcelos, Carolinne Abreu, Katya Martinez Almeida, Camila Bitencourt de Andrade, Jhenyfer Thalyta Campos Angelo, Ghislaine Gonçalvez de Araújo Arcanjo, Bianca Maria Silva Menezes Arruda, Wellyngthon Espindola Ayala, Adelita Agripina Refosco Barbosa, Felipe Zampieri Vieira Batista, Fabiani de Morais Batista, Miriam de Jesus Costa, Mariana Garcia Croda, Lais Alves da Cruz, Roberta Carolina Pereira Diogo, Rodrigo Cezar Dutra Escobar, Iara Rodrigues Fernandes, Leticia Ramires Figueiredo, Leandro Galdino Cavalcanti Gonçalves, Sarita Lahdo, Joyce dos Santos Lencina, Guilherme Teodoro de Lima, Bruna Tayara LEOPOLDINA MEIRELES, Debora Quadros Moreira, Lilian Batista Silva Muranaka, Adriely de Oliveira, Karla Regina Warszawski de Oliveira, Matheus Vieira de Oliveira, Roberto Dias de Oliveira, Andrea Antonia Souza de Almeida dos Reis Pereira, Marco Puga, Caroliny Veron Ramos, Thaynara Haynara Souza da Rosa, Karla Lopes dos Santos, Claudinalva Ribeiro dos Santos, Dyenyffer Stéffany Leopoldina dos Santos, Karina Marques Santos, Paulo César Pereira da Silva, Paulo Victor Rocha da Silva, Débora dos Santos Silva, Patricia Vieira da Silva, Bruno Freitas da Rosa Soares, Mariana Gazzoni Sperotto, Mariana Mayumi Tadokoro, Daniel Tsuha, Hugo Miguel Ramos Vieira, Margareth Maria Pretti Dalcolmo, Cíntia Maria Lopes Alves da Paixão, Gabriela Corrêa E Castro, Simone Silva Collopy, Renato da Costa Silva, Samyra Almeida da Silveira, Alda Maria Da-Cruz, Alessandra Maria da Silva Passos de Carvalho, Rita de Cássia Batista, Maria Luciana Silva De Freitas, Aline Gerhardt de Oliveira Ferreira, Ana Paula Conceição de Souza, Paola Cerbino Doblas, Ayla Alcoforado da Silva dos Santos, Vanessa Cristine de Moraes dos Santos, Dayane Alves dos Santos Gomes, Anderson Lage Fortunato, Adriano Gomes-Silva, Monique Pinto Gonçalves, Paulo Leandro Garcia Meireless Junior, Estela Martins da Costa Carvalho, Fernando do Couto Motta, Ligia Maria Olivo de Mendonça, Girlene dos Santos Pandine, Rosa Maria Plácido Pereira, Ivan Ramos Maia, Jorge Luiz da Rocha, João Victor Paiva Romano, Glauce dos Santos, Erica Fernandes da Silva, Marilda Agudo Mendonça Teixeira de Siqueira, Ágatha Cristinne Prudêncio Soares, Sandra Franch Arroyo, Henny Ophorst-den Besten, Anna Boon, Karin M. Brakke, Axel Janssen, Marijke A.H. Koopmans, Toos Lemmens, Titia Leurink, Engelien Septer-Bijleveld, Kimberly Stadhouders, Darren Troeman, Marije van der Waal, Marjoleine van Opdorp, Nicolette van Sluis, Beatrijs Wolters, Jan Kluytmans, Jannie Romme, Wouter van den Bijllaardt, Linda van Mook, M.M.L (Miranda) van Rijen, P.M.G. Filius, Jet Gisolf, Frances Greven, Danique Huijbens, Robert Jan Hassing, R.C. Pon, Lieke Preijers, J.H. van Leusen, Harald Verheij, Wim Boersma, Evelien Brans, Paul Kloeg, Kitty Molenaar-Groot, Nhat Khanh Nguyen, Nienke Paternotte, Anke Rol, Lida Stooper, Helga Dijkstra, Esther Eggenhuizen, Lucas Huijs, Simone Moorlag, Mihai Netea, Eva Pranger, Esther Taks, Jaap ten Oever, Rob ter Heine, Kitty Blauwendraat, Bob Meek, Isil Erkaya, Houda Harbech, Nienke Roescher, Rifka Peeters, Menno te Riele, Carmen Zhou, Esther Calbo, Cristina Badia Marti, Emma Triviño Palomares, Tomás Perez Porcuna, Anabel Barriocanal, Ana Maria Barriocanal, Irma Casas, Jose Dominguez, Maria Esteve, Alicia Lacoma, Irene Latorre, Gemma Molina, Barbara Molina, Antoni Rosell, Sandra Vidal, Lydia Barrera, Natalia Bustos, Ines Portillo Calderón, David Gutierrez Campos, Jose Manuel Carretero, Angel Dominguez Castellano, Renato Compagnone, Encarnacion Ramirez de Arellano, Almudena de la Serna, Maria Dolores del Toro Lopez, Marie-Alix Clement Espindola, Ana Belen Martin Gutierrez, Alvaro Pascual Hernandez, Virginia Palomo Jiménez, Elisa Moreno, Nicolas Navarrete, Teresa Rodriguez Paño, Jesús Rodríguez-Baño, Enriqueta Tristán, Maria Jose Rios Villegas, Atsegiñe Canga Garces, Erika Castro Amo, Raquel Coya Guerrero, Josune Goikoetxea, Leticia Jorge, Cristina Perez, María Carmen Fariñas Álvarez, Manuel Gutierrez Cuadra, Francisco Arnaiz de las Revillas Almajano, Pilar Bohedo Garcia, Teresa Giménez Poderos, Claudia González Rico, Blanca Sanchez, Olga Valero, Noelia Vega, Anna Barnes, Helen Catterick, Tim Cranston, Phoebe Dawe, Emily Fletcher, Liam Fouracre, Alison Gifford, Neil Gow, John Kirkwood, Christopher Martin, Amy McAnew, Marcus Mitchell, Georgina Newman, Abby O'Connell, Jakob Onysk, Lynne Quinn, Shelley Rhodes, Samuel Stone, Lorrie Symons, Harry Tripp, Darcy Watkins, Bethany Whale, Alex Harding, Gemma Lockhart, Kate Sidaway-Lee, Sam Hilton, Sarah Manton, Daniel Webber-Rookes, Rachel Winder, James Moore, Freya Bateman, Michael Gibbons, Bridget Knight, Julie Moss, Sarah Statton, Josephine Studham, Lydia Hall, Will Moyle, and Tamsin Venton
Subjects: Bacille Calmette-Guérin (BCG) vaccine, Immunity, Heterologous, Health personnel, Randomised controlled trial, Primary prevention, Medicine (General), R5-920
Abstract: Summary: Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.
Published: 2024
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3. Specific and off-target immune responses following COVID-19 vaccination with ChAdOx1-S and BNT162b2 vaccines—an exploratory sub-study of the BRACE trialResearch in context

Author: Nicole L. Messina, Susie Germano, Rebecca McElroy, Rhian Bonnici, Branka Grubor-Bauk, David J. Lynn, Ellie McDonald, Suellen Nicholson, Kirsten P. Perrett, Laure F. Pittet, Rajeev Rudraraju, Natalie E. Stevens, Kanta Subbarao, Nigel Curtis, Andrew Davidson, Kaya Gardiner, Amanda Gwee, Tenaya Jamieson, Nicole Messina, Thilanka Morawakage, Susan Perlen, Kirsten Perrett, Laure Pittet, Amber Sastry, Jia Wei Teo, Francesca Orsini, Katherine Lee, Cecilia Moore, Suzanna Vidmar, Rashida Ali, Ross Dunn, Peta Edler, Grace Gell, Casey Goodall, Richard Hall, Ann Krastev, Nathan La, Nick McPhate, Thao Nguyen, Jack Ren, Luke Stevens, Ahmed Alamrousi, Thanh Dang, Jenny Hua, Monica Razmovska, Scott Reddiex, Xiaofang Wang, Jeremy Anderson, Kristy Azzopardi, Vicki Bennett-Wood, Anna Czajko, Nadia Mazarakis, Conor McCafferty, Frances Oppedisano, Belinda Ortika, Casey Pell, Leena Spry, Ryan Toh, Sunitha Velagapudi, Amanda Vlahos, Ashleigh Wee-Hee, Pedro Ramos, Karina De La Cruz, Dinusha Gamage, Anushka Karunanayake, Isabella Mezzetti, Benjamin Ong, Ronita Singh, Enoshini Sooriyarachchi, Natalie Cain, Rianne Brizuela, Han Huang, Veronica Abruzzo, Morgan Bealing, Patricia Bimboese, Kirsty Bowes, Emma Burrell, Joyce Chan, Jac Cushnahan, Hannah Elborough, Olivia Elkington, Kieran Fahey, Monique Fernandez, Catherine Flynn, Sarah Fowler, Marie Gentile Andrit, Bojana Gladanac, Catherine Hammond, Norine Ma, Sam Macalister, Emmah Milojevic, Jesutofunmi Mojeed, Jill Nguyen, Liz O’Donnell, Nadia Olivier, Isabelle Ooi, Stephanie Reynolds, Lisa Shen, Barb Sherry, Judith Spotswood, Jamie Wedderburn, Angela Younes, Donna Legge, Jason Bell, Jo Cheah, Annie Cobbledick, Kee Lim, Sonja Elia, Lynne Addlem, Anna Bourke, Clare Brophy, Nadine Henare, Narelle Jenkins, Francesca Machingaifa, Skye Miller, Kirsten Mitchell, Sigrid Pitkin, Kate Wall, Paola Villanueva, Nigel Crawford, Wendy Norton, Niki Tan, Thilakavathi Chengodu, Diane Dawson, Victoria Gordon, Tony Korman, Jess O’Bryan, Sophie Agius, Samantha Bannister, Jess Bucholc, Alison Burns, Beatriz Camesella, John Carlin, Marianna Ciaverella, Maxwell Curtis, Stephanie Firth, Christina Guo, Matthew Hannan, Erin Hill, Sri Joshi, Katherine Lieschke, Megan Mathers, Sasha Odoi, Ashleigh Rak, Chris Richards, Leah Steve, Carolyn Stewart, Eva Sudbury, Helen Thomson, Emma Watts, Fiona Williams, Angela Young, Penny Glenn, Andrew Kaynes, Amandine Philippart De Floy, Sandy Buchanan, Thijs Sondag, Ivy Xie, Harriet Edmund, Bridie Byrne, Tom Keeble, Belle Ngien, Fran Noonan, Michelle Wearing-Smith, Alison Clarke, Pemma Davies, Oliver Eastwood, Alric Ellinghaus, Rachid Ghieh, Zahra Hilton, Emma Jennings, Athina Kakkos, Iris Liang, Katie Nicol, Sally O’Callaghan, Helen Osman, Gowri Rajaram, Sophia Ratcliffe, Victoria Rayner, Ashleigh Salmon, Angela Scheppokat, Aimee Stevens, Rebekah Street, Nicholas Toogood, Nicholas Wood, Twinkle Bahaduri, Therese Baulman, Jennifer Byrne, Candace Carter, Mary Corbett, Aiken Dao, Maria Desylva, Andrew Dunn, Evangeline Gardiner, Rosemary Joyce, Rama Kandasamy, Craig Munns, Lisa Pelayo, Ketaki Sharma, Katrina Sterling, Caitlin Uren, Clinton Colaco, Mark Douglas, Kate Hamilton, Adam Bartlett, Brendan McMullan, Pamela Palasanthiran, Phoebe Williams, Justin Beardsley, Nikki Bergant, Renier Lagunday, Kristen Overton, Jeffrey Post, Yasmeen Al-Hindawi, Sarah Barney, Anthony Byrne, Lee Mead, Marshall Plit, David Lynn, Saoirse Benson, Stephen Blake, Rochelle Botten, Tee Yee Chern, Georgina Eden, Liddy Griffith, Jane James, Miriam Lynn, Angela Markow, Domenic Sacca, Natalie Stevens, Steve Wesselingh, Catriona Doran, Simone Barry, Alice Sawka, Sue Evans, Louise Goodchild, Christine Heath, Meredith Krieg, Helen Marshall, Mark McMillan, Mary Walker, Peter Richmond, Nelly Amenyogbe, Christina Anthony, Annabelle Arnold, Beth Arrowsmith, Rym Ben-Othman, Sharon Clark, Jemma Dunnill, Nat Eiffler, Krist Ewe, Carolyn Finucane, Lorraine Flynn, Camille Gibson, Lucy Hartnell, Elysia Hollams, Heidi Hutton, Lance Jarvis, Jane Jones, Jan Jones, Karen Jones, Jennifer Kent, Tobias Kollmann, Debbie Lalich, Wenna Lee, Rachel Lim, Sonia McAlister, Fiona McDonald, Andrea Meehan, Asma Minhaj, Lisa Montgomery, Melissa O’Donnell, Jaslyn Ong, Joanne Ong, Kimberley Parkin, Glady Perez, Catherine Power, Shadie Rezazadeh, Holly Richmond, Sally Rogers, Nikki Schultz, Margaret Shave, Patrycja Skut, Lisa Stiglmayer, Alexandra Truelove, Ushma Wadia, Rachael Wallace, Justin Waring, Michelle England, Erin Latkovic, Laurens Manning, Susan Herrmann, Michaela Lucas, Marcus Lacerda, Paulo Henrique Andrade, Fabiane Bianca Barbosa, Dayanne Barros, Larissa Brasil, Ana Greyce Capella, Ramon Castro, Erlane Costa, Dilcimar de Souza, Maianne Dias, José Dias, Klenilson Ferreira, Paula Figueiredo, Thamires Freitas, Ana Carolina Furtado, Larissa Gama, Vanessa Godinho, Cintia Gouy, Daniele Hinojosa, Bruno Jardim, Tyane Jardim, Joel Junior, Augustto Lima, Bernardo Maia, Adriana Marins, Kelry Mazurega, Tercilene Medeiros, Rosangela Melo, Marinete Moraes, Elizandra Nascimento, Juliana Neves, Maria Gabriela Oliveira, Thais Oliveira, Ingrid Oliveira, Arthur Otsuka, Rayssa Paes, Handerson Pereira, Gabrielle Pereira, Christiane Prado, Evelyn Queiroz, Laleyska Rodrigues, Bebeto Rodrigues, Vanderson Sampaio, Anna Gabriela Santos, Daniel Santos, Tilza Santos, Evelyn Santos, Ariandra Sartim, Ana Beatriz Silva, Juliana Silva, Emanuelle Silva, Mariana Simão, Caroline Soares, Antonny Sousa, Alexandre Trindade, Fernando Val, Adria Vasconcelos, Heline Vasconcelos, Julio Croda, Carolinne Abreu, Katya Martinez Almeida, Camila Bitencourt de Andrade, Jhenyfer Thalyta Campos Angelo, Ghislaine Gonçalvez de Araújo Arcanjo, Bianca Maria Silva Menezes Arruda, Wellyngthon Espindola Ayala, Adelita Agripina Refosco Barbosa, Felipe Zampieri Vieira Batista, Fabiani de Morais Batista, Miriam de Jesus Costa, Mariana Garcia Croda, Lais Alves da Cruz, Roberta Carolina Pereira Diogo, Rodrigo Cezar Dutra Escobar, Iara Rodrigues Fernandes, Leticia Ramires Figueiredo, Leandro Galdino Cavalcanti Gonçalves, Sarita Lahdo, Joyce dos Santos Lencina, Guilherme Teodoro de Lima, Larissa Santos Matos, Bruna Tayara Leopoldina Meireles, Debora Quadros Moreira, Lilian Batista Silva Muranaka, Adriely de Oliveira, Karla Regina Warszawski de Oliveira, Matheus Vieira de Oliveira, Roberto Dias de Oliveira, Andrea Antonia Souza de Almeida dos Reis Pereira, Marco Puga, Caroliny Veron Ramos, Thaynara Haynara Souza da Rosa, Karla Lopes dos Santos, Claudinalva Ribeiro dos Santos, Dyenyffer Stéffany Leopoldina dos Santos, Karina Marques Santos, Paulo César Pereira da Silva, Paulo Victor Rocha da Silva, Débora dos Santos Silva, Patricia Vieira da Silva, Bruno Freitas da Rosa Soares, Mariana Gazzoni Sperotto, Mariana Mayumi Tadokoro, Daniel Tsuha, Hugo Miguel Ramos Vieira, Margareth Maria Pretti Dalcolmo, Cíntia Maria Lopes Alves da Paixão, Gabriela Corrêa E Castro, Simone Silva Collopy, Renato da Costa Silva, Samyra Almeida da Silveira, Alda Maria Da-Cruz, Alessandra Maria da Silva Passos de Carvalho, Rita de Cássia Batista, Maria Luciana Silva De Freitas, Aline Gerhardt de Oliveira Ferreira, Ana Paula Conceição de Souza, Paola Cerbino Doblas, Ayla Alcoforado da Silva dos Santos, Vanessa Cristine de Moraes dos Santos, Dayane Alves dos Santos Gomes, Anderson Lage Fortunato, Adriano Gomes-Silva, Monique Pinto Gonçalves, Paulo Leandro Garcia Meireless Junior, Estela Martins da Costa Carvalho, Fernando do Couto Motta, Ligia Maria Olivo de Mendonça, Girlene dos Santos Pandine, Rosa Maria Plácido Pereira, Ivan Ramos Maia, Jorge Luiz da Rocha, João Victor Paiva Romano, Glauce dos Santos, Erica Fernandes da Silva, Marilda Agudo Mendonça Teixeira de Siqueira, Ágatha Cristinne Prudêncio Soares, Marc Bonten, Sandra Franch Arroyo, Henny Ophorst-den Besten, Anna Boon, Karin M. Brakke, Axel Janssen, Marijke A.H. Koopmans, Toos Lemmens, Titia Leurink, Cristina Prat-Aymerich, Engelien Septer-Bijleveld, Kimberly Stadhouders, Darren Troeman, Marije van der Waal, Marjoleine van Opdorp, Nicolette van Sluis, Beatrijs Wolters, Jan Kluytmans, Jannie Romme, Wouter van den Bijllaardt, Linda van Mook, M.M.L (Miranda) van Rijen, Margreet Filius, Jet Gisolf, Frances Greven, Danique Huijbens, Robert Jan Hassing, Roos Pon, Lieke Preijers, Joke van Leusen, Harald Verheij, Wim Boersma, Evelien Brans, Paul Kloeg, Kitty Molenaar-Groot, Nhat Khanh Nguyen, Nienke Paternotte, Anke Rol, Lida Stooper, Helga Dijkstra, Esther Eggenhuizen, Lucas Huijs, Simone Moorlag, Mihai Netea, Eva Pranger, Esther Taks, Jaap ten Oever, Rob ter Heine, Kitty Blauwendraat, Bob Meek, Isil Erkaya, Houda Harbech, Nienke Roescher, Rifka Peeters, Menno te Riele, Carmen Zhou, Esther Calbo, Cristina Badia Marti, Emma Triviño Palomares, Tomás Perez Porcuna, Anabel Barriocanal, Ana Maria Barriocanal, Irma Casas, Jose Dominguez, Maria Esteve, Alicia Lacoma, Irene Latorre, Gemma Molina, Barbara Molina, Antoni Rosell, Sandra Vidal, Lydia Barrera, Natalia Bustos, Ines Portillo Calderón, David Gutierrez Campos, Jose Manuel Carretero, Angel Dominguez Castellano, Renato Compagnone, Encarnacion Ramirez de Arellano, Almudena de la Serna, Maria Dolores del Toro Lopez, Marie-Alix Clement Espindola, Ana Belen Martin Gutierrez, Alvaro Pascual Hernandez, Virginia Palomo Jiménez, Elisa Moreno, Nicolas Navarrete, Teresa Rodriguez Paño, Jesús Rodríguez-Baño, Enriqueta Tristán, Maria Jose Rios Villegas, Atsegiñe Canga Garces, Erika Castro Amo, Raquel Coya Guerrero, Josune Goikoetxea, Leticia Jorge, Cristina Perez, María Carmen Fariñas Álvarez, Manuel Gutierrez Cuadra, Francisco Arnaiz de las Revillas Almajano, Pilar Bohedo Garcia, Teresa Giménez Poderos, Claudia González Rico, Blanca Sanchez, Olga Valero, Noelia Vega, John Campbell, Anna Barnes, Helen Catterick, Tim Cranston, Phoebe Dawe, Emily Fletcher, Liam Fouracre, Alison Gifford, John Kirkwood, Christopher Martin, Amy McAnew, Marcus Mitchell, Georgina Newman, Abby O’Connell, Jakob Onysk, Lynne Quinn, Shelley Rhodes, Samuel Stone, Lorrie Symons, Harry Tripp, Adilia Warris, Darcy Watkins, Bethany Whale, Alex Harding, Gemma Lockhart, Kate Sidaway-Lee, Sam Hilton, Sarah Manton, Daniel Webber-Rookes, Rachel Winder, James Moore, Freya Bateman, Michael Gibbons, Bridget Knight, Julie Moss, Sarah Statton, Josephine Studham, Lydia Hall, Will Moyle, and Tamsin Venton
Subjects: Vaccine, Off-target, Immunoregulation, Cytokine, SARS-CoV-2, Heterologous immunity, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Methods: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Findings: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. Interpretation: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Funding: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children’s. BRACE trial funding is detailed in acknowledgements.
Published: 2024
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4. Breastfeeding and Neonatal Age Influence Neutrophil-Driven Ontogeny of Blood Cell Populations in the First Week of Human Life

Author: Sebastiano Montante, Rym Ben-Othman, Nelly Amenyogbe, Asimenia Angelidou, Anita van den Biggelaar, Bing Cai, Yixuan Chen, Alansana Darboe, Joann Diray-Arce, Rebecca Ford, Olubukola Idoko, Amy Lee, Mandy Lo, Kerry McEnaney, Mehrnoush Malek, David Martino, Geraldine Masiria, Oludare A. Odumade, William Pomat, Casey Shannon, Kinga Smolen, The EPIC Consortium, Al Ozonoff, Peter Richmond, Scott Tebbutt, Ofer Levy, Beate Kampmann, Ryan Brinkman, and Tobias Kollmann
Subjects: Immunologic diseases. Allergy, RC581-607
Abstract: The first few days of life are characterized by rapid external and internal changes that require substantial immune system adaptations. Despite growing evidence of the impact of this period on lifelong immune health, this period remains largely uncharted. To identify factors that may impact the trajectory of immune development, we conducted stringently standardized, high-throughput phenotyping of peripheral white blood cell (WBC) populations from 796 newborns across two distinct cohorts (The Gambia, West Africa; Papua New Guinea, Melanesia) in the framework of a Human Immunology Project Consortium (HIPC) study. Samples were collected twice from each newborn during the first week of life, first at Day of Life 0 (at birth) and then subsequently at Day of Life 1, 3, or 7 depending on the randomization group the newborn belongs to. The subsequent analysis was conducted at an unprecedented level of detail using flow cytometry and an unbiased automated gating algorithm. The results showed that WBC composition in peripheral blood changes along patterns highly conserved across populations and environments. Changes across days of life were most pronounced in the innate myeloid compartment. Breastfeeding, and at a smaller scale neonatal vaccination, were associated with changes in peripheral blood neutrophil and monocyte cell counts. Our results suggest a common trajectory of immune development in newborns and possible association with timing of breastfeeding initiation, which may contribute to immune-mediated protection from infection in early life. These data begin to outline a specific window of opportunity for interventions that could deliberately direct WBC composition, and with that, immune trajectory and thus ontogeny in early life. This trial is registered with NCT03246230.
Published: 2024
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5. The PRotective Effect of Maternal Immunisation on preTerm birth: characterising the Underlying mechanisms and Role in newborn immune function: the PREMITUR study protocol

Author: Michelle L. Giles, Stephen Cole, Jessica O’Bryan, Sushena Krishnaswamy, Rym Ben-Othman, Nelly Amenyogbe, Mary-Ann Davey, and Tobias Kollmann
Subjects: pregnancy, vaccination, preterm birth, influenza, pertussis, Immunologic diseases. Allergy, RC581-607
Abstract: Maternal immunisation, a low cost and high efficacy intervention is recommended for its pathogen specific protection. Evidence suggests that maternal immunisation has another significant impact: reduction of preterm birth (PTB), the single greatest cause of childhood morbidity and mortality globally. Our overarching question is: how does maternal immunisation modify the immune system in pregnant women and/or their newborn to reduce adverse pregnancy outcomes and enhance the newborn infant’s capacity to protect itself from infectious diseases during early childhood? To answer this question we are conducting a multi-site, prospective observational cohort study collecting maternal and infant biological samples at defined time points during pregnancy and post-partum from nulliparous women. We aim to enrol 400 women and determine the immune trajectory in pregnancy and the impact of maternal immunisation (including influenza, pertussis and/or COVID-19 vaccines) on this trajectory. The results are expected to identify areas that can be targeted for future intervention studies.
Published: 2023
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6. Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trialResearch in context

Author: Laure F. Pittet, Cecilia L. Moore, Ellie McDonald, Simone Barry, Marc Bonten, John Campbell, Julio Croda, Margareth Dalcolmo, Andrew Davidson, Mark W. Douglas, Kaya Gardiner, Amanda Gwee, Bruno Jardim, Marcus V.G. Lacerda, Michaela Lucas, David J. Lynn, Laurens Manning, Roberto D. de Oliveira, Kirsten P. Perrett, Cristina Prat-Aymerich, Peter C. Richmond, Jorge L. Rocha, Jesus Rodriguez-Baño, Adilia Warris, Nicholas J. Wood, Nicole L. Messina, Nigel Curtis, Tenaya Jamieson, Nicole Messina, Thilanka Morawakage, Susan Perlen, Kirsten Perrett, Laure Pittet, Amber Sastry, Jia Wei Teo, Francesca Orsini, Katherine Lee, Cecilia Moore, Suzanna Vidmar, Rashida Ali, Ross Dunn, Peta Edler, Grace Gell, Casey Goodall, Richard Hall, Ann Krastev, Nathan La, Nick McPhate, Thao Nguyen, Jack Ren, Luke Stevens, Ahmed Alamrousi, Rhian Bonnici, Thanh Dang, Susie Germano, Jenny Hua, Rebecca McElroy, Monica Razmovska, Scott Reddiex, Xiaofang Wang, Jeremy Anderson, Kristy Azzopardi, Vicki Bennett-Wood, Anna Czajko, Nadia Mazarakis, Conor McCafferty, Frances Oppedisano, Belinda Ortika, Casey Pell, Leena Spry, Ryan Toh, Sunitha Velagapudi, Amanda Vlahos, Ashleigh Wee-Hee, Pedro Ramos, Karina De La Cruz, Dinusha Gamage, Anushka Karunanayake, Isabella Mezzetti, Benjamin Ong, Ronita Singh, Enoshini Sooriyarachchi, Suellen Nicholson, Natalie Cain, Rianne Brizuela, Han Huang, Veronica Abruzzo, Morgan Bealing, Patricia Bimboese, Kirsty Bowes, Emma Burrell, Joyce Chan, Jac Cushnahan, Hannah Elborough, Olivia Elkington, Kieran Fahey, Monique Fernandez, Catherine Flynn, Sarah Fowler, Marie Gentile Andrit, Bojana Gladanac, Catherine Hammond, Norine Ma, Sam Macalister, Emmah Milojevic, Jesutofunmi Mojeed, Jill Nguyen, Liz O'Donnell, Nadia Olivier, Isabelle Ooi, Stephanie Reynolds, Lisa Shen, Barb Sherry, Judith Spotswood, Jamie Wedderburn, Angela Younes, Donna Legge, Jason Bell, Jo Cheah, Annie Cobbledick, Kee Lim, Sonja Elia, Lynne Addlem, Anna Bourke, Clare Brophy, Nadine Henare, Narelle Jenkins, Francesca Machingaifa, Skye Miller, Kirsten Mitchell, Sigrid Pitkin, Kate Wall, Paola Villanueva, Nigel Crawford, Wendy Norton, Niki Tan, Thilakavathi Chengodu, Diane Dawson, Victoria Gordon, Tony Korman, Jess O'Bryan, Sophie Agius, Samantha Bannister, Jess Bucholc, Alison Burns, Beatriz Camesella, John Carlin, Marianna Ciaverella, Maxwell Curtis, Stephanie Firth, Christina Guo, Matthew Hannan, Erin Hill, Sri Joshi, Katherine Lieschke, Megan Mathers, Sasha Odoi, Ashleigh Rak, Chris Richards, Leah Steve, Carolyn Stewart, Eva Sudbury, Helen Thomson, Emma Watts, Fiona Williams, Angela Young, Penny Glenn, Andrew Kaynes, Amandine Philippart De Floy, Sandy Buchanan, Thijs Sondag, Ivy Xie, Harriet Edmund, Bridie Byrne, Tom Keeble, Belle Ngien, Fran Noonan, Michelle Wearing-Smith, Alison Clarke, Pemma Davies, Oliver Eastwood, Alric Ellinghaus, Rachid Ghieh, Zahra Hilton, Emma Jennings, Athina Kakkos, Iris Liang, Katie Nicol, Sally O'Callaghan, Helen Osman, Gowri Rajaram, Sophia Ratcliffe, Victoria Rayner, Ashleigh Salmon, Angela Scheppokat, Aimee Stevens, Rebekah Street, Nicholas Toogood, Nicholas Wood, Twinkle Bahaduri, Therese Baulman, Jennifer Byrne, Candace Carter, Mary Corbett, Aiken Dao, Maria Desylva, Andrew Dunn, Evangeline Gardiner, Rosemary Joyce, Rama Kandasamy, Craig Munns, Lisa Pelayo, Ketaki Sharma, Katrina Sterling, Caitlin Uren, Clinton Colaco, Mark Douglas, Kate Hamilton, Adam Bartlett, Brendan McMullan, Pamela Palasanthiran, Phoebe Williams, Justin Beardsley, Nikki Bergant, Renier Lagunday, Kristen Overton, Jeffrey Post, Yasmeen Al-Hindawi, Sarah Barney, Anthony Byrne, Lee Mead, Marshall Plit, David Lynn, Saoirse Benson, Stephen Blake, Rochelle Botten, Tee Yee Chern, Georgina Eden, Liddy Griffith, Jane James, Miriam Lynn, Angela Markow, Domenic Sacca, Natalie Stevens, Steve Wesselingh, Catriona Doran, Alice Sawka, Sue Evans, Louise Goodchild, Christine Heath, Meredith Krieg, Helen Marshall, Mark McMillan, Mary Walker, Peter Richmond, Nelly Amenyogbe, Christina Anthony, Annabelle Arnold, Beth Arrowsmith, Rym Ben-Othman, Sharon Clark, Jemma Dunnill, Nat Eiffler, Krist Ewe, Carolyn Finucane, Lorraine Flynn, Camille Gibson, Lucy Hartnell, Elysia Hollams, Heidi Hutton, Lance Jarvis, Jane Jones, Jan Jones, Karen Jones, Jennifer Kent, Tobias Kollmann, Debbie Lalich, Wenna Lee, Rachel Lim, Sonia McAlister, Fiona McDonald, Andrea Meehan, Asma Minhaj, Lisa Montgomery, Melissa O'Donnell, Jaslyn Ong, Joanne Ong, Kimberley Parkin, Glady Perez, Catherine Power, Shadie Rezazadeh, Holly Richmond, Sally Rogers, Nikki Schultz, Margaret Shave, Patrycja Skut, Lisa Stiglmayer, Alexandra Truelove, Ushma Wadia, Rachael Wallace, Justin Waring, Michelle England, Erin Latkovic, Susan Herrmann, Marcus Lacerda, Paulo Henrique Andrade, Fabiane Bianca Barbosa, Dayanne Barros, Larissa Brasil, Ana Greyce Capella, Ramon Castro, Erlane Costa, Dilcimar de Souza, Maianne Dias, José Dias, Klenilson Ferreira, Paula Figueiredo, Thamires Freitas, Ana Carolina Furtado, Larissa Gama, Vanessa Godinho, Cintia Gouy, Daniele Hinojosa, Tyane Jardim, Joel Junior, Augustto Lima, Bernardo Maia, Adriana Marins, Kelry Mazurega, Tercilene Medeiros, Rosangela Melo, Marinete Moraes, Elizandra Nascimento, Juliana Neves, Maria Gabriela Oliveira, Thais Oliveira, Ingrid Oliveira, Arthur Otsuka, Rayssa Paes, Handerson Pereira, Gabrielle Pereira, Christiane Prado, Evelyn Queiroz, Laleyska Rodrigues, Bebeto Rodrigues, Vanderson Sampaio, Anna Gabriela Santos, Daniel Santos, Tilza Santos, Evelyn Santos, Ariandra Sartim, Ana Beatriz Silva, Juliana Silva, Emanuelle Silva, Mariana Simão, Caroline Soares, Antonny Sousa, Alexandre Trindade, Fernando Val, Adria Vasconcelos, Heline Vasconcelos, Carolinne Abreu, Katya Martinez Almeida, Camila Bitencourt de Andrade, Jhenyfer Thalyta Campos Angelo, Ghislaine Gonçalvez de Araújo Arcanjo, Bianca Maria Silva Menezes Arruda, Wellyngthon Espindola Ayala, Adelita Agripina Refosco Barbosa, Felipe Zampieri Vieira Batista, Fabiani de Morais Batista, Miriam de Jesus Costa, Mariana Garcia Croda, Lais Alves da Cruz, Roberta Carolina Pereira Diogo, Rodrigo Cezar Dutra Escobar, Iara Rodrigues Fernandes, Leticia Ramires Figueiredo, Leandro Galdino Cavalcanti Gonçalves, Sarita Lahdo, Joyce dos Santos Lencina, Guilherme Teodoro de Lima, Larissa Santos Matos, Bruna Tayara Leopoldina Meireles, Debora Quadros Moreira, Lilian Batista Silva Muranaka, Adriely de Oliveira, Karla Regina Warszawski de Oliveira, Matheus Vieira de Oliveira, Roberto Dias de Oliveira, Andrea Antonia Souza de Almeida dos Reis Pereira, Marco Puga, Caroliny Veron Ramos, Thaynara Haynara Souza da Rosa, Karla Lopes dos Santos, Claudinalva Ribeiro dos Santos, Dyenyffer Stéffany Leopoldina dos Santos, Karina Marques Santos, Paulo César Pereira da Silva, Paulo Victor Rocha da Silva, Débora dos Santos Silva, Patricia Vieira da Silva, Bruno Freitas da Rosa Soares, Mariana Gazzoni Sperotto, Mariana Mayumi Tadokoro, Daniel Tsuha, Hugo Miguel Ramos Vieira, Margareth Maria Pretti Dalcolmo, Cíntia Maria Lopes Alves da Paixão, Gabriela Corrêa E Castro, Simone Silva Collopy, Renato da Costa Silva, Samyra Almeida da Silveira, Alda Maria Da-Cruz, Alessandra Maria da Silva Passos de Carvalho, Rita de Cássia Batista, Maria Luciana Silva De Freitas, Aline Gerhardt de Oliveira Ferreira, Ana Paula Conceição de Souza, Paola Cerbino Doblas, Ayla Alcoforado da Silva dos Santos, Vanessa Cristine de Moraes dos Santos, Dayane Alves dos Santos Gomes, Anderson Lage Fortunato, Adriano Gomes-Silva, Monique Pinto Gonçalves, Paulo Leandro Garcia Meireless Junior, Estela Martins da Costa Carvalho, Fernando do Couto Motta, Ligia Maria Olivo de Mendonça, Girlene dos Santos Pandine, Rosa Maria Plácido Pereira, Ivan Ramos Maia, Jorge Luiz da Rocha, João Victor Paiva Romano, Glauce dos Santos, Erica Fernandes da Silva, Marilda Agudo Mendonça Teixeira de Siqueira, Ágatha Cristinne Prudêncio Soares, Sandra Franch Arroyo, Henny Ophorst-den Besten, Anna Boon, Karin M. Brakke, Axel Janssen, Marijke A.H. Koopmans, Toos Lemmens, Titia Leurink, Engelien Septer-Bijleveld, Kimberly Stadhouders, Darren Troeman, Marije van der Waal, Marjoleine van Opdorp, Nicolette van Sluis, Beatrijs Wolters, Jan Kluytmans, Jannie Romme, Wouter van den Bijllaardt, Linda van Mook, M.M.L (Miranda) van Rijen, P.M.G. Filius, Jet Gisolf, Frances Greven, Danique Huijbens, Robert Jan Hassing, R.C. Pon, Lieke Preijers, J.H. van Leusen, Harald Verheij, Wim Boersma, Evelien Brans, Paul Kloeg, Kitty Molenaar-Groot, Nhat Khanh Nguyen, Nienke Paternotte, Anke Rol, Lida Stooper, Helga Dijkstra, Esther Eggenhuizen, Lucas Huijs, Simone Moorlag, Mihai Netea, Eva Pranger, Esther Taks, Jaap ten Oever, Rob ter Heine, Kitty Blauwendraat, Bob Meek, Isil Erkaya, Houda Harbech, Nienke Roescher, Rifka Peeters, Menno te Riele, Carmen Zhou, Esther Calbo, Cristina Badia Marti, Emma Triviño Palomares, Tomás Perez Porcuna, Anabel Barriocanal, Ana Maria Barriocanal, Irma Casas, Jose Dominguez, Maria Esteve, Alicia Lacoma, Irene Latorre, Gemma Molina, Barbara Molina, Antoni Rosell, Sandra Vidal, Lydia Barrera, Natalia Bustos, Ines Portillo Calderón, David Gutierrez Campos, Jose Manuel Carretero, Angel Dominguez Castellano, Renato Compagnone, Encarnacion Ramirez de Arellano, Almudena de la Serna, Maria Dolores del Toro Lopez, Marie-Alix Clement Espindola, Ana Belen Martin Gutierrez, Alvaro Pascual Hernandez, Virginia Palomo Jiménez, Elisa Moreno, Nicolas Navarrete, Teresa Rodriguez Paño, Jesús Rodríguez-Baño, Enriqueta Tristán, Maria Jose Rios Villegas, Atsegiñe Canga Garces, Erika Castro Amo, Raquel Coya Guerrero, Josune Goikoetxea, Leticia Jorge, Cristina Perez, María Carmen Fariñas Álvarez, Manuel Gutierrez Cuadra, Francisco Arnaiz de las Revillas Almajano, Pilar Bohedo Garcia, Teresa Giménez Poderos, Claudia González Rico, Blanca Sanchez, Olga Valero, Noelia Vega, Anna Barnes, Helen Catterick, Tim Cranston, Phoebe Dawe, Emily Fletcher, Liam Fouracre, Alison Gifford, John Kirkwood, Christopher Martin, Amy McAnew, Marcus Mitchell, Georgina Newman, Abby O'Connell, Jakob Onysk, Lynne Quinn, Shelley Rhodes, Samuel Stone, Lorrie Symons, Harry Tripp, Darcy Watkins, Bethany Whale, Alex Harding, Gemma Lockhart, Kate Sidaway-Lee, Sam Hilton, Sarah Manton, Daniel Webber-Rookes, Rachel Winder, James Moore, Freya Bateman, Michael Gibbons, Bridget Knight, Julie Moss, Sarah Statton, Josephine Studham, Lydia Hall, Will Moyle, and Tamsin Venton
Subjects: Herpes simplex virus, Cold sore, Herpes labialis, Bacille Calmette-Guérin, Mycobacterium bovis, Prevention, Medicine (General), R5-920
Abstract: Summary: Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2−8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27–2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32–0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69–3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26–0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3–2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.
Published: 2023
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7. Metagenomic Characterisation of the Gut Microbiome and Effect of Complementary Feeding on Bifidobacterium spp. in Australian Infants

Author: Kimberley Parkin, Debra J. Palmer, Valerie Verhasselt, Nelly Amenyogbe, Matthew N. Cooper, Claus T. Christophersen, Susan L. Prescott, Desiree Silva, and David Martino
Subjects: gut microbiome, shotgun metagenomics, breastfeeding, Bifidobacterium, complementary feeding, the ORIGINS project, Biology (General), QH301-705.5
Abstract: Complementary feeding induces dramatic ecological shifts in the infant gut microbiota toward more diverse compositions and functional metabolic capacities, with potential implications for immune and metabolic health. The aim of this study was to examine whether the age at which solid foods are introduced differentially affects the microbiota in predominantly breastfed infants compared with predominantly formula-fed infants. We performed whole-genome shotgun metagenomic sequencing of infant stool samples from a cohort of six-month-old Australian infants enrolled in a nested study within the ORIGINS Project longitudinal birth cohort. Infants born preterm or those who had been administered antibiotics since birth were excluded. The taxonomic composition was highly variable among individuals at this age. Predominantly formula-fed infants exhibited a higher microbiome diversity than predominantly breastfed infants. Among the predominantly breastfed infants, the introduction of solid foods prior to five months of age was associated with higher alpha diversity than solid food introduction after six months of age, primarily due to the loss of Bifidobacterium infantis. In contrast, the age at which solid food was introduced was not associated with the overall change in diversity among predominantly formula-fed infants but was associated with compositional changes in Escherichia abundance. Examining the functional capacity of the microbiota in relation to these changes, we found that the introduction of solid foods after six months of age was associated with elevated one-carbon compound metabolic pathways in both breastfed and formula-fed infants, although the specific metabolic sub-pathways differed, likely reflecting different taxonomic compositions. Our findings suggest that the age of commencement of solid foods influences the gut microbiota composition differently in predominantly breastfed infants than in predominantly formula-fed infants.
Published: 2024
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8. Bacterial and Fungal Gut Community Dynamics Over the First 5 Years of Life in Predominantly Rural Communities in Ghana

Author: Nelly Amenyogbe, Dennis Adu-Gyasi, Yeetey Enuameh, Kwaku Poku Asante, Dennis Gyasi Konadu, Seyram Kaali, David Dosoo, Pinaki Panigrahi, Tobias R. Kollmann, William W. Mohn, and Seth Owusu-Agyei
Subjects: breast milk, child, fungi, bacteria, post partum microbiome, Microbiology, QR1-502
Abstract: BackgroundBacterial and fungal microbiotas are increasingly recognized as important in health and disease starting early in life. However, microbiota composition has not yet been investigated in most rural, low-resource settings, and in such settings, bacterial and fungal microbiotas have not been compared. Thus, we applied 16S and ITS2 amplicon sequencing, respectively, to investigate bacterial and fungal fecal microbiotas in rural Ghanaian children cross-sectionally from birth to 5 years of age. Corresponding maternal fecal and breast milk microbiotas were additionally investigated.ResultsWhile bacterial communities differed systematically across the age spectrum in composition and diversity, the same was not observed for the fungal microbiota. We also identified a novel and dramatic change in the maternal postpartum microbiota. This change included much higher abundance of Escherichia coli and much lower abundance of Prevotella in the first vs. fourth week postpartum. While infants shared more bacterial taxa with their mother’s stool and breast milk than with those of unrelated mothers, there were far fewer shared fungal taxa.ConclusionGiven the known ability of commensal fungi to influence host health, the distinct pattern of their acquisition likely has important health consequences. Similarly, the dynamics of mothers’ bacterial microbiotas around the time of birth may have important consequences for their children’s health. Both topics require further study.
Published: 2021
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9. Dynamic molecular changes during the first week of human life follow a robust developmental trajectory

Author: Amy H. Lee, Casey P. Shannon, Nelly Amenyogbe, Tue B. Bennike, Joann Diray-Arce, Olubukola T. Idoko, Erin E. Gill, Rym Ben-Othman, William S. Pomat, Simon D. van Haren, Kim-Anh Lê Cao, Momoudou Cox, Alansana Darboe, Reza Falsafi, Davide Ferrari, Daniel J. Harbeson, Daniel He, Cai Bing, Samuel J. Hinshaw, Jorjoh Ndure, Jainaba Njie-Jobe, Matthew A. Pettengill, Peter C. Richmond, Rebecca Ford, Gerard Saleu, Geraldine Masiria, John Paul Matlam, Wendy Kirarock, Elishia Roberts, Mehrnoush Malek, Guzmán Sanchez-Schmitz, Amrit Singh, Asimenia Angelidou, Kinga K. Smolen, The EPIC Consortium, Ryan R. Brinkman, Al Ozonoff, Robert E. W. Hancock, Anita H. J. van den Biggelaar, Hanno Steen, Scott J. Tebbutt, Beate Kampmann, Ofer Levy, and Tobias R. Kollmann
Subjects: Science
Abstract: The first week of life impacts health for all of life, but the mechanisms are little-understood. Here the authors extract multi-omic data from small volumes of blood to study the dynamic molecular changes during the first week of life, revealing a robust developmental trajectory common to different populations.
Published: 2019
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10. Biogeography of the Relationship between the Child Gut Microbiome and Innate Immune System

Author: Nelly Amenyogbe, Pedro Dimitriu, Kinga K. Smolen, Eric M. Brown, Casey P. Shannon, Scott J. Tebbutt, Phillip J. Cooper, Arnaud Marchant, Tessa Goetghebuer, Monika Esser, Brett B. Finlay, Tobias R. Kollmann, and William W. Mohn
Subjects: Microbiology, QR1-502
Abstract: Both the gut microbiome and innate immunity are known to differ across biogeographically diverse human populations. The gut microbiome has been shown to directly influence systemic immunity in animal models.
Published: 2021
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11. Multi-Omic Data Integration Allows Baseline Immune Signatures to Predict Hepatitis B Vaccine Response in a Small Cohort

Author: Casey P. Shannon, Travis M. Blimkie, Rym Ben-Othman, Nicole Gladish, Nelly Amenyogbe, Sibyl Drissler, Rachel D. Edgar, Queenie Chan, Mel Krajden, Leonard J. Foster, Michael S. Kobor, William W. Mohn, Ryan R. Brinkman, Kim-Anh Le Cao, Richard H. Scheuermann, Scott J. Tebbutt, Robert E.W. Hancock, Wayne C. Koff, Tobias R. Kollmann, Manish Sadarangani, and Amy Huei-Yi Lee
Subjects: multi-omic analysis, hepatitis B vaccination, baseline immunity, network analysis, vaccine response, Immunologic diseases. Allergy, RC581-607
Abstract: BackgroundVaccination remains one of the most effective means of reducing the burden of infectious diseases globally. Improving our understanding of the molecular basis for effective vaccine response is of paramount importance if we are to ensure the success of future vaccine development efforts.MethodsWe applied cutting edge multi-omics approaches to extensively characterize temporal molecular responses following vaccination with hepatitis B virus (HBV) vaccine. Data were integrated across cellular, epigenomic, transcriptomic, proteomic, and fecal microbiome profiles, and correlated to final HBV antibody titres.ResultsUsing both an unsupervised molecular-interaction network integration method (NetworkAnalyst) and a data-driven integration approach (DIABLO), we uncovered baseline molecular patterns and pathways associated with more effective vaccine responses to HBV. Biological associations were unravelled, with signalling pathways such as JAK-STAT and interleukin signalling, Toll-like receptor cascades, interferon signalling, and Th17 cell differentiation emerging as important pre-vaccination modulators of response.ConclusionThis study provides further evidence that baseline cellular and molecular characteristics of an individual’s immune system influence vaccine responses, and highlights the utility of integrating information across many parallel molecular datasets.
Published: 2020
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12. Corrigendum: Clinical Protocol for a Longitudinal Cohort Study Employing Systems Biology to Identify Markers of Vaccine Immunogenicity in Newborn Infants in The Gambia and Papua New Guinea

Author: Olubukola T. Idoko, Kinga K. Smolen, Oghenebrume Wariri, Abdulazeez Imam, Casey P. Shannon, Tida Dibassey, Joann Diray-Arce, Alansana Darboe, Julia Strandmark, Rym Ben-Othman, Oludare A. Odumade, Kerry McEnaney, Nelly Amenyogbe, William S. Pomat, Simon van Haren, Guzmán Sanchez-Schmitz, Ryan R. Brinkman, Hanno Steen, Robert E. W. Hancock, Scott J. Tebbutt, Peter C. Richmond, Anita H. J. van den Biggelaar, Tobias R. Kollmann, Ofer Levy, Al Ozonoff, and Beate Kampmann
Subjects: markers, newborn, vaccine, immunogenicity, systems biology, OMICS, Pediatrics, RJ1-570
Published: 2020
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13. Systems Biology Methods Applied to Blood and Tissue for a Comprehensive Analysis of Immune Response to Hepatitis B Vaccine in Adults

Author: Rym Ben-Othman, Bing Cai, Aaron C. Liu, Natallia Varankovich, Daniel He, Travis M. Blimkie, Amy H. Lee, Erin E. Gill, Mark Novotny, Brian Aevermann, Sibyl Drissler, Casey P. Shannon, Sarah McCann, Kim Marty, Gordean Bjornson, Rachel D. Edgar, David Tse Shen Lin, Nicole Gladish, Julia Maclsaac, Nelly Amenyogbe, Queenie Chan, Alba Llibre, Joyce Collin, Elise Landais, Khoa Le, Samantha M. Reiss, Wayne C. Koff, Colin Havenar-Daughton, Manraj Heran, Bippan Sangha, David Walt, Mel Krajden, Shane Crotty, Devin Sok, Bryan Briney, Dennis R. Burton, Darragh Duffy, Leonard J. Foster, William W. Mohn, Michael S. Kobor, Scott J. Tebbutt, Ryan R. Brinkman, Richard H. Scheuermann, Robert E. W. Hancock, Tobias R. Kollmann, and Manish Sadarangani
Subjects: multi-omic, single cell, lymph node, gene expression, bio-informatic, immunimonitoring, Immunologic diseases. Allergy, RC581-607
Abstract: Conventional vaccine design has been based on trial-and-error approaches, which have been generally successful. However, there have been some major failures in vaccine development and we still do not have highly effective licensed vaccines for tuberculosis, HIV, respiratory syncytial virus, and other major infections of global significance. Approaches at rational vaccine design have been limited by our understanding of the immune response to vaccination at the molecular level. Tools now exist to undertake in-depth analysis using systems biology approaches, but to be fully realized, studies are required in humans with intensive blood and tissue sampling. Methods that support this intensive sampling need to be developed and validated as feasible. To this end, we describe here a detailed approach that was applied in a study of 15 healthy adults, who were immunized with hepatitis B vaccine. Sampling included ~350 mL of blood, 12 microbiome samples, and lymph node fine needle aspirates obtained over a ~7-month period, enabling comprehensive analysis of the immune response at the molecular level, including single cell and tissue sample analysis. Samples were collected for analysis of immune phenotyping, whole blood and single cell gene expression, proteomics, lipidomics, epigenetics, whole blood response to key immune stimuli, cytokine responses, in vitro T cell responses, antibody repertoire analysis and the microbiome. Data integration was undertaken using different approaches—NetworkAnalyst and DIABLO. Our results demonstrate that such intensive sampling studies are feasible in healthy adults, and data integration tools exist to analyze the vast amount of data generated from a multi-omics systems biology approach. This will provide the basis for a better understanding of vaccine-induced immunity and accelerate future rational vaccine design.
Published: 2020
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14. Clinical Protocol for a Longitudinal Cohort Study Employing Systems Biology to Identify Markers of Vaccine Immunogenicity in Newborn Infants in The Gambia and Papua New Guinea

Author: Olubukola T. Idoko, Kinga K. Smolen, Oghenebrume Wariri, Abdulazeez Imam, Casey P. Shannon, Tida Dibassey, Joann Diray-Arce, Alansana Darboe, Julia Strandmark, Rym Ben-Othman, Oludare A. Odumade, Kerry McEnaney, Nelly Amenyogbe, William S. Pomat, Simon van Haren, Guzmán Sanchez-Schmitz, Ryan R. Brinkman, Hanno Steen, Robert E. W. Hancock, Scott J. Tebbutt, Peter C. Richmond, Anita H. J. van den Biggelaar, Tobias R. Kollmann, Ofer Levy, Al Ozonoff, and Beate Kampmann
Subjects: markers, newborn, vaccine, immunogenicity, systems biology, OMICS, Pediatrics, RJ1-570
Abstract: Background: Infection contributes to significant morbidity and mortality particularly in the very young and in low- and middle-income countries. While vaccines are a highly cost-effective tool against infectious disease little is known regarding the cellular and molecular pathways by which vaccines induce protection at an early age. Immunity is distinct in early life and greater precision is required in our understanding of mechanisms of early life protection to inform development of new pediatric vaccines.Methods and Analysis: We will apply transcriptomic, proteomic, metabolomic, multiplex cytokine/chemokine, adenosine deaminase, and flow cytometry immune cell phenotyping to delineate early cellular and molecular signatures that correspond to vaccine immunogenicity. This approach will be applied to a neonatal cohort in The Gambia (N ~ 720) receiving at birth: (1) Hepatitis B (HepB) vaccine alone, (2) Bacille Calmette Guerin (BCG) vaccine alone, or (3) HepB and BCG vaccines, (4) HepB and BCG vaccines delayed till day 10 at the latest. Each study participant will have a baseline peripheral blood sample drawn at DOL0 and a second blood sample at DOL1,−3, or−7 as well as late timepoints to assess HepB vaccine immunogenicity. Blood will be fractionated via a “small sample big data” standard operating procedure that enables multiple downstream systems biology assays. We will apply both univariate and multivariate frameworks and multi-OMIC data integration to identify features associated with anti-Hepatitis B (anti-HB) titer, an established correlate of protection. Cord blood sample collection from a subset of participants will enable human in vitro modeling to test mechanistic hypotheses identified in silico regarding vaccine action. Maternal anti-HB titer and the infant microbiome will also be correlated with our findings which will be validated in a smaller cohort in Papua New Guinea (N ~ 80).Ethics and Dissemination: The study has been approved by The Gambia Government/MRCG Joint Ethics Committee and The Boston Children's Hospital Institutional Review Board. Ethics review is ongoing with the Papua New Guinea Medical Research Advisory Committee. All de-identified data will be uploaded to public repositories following submission of study output for publication. Feedback meetings will be organized to disseminate output to the study communities.Clinical Trial Registration: Clinicaltrials.gov Registration Number: NCT03246230
Published: 2020
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15. Robust health-score based survival prediction for a neonatal mouse model of polymicrobial sepsis.

Author: Byron Brook, Danny Harbeson, Nelly Amenyogbe, Rym Ben-Othman, Tobias R Kollmann, and Radhouane Aniba
Subjects: Medicine, Science
Abstract: Infectious disease and sepsis represent a serious problem for all, but especially in early life. Much of the increase in morbidity and mortality due to infection in early life is presumed to relate to fundamental differences between neonatal and adult immunity. Mechanistic insight into the way newborns' immune systems handle infectious threats is lacking; as a result, there has only been limited success in providing effective immunomodulatory interventions to reduce infectious mortality. Given the complexity of the host-pathogen interactions, neonatal mouse models can offer potential avenues providing valuable data. However, the small size of neonatal mice hampers the ability to collect biological samples without sacrificing the animals. Further, the lack of a standardized metric to quantify newborn mouse health increases reliance on correlative biomarkers without a known relationship to 'clinical' outcome. To address this bottleneck, we developed a system that allows assessment of neonatal mouse health in a readily standardized and quantifiable manner. The resulting health scores require no special equipment or sample collection and can be assigned in less than 20 seconds. Importantly, the health scores are highly predictive of survival. A classifier built on our health score revealed a positive relationship between reduced bacterial load and survival, demonstrating how this scoring system can be used to bridge the gap between assumed relevance of biomarkers and the clinical outcome of interest. Adoption of this scoring system will not only provide a robust metric to assess health of newborn mice but will also allow for objective, prospective studies of infectious disease and possible interventions in early life.
Published: 2019
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16. Outgrowing the Immaturity Myth: The Cost of Defending From Neonatal Infectious Disease

Author: Danny Harbeson, Rym Ben-Othman, Nelly Amenyogbe, and Tobias R. Kollmann
Subjects: neonate, infection, defense, tolerance, sepsis, Immunologic diseases. Allergy, RC581-607
Abstract: Newborns suffer high rates of mortality due to infectious disease—this has been generally regarded to be the result of an “immature” immune system with a diminished disease-fighting capacity. However, the immaturity dogma fails to explain (i) greater pro-inflammatory responses than adults in vivo and (ii) the ability of neonates to survive a significantly higher blood pathogen burden than of adults. To reconcile the apparent contradiction of clinical susceptibility to disease and the host immune response findings when contrasting newborn to adult, it will be essential to capture the entirety of available host-defense strategies at the newborn’s disposal. Adults focus heavily on the disease resistance approach: pathogen reduction and elimination. Newborn hyperactive innate immunity, sensitivity to immunopathology, and the energetic requirements of growth and development (immune and energy costs), however, preclude them from having an adult-like resistance response. Instead, newborns also may avail themselves of disease tolerance (minimizing immunopathology without reducing pathogen load), as a disease tolerance approach provides a counterbalance to the dangers of a heightened innate immunity and has lower-associated immune costs. Further, disease tolerance allows for the establishment of a commensal bacterial community without mounting an unnecessarily dangerous immune resistance response. Since disease tolerance has its own associated costs (immune suppression leading to unchecked pathogen proliferation), it is the maintenance of homeostasis between disease tolerance and disease resistance that is critical to safe and effective defense against infections in early life. This paradigm is consistent with nearly all of the existing evidence.
Published: 2018
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17. Early-Life Host–Microbiome Interphase: The Key Frontier for Immune Development

Author: Nelly Amenyogbe, Tobias R. Kollmann, and Rym Ben-Othman
Subjects: microbiome, immunity and infections, ontogeny, immune diseases, probiotics, Pediatrics, RJ1-570
Abstract: Human existence can be viewed as an “animal in a microbial world.” A healthy interaction of the human host with the microbes in and around us heavily relies on a well-functioning immune system. As development of both the microbiota and the host immune system undergo rapid changes in early life, it is not surprising that even minor alterations during this co-development can have profound consequences. Scrutiny of existing data regarding pre-, peri-, as well as early postnatal modulators of newborn microbiota indeed suggest strong associations with several immune-mediated diseases with onset far beyond the newborn period. We here summarize these data and extract overarching themes. This same effort in turn sets the stage to guide effective countermeasures, such as probiotic administration. The objective of our review is to highlight the interaction of host immune ontogeny with the developing microbiome in early life as a critical window of susceptibility for lifelong disease, as well as to identify the enormous potential to protect and promote lifelong health by specifically targeting this window of opportunity.
Published: 2017
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18. Implications of Non-Specific Effects for Testing, Approving, and Regulating Vaccines

Author: Christine Stabell Benn, Nelly Amenyogbe, Anders Björkman, Jorge Domínguez-Andrés, Eleanor N. Fish, Katie L. Flanagan, Sabra L. Klein, Tobias R. Kollmann, Kirsten Ohm Kyvik, Mihai G. Netea, Naja Hulvej Rod, Frederik Schaltz-Buchholzer, Frank Shann, Liisa Selin, Sanne M. Thysen, and Peter Aaby
Subjects: Pharmacology, BCG VACCINATION, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], INFANTS, DIPHTHERIA-TETANUS-PERTUSSIS, Toxicology, MALE MORTALITY, FEMALE, POLIO, All institutes and research themes of the Radboud University Medical Center, TRIALS, SEX, Pharmacology (medical), GUINEA-BISSAU, TITER MEASLES IMMUNIZATION
Abstract: The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have “non-specific effects” affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I–III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure. The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have "non-specific effects" affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I-III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure.
Published: 2023

19. Mortality Risk Among Frail Neonates and Maternal BCG Vaccine Scar Status: Observational Study From Guinea-Bissau

Author: Frederik Schaltz-Buchholzer, Peter Aaby, Isaquel Silva, Ivan Monteiro, Tobias R Kollmann, Nelly Amenyogbe, Morten Bjerregaard-Andersen, and Christine Stabell Benn
Subjects: Infectious Diseases, Immunology and Allergy
Abstract: Background Maternal priming with the Bacille Calmette-Guérin (BCG) vaccine has been associated with reduced offspring mortality rates. We investigated this association in a cohort of frail neonates. Methods We performed an observational study within a randomized BCG trial conducted at the neonatal intensive care unit (NICU) in Guinea-Bissau from 2015 to 2017. At NICU admission and after informed consent, the maternal scar status was evaluated by visual inspection before neonates were randomized 1:1 to receive BCG + oral polio vaccine immediately or at hospital discharge. Stratified by maternal scar status, we assessed overall in-hospital and postdischarge mortality rates through 42 days of age in Cox proportional hazards models providing adjusted mortality rate ratios (aMRRs). Results Overall, 62% of mothers (903 of 1451) had a BCG vaccine scar. During NICU admission, the mortality risk was 1.7% (15 of 903) for neonates born to mothers with a scar versus 3.3% (18 of 548) for those born to mothers with no scar; the aMRR for maternal scar versus no scar was 0.53 (95% CI, .26–1.05), 0.39 (95% CI, .13–1.05) for unvaccinated and 0.70 (95% CI, .26–1.87) for vaccinated neonates. Conclusions This small study indicates that maternal BCG vaccine might be associated with reduced all-cause NICU mortality rate. If confirmed elsewhere, this finding would have substantial ramifications for global health.
Published: 2022

20. BCG-induced trained immunity and emergency granulopoiesis in pathogen agnostic effects of the vaccine

Author: Henok Andualem, Elysia Hollams, Tobias R. Kollmann, and Nelly Amenyogbe
Subjects: Structural Biology, Molecular Biology
Published: 2023

21. Immediate Bacille Calmette-Guérin Vaccination to Neonates Requiring Perinatal Treatment at the Maternity Ward in Guinea-Bissau: A Randomized Controlled Trial

Author: Peter Aaby, Morten Bjerregaard-Andersen, Simone Faurholt Simonsen, Christian N Golding, Kristina Lindberg Larsen, Christine Stabell Benn, Tobias R. Kollmann, Nelly Amenyogbe, Ivan Monteiro, Frederik Schaltz-Buchholzer, Luis Camala, and Hannah Nørtoft Frankel
Subjects: Male, Pediatrics, medicine.medical_specialty, neonatal mortality, Randomization, Neonatal intensive care unit, 030231 tropical medicine, vaccination at birth, Bacille Calmette Guerin, Communicable Diseases, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Intensive Care Units, Neonatal, Infant Mortality, medicine, Humans, Immunology and Allergy, Guinea-Bissau, Hospital Mortality, 030212 general & internal medicine, Proportional hazards model, business.industry, Mortality rate, Vaccination, Infant, Newborn, Infant, bacille Calmette-Guérin vaccine, Survival Analysis, 3. Good health, Infectious Diseases, Guinea bissau, nonspecific effects of vaccines, BCG Vaccine, Female, business, Poliomyelitis
Abstract: Background Randomized controlled trials (RCTs) indicate that bacille Calmette-Guérin (BCG) vaccination provides broad beneficial “nonspecific” protection against infections. We investigated the effect on in-hospital mortality of providing BCG immediately upon admission to a neonatal intensive care unit (NICU), rather than BCG-at-discharge. The pretrial NICU mortality was 13% and we hypothesized that BCG would reduce mortality by 40%. Methods Parallel-group, open-label RCT was initiated in 2013 in Guinea-Bissau. Neonatal intensive care unit-admitted neonates were randomized 1:1 to BCG + oral polio vaccine (OPV) immediately (intervention) versus BCG + OPV at hospital discharge (control; usual practice). The trial was discontinued due to decreasing in-hospital mortality and major NICU restructuring. We assessed overall and disease-specific mortality by randomization allocation in cox proportional hazards models providing mortality rate ratios (MRRs). Results We recruited 3353 neonates, and the overall mortality was 3.1% (52 of 1676) for BCG-vaccinated neonates versus 3.3% (55 of 1677) for controls (MRR = 0.94; 0.64–1.36). For noninfectious causes of death, the MRR was 1.20 (0.70–2.07), and there tended to be fewer deaths from infections in the BCG group (N = 14) than among controls (N = 21) (MRR = 0.65; 0.33–1.28). Conclusions Providing BCG + OPV to frail neonates was safe and might protect against fatal infection in the immediate newborn period. Deaths due to prematurity and perinatal complications were unaffected by BCG.
Published: 2021

22. Mortality risk among frail neonates might be associated with maternal BCG scar status: Observational study from Guinea-Bissau

Author: Frederik, Schaltz-Buchholzer, Peter, Aaby, Isaquel, Silva, Ivan, Monteiro, Tobias R, Kollmann, Nelly, Amenyogbe, Morten, Bjerregaard-Andersen, and Christine Stabell, Benn
Abstract: Maternal priming with Bacille Calmette-Guérin (BCG) has been associated with reduced offspring mortality. We investigated this association in a cohort of frail neonates.We performed an observational study within a randomized BCG trial conducted at the Neonatal Intensive Care Unit (NICU) in Guinea-Bissau from 2015-2017. At NICU admission and following informed consent, the maternal scar status was evaluated by visual inspection before neonates were randomized 1:1 to receive BCG + Oral Polio Vaccine (OPV) immediately versus BCG + OPV at hospital discharge. Stratified by maternal scar status, we assessed overall in-hospital and post-discharge mortality up to 42 days of age in Cox Proportional Hazards models providing adjusted Mortality Rate Ratios (aMRRs).62% (903/1451) of mothers had a BCG scar. During NICU admission, the mortality risk was 1.7% (15/903) for neonates born to mothers with a scar vs 3.3% (18/548) for those born to mothers with no scar, the maternal scar/no scar aMRR = 0.53 (0.26-1.05); the aMRR was 0.39 (0.13-1.05) for unvaccinated neonates and 0.70 (0.26-1.87) for vaccinated neonates.This small study indicates that maternal BCG might be associated with reduced all-cause NICU mortality. If confirmed elsewhere, this finding would have substantial ramifications for global health.
Published: 2021

23. Biogeography of the Relationship between the Child Gut Microbiome and Innate Immune System

Author: B. Brett Finlay, Tobias R. Kollmann, Scott J. Tebbutt, William W. Mohn, Casey P. Shannon, Monika Esser, Tessa Goetghebuer, Pedro A. Dimitriu, Eric M. Brown, Nelly Amenyogbe, Phillip J. Cooper, Kinga K. Smolen, and Arnaud Marchant
Subjects: Male, gut microbiome, Feces, 0302 clinical medicine, Prevotella, innate immunity, Genetics, Innate immunity, 0303 health sciences, biology, digestive, oral, and skin physiology, Pattern recognition receptor, Biodiversity, Fecal Microbiota Transplantation, QR1-502, 3. Good health, Phylogeography, Biogeography, Child, Preschool, Cytokines, Female, Research Article, Canada, chemical and pharmacologic phenomena, digestive system, Microbiology, Host-Microbe Biology, 03 medical and health sciences, Immune system, Virology, Animals, Germ-Free Life, Humans, Microbiome, biogeography, 030304 developmental biology, Gut microbiome, Innate immune system, Bacteria, Host Microbial Interactions, Infant, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Immunity, Innate, Toll-Like Receptor 2, Gastrointestinal Microbiome, Ingénierie biomédicale, TLR2, Immune System, bacteria, Bacteroides, Microbiologie et protistologie [bacteriol.virolog.mycolog.], 030215 immunology
Abstract: The gut microbiome is a well-recognized modulator of host immunity, and its compositions differ between geographically separated human populations. Systemic innate immune responses to microbial derivatives also differ between geographically distinct human populations. However, the potential role of the microbiome in mediating geographically varied immune responses is unexplored. We here applied 16S amplicon sequencing to profile the stool microbiome and, in parallel, meas-ured whole-blood innate immune cytokine responses to several pattern recognition receptor (PRR) agonists among 2-year-old children across biogeographically diverse settings. Microbiomes differed mainly between high-and low-resource environments and were not strongly associated with other demographic factors. We found strong correlations between responses to Toll-like receptor 2 (TLR2) and relative abundances of Bacteroides and Prevotella populations, shared among Canadian and Ecuadorean children. Additional correlations between responses to TLR2 and bacterial populations were specific to individual geographic cohorts. As a proof of con-cept, we gavaged germfree mice with human donor stools and found murine sple-nocyte responses to TLR stimulation were consistent with responses of the corresponding human donor populations. This study identified differences in immune responses corre-lating to gut microbiomes across biogeographically diverse settings and evaluated biological plausibility using a mouse model. This insight paves the way to guide optimiza-tion of population-specific interventions aimed to improve child health outcomes. IMPORTANCE Both the gut microbiome and innate immunity are known to differ across biogeographically diverse human populations. The gut microbiome has been shown to directly influence systemic immunity in animal models. With this, modulation of the gut microbiome represents an attractive avenue to improve child health outcomes associated with altered immunity using population-specific approaches. However, there are very scarce data available to determine which members of the gut microbiome are associated with specific immune responses and how these differ around the world, creating a substantial barrier to rationally designing such interven-tions. This study addressed this knowledge gap by identifying relationships between distinct bacterial taxa and cytokine responses to specific microbial agonists across highly diverse settings. Furthermore, we provide evidence that immunomodulatory effects of region-specific stool microbiomes can be partially recapitulated in germfree mice. This is an important contribution toward improving global child health by targeting the gut microbiome., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2021

24. Immunisation with the BCG and DTPw vaccines induces different programs of trained immunity in mice

Author: David J. Lynn, Marjolein van Wolfswinkel, Nelly Amenyogbe, Natalie E. Stevens, Miriam A. Lynn, Damon J. Tumes, Winnie Bao, Tobias R. Kollmann, Feargal J. Ryan, Helen Marshall, Byron Brook, Stevens, Natalie E, van Wolfswinkel, Marjolein, Bao,Winnie, Ryan, Feargal J, Brook, Byron, Amenyogbe, Nelly, Marshall, Helen S, Lynn, Miriam A, Kollmann, Tobias R, Tumes, Damon J, and Lynn, David J
Subjects: vaccine nonspecific effects, Whooping Cough, 030231 tropical medicine, innate immune memory, trained immunity, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Immunity, medicine, Animals, dendritic cells, 030212 general & internal medicine, Diphtheria-Tetanus-Pertussis Vaccine, Haemophilus Vaccines, Innate immune system, Tetanus, General Veterinary, General Immunology and Microbiology, business.industry, Diphtheria, Monocyte, Vaccination, Public Health, Environmental and Occupational Health, vaccination, medicine.disease, Antibodies, Bacterial, Infectious Diseases, medicine.anatomical_structure, Immunology, BCG Vaccine, Molecular Medicine, Female, Immunization, business, BCG vaccine
Abstract: In addition to providing pathogen-specific immunity, vaccines can also confer nonspecific effects (NSEs) on mortality and morbidity unrelated to the targeted disease. Immunisation with live vaccines, such as the BCG vaccine, has generally been associated with significantly reduced all-cause infant mortality. In contrast, some inactivated vaccines, such as the diphtheria, tetanus, whole-cell pertussis (DTPw) vaccine, have been controversially associated with increased all-cause mortality especially in female infants in high-mortality settings. The NSEs associated with BCG have been attributed, in part, to the induction of trained immunity, an epigenetic and metabolic reprograming of innate immune cells, increasing their responsiveness to subsequent microbial encounters. Whether non-live vaccines such as DTPw induce trained immunity is currently poorly understood. Here, we report that immunisation of mice with DTPw induced a unique program of trained immunity in comparison to BCG immunised mice. Altered monocyte and DC cytokine responses were evident in DTPw immunised mice even months after vaccination. Furthermore, splenic cDCs from DTPw immunised mice had altered chromatin accessibility at loci involved in immunity and metabolism, suggesting that these changes were epigenetically mediated. Interestingly, changing the order in which the BCG and DTPw vaccines were co-administered to mice altered subsequent trained immune responses. Given these differences in trained immunity, we also assessed whether administration of these vaccines altered susceptibility to sepsis in two different mouse models. Immunisation with either BCG or a DTPw-containing vaccine prior to the induction of sepsis did not significantly alter survival. Further studies are now needed to more fully investigate the potential consequences of DTPw induced trained immunity in different contexts and to assess whether other non-live vaccines also induce similar changes. Refereed/Peer-reviewed
Published: 2020

25. A place for neutrophils in the beneficial pathogen-agnostic effects of the BCG vaccine

Author: Tobias R. Kollmann, Byron Brook, Frederick Schaltz-Buchholzer, Rym Ben-Othman, and Nelly Amenyogbe
Subjects: Neutrophils, 030231 tropical medicine, Disease, Non-specific effects, Monocytes, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunity, Medicine, Humans, Tuberculosis, BCG, 030212 general & internal medicine, Innate immune system, General Veterinary, General Immunology and Microbiology, business.industry, Monocyte, Neutrophil, Vaccination, Public Health, Environmental and Occupational Health, Infectious Diseases, medicine.anatomical_structure, Infectious disease (medical specialty), Immunology, BCG Vaccine, Molecular Medicine, business, BCG vaccine
Abstract: The BCG vaccine has long been recognized for reducing the risk to suffer from infectious diseases unrelated to its target disease, tuberculosis. Evidence from human trials demonstrate substantial reductions in all-cause mortality, especially in the first week of life. Observational studies have identified an association between BCG vaccination and reduced risk of respiratory infectious disease and clinical malaria later in childhood. The mechanistic basis for these pathogen-agnostic benefits, also known as beneficial non-specific effects (NSE) of BCG have been attributed to trained immunity, or epigenetic reprogramming of hematopoietic cells that give rise to innate immune cells responding more efficiently to a broad range of pathogens. Furthermore, within trained immunity, the focus so far has been on enhanced monocyte function. However, polymorphonuclear cells, namely neutrophils, are not only major constituents of the hematopoietic compartment but functionally as well as numerically represent a prominent component of the immune system. The beneficial NSEs of the BCG vaccine on newborn sepsis was recently demonstrated to be driven by a BCG-mediated numeric increase of neutrophils (emergency granulopoiesis (EG)). And experimental evidence in animal models suggest that BCG can modulate neutrophil function as well. Together, these findings suggest that neutrophils are crucial to at least the immediate beneficial NSE of the BCG vaccine. Efforts to uncover the full gamut of mechanisms underpinning the broad beneficial effects of BCG should therefore include neutrophils at the forefront.
Published: 2020

26. Innate Immune Responses and Gut Microbiomes Distinguish HIV-Exposed from HIV-Unexposed Children in a Population-Specific Manner

Author: Patricia Cho, Bing Cai, Evelyn J. Maan, Monika Esser, Casey P. Shannon, Kinga K. Smolen, Hélène C. F. Côté, Nelly Amenyogbe, William W. Mohn, Tessa Goetghebuer, Candice E. Ruck, Tobias R. Kollmann, Scott Sj Tebbutt, Amy L. Slogrove, Edgardo S. Fortuno, Arnaud Marchant, Pedro A. Dimitriu, and Ariane Alimenti
Subjects: Male, Canada, Immunology, Population, Human immunodeficiency virus (HIV), HIV Infections, Biology, medicine.disease_cause, Cohort Studies, Feces, South Africa, Immune system, Belgium, Innate response, Population specific, medicine, Immunology and Allergy, Humans, Microbiome, education, education.field_of_study, Innate immune system, Geography, Altered immunity, Infant, Sciences bio-médicales et agricoles, Immunity, Innate, Gastrointestinal Microbiome, Child, Preschool, Clinical and Human Immunology, Female
Abstract: In both high-and low-income countries, HIV-negative children born to HIV-positive mothers (HIVexposed, uninfected [HEU]) are more susceptible to severe infection than HIV-unexposed, uninfected (HUU) children, with altered innate immunity hypothesized to be a cause. Both the gut microbiome and systemic innate immunity differ across biogeographically distinct settings, and the two are known to influence each other. And although the gut microbiome is influenced by HIV infection and may contribute to altered immunity, the biogeography of immune-microbiome correlations among HEU children have not been investigated. To address this, we compared the innate response and the stool microbiome of 2-y-old HEU and HUU children from Belgium, Canada, and South Africa to test the hypothesis that region-specific immune alterations directly correlate to differences in their stool microbiomes.We did not detect a universal immune or microbiome signature underlying differences between HEU versus HUU that was applicable to all children. But as hypothesized, population-specific differences in stool microbiomes were readily detected and included reduced abundances of short-chain fatty acid producing bacteria in Canadian HEU children. Furthermore, we did not identify innate immune-microbiome associations that distinguished HEU from HUU children in any population. These findings suggest that maternal HIV infection is independently associated with differences in both innate immunity and the stool microbiome in a biogeographical population-specific way., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2020

27. Feasibility of manual white blood cell counts as a predictor of neonatal sepsis in a low-resource setting

Author: Frederik Schaltz-Buchholzer, Tobias R. Kollmann, Clara Clipet-Jensen, Nelly Amenyogbe, Christian N. Golding, Christine Stabell Benn, Lilica Sanca, Kate Chipperfield, and Nicholas Au
Subjects: medicine.medical_specialty, leukocyte count, neonatal sepsis, western africa, law.invention, Sepsis, Leukocyte Count, Randomized controlled trial, law, White blood cell, Internal medicine, oral poliovirus vaccine, medicine, Humans, Guinea-Bissau, Prospective Studies, Child, Prospective cohort study, Neonatal sepsis, business.industry, Infant, Newborn, Public Health, Environmental and Occupational Health, General Medicine, medicine.disease, Vaccination, Infectious Diseases, medicine.anatomical_structure, Immunization, newborn infant, BCG Vaccine, Feasibility Studies, Parasitology, Neonatal Sepsis, business, BCG vaccine
Abstract: BackgroundManual white blood cell (WBC) differential counts as a predictor for neonatal sepsis development in a low-resource setting have not been thoroughly evaluated. We hypothesized that manual differentiation (specifically immature:total [I:T] neutrophil ratios) would be feasible and useful as an adjunct to predict early-onset neonatal sepsis (EONS). Secondarily, we hypothesized that vaccination with bacillus Calmette-Guérin (BCG) and oral polio vaccine (OPV) could alter WBC differential counts and thus might reduce its predictive performance.MethodsWe performed a prospective cohort study within a randomized trial, randomizing healthy, high-risk newborns admitted to the nursery at the national hospital in Guinea-Bissau 1:1 to BCG+OPV at admission or at discharge (usual practice). Thin capillary blood films were prepared at 2 d of age in a subset of 268 neonates. WBC counts were assessed by microscopy and neonates were followed up for sepsis development within 2 weeks.ResultsNinety-eight percent (264/268) of smears provided interpretable reads. Of the 264 children, 136 had been randomized to receive BCG+OPV prior to sampling; the remaining 128 were vaccinated at discharge. The I:T ratio (average 0.017) was lower among children who did not develop clinical sepsis but did not predict sepsis (p=0.70). Only three children had an I:T ratio >0.2 (associated with a higher probability of clinical sepsis in previous studies) but did not develop sepsis. Immunization did not alter WBC composition.ConclusionsManual WBC differentials are feasible in low-resource settings. WBC differentials are not affected by standard newborn immunization. However, the I:T ratio had no value in predicting subsequent development of sepsis.
Published: 2020

28. Maternal HIV infection alters antimicrobial immunity in exposed and uninfected infants

Author: Arnaud Marchant, Tobias R. Kollmann, Nelly Amenyogbe, and Tessa Goetghebuer
Subjects: Microbiology (medical), Microbiologie et protistologie [parasitologie hum. et anim.], Pédiatrie, HIV Infections, Maternal hiv, Antibodies, Pregnancy, Immunity, Humans, Medicine, Pregnancy Complications, Infectious, Pathologie maladies infectieuses, Immune activation, biology, business.industry, Infant, Newborn, Infant, Antimicrobial, Immunity, Innate, Infectious Disease Transmission, Vertical, Microbiologie et protistologie [entomologie,phytoparasitolog.], Infectious Diseases, Pediatrics, Perinatology and Child Health, Immunology, biology.protein, Maternal HIV infection, Female, HIV-exposed uninfected children, Antibody, business, Microbiologie et protistologie [bacteriol.virolog.mycolog.], Immunity, Maternally-Acquired
Abstract: SCOPUS: re.j, info:eu-repo/semantics/published
Published: 2020

29. BCG vaccination–induced emergency granulopoiesis provides rapid protection from neonatal sepsis

Author: Bing Cai, James L. Wynn, Aaron C Liu, Kristina Lindberg Larsen, Joe Huang, Tobias R. Kollmann, Ofer Levy, Peter Aaby, Scott J. Tebbutt, Morten Bjerregaard-Andersen, Christine Stabell Benn, Lilica Sanca, Casey P. Shannon, Natallia Varankovich, Freddy Francis, Daniel He, Christian N. Golding, Beate Kampmann, Byron Brook, Frank Shann, Rym Ben-Othman, Rusung Tan, Danny Harbeson, Nelly Amenyogbe, Adrian K. Charles, Winnie Bao, and Frederik Schaltz-Buchholzer
Subjects: Neonatal sepsis, business.industry, Vaccination, Infant, Newborn, General Medicine, Granulocyte, medicine.disease, Systemic inflammation, Granulopoiesis, Article, Hematopoiesis, Granulocyte colony-stimulating factor, Sepsis, medicine.anatomical_structure, Granulocyte Colony-Stimulating Factor, Immunology, medicine, Humans, Tumor necrosis factor alpha, Neonatal Sepsis, medicine.symptom, business
Abstract: Death from sepsis in the neonatal period remains a serious threat for millions. Within 3 days of administration, bacille Calmette-Guérin (BCG) vaccination can reduce mortality from neonatal sepsis in human newborns, but the underlying mechanism for this rapid protection is unknown. We found that BCG was also protective in a mouse model of neonatal polymicrobial sepsis, where it induced granulocyte colony-stimulating factor (G-CSF) within hours of administration. This was necessary and sufficient to drive emergency granulopoiesis (EG), resulting in a marked increase in neutrophils. This increase in neutrophils was directly and quantitatively responsible for protection from sepsis. Rapid induction of EG after BCG administration also occurred in three independent cohorts of human neonates.
Published: 2020

30. Ontogeny of plasma cytokine and chemokine concentrations across the first week of human life

Author: Tobias R. Kollmann, Ofer Levy, Al Ozonoff, Simon D. van Haren, Kinga K Smolen, Scott J. Tebbutt, Casey P. Shannon, Beate Kampmann, Alec L. Plotkin, Jensen Pak, Nelly Amenyogbe, Alansana Darboe, Oludare A. Odumade, and Olubukola T. Idoko
Subjects: Male, Chemokine, Time Factors, medicine.medical_treatment, Immunology, Disease, Biochemistry, Article, CCL5, Infant immune, Cohort Studies, Immune system, medicine, Humans, Immunology and Allergy, CXCL10, Interleukin 8, Molecular Biology, Innate immune system, biology, business.industry, Age Factors, Infant, Newborn, Hematology, Cytokine, Ontogeny, biology.protein, Cytokines, Innate immune, Female, Chemokines, business
Abstract: Introduction/background & aims Early life is marked by distinct and rapidly evolving immunity and increased susceptibility to infection. The vulnerability of the newborn reflects development of a complex immune system in the face of rapidly changing demands during the transition to extra-uterine life. Cytokines and chemokines contribute to this dynamic immune signaling network and can be altered by many factors, such as infection. Newborns undergo dynamic changes important to health and disease, yet there is limited information regarding human neonatal plasma cytokine and chemokine concentrations over the first week of life. The few available studies are limited by small sample size, cross-sectional study design, or focus on perturbed host states like severe infection or prematurity. To characterize immune ontogeny among healthy full-term newborns, we assessed plasma cytokine and chemokine concentrations across the first week of life in a robust longitudinal cohort of healthy, full-term African newborns. Methods We analyzed a subgroup of a cohort of healthy newborns at the Medical Research Council Unit in The Gambia (West Africa; N = 608). Peripheral blood plasma was collected from all study participants at birth (day of life (DOL) 0) and at one follow-up time point at DOL 1, 3, or 7. Plasma cytokine and chemokine concentrations were measured by bead-based cytokine multiplex assay. Unsupervised clustering was used to identify patterns in plasma cytokine and chemokine ontogeny during early life. Results We observed an increase across the first week of life in plasma Th1 cytokines such as IFNγ and CXCL10 and a decrease in Th2 and anti-inflammatory cytokines such as IL-6 and IL-10, and chemokines such as CXCL8. In contrast, other cytokines and chemokines (e.g. IL-4 and CCL5, respectively) remained unchanged during the first week of life. This robust ontogenetic pattern did not appear to be affected by gestational age or sex. Conclusions Ontogeny is a strong driver of newborn plasma-based levels of cytokines and chemokines throughout the first week of life with a rising IFNγ axis suggesting post-natal upregulation of host defense pathways. Our study will prove useful to the design and interpretation of future studies aimed at understanding the neonatal immune system during health and disease.
Published: 2021

31. Robust health-score based survival prediction for a neonatal mouse model of polymicrobial sepsis

Author: Rym Ben-Othman, Radhouane Aniba, Tobias R. Kollmann, Nelly Amenyogbe, Danny Harbeson, and Byron Brook
Subjects: 0301 basic medicine, Male, Physiology, Psychological intervention, Pathology and Laboratory Medicine, Biochemistry, Mice, 0302 clinical medicine, Reflexes, Medicine and Health Sciences, Health Status Indicators, Health score, Prospective cohort study, Materials, Multidisciplinary, Neonatal mouse, Animal Models, 3. Good health, Body Fluids, Blood, Experimental Organism Systems, Physical Sciences, Medicine, Female, Sample collection, Neonatal Sepsis, Anatomy, Research Article, medicine.medical_specialty, Science, Materials Science, MEDLINE, Mouse Models, Research and Analysis Methods, Sepsis, 03 medical and health sciences, Reflex, Righting, Model Organisms, Signs and Symptoms, Diagnostic Medicine, medicine, Animals, Humans, Intensive care medicine, business.industry, Infant, Newborn, Biology and Life Sciences, Neonates, medicine.disease, Bacterial Load, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Slurries, Animals, Newborn, Infectious disease (medical specialty), Mixtures, Animal Studies, business, 030217 neurology & neurosurgery, Biomarkers, Neuroscience, Developmental Biology
Abstract: Infectious disease and sepsis represent a serious problem for all, but especially in early life. Much of the increase in morbidity and mortality due to infection in early life is presumed to relate to fundamental differences between neonatal and adult immunity. Mechanistic insight into the way newborns' immune systems handle infectious threats is lacking; as a result, there has only been limited success in providing effective immunomodulatory interventions to reduce infectious mortality. Given the complexity of the host-pathogen interactions, neonatal mouse models can offer potential avenues providing valuable data. However, the small size of neonatal mice hampers the ability to collect biological samples without sacrificing the animals. Further, the lack of a standardized metric to quantify newborn mouse health increases reliance on correlative biomarkers without a known relationship to 'clinical' outcome. To address this bottleneck, we developed a system that allows assessment of neonatal mouse health in a readily standardized and quantifiable manner. The resulting health scores require no special equipment or sample collection and can be assigned in less than 20 seconds. Importantly, the health scores are highly predictive of survival. A classifier built on our health score revealed a positive relationship between reduced bacterial load and survival, demonstrating how this scoring system can be used to bridge the gap between assumed relevance of biomarkers and the clinical outcome of interest. Adoption of this scoring system will not only provide a robust metric to assess health of newborn mice but will also allow for objective, prospective studies of infectious disease and possible interventions in early life.
Published: 2019

32. Dynamic molecular changes during the first week of human life follow a robust developmental trajectory

Author: Tue Tb Bennike, Tobias R. Kollmann, Alansana Darboe, Peter Richmond, Hanno Steen, Ofer Levy, Asimenia Angelidou, Mehrnoush Malek, Casey P. Shannon, Daniel He, Anita Ahj van den Biggelaar, Guzman Sanchez-Schmitz, Ahwon Lee, Cai Bing, Elishia Roberts, Kim-Anh Lê Cao, Jorjoh Ndure, Joann Diray-Arce, Davide Ferrari, Reza Falsafi, Jainaba Njie-Jobe, Kinga K. Smolen, Momoudou Cox, Geraldine Masiria, William Ws Pomat, Rym Ben-Othman, Amrit Singh, Ryan Rr Brinkman, Erin E. Gill, John Paul Matlam, Scott Sj Tebbutt, Nelly Amenyogbe, Samuel Sj Hinshaw, Rebecca Ford, Robert E. W. Hancock, Daniel Dj Harbeson, G Saleu, Simon Sd van Haren, Matthew Ma Pettengill, Al Ozonoff, Olubukola Ot Idoko, Beate Kampmann, and Wendy Kirarock
Subjects: 0301 basic medicine, Proteomics, Science, Systems biology, Ontogeny, Infant, Newborn/blood, General Physics and Astronomy, 02 engineering and technology, Disease, Computational biology, Biology, Cytokines/blood, Article, General Biochemistry, Genetics and Molecular Biology, Immunophenotyping, Cohort Studies, 03 medical and health sciences, Papua New Guinea, Child Development, Metabolomics, Humans, lcsh:Science, Child Development/physiology, Multidisciplinary, Gene Expression Profiling, Systems Biology, Infant, Newborn, General Chemistry, Sciences bio-médicales et agricoles, 021001 nanoscience & nanotechnology, Child development, Gene expression profiling, 030104 developmental biology, Developmental trajectory, Chemokines/blood, Cytokines, lcsh:Q, Gambia, Chemokines, 0210 nano-technology
Abstract: Systems biology can unravel complex biology but has not been extensively applied to human newborns, a group highly vulnerable to a wide range of diseases. We optimized methods to extract transcriptomic, proteomic, metabolomic, cytokine/chemokine, and single cell immune phenotyping data from, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2019

33. Probiotic Studies in Neonatal Mice Using Gavage

Author: Kris Andrews, Aaron C Liu, Tobias R. Kollmann, Danny Harbeson, Rym Ben-Othman, Natallia Varankovich, Byron Brook, Pinaki Panigrahi, Ben Dai, Shelly A. McErlane, Freddy Francis, Bing Cai, and Nelly Amenyogbe
Subjects: Dose, General Chemical Engineering, Administration, Oral, Physiology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, law.invention, Mice, Probiotic, law, Animals, Medicine, Microbiome, Gastrointestinal tract, biology, General Immunology and Microbiology, business.industry, Probiotics, General Neuroscience, Disease progression, biology.organism_classification, Disease Models, Animal, Real-time polymerase chain reaction, Animals, Newborn, Irritation, business, Lactobacillus plantarum
Abstract: Adult mouse models have been widely used to understand the mechanism behind disease progression in humans. The applicability of studies done in adult mouse models to neonatal diseases is limited. To better understand disease progression, host responses and long-term impact of interventions in neonates, a neonatal mouse model likely is a better fit. The sparse use of neonatal mouse models can in part be attributed to the technical difficulties of working with these small animals. A neonatal mouse model was developed to determine the effects of probiotic administration in early life and to specifically assess the ability to establish colonization in the newborn mouse intestinal tract. Specifically, to assess probiotic colonization in the neonatal mouse, Lactobacillus plantarum (LP) was delivered directly into the neonatal mouse gastrointestinal tract. To this end, LP was administered to mice by feeding through intra-esophageal (IE) gavage. A highly reproducible method was developed to standardize the process of IE gavage that allows an accurate administration of probiotic dosages while minimizing trauma, an aspect particularly important given the fragility of newborn mice. Limitations of this process include possibilities of esophageal irritation or damage and aspiration if gavaged incorrectly. This approach represents an improvement on current practices because IE gavage into the distal esophagus reduces the chances of aspiration. Following gavage, the colonization profile of the probiotic was traced using quantitative polymerase chain reaction (qPCR) of the extracted intestinal DNA with LP specific primers. Different litter settings and cage management techniques were used to assess the potential for colonization-spread. The protocol details the intricacies of IE neonatal mouse gavage and subsequent colonization quantification with LP.
Published: 2019

34. A Controlled Mouse Model for Neonatal Polymicrobial Sepsis

Author: Byron Brook, Danny Harbeson, James L. Wynn, Nelly Amenyogbe, Aaron C Liu, Natallia Varankovich, Freddy Francis, Rym Ben-Othman, Bing Cai, and Tobias R. Kollmann
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, General Chemical Engineering, Day of life, Pilot Projects, Disease, Survival outcome, General Biochemistry, Genetics and Molecular Biology, Sepsis, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, Animals, Humans, Intensive care medicine, Cecum, Neonatal sepsis, General Immunology and Microbiology, business.industry, General Neuroscience, Infant, Newborn, Neonatal mouse, medicine.disease, Gastrointestinal Contents, Disease Models, Animal, 030104 developmental biology, Homogeneous, Neonatal Sepsis, business, Polymicrobial sepsis, 030217 neurology & neurosurgery
Abstract: Neonatal sepsis remains a global burden. A preclinical model to screen effective prophylactic or therapeutic interventions is needed. Neonatal mouse polymicrobial sepsis can be induced by injecting cecal slurry intraperitoneally into day of life 7 mice and monitoring them for the following week. Presented here are the detailed steps necessary for the implementation of this neonatal sepsis model. This includes making a homogeneous cecal slurry stock, diluting it to a weight- and litter-adjusted dose, an outline of the monitoring schedule, and a definition of observed health categories used to define humane endpoints. The generation of a homogeneous cecal slurry stock from pooled donors allows for the administration into many litters over time, reducing the variation between donors, and preventing the use of potentially toxic glycerol. The monitoring strategy used allows for the anticipation of survival outcome and the identification of mice that would later progress to death, allowing for an earlier identification of the humane endpoint. Two main behavioral features are used to define the health scores, namely, the ability of the neonatal mice to right themselves when placed on their back and their level of mobility. These criteria could potentially be applied to address humane endpoints in other studies of neonatal disease in mice, as long as a pilot study is performed to confirm accuracy. In conclusion, this approach provides a standardized method to model newborn sepsis in mice, while providing resources to assess animal welfare used to define early humane endpoints for challenged animals.
Published: 2019

35. Reduced genetic potential for butyrate fermentation in the gut microbiome of infants who develop allergic sensitization

Author: Padmaja Subbarao, Darlene L.Y. Dai, Tobias R. Kollmann, Hind Sbihi, Theo J. Moraes, Erick Cardenas, Diana L. Lefebvre, Pedro A. Dimitriu, Alissa Cait, Piush J. Mandhane, A.B. Becker, Jessica Cait, Stuart E. Turvey, Leah T. Stiemsma, Malcolm R. Sears, Meghan B. Azad, William W. Mohn, and Nelly Amenyogbe
Subjects: Male, 0301 basic medicine, Allergy, Immunology, Butyrate, Carbohydrate metabolism, Biology, Allergic sensitization, Atopy, 03 medical and health sciences, 0302 clinical medicine, Hypersensitivity, medicine, Humans, Immunology and Allergy, Longitudinal Studies, Prospective Studies, Microbiome, 2. Zero hunger, Bacteria, Short-chain fatty acid, Infant, medicine.disease, Gastrointestinal Microbiome, 3. Good health, 030104 developmental biology, 030228 respiratory system, Child, Preschool, Butyric Acid, Carbohydrate Metabolism, Dysbiosis, Metagenome, Female
Abstract: Background Allergic disease is the most frequent chronic health issue in children and has been linked to early-life gut microbiome dysbiosis. Many lines of evidence suggest that microbially derived short-chain fatty acids, and particularly butyrate, can promote immune tolerance. Objective We sought to determine whether bacterial butyrate production in the gut during early infancy is protective against the development of atopic disease in children. Methods We used shotgun metagenomic analysis to determine whether dysbiosis in butyrate fermentation could be identified in human infants, before their developing allergic disease. Results We found that the microbiome of infants who went on to develop allergic sensitization later in childhood lacked genes encoding key enzymes for carbohydrate breakdown and butyrate production. Conclusions Our findings support the importance of microbial carbohydrate metabolism during early infancy in protecting against the development of allergies.
Published: 2019

36. Neonatal BCG Vaccination Influences Cytokine Responses to Toll-like Receptor Ligands and Heterologous Antigens

Author: Susan Donath, Katie L. Flanagan, Nicole L Messina, Susan Germano, Tobias R. Kollmann, Roy M. Robins-Browne, Kaya Gardiner, Mihai G. Netea, Nigel Curtis, Bridget Freyne, Dan Casalaz, and Nelly Amenyogbe
Subjects: 0301 basic medicine, Adult, Male, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Heterologous, Ligands, 03 medical and health sciences, 0302 clinical medicine, Immune system, All institutes and research themes of the Radboud University Medical Center, 030225 pediatrics, Antigens, Heterophile, Immunology and Allergy, Medicine, Humans, Interleukin 6, Chemokine CCL4, Chemokine CCL2, Chemokine CCL3, biology, business.industry, Interleukin-6, Toll-Like Receptors, Vaccination, Toll-Like Receptor 2, Interleukin-10, TLR2, Interleukin 10, 030104 developmental biology, Infectious Diseases, Interleukin 1 receptor antagonist, Immunology, biology.protein, BCG Vaccine, Cytokines, Female, business, BCG vaccine
Abstract: Background.BCG vaccination is associated with a reduction in all-cause infant mortality in high-mortality settings. The under-lying mechanisms remain uncertain, but long-term modulation of the innate immune response (trained immunity) may be involved.Methods.Whole-blood specimens, collected 7 days after randomization from 212 neonates enrolled in a randomized trial of neo-natal BCG vaccination, were stimulated with killed pathogens and Toll-like receptor (TLR) ligands to interrogate cytokine responses.Results.BCG-vaccinated infants had increased production of interleukin 6 (IL-6) in unstimulated samples and decreased pro-duction of interleukin 1 receptor antagonist, IL-6, and IL-10 and the chemokines macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and monocyte chemoattractant protein 1 (MCP-1) following stimulation with peptidoglycan (TLR2) and R848 (TLR7/8). BCG-vaccinated infants also had decreased MCP-1 responses following stimulation with heterologous pathogens. Sex and maternal BCG vaccination status interacted with neonatal BCG vaccination.Conclusions.Neonatal BCG vaccination influences cytokine responses to TLR ligands and heterologous pathogens. This effect is characterized by decreased antiinflammatory cytokine and chemokine responses in the context of higher levels of IL-6 in unstim-ulated samples. This supports the hypothesis that BCG vaccination modulates the innate immune system. Further research is war-ranted to determine whether there is an association between these findings and the beneficial nonspecific (heterologous) effects of BCG vaccine on all-cause mortality.
Published: 2017

37. Early-Life Host–Microbiome Interphase: The Key Frontier for Immune Development

Author: Tobias R. Kollmann, Rym Ben-Othman, and Nelly Amenyogbe
Subjects: 0301 basic medicine, Window of opportunity, Host (biology), immunity and infections, lcsh:RJ1-570, microbiome, lcsh:Pediatrics, immune diseases, Review, Disease, Biology, Pediatrics, Early life, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immune system, ontogeny, probiotics, 030225 pediatrics, Pediatrics, Perinatology and Child Health, Immunology, Immune Diseases, Microbiome, Neuroscience
Abstract: Human existence can be viewed as an “animal in a microbial world.” A healthy interaction of the human host with the microbes in and around us heavily relies on a well-functioning immune system. As development of both the microbiota and the host immune system undergo rapid changes in early life, it is not surprising that even minor alterations during this co-development can have profound consequences. Scrutiny of existing data regarding pre-, peri-, as well as early postnatal modulators of newborn microbiota indeed suggest strong associations with several immune-mediated diseases with onset far beyond the newborn period. We here summarize these data and extract overarching themes. This same effort in turn sets the stage to guide effective countermeasures, such as probiotic administration. The objective of our review is to highlight the interaction of host immune ontogeny with the developing microbiome in early life as a critical window of susceptibility for lifelong disease, as well as to identify the enormous potential to protect and promote lifelong health by specifically targeting this window of opportunity.
Published: 2017

38. Systems vaccinology: a promise for the young and the poor

Author: Tobias R. Kollmann, Ofer Levy, and Nelly Amenyogbe
Subjects: medicine.medical_specialty, Aging, Vaccines, Systems Analysis, business.industry, Childhood vaccination, Small sample, Disease, Articles, General Biochemistry, Genetics and Molecular Biology, Young infants, Vaccination, Molecular network, Immunization, Immunology, Communicable Disease Control, Medicine, Vulnerable population, Humans, General Agricultural and Biological Sciences, business, Intensive care medicine, Poverty
Abstract: As a child, the risk of suffering and dying from infection is higher the younger you are; and higher, the less developed a region you are born in. Childhood vaccination programmes have greatly reduced mortality around the world, but least so for the very young among the very poor of the world. This appears partly owing to suboptimal vaccine effectiveness. Unfortunately, although most vaccines are administered to the newborn and very young infant (less than or equal to two months), we know the least about their host response to vaccination. We thus currently lack the knowledge to guide efforts aimed at improving vaccine effectiveness in this vulnerable population. Systems vaccinology, the study of molecular networks activated by immunization, has begun to provide unprecedented insights into mechanisms leading to vaccine-induced protection from infection or disease. However, all published reports of systems vaccinology have focused on either adults or at most children and older infants, not those most in need, i.e. newborns and very young infants. Given that the tools of systems vaccinology work perfectly well with very small sample volumes, it is time we deliver the promise that systems vaccinology holds for those most in need of vaccine-mediated protection from infection.
Published: 2015

39. The Intestinal Microbiome in Early Life: Health and Disease

Author: Nelly Amenyogbe, Eric M. Brown, Marie-Claire Arrieta, Leah T. Stiemsma, and B. Brett Finlay
Subjects: intestinal microbiota, lcsh:Immunologic diseases. Allergy, Pediatric disease, Immunology, Review Article, Disease, Biology, Gut flora, Microbial dysbiosis, digestive system, Child microbiota, 03 medical and health sciences, Immune system, medicine, Immunology and Allergy, 030304 developmental biology, 0303 health sciences, 030306 microbiology, Immune-mediated disease, medicine.disease, biology.organism_classification, Obesity, Early life, 3. Good health, Intestinal Microbiome, Intestinal dysbiosis, lcsh:RC581-607, Dysbiosis
Abstract: Human microbial colonization begins at birth and continues to develop and modulate in species abundance for about three years, until the microbiota becomes adult-like. During the same time period, children experience significant developmental changes that influence their current health status as well as their immune system. An ever-expanding number of articles associate several diseases with early life imbalances of the gut microbiota, also referred to as gut microbial dysbiosis. Whether early life dysbiosis precedes and plays a role in disease pathogenesis, or simply originates from the disease process itself is a question that is beginning to be answered in a few diseases, including IBD, obesity and asthma. This review describes the gut microbiome structure and function during the formative first years of life, as well as the environmental factors that determine its composition. It also aims to discuss the recent advances in understanding the role of the early life gut microbiota in the development of immune-mediated, metabolic, and neurological diseases. A greater understanding of how the early life gut microbiota impacts our immune development could potentially lead to novel microbial-derived therapies that target disease prevention at an early age.
Published: 2014

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