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1. Validation of a host blood transcriptomic biomarker for pulmonary tuberculosis in people living with HIV: a prospective diagnostic and prognostic accuracy study

Author

Abrahams, Charmaine, Africa, Hadn, Ahlers, Petri, Arendsen, Denis, Badimo, Tebogo, Baepanye, Kagiso, Baepanye, Kesenogile Edna, Bande, Bianca, Batyi, Nomfuneko Cynthia, Beukes, Roslyn, Bontsi, Laudicia Tshenolo, Booi, Obakeng Peter, Botha, Mari Cathrin, Braaf, Samentra, Buhlungu, Sivuyile, Carstens, Alida, Chauke, Kgomotso Violet, Chinappa, Thilagavathy, Chung, Eva, Chung, Michelle, Clarke, Ken, Cloete, Yolundi, Coetzee, Lorraine, Collignon, Marelize, Companie, Alessandro, Corris, Cara-mia, Cwaile, Mooketsi Theophillius, Cwele, Thobelani, Davids, Ilse, Davies, Isabella Johanna, De Klerk, Emilia, de Kock, Marwou, Dhlamini, Audrey Lebohang, Diamond, Bongani, Didloff, Maria, Dlamini, Celaphiwe, Dolo, Palesa, Eyre, Candice, Feni, Tebogo, Ferreira, Juanita, Ferus, Christal, Fisher, Michelle, Flinn, Marika, Fransman, Bernadine, Galane, Welseh Phindile, Geldenhuys, Hennie, Gempies, Diann, Goliath, Thelma, Govender, Dhineshree, Gregg, Yolande, Gumede, Goodness, Gwamada, Zanele, Halti, Senzo, Hassiem, Rieyaat, Herling, Roxane, Herselman, Yulandi, Hughes, Ellis, Issel, Henry, Iyemosolo, Blanchard Mbay, Jali, Zandile, Janse Van Rensburg, Bonita, Jansen, Ruwiyda, Jeleni, James Michael, Jonkane, Olebogeng, Julies, Fabio, Kafaar, Fazlin, Kasongo, Christian Mabika, Keffers, Sophie, Kekana, Boitumelo Sophy, Kekana, Sebaetseng Jeanette, Kelepu, Xoliswa, Khanyile, Lungile, Khobedi, Gomotsegang Virginia, Khomba, Gloria, Khoza, Lucky Sipho, King, Marietjie, Kolobe, Gloria Keitumetse, Kruger, Sandra, Kruger, Jaftha, Kunene, Ndlela Israel, Lakay, Sunelza, Lakhi, Aneesa, Langa, Nondumiso, Ledwaba, Hildah, Lekagane, Lerato Julia, Lekotloane, Sheiley Christina, Leopeng, Thelma, Louw, Ilze Jeanette, Luabeya, Angelique Kany Kany, Lusale, Sarah Teboso, Maatjie, Perfect Tiisetso, Mabasa, Immaculate, Mabe, Tshegofatso Dorah, Mabena, Kamogelo Fortunate, Mabuza, Nkosinathi Charles, Mabwe, Simbarashe, Madikwe, Johanna Thapelo, Madikwe, Octavia Mahkosazana, Maebana, Rapontwana Letlhogonolo, Magwasha, Malobisa Sylvester, Majola, Molly, Makhetha, Mantai, Makhethe, Lebohang, Malay, Vernon, Manzini, Vutlhari-I-Vunhenha Fairlord, Maphanga, Jabu, Maphanga, Nonhle, Market, Juanita, Maroele, Isholedi Samuel, Masibi, Omphile Petunia, Mathabanzini, July Rocky, Mathode, Tendamudzimu Ivan, Matsane, Ellen Ditaba, Mbata, Lungile, Meyer, Faheema, Mhandire, Nyasha Karen, Miga, Thembisiwe, Mkhize, Nosisa Charity Thandeka, Mkhokho, Caroline, Mkwalase, Neo Hilda, Mnqonywa, Nondzakazi, Moche, Karabo, Modisaotsile, Brenda Matshidiso, Mokgetsengoane, Patricia Pakiso, Mokone, Selemeng Matseliso Carol, Molatlhegi, Kegomoditswe Magdeline, Molefe, Thuso Andrew, Moloko, Joseph Panie, Molosi, Kabelo, Molotsi, Motlatsi Evelyn, Montwedi, Tebogo Edwin, Monyemangene, Boikanyo Dinah, Mooketsi, Hellen Mokopi, Moses, Miriam, Mosito, Boitumelo, Mosito, Tshplpfelo Mapula, Mosweu, Ireen Lesebang, Mothaga, Primrose, Motlagomang, Banyana Olga, Mouton, Angelique, Mpofu, Onesisa, Mthembu, Funeka Nomvula, Mtlali, Mpho, Ndlovu, Nhlamulo, Ngcobo, Nompumelelo, Noble, Julia, Ntamo, Bantubonke Bertrum, Ntanjana, Gloria, Ntshauba, Tedrius, Opperman, Fajwa, Padayatchi, Nesri, Papalagae, Thandiwe, Petersen, Christel, Phakathi, Themba, Phatshwane, Mapule Ozma, Plaatjie, Patiswa, Pretorius, Abe, Rameetse, Victor Kgothatso, Ramjit, Dirhona, Ratangee, Frances, Ratangee, Maigan, Sanyaka, Pearl Nomsa, Sato, Alicia, Schoeman, Elisma, Schreuder, Constance, Seabela, Letlhogonolo, Segaetsho, Kelebogile Magdeline, Sein, Ni Ni, Selepe, Raesibe Agnes Pearl, Senne, Melissa Neo, September, Alison, September, Cashwin, Serake, Moeti, Shenje, Justin, Shezi, Thandiwe, Shezi, Sifiso Cornelius, Sing, Phindile, Singh, Chandrapharbha, Sithetho, Zona, Solomons, Dorothy, Stanley, Kim, Steyn, Marcia, Stofile, Bongiwe, Stryers, Sonia, Swanepoel, Liticia, Swarts, Anne, Thaba, Mando Mmakhora, Theko, Lethabo Collen, Thembela, Philile, Thompo, Mugwena, Toefy, Asma, Toto, Khayalethu, Tsagae, Dimakatso Sylvia, Tsamane, Ayanda, Tshikovhi, Vincent, Tswaile, Lebogang Isaac, Tyambetyu, Petrus, Tönsing, Susanne, Valley, Habibullah, van der Merwe, Linda, van Rooyen, Elma, Veldsman, Ashley, Veldtsman, Helen, Vollenhoven, Kelvin, Zaca, Londiwe, Zimri, Elaine, Zulu, Mbali, Mendelsohn, Simon C, Fiore-Gartland, Andrew, Penn-Nicholson, Adam, Mulenga, Humphrey, Mbandi, Stanley Kimbung, Borate, Bhavesh, Hadley, Katie, Hikuam, Chris, Musvosvi, Munyaradzi, Bilek, Nicole, Erasmus, Mzwandile, Jaxa, Lungisa, Raphela, Rodney, Nombida, Onke, Kaskar, Masooda, Sumner, Tom, White, Richard G, Innes, Craig, Brumskine, William, Hiemstra, Andriëtte, Malherbe, Stephanus T, Hassan-Moosa, Razia, Tameris, Michèle, Walzl, Gerhard, Naidoo, Kogieleum, Churchyard, Gavin, Scriba, Thomas J, and Hatherill, Mark

Published
2021
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2. Safety and immunogenicity of the adjunct therapeutic vaccine ID93 + GLA-SE in adults who have completed treatment for tuberculosis: a randomised, double-blind, placebo-controlled, phase 2a trial

Author

Beckmann, Anna Marie, Hsu, Fan-Chi, Albertson, Sarah, Veldsman, Ashley, Schreuder, Constance, Smit, Erica, Cloete, Yolundi, Ontong, Cynthia, Filander, Elisabeth, Jacobs, Gail, Keyser, Alana, Africa, Hadn, Mulenga, Humphrey, Noble, Julia, Makhethe, Lebohang, Steyn, Marcia, de Kock, Marwou, Quaqua, Nambitha, Lu, Yiwen, Gutschmidt, Andrea, Thienemann, Friedrich, Kahn, Stuart, Mouton, Angelique, Van Rooyen, Elma, Opperman, Fajwa, Swarts, Ann, Van Schalkwyk, Amaryl, Herselman, Yolandi, Hofmeester, Devona, Amsterdam, Julia, Hassanally, Leya, van der Merwe, Linda, Companie, Alessandro, Rossouw, Susan, Jones, Carolyn, Botes, Natasja, van der Riet, Elize, Goliath, Sandra, Kruger, Sandra, Sinandile, Eunice, Day, Tracey A, Penn-Nicholson, Adam, Luabeya, Angelique Kany Kany, Fiore-Gartland, Andrew, Du Plessis, Nelita, Loxton, Andre G, Vergara, Julie, Rolf, Tom A, Reid, Tim D, Toefy, Asma, Shenje, Justin, Geldenhuys, Hendrik, Tameris, Michele, Mabwe, Simbarashe, Bilek, Nicole, Bekker, Linda-Gail, Diacon, Andreas, Walzl, Gerhard, Ashman, Jill, Frevol, Aude, Sagawa, Zachary K, Lindestam Arlehamn, Cecilia, Sette, Alessandro, Reed, Steven G, Coler, Rhea N, Scriba, Thomas J, and Hatherill, Mark

Published
2021
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3. Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial

Author

Baepanye, Kesenogile, Baepanye, Tshepiso, Clarke, Ken, Collignon, Marelize, Dlamini, Audrey, Eyre, Candice, Feni, Tebogo, Fikizolo, Moogo, Galane, Phinda, Goliath, Thelma, Gangat, Alia, Malefo-Grootboom, Shirley, Janse van Rensburg, Elba, Janse van Rensburg, Bonita, Kekana, Sophy, Zietsman, Marietjie, Kock, Adrianne, Kunene, Israel, Lakhi, Aneessa, Langa, Nondumiso, Ledwaba, Hilda, Luphoko, Marillyn, Mabasa, Immaculate, Mabe, Dorah, Mabuza, Nkosinathi, Majola, Molly, Makhetha, Mantai, Makoanyane, Mpho, Makhubalo, Blossom, Malay, Vernon, Market, Juanita, Matshego, Selvy, Mbipa, Nontsikelelo, Mmotsa, Tsiamo, Modipa, Sylvester, Mopati, Samuel, Moswegu, Palesa, Mothaga, Primrose, Muller, Dorothy, Nchwe, Grace, Nel, Maryna, Nhlangulela, Lindiwe, Ntamo, Bantubonke, Ntoahae, Lawerence, Ntshauba, Tedrius, Sanyaka, Nomsa, Seabela, Letlhogonolo, Selepe, Pearl, Senne, Melissa, Serake, MG, Thlapi, Maria, Tshikovhi, Vincent, Tswaile, Lebogang, van Aswegen, Amanda, Mbata, Lungile, Takavamanya, Constance, Pinho, Pedro, Mdlulu, John, Taljaard, Marthinette, Slabbert, Naydene, Sayed, Sharfuddin, Nielson, Tanya, Ni Sein, Ni, Govender, Dhineshree, Chinappa, Tilagavathy, Zulu, Mbali Ignatia, Maphanga, Nonhle Bridgette, Hlathi, Senzo Ralph, Gumede, Goodness Khanyisile, Shezi, Thandiwe Yvonne, Maphanga, Jabulisiwe Lethabo, Jali, Zandile Patrica, Cwele, Thobelani, Gwamanda, Nonhlanhla Zanele Elsie, Dlamini, Celaphiwe, Sing, Zibuyile Phindile Penlee, Ntanjana, Ntombozuko Gloria, Nzimande, Sphelele Simo, Mbatha, Siyabonga, Maharaj, Bhavna, Moosa, Atika, Corris, Cara-Mia, Kafaar, Fazlin, Geldenhuys, Hennie, Luabeya, Angelique Kany Kany, Shenje, Justin, Botes, Natasja, Rossouw, Susan, Africa, Hadn, Diamond, Bongani, Braaf, Samentra, Stryers, Sonia, Carstens, Alida, Jansen, Ruwiyda, Mabwe, Simbarashe, Mulenga, Humphrey, Herling, Roxane, Veldsman, Ashley, Makhete, Lebohgang, Steyn, Marcia, Buhlungu, Sivuyile, Erasmus, Margareth, Davids, Ilse, Plaatjie, Patiswa, Companie, Alessandro, Ratangee, Frances, Veldtsman, Helen, Petersen, Christel, Abrahams, Charmaine, Moses, Miriam, Kelepu, Xoliswa, Gregg, Yolande, Swanepoel, Liticia, Magawu, Nomsitho, Cetywayo, Nompumelelo, Mactavie, Lauren, Valley, Habibullah, Filander, Elizabeth, Nqakala, Nambitha, Maasdorp, Elizna, Khoury, Justine, Kriel, Belinda, Smith, Bronwyn, Muller, Liesel, Tonsing, Susanne, Loxton, Andre, Hiemstra, Andriette, Ahlers, Petri, Flinn, Marika, Chung, Eva, Chung, Michelle, Sato, Alicia, Scriba, Thomas J, Fiore-Gartland, Andrew, Penn-Nicholson, Adam, Kimbung Mbandi, Stanley, Borate, Bhavesh, Mendelsohn, Simon C, Hadley, Katie, Hikuam, Chris, Kaskar, Masooda, Musvosvi, Munyaradzi, Bilek, Nicole, Self, Steven, Sumner, Tom, White, Richard G, Erasmus, Mzwandile, Jaxa, Lungisa, Raphela, Rodney, Innes, Craig, Brumskine, William, Hiemstra, Andriëtte, Malherbe, Stephanus T, Hassan-Moosa, Razia, Tameris, Michèle, Walzl, Gerhard, Naidoo, Kogieleum, Churchyard, Gavin, and Hatherill, Mark

Published
2021
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4. OA-490 Safety, reactogenicity and immunogenicity of MTBVAC in newborns in a TB endemic area: a phase 2a randomized, double-blind, dose-defining trial

Author

Tameris, Michele, primary, Barja, Sara, additional, Rozot, Virginie, additional, Imbratta, Claire, additional, Musvosvi, Munyaradzi, additional, Jelsbak, Ingrid Murillo, additional, Geldenhuys, Hennie, additional, Shenje, Justin, additional, Luabeya, Angelique, additional, Mendelsohn, Simon, additional, Tredoux, Nicolette, additional, Fisher, Michelle, additional, Bilek, Nicole, additional, Asma, Toefy, additional, Mabwe, Simbarashe, additional, Doce, Juana, additional, Aguilo, Nacho, additional, Marinova, Dessislava, additional, Puentes, Eugenia, additional, Martin, Carlos, additional, Mukherjee, Rajat, additional, Scriba, Thomas, additional, and Hatherill, Mark, additional

Published
2023
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5. Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial

Author

Africa, Hadn, Arendsen, Denis, Botes, Natasja, Cloete, Yolundi, De Kock, Marwou, Erasmus, Margaret, Jack, Lungisa, Kafaar, Fazlin, Kalepu, Xoliswa, Khomba, Nondumiso Gloria, Kruger, Sandra, Leopeng, Thelma, Makhethe, Lebohang, Mouton, Angelique, Mulenga, Humphrey, Musvosvi, Munyaradzi, Noble, Julia, Opperman, Fajwa, Reid, Tim, Rossouw, Susan, Schreuder, Constance, Smit, Erica, Steyn, Marcia, Tyambethu, Petrus, Van Rooyen, Elma, Veldsman, Ashley, Tameris, Michele, Mearns, Helen, Penn-Nicholson, Adam, Gregg, Yolande, Bilek, Nicole, Mabwe, Simbarashe, Geldenhuys, Hennie, Shenje, Justin, Luabeya, Angelique Kany Kany, Murillo, Ingrid, Doce, Juana, Aguilo, Nacho, Marinova, Dessislava, Puentes, Eugenia, Rodríguez, Esteban, Gonzalo-Asensio, Jesús, Fritzell, Bernard, Thole, Jelle, Martin, Carlos, Scriba, Thomas J, and Hatherill, Mark

Published
2019
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6. Safety and immunogenicity of the novel tuberculosis vaccine ID93 + GLA-SE in BCG-vaccinated healthy adults in South Africa: a randomised, double-blind, placebo-controlled phase 1 trial

Author

Penn-Nicholson, Adam, Tameris, Michele, Smit, Erica, Day, Tracey A, Musvosvi, Munyaradzi, Jayashankar, Lakshmi, Vergara, Julie, Mabwe, Simbarashe, Bilek, Nicole, Geldenhuys, Hendrik, Luabeya, Angelique Kany-Kany, Ellis, Ruth, Ginsberg, Ann M, Hanekom, Willem A, Reed, Steven G, Coler, Rhea N, Scriba, Thomas J, and Hatherill, Mark

Published
2018
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7. Qualification of the differential leukocyte count and immunophenotyping in cryopreserved ex vivo whole blood assay.

Author

Imbratta, Claire, Gela, Anele, Bilek, Nicole, Mabwe, Simbarashe, Cloete, Yolundi, Mortensen, Rasmus, Borges, Álvaro H., Maenetje, Pholo, Mlotshwa, Mandla, Churchyard, Gavin, Sudi, Lwitiho, Sabi, Issa, Meewes, Peter, Wallis, Carole L., Hatherill, Mark, Scriba, Thomas J., and Nemes, Elisa

Abstract

We developed a flow cytometry‐based assay, termed Differential Leukocyte Counting and Immunophenotyping in Cryopreserved Ex vivo whole blood (DLC‐ICE), that allows quantification of absolute counts and frequencies of leukocyte subsets and measures expression of activation, phenotypic and functional markers. We evaluated the performance of the DLC‐ICE assay by determining inter‐operator variability for processing fresh whole blood (WB) from healthy donors collected at multiple clinical sites. In addition, we assessed inter‐operator variability for staining of fixed cells and robustness across different anticoagulants. Accuracy was evaluated by comparing DLC‐ICE measurements to real‐time cell enumeration using an accredited hematology analyzer. Finally, we developed and tested the performance of a 27‐colour immunophenotyping panel on cryopreserved fixed WB and compared results to matched fresh WB. Overall, we observed <20% variability in absolute counts and frequencies of granulocytes, monocytes and lymphocytes (T, B and NK cells) when fresh WB was collected in different anti‐coagulant tubes, processed or stained by independent operators. Absolute cell counts measured across operators and anti‐coagulants using the DLC‐ICE method exhibited excellent correlation with the reference method, complete blood count (CBC) with differential, measured using a hematology analyzer (r2 > 0.9 for majority of measurements). A comparison of leukocyte immunophenotyping on fresh WB versus DLC‐ICE processed blood yielded equivalent and linear results over a wide dynamic range (r2 = 0.94 over 10–104 cells/μL). These results demonstrate low variability across trained operators, high robustness, linearity and accuracy, supporting utility of the DLC‐ICE assay for large cohort studies involving multiple clinical research sites. [ABSTRACT FROM AUTHOR]

Published
2023
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8. Live-Attenuated M. Tuberculosis Vaccine, MTBVAC, in Adults with or Without M. Tuberculosis Sensitization: A Phase 1b/2a Randomized, Controlled, Double-Blind, Dose-Escalation Trial

Author

Luabeya, Angelique Kany Kany, primary, Rozot, Virginie, additional, Imbratta, Claire, additional, Ratangee, Frances, additional, Shenje, Justin, additional, Tameris, Michèle, additional, Mendelsohn, Simon C., additional, Geldenhuys, Hennie, additional, Fisher, Michelle, additional, Musvosvi, Munyaradzi, additional, Mulenga, Humphrey, additional, Bilek, Nicole, additional, Mabwe, Simbarashe, additional, Murillo Jelsbak, Ingrid, additional, Rodríguez, Esteban, additional, Puentes, Eugenia, additional, Doce, Juana, additional, Aguilo, Nacho, additional, Martin, Carlos, additional, Pillay, Cadwill, additional, Tait, Dereck, additional, Schrager, Lewis, additional, Russell, Marisa, additional, Rutkowski, Kathryn, additional, Hunt, Devin, additional, Scriba, Thomas J., additional, and Hatherill, Mark, additional

Published
2023
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9. Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses

Author

Llibre, Alba, primary, Smith, Nikaïa, additional, Rouilly, Vincent, additional, Musvosvi, Munyaradzi, additional, Nemes, Elisa, additional, Posseme, Céline, additional, Mabwe, Simbarashe, additional, Charbit, Bruno, additional, Mbandi, Stanley Kimbung, additional, Filander, Elizabeth, additional, Africa, Hadn, additional, Saint-André, Violaine, additional, Bondet, Vincent, additional, Bost, Pierre, additional, Mulenga, Humphrey, additional, Bilek, Nicole, additional, Albert, Matthew L., additional, Scriba, Thomas J., additional, and Duffy, Darragh, additional

Published
2022
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10. Optimization and Interpretation of Serial QuantiFERON Testing to Measure Acquisition of Mycobacterium tuberculosis Infection

Author

Nemes, Elisa, Rozot, Virginie, Geldenhuys, Hennie, Bilek, Nicole, Mabwe, Simbarashe, Abrahams, Deborah, Makhethe, Lebohang, Erasmus, Mzwandile, Keyser, Alana, Toefy, Asma, Cloete, Yolundi, Ratangee, Frances, Blauenfeldt, Thomas, Ruhwald, Morten, Walzl, Gerhard, Smith, Bronwyn, Loxton, Andre G., Hanekom, Willem A., Andrews, Jason R., Lempicki, Maria D., Ellis, Ruth, Ginsberg, Ann M., Hatherill, Mark, and Scriba, Thomas J.

Published
2017
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11. Diagnostic Accuracy of Early Secretory Antigenic Target-6–Free Interferon-gamma Release Assay Compared to QuantiFERON-TB Gold In-tube

Author

Nemes, Elisa, Abrahams, Deborah, Scriba, Thomas J, Ratangee, Frances, Keyser, Alana, Makhethe, Lebohang, Erasmus, Mzwandile, Mabwe, Simbarashe, Bilek, Nicole, Rozot, Virginie, Geldenhuys, Hennie, Hatherill, Mark, Lempicki, Maria D, Holm, Line Lindebo, Bogardus, Leah, Ginsberg, Ann M, Blauenfeldt, Thomas, Smith, Bronwyn, Ellis, Ruth D, Loxton, Andre G, Walzl, Gerhard, Andersen, Peter, and Ruhwald, Morten

Subjects
Male, Antigens, Bacterial, Adolescent, diagnosis, Reproducibility of Results, Mycobacterium tuberculosis, bacterial infections and mycoses, Cohort Studies, Interferon-gamma, Editorial Commentary, Major Articles and Commentaries, tuberculosis infection, Bacterial Proteins, ROC Curve, IFN-γ release assay, Humans, Tuberculosis, Female, Reagent Kits, Diagnostic, qualification, Child, Tuberculosis Vaccines, Interferon-gamma Release Tests
Abstract

Background Early secretory antigenic target-6 (ESAT-6) is an immunodominant Mycobacterium tuberculosis (M.tb) antigen included in novel vaccines against tuberculosis (TB) and in interferon-gamma (IFN-γ) release assays (IGRAs). Therefore, the availability of an ESAT-6–free IGRA is essential to determine M.tb infection status following vaccination with ESAT-6–containing vaccines. We aimed to qualify a recently developed ESAT-6–free IGRA and to assess its diagnostic performance in comparison to QuantiFERON-TB Gold In-tube (QFT). Methods Participants with different levels of M.tb exposure and TB disease were enrolled to determine the ESAT-6–free IGRA cutoff, test assay performance in independent cohorts compared to standard QFT, and perform a technical qualification of antigen-coated blood collection tubes. Results ESAT-6–free IGRA antigen recognition was evaluated in QFT-positive and QFT-negative South African adolescents. The ESAT-6–free IGRA cutoff was established at 0.61 IU/mL, based on receiver operating characteristic analysis in M.tb-unexposed controls and microbiologically confirmed pulmonary TB patients. In an independent cohort of healthy adolescents, levels of IFN-γ released in QFT and ESAT-6–free IGRA were highly correlated (P < .0001, r = 0.83) and yielded comparable positivity rates, 41.5% and 43.5%, respectively, with 91% concordance between the tests (kappa = 0.82; 95% confidence interval, 0.74–0.90; McNemar test P = .48). ESAT-6–free IGRA blood collection tubes had acceptable lot-to-lot variability, precision, and stability. Conclusions The novel ESAT-6–free IGRA had diagnostic accuracy comparable to QFT and is suitable for use in clinical trials to assess efficacy of candidate TB vaccines to prevent established M.tb infection., The novel early secretory antigenic target-6 (ESAT-6)–free interferon-gamma release assay has comparable diagnostic performance for Mycobacterium tuberculosis (M.tb) infection as the QuantiFERON-TB Gold assay and is suitable for diagnosing M.tb infection in clinical trials of ESAT-6–containing tuberculosis vaccines.

Published
2019

12. Validation of a host blood transcriptomic biomarker for pulmonary tuberculosis in people living with HIV: a prospective diagnostic and prognostic accuracy study

Author

Mendelsohn, Simon C, primary, Fiore-Gartland, Andrew, additional, Penn-Nicholson, Adam, additional, Mulenga, Humphrey, additional, Mbandi, Stanley Kimbung, additional, Borate, Bhavesh, additional, Hadley, Katie, additional, Hikuam, Chris, additional, Musvosvi, Munyaradzi, additional, Bilek, Nicole, additional, Erasmus, Mzwandile, additional, Jaxa, Lungisa, additional, Raphela, Rodney, additional, Nombida, Onke, additional, Kaskar, Masooda, additional, Sumner, Tom, additional, White, Richard G, additional, Innes, Craig, additional, Brumskine, William, additional, Hiemstra, Andriëtte, additional, Malherbe, Stephanus T, additional, Hassan-Moosa, Razia, additional, Tameris, Michèle, additional, Walzl, Gerhard, additional, Naidoo, Kogieleum, additional, Churchyard, Gavin, additional, Scriba, Thomas J, additional, Hatherill, Mark, additional, Abrahams, Charmaine, additional, Africa, Hadn, additional, Ahlers, Petri, additional, Arendsen, Denis, additional, Badimo, Tebogo, additional, Baepanye, Kagiso, additional, Baepanye, Kesenogile Edna, additional, Bande, Bianca, additional, Batyi, Nomfuneko Cynthia, additional, Beukes, Roslyn, additional, Bontsi, Laudicia Tshenolo, additional, Booi, Obakeng Peter, additional, Botha, Mari Cathrin, additional, Braaf, Samentra, additional, Buhlungu, Sivuyile, additional, Carstens, Alida, additional, Chauke, Kgomotso Violet, additional, Chinappa, Thilagavathy, additional, Chung, Eva, additional, Chung, Michelle, additional, Clarke, Ken, additional, Cloete, Yolundi, additional, Coetzee, Lorraine, additional, Collignon, Marelize, additional, Companie, Alessandro, additional, Corris, Cara-mia, additional, Cwaile, Mooketsi Theophillius, additional, Cwele, Thobelani, additional, Davids, Ilse, additional, Davies, Isabella Johanna, additional, De Klerk, Emilia, additional, de Kock, Marwou, additional, Dhlamini, Audrey Lebohang, additional, Diamond, Bongani, additional, Didloff, Maria, additional, Dlamini, Celaphiwe, additional, Dolo, Palesa, additional, Eyre, Candice, additional, Feni, Tebogo, additional, Ferreira, Juanita, additional, Ferus, Christal, additional, Fisher, Michelle, additional, Flinn, Marika, additional, Fransman, Bernadine, additional, Galane, Welseh Phindile, additional, Geldenhuys, Hennie, additional, Gempies, Diann, additional, Goliath, Thelma, additional, Govender, Dhineshree, additional, Gregg, Yolande, additional, Gumede, Goodness, additional, Gwamada, Zanele, additional, Halti, Senzo, additional, Hassiem, Rieyaat, additional, Herling, Roxane, additional, Herselman, Yulandi, additional, Hughes, Ellis, additional, Issel, Henry, additional, Iyemosolo, Blanchard Mbay, additional, Jali, Zandile, additional, Janse Van Rensburg, Bonita, additional, Jansen, Ruwiyda, additional, Jeleni, James Michael, additional, Jonkane, Olebogeng, additional, Julies, Fabio, additional, Kafaar, Fazlin, additional, Kasongo, Christian Mabika, additional, Keffers, Sophie, additional, Kekana, Boitumelo Sophy, additional, Kekana, Sebaetseng Jeanette, additional, Kelepu, Xoliswa, additional, Khanyile, Lungile, additional, Khobedi, Gomotsegang Virginia, additional, Khomba, Gloria, additional, Khoza, Lucky Sipho, additional, King, Marietjie, additional, Kolobe, Gloria Keitumetse, additional, Kruger, Sandra, additional, Kruger, Jaftha, additional, Kunene, Ndlela Israel, additional, Lakay, Sunelza, additional, Lakhi, Aneesa, additional, Langa, Nondumiso, additional, Ledwaba, Hildah, additional, Lekagane, Lerato Julia, additional, Lekotloane, Sheiley Christina, additional, Leopeng, Thelma, additional, Louw, Ilze Jeanette, additional, Luabeya, Angelique Kany Kany, additional, Lusale, Sarah Teboso, additional, Maatjie, Perfect Tiisetso, additional, Mabasa, Immaculate, additional, Mabe, Tshegofatso Dorah, additional, Mabena, Kamogelo Fortunate, additional, Mabuza, Nkosinathi Charles, additional, Mabwe, Simbarashe, additional, Madikwe, Johanna Thapelo, additional, Madikwe, Octavia Mahkosazana, additional, Maebana, Rapontwana Letlhogonolo, additional, Magwasha, Malobisa Sylvester, additional, Majola, Molly, additional, Makhetha, Mantai, additional, Makhethe, Lebohang, additional, Malay, Vernon, additional, Manzini, Vutlhari-I-Vunhenha Fairlord, additional, Maphanga, Jabu, additional, Maphanga, Nonhle, additional, Market, Juanita, additional, Maroele, Isholedi Samuel, additional, Masibi, Omphile Petunia, additional, Mathabanzini, July Rocky, additional, Mathode, Tendamudzimu Ivan, additional, Matsane, Ellen Ditaba, additional, Mbata, Lungile, additional, Meyer, Faheema, additional, Mhandire, Nyasha Karen, additional, Miga, Thembisiwe, additional, Mkhize, Nosisa Charity Thandeka, additional, Mkhokho, Caroline, additional, Mkwalase, Neo Hilda, additional, Mnqonywa, Nondzakazi, additional, Moche, Karabo, additional, Modisaotsile, Brenda Matshidiso, additional, Mokgetsengoane, Patricia Pakiso, additional, Mokone, Selemeng Matseliso Carol, additional, Molatlhegi, Kegomoditswe Magdeline, additional, Molefe, Thuso Andrew, additional, Moloko, Joseph Panie, additional, Molosi, Kabelo, additional, Molotsi, Motlatsi Evelyn, additional, Montwedi, Tebogo Edwin, additional, Monyemangene, Boikanyo Dinah, additional, Mooketsi, Hellen Mokopi, additional, Moses, Miriam, additional, Mosito, Boitumelo, additional, Mosito, Tshplpfelo Mapula, additional, Mosweu, Ireen Lesebang, additional, Mothaga, Primrose, additional, Motlagomang, Banyana Olga, additional, Mouton, Angelique, additional, Mpofu, Onesisa, additional, Mthembu, Funeka Nomvula, additional, Mtlali, Mpho, additional, Ndlovu, Nhlamulo, additional, Ngcobo, Nompumelelo, additional, Noble, Julia, additional, Ntamo, Bantubonke Bertrum, additional, Ntanjana, Gloria, additional, Ntshauba, Tedrius, additional, Opperman, Fajwa, additional, Padayatchi, Nesri, additional, Papalagae, Thandiwe, additional, Petersen, Christel, additional, Phakathi, Themba, additional, Phatshwane, Mapule Ozma, additional, Plaatjie, Patiswa, additional, Pretorius, Abe, additional, Rameetse, Victor Kgothatso, additional, Ramjit, Dirhona, additional, Ratangee, Frances, additional, Ratangee, Maigan, additional, Sanyaka, Pearl Nomsa, additional, Sato, Alicia, additional, Schoeman, Elisma, additional, Schreuder, Constance, additional, Seabela, Letlhogonolo, additional, Segaetsho, Kelebogile Magdeline, additional, Sein, Ni Ni, additional, Selepe, Raesibe Agnes Pearl, additional, Senne, Melissa Neo, additional, September, Alison, additional, September, Cashwin, additional, Serake, Moeti, additional, Shenje, Justin, additional, Shezi, Thandiwe, additional, Shezi, Sifiso Cornelius, additional, Sing, Phindile, additional, Singh, Chandrapharbha, additional, Sithetho, Zona, additional, Solomons, Dorothy, additional, Stanley, Kim, additional, Steyn, Marcia, additional, Stofile, Bongiwe, additional, Stryers, Sonia, additional, Swanepoel, Liticia, additional, Swarts, Anne, additional, Thaba, Mando Mmakhora, additional, Theko, Lethabo Collen, additional, Thembela, Philile, additional, Thompo, Mugwena, additional, Toefy, Asma, additional, Toto, Khayalethu, additional, Tsagae, Dimakatso Sylvia, additional, Tsamane, Ayanda, additional, Tshikovhi, Vincent, additional, Tswaile, Lebogang Isaac, additional, Tyambetyu, Petrus, additional, Tönsing, Susanne, additional, Valley, Habibullah, additional, van der Merwe, Linda, additional, van Rooyen, Elma, additional, Veldsman, Ashley, additional, Veldtsman, Helen, additional, Vollenhoven, Kelvin, additional, Zaca, Londiwe, additional, Zimri, Elaine, additional, and Zulu, Mbali, additional

Published
2021
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13. Safety and immunogenicity of the adjunct therapeutic vaccine ID93 + GLA-SE in adults who have completed treatment for tuberculosis: a randomised, double-blind, placebo-controlled, phase 2a trial

Author

Day, Tracey A, primary, Penn-Nicholson, Adam, additional, Luabeya, Angelique Kany Kany, additional, Fiore-Gartland, Andrew, additional, Du Plessis, Nelita, additional, Loxton, Andre G, additional, Vergara, Julie, additional, Rolf, Tom A, additional, Reid, Tim D, additional, Toefy, Asma, additional, Shenje, Justin, additional, Geldenhuys, Hendrik, additional, Tameris, Michele, additional, Mabwe, Simbarashe, additional, Bilek, Nicole, additional, Bekker, Linda-Gail, additional, Diacon, Andreas, additional, Walzl, Gerhard, additional, Ashman, Jill, additional, Frevol, Aude, additional, Sagawa, Zachary K, additional, Lindestam Arlehamn, Cecilia, additional, Sette, Alessandro, additional, Reed, Steven G, additional, Coler, Rhea N, additional, Scriba, Thomas J, additional, Hatherill, Mark, additional, Beckmann, Anna Marie, additional, Hsu, Fan-Chi, additional, Albertson, Sarah, additional, Veldsman, Ashley, additional, Schreuder, Constance, additional, Smit, Erica, additional, Cloete, Yolundi, additional, Ontong, Cynthia, additional, Filander, Elisabeth, additional, Jacobs, Gail, additional, Keyser, Alana, additional, Africa, Hadn, additional, Mulenga, Humphrey, additional, Noble, Julia, additional, Makhethe, Lebohang, additional, Steyn, Marcia, additional, de Kock, Marwou, additional, Quaqua, Nambitha, additional, Lu, Yiwen, additional, Gutschmidt, Andrea, additional, Thienemann, Friedrich, additional, Kahn, Stuart, additional, Mouton, Angelique, additional, Van Rooyen, Elma, additional, Opperman, Fajwa, additional, Swarts, Ann, additional, Van Schalkwyk, Amaryl, additional, Herselman, Yolandi, additional, Hofmeester, Devona, additional, Amsterdam, Julia, additional, Hassanally, Leya, additional, van der Merwe, Linda, additional, Companie, Alessandro, additional, Rossouw, Susan, additional, Jones, Carolyn, additional, Botes, Natasja, additional, van der Riet, Elize, additional, Goliath, Sandra, additional, Kruger, Sandra, additional, and Sinandile, Eunice, additional

Published
2021
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14. Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial

Author

Scriba, Thomas J, primary, Fiore-Gartland, Andrew, additional, Penn-Nicholson, Adam, additional, Mulenga, Humphrey, additional, Kimbung Mbandi, Stanley, additional, Borate, Bhavesh, additional, Mendelsohn, Simon C, additional, Hadley, Katie, additional, Hikuam, Chris, additional, Kaskar, Masooda, additional, Musvosvi, Munyaradzi, additional, Bilek, Nicole, additional, Self, Steven, additional, Sumner, Tom, additional, White, Richard G, additional, Erasmus, Mzwandile, additional, Jaxa, Lungisa, additional, Raphela, Rodney, additional, Innes, Craig, additional, Brumskine, William, additional, Hiemstra, Andriëtte, additional, Malherbe, Stephanus T, additional, Hassan-Moosa, Razia, additional, Tameris, Michèle, additional, Walzl, Gerhard, additional, Naidoo, Kogieleum, additional, Churchyard, Gavin, additional, Hatherill, Mark, additional, Baepanye, Kesenogile, additional, Baepanye, Tshepiso, additional, Clarke, Ken, additional, Collignon, Marelize, additional, Dlamini, Audrey, additional, Eyre, Candice, additional, Feni, Tebogo, additional, Fikizolo, Moogo, additional, Galane, Phinda, additional, Goliath, Thelma, additional, Gangat, Alia, additional, Malefo-Grootboom, Shirley, additional, Janse van Rensburg, Elba, additional, Janse van Rensburg, Bonita, additional, Kekana, Sophy, additional, Zietsman, Marietjie, additional, Kock, Adrianne, additional, Kunene, Israel, additional, Lakhi, Aneessa, additional, Langa, Nondumiso, additional, Ledwaba, Hilda, additional, Luphoko, Marillyn, additional, Mabasa, Immaculate, additional, Mabe, Dorah, additional, Mabuza, Nkosinathi, additional, Majola, Molly, additional, Makhetha, Mantai, additional, Makoanyane, Mpho, additional, Makhubalo, Blossom, additional, Malay, Vernon, additional, Market, Juanita, additional, Matshego, Selvy, additional, Mbipa, Nontsikelelo, additional, Mmotsa, Tsiamo, additional, Modipa, Sylvester, additional, Mopati, Samuel, additional, Moswegu, Palesa, additional, Mothaga, Primrose, additional, Muller, Dorothy, additional, Nchwe, Grace, additional, Nel, Maryna, additional, Nhlangulela, Lindiwe, additional, Ntamo, Bantubonke, additional, Ntoahae, Lawerence, additional, Ntshauba, Tedrius, additional, Sanyaka, Nomsa, additional, Seabela, Letlhogonolo, additional, Selepe, Pearl, additional, Senne, Melissa, additional, Serake, MG, additional, Thlapi, Maria, additional, Tshikovhi, Vincent, additional, Tswaile, Lebogang, additional, van Aswegen, Amanda, additional, Mbata, Lungile, additional, Takavamanya, Constance, additional, Pinho, Pedro, additional, Mdlulu, John, additional, Taljaard, Marthinette, additional, Slabbert, Naydene, additional, Sayed, Sharfuddin, additional, Nielson, Tanya, additional, Ni Sein, Ni, additional, Govender, Dhineshree, additional, Chinappa, Tilagavathy, additional, Zulu, Mbali Ignatia, additional, Maphanga, Nonhle Bridgette, additional, Hlathi, Senzo Ralph, additional, Gumede, Goodness Khanyisile, additional, Shezi, Thandiwe Yvonne, additional, Maphanga, Jabulisiwe Lethabo, additional, Jali, Zandile Patrica, additional, Cwele, Thobelani, additional, Gwamanda, Nonhlanhla Zanele Elsie, additional, Dlamini, Celaphiwe, additional, Sing, Zibuyile Phindile Penlee, additional, Ntanjana, Ntombozuko Gloria, additional, Nzimande, Sphelele Simo, additional, Mbatha, Siyabonga, additional, Maharaj, Bhavna, additional, Moosa, Atika, additional, Corris, Cara-Mia, additional, Kafaar, Fazlin, additional, Geldenhuys, Hennie, additional, Luabeya, Angelique Kany Kany, additional, Shenje, Justin, additional, Botes, Natasja, additional, Rossouw, Susan, additional, Africa, Hadn, additional, Diamond, Bongani, additional, Braaf, Samentra, additional, Stryers, Sonia, additional, Carstens, Alida, additional, Jansen, Ruwiyda, additional, Mabwe, Simbarashe, additional, Herling, Roxane, additional, Veldsman, Ashley, additional, Makhete, Lebohgang, additional, Steyn, Marcia, additional, Buhlungu, Sivuyile, additional, Erasmus, Margareth, additional, Davids, Ilse, additional, Plaatjie, Patiswa, additional, Companie, Alessandro, additional, Ratangee, Frances, additional, Veldtsman, Helen, additional, Petersen, Christel, additional, Abrahams, Charmaine, additional, Moses, Miriam, additional, Kelepu, Xoliswa, additional, Gregg, Yolande, additional, Swanepoel, Liticia, additional, Magawu, Nomsitho, additional, Cetywayo, Nompumelelo, additional, Mactavie, Lauren, additional, Valley, Habibullah, additional, Filander, Elizabeth, additional, Nqakala, Nambitha, additional, Maasdorp, Elizna, additional, Khoury, Justine, additional, Kriel, Belinda, additional, Smith, Bronwyn, additional, Muller, Liesel, additional, Tonsing, Susanne, additional, Loxton, Andre, additional, Hiemstra, Andriette, additional, Ahlers, Petri, additional, Flinn, Marika, additional, Chung, Eva, additional, Chung, Michelle, additional, and Sato, Alicia, additional

Published
2021
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15. Immune profiling enables stratification of patients with active TB disease or M. tuberculosis infection

Author

Duffy, Darragh, Nemes, Elisa, Llibre, Alba, Rouilly, Vincent, Musvosvi, Munyaradzi, Smith, Nikaïa, Filander, Elizabeth, Africa, Hadn, Mabwe, Simbarashe, Jaxa, Lungisa, Charbit, Bruno, Mulenga, Humphrey, Milieu Intérieur, Consortium, Tameris, Michele, Walzl, Gerhard, Malherbe, Stephanus, Thomas, Stephanie, Hatherill, Mark, Bilek, Nicole, Scriba, Thomas, Albert, Matthew, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Cape Town, Datactix, Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Stellenbosch University, Insitro [San Francisco], We acknowledge the Bill and Melinda Gates Foundation (OPP1114368) for funding the study and additional support from the French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence ' Milieu Intérieur' Grant ANR-10-LABX-69-01. For clinical collection of TB patient samples included in the replication cohort we acknowledge support from the Bill and Melinda Gates Foundation (OPP1155128), the European and Developing Countries Clinical Trials Partnership (96425), and the Intramural Research Program of the NIAID, NIH, and the National Institutes of Health (1U01AI115619-01). EN is an International Society for Advancement of Cytometry (ISAC) Marylou Ingram Scholar and AL was supported by the Fondation Recherche Médicale (SPF20170938617)., We acknowledge the UTechS CB and Icareb platforms of the Center for Translational Research, Institut Pasteur. We are grateful to the study participants and the SATVI clinical and laboratory teams., The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker), Andres Alcover, Hugues Aschard, Kalla Astrom (Lund University), Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay (EPFL, Lausanne) Odile Gelpi, Ivo Gomperts-Boneca, Milena Hasan, Serge Hercberg (Université Paris 13), Olivier Lantz (Institut Curie), Claude Leclerc, Hugo Mouquet, Etienne Patin, Sandra Pellegrini, Stanislas Pol (Hôpital Côchin), Antonio Rausell (INSERM UMR 1163 –Institut Imagine), Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis (Institut Curie), Frédéric Tangy, Eric Tartour (Hôpital Européen George Pompidou), Antoine Toubert (Hôpital Saint-Louis), Mathilde Touvier (Université Paris 13), Marie-Noëlle Ungeheuer, Matthew L. Albert (Insitro), Darragh Duffy, Lluis Quintana-Murci, ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]

Subjects
Patient stratification, Tuberculosis, biomarkers, [SDV.IMM]Life Sciences [q-bio]/Immunology, bacterial infections and mycoses, Immune profiling, cytokines
Abstract

International audience; BackgroundTuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and is a major public health problem. Clinical challenges include the lack of a blood-based test for active disease. Current blood-based tests, such as QuantiFERON (QFT) do not distinguish active TB disease from asymptomatic Mtb infection.MethodsWe hypothesized that TruCulture, an immunomonitoring method for whole blood stimulation, could discriminate active disease from latent Mtb infection (LTBI). We stimulated whole blood from active TB patients and compared to LTBI donors. Mtb- specific antigens and live bacillus Calmette-Guerin (BCG) were used as stimuli, with direct comparison to QFT. Protein analyses were performed using conventional and digital ELISA, as well as Luminex.ResultsTruCulture showed discrimination of active TB cases from LTBI (p < 0.0001 AUC = 0.81) as compared to QFT (p = 0.45 AUC = 0.56), based on an IFNγ readout after Mtb antigen stimulation. This result was replicated in an independent cohort (AUC = 0.89). In exploratory analyses, TB stratification could be further improved by the Mtb Ag/BCG IFNγ ratio (p < 0.0001 AUC = 0.91). Finally, the combination of digital ELISA and transcriptional analysis showed that LTBI donors with high IFNγ clustered with TB patients, suggesting the possibility to identify sub-clinical disease.ConclusionsTruCulture offers a next-generation solution for whole blood stimulation and immunomonitoring with the possibility to discriminate active and latent infection.

Published
2020

16. Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial

Author

Tameris, Michele, Mearns, Helen, Penn-Nicholson, Adam, Gregg, Yolande, Bilek, Nicole, Mabwe, Simbarashe, Geldenhuys, Hennie, Shenje, Justin, Luabeya, Angelique Kany K., Murillo, Ingrid, Doce, Juana, Aguilo, Nacho, Marinova, Dessislava, Puentes, Eugenia, Rodríguez, Esteban, Gonzalo-Asensiom, Jesús, Fritzell, Bernard, Thole, Jelle, Martin, Carlos, Scriba, Thomas J., Hatherill, Mark, Africa, Hadn, Arendsen, Denis, Botes, Natasja, Cloete, Yolundi, De Kock, Marwou, Erasmus, Margaret, Jack, Lungisa, Kafaar, Fazlin, Kalepu, Xoliswa, Khomba, Nondumiso Gloria, Kruger, Sandra, Leopeng, Thelma, Makhethe, Lebohang, Mouton, Angelique, Mulenga, Humphrey, Musvosvi, Munyaradzi, Noble, Julia, Opperman, Fajwa, Reid, Tim, Rossouw, Susan, Schreuder, Constance, Smit, Erica, Steyn, Marcia, Tyambethu, Petrus, Van Rooyen, Elma, Veldsman, Ashley, and MTBVAC Clinical Trial Team

Abstract

Background: Infants are a key target population for new tuberculosis vaccines. We assessed the safety and immunogenicity of the live-attenuated Mycobacterium tuberculosis vaccine candidate MTBVAC in adults and infants in a region where transmission of tuberculosis is very high. Methods: We did a randomised, double-blind, BCG-controlled, dose-escalation trial at the South African Tuberculosis Vaccine Initiative site near Cape Town, South Africa. Healthy adult community volunteers who were aged 18–50 years, had received BCG vaccination as infants, were HIV negative, had negative interferon-¿ release assay (IGRA) results, and had no personal history of tuberculosis or current household contact with someone with tuberculosis were enrolled in a safety cohort. Infants born to HIV-negative women with no personal history of tuberculosis or current household contact with a person with tuberculosis and who were 96 h old or younger, generally healthy, and had not yet received routine BCG vaccination were enrolled in a separate infant cohort. Eligible adults were randomly assigned (1:1) to receive either BCG Vaccine SSI (5 × 105 colony forming units [CFU] of Danish strain 1331 in 0·1 mL diluent) or MTBVAC (5 × 105 CFU in 0·1 mL) intradermally in the deltoid region of the arm. After favourable review of 28-day reactogenicity and safety data in the adult cohort, infants were randomly assigned (1:3) to receive either BCG Vaccine SSI (2·5 × 105 CFU in 0·05 mL diluent) or MTBVAC in three sequential cohorts of increasing MTBVAC dose (2·5 × 103 CFU, 2·5 × 104 CFU, and 2·5 × 105 CFU in 0·05 mL) intradermally in the deltoid region of the arm. QuantiFERON-TB Gold In-Tube IGRA was done on days 180 and 360. For both randomisations, a pre-prepared block randomisation schedule was used. Participants (and their parents or guardians in the case of infant participants), investigators, and other clinical and laboratory staff were masked to intervention allocation. The primary outcomes, which were all measured in the infant cohort, were solicited and unsolicited local adverse events and serious adverse events until day 360; non-serious systemic adverse events until day 28 and vaccine-specific CD4 and CD8 T-cell responses on days 7, 28, 70, 180, and 360. Secondary outcomes measured in adults were local injection-site and systemic reactions and haematology and biochemistry at study day 7 and 28. Safety analyses and immunogenicity analyses were done in all participants who received a dose of vaccine. This trial is registered with ClinicalTrials.gov, number NCT02729571. Findings: Between Sept 29, 2015, and Nov 16, 2015, 62 adults were screened and 18 were enrolled and randomly assigned, nine each to the BCG and MTBVAC groups. Between Feb 12, 2016, and Sept 21, 2016, 36 infants were randomly assigned—eight to the BCG group, nine to the 2·5 × 103 CFU MTBVAC group, nine to the 2·5 × 104 CFU group, and ten to the 2·5 × 105 CFU group. Mild injection-site reactions occurred only in infants in the BCG and the 2·5 × 105 CFU MTBVAC group, with no evidence of local or regional injection-site complications. Systemic adverse events were evenly distributed across BCG and MTBVAC dose groups, and were mostly mild in severity. Eight serious adverse events were reported in seven vaccine recipients (one adult MTBVAC recipient, one infant BCG recipient, one infant in the 2·5 × 103 CFU MTBVAC group, two in the 2·5 × 104 CFU MTBVAC group, and two in the 2·5 × 105 CFU MTBVAC group), including one infant in the 2·5 × 103 CFU MTBVAC group treated for unconfirmed tuberculosis and one in the 2·5 × 105 CFU MTBVAC group treated for unlikely tuberculosis. One infant died as a result of possible viral pneumonia. Vaccination with all MTBVAC doses induced durable antigen-specific T-helper-1 cytokine-expressing CD4 cell responses in infants that peaked 70 days after vaccination and were detectable 360 days after vaccination. For the highest MTBVAC dose (ie, 2·5 × 105 CFU), these responses exceeded responses induced by an equivalent dose of the BCG vaccine up to 360 days after vaccination. Dose-related IGRA conversion was noted in three (38%) of eight infants in the 2·5 × 103 CFU MTBVAC group, six (75%) of eight in the 2·5 × 104 CFU MTBVAC group, and seven (78%) of nine in the 2·5 × 105 CFU MTBVAC group at day 180, compared with none of seven infants in the BCG group. By day 360, IGRA reversion had occurred in all three infants (100%) in the 2·5 × 103 CFU MTBVAC group, four (67%) of the six in the 2·5 × 104 CFU MTBVAC group, and three (43%) of the seven in the 2·5 × 105 CFU MTBVAC group. Interpretation: MTBVAC had acceptable reactogenicity, and induced a durable CD4 cell response in infants. The evidence of immunogenicity supports progression of MTBVAC into larger safety and efficacy trials, but also confounds interpretation of tests for M tuberculosis infection, highlighting the need for stringent endpoint definition. Funding: Norwegian Agency for Development Cooperation, TuBerculosis Vaccine Initiative, UK Department for International Development, and Biofabri.

Published
2020

17. Peripheral Blood Mucosal-Associated Invariant T Cells in Tuberculosis Patients and Healthy Mycobacterium tuberculosis-Exposed Controls

Author

Suliman, Sara, primary, Gela, Anele, additional, Mendelsohn, Simon C, additional, Iwany, Sarah K, additional, Tamara, Kattya Lopez, additional, Mabwe, Simbarashe, additional, Bilek, Nicole, additional, Darboe, Fatoumatta, additional, Fisher, Michelle, additional, Corbett, Alexandra J, additional, Kjer-Nielsen, Lars, additional, Eckle, Sidonia B G, additional, Huang, Chuan-Chin, additional, Zhang, Zibiao, additional, Lewinsohn, David M, additional, McCluskey, James, additional, Rossjohn, Jamie, additional, Hatherill, Mark, additional, León, Segundo R, additional, Calderon, Roger I, additional, Lecca, Leonid, additional, Murray, Megan, additional, Scriba, Thomas J, additional, Van Rhijn, Ildiko, additional, and Moody, D Branch, additional

Published
2020
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18. Longitudinal Dynamics of a Blood Transcriptomic Signature of Tuberculosis.

Author

Mulenga, Humphrey, Musvosvi, Munyaradzi, Mendelsohn, Simon C., Penn-Nicholson, Adam, Mbandi, Stanley Kimbung, Fiore-Gartland, Andrew, Tameris, Michele, Mabwe, Simbarashe, Africa, Hadn, Bilek, Nicole, Kafaar, Fazlin, Khader, Shabaana A., Carstens, Balie, Hadley, Katie, Hikuam, Chris, Erasmus, Mzwandile, Jaxa, Lungisa, Raphela, Rodney, Nombida, Onke, and Kaskar, Masooda

Subjects
TUBERCULOSIS, BIOMARKERS, RESPIRATORY infections, HIV, MESSENGER RNA
Abstract

Rationale: Performance of blood transcriptomic tuberculosis (TB) signatures in longitudinal studies and effects of TB-preventive therapy and coinfection with HIV or respiratory organisms on transcriptomic signatures has not been systematically studied. Objectives: We evaluated longitudinal kinetics of an 11-gene blood transcriptomic TB signature, RISK11, and effects of TB-preventive therapy (TPT) and respiratory organisms on RISK11 signature score, in HIV-uninfected and HIV-infected individuals. Methods: RISK11 was measured in a longitudinal study of RISK11-guided TPT in HIV-uninfected adults, a cross-sectional respiratory organisms cohort, or a longitudinal study in people living with HIV (PLHIV). HIV-uninfected RISK11+ participants were randomized to TPT or no TPT; RISK11- participants received no TPT. PLHIV received standard-of-care antiretroviral therapy and TPT. In the cross-sectional respiratory organisms cohort, viruses and bacteria in nasopharyngeal and oropharyngeal swabs were quantified by real-time quantitative PCR. Measurements and Main Results: RISK11+ status was transient in most of the 128 HIV-negative participants with longitudinal samples; more than 70% of RISK11+ participants reverted to RISK11- by 3 months, irrespective of TPT. By comparison, reversion from a RISK11+ state was less common in 645 PLHIV (42.1%). Non-HIV viral and nontuberculous bacterial organisms were detected in 7.2% and 38.9% of the 1,000 respiratory organisms cohort participants, respectively, and among those investigated for TB, 3.8% had prevalent disease. Median RISK11 scores (%) were higher in participants with viral organisms alone (46.7%), viral and bacterial organisms (42.8%), or prevalent TB (85.7%) than those with bacterial organisms other than TB (13.4%) or no organisms (14.2%). RISK11 could not discriminate between prevalent TB and viral organisms. Conclusions: Positive RISK11 signature status is often transient, possibly due to intercurrent viral infection, highlighting potentially important challenges for implementation of these biomarkers as new tools for TB control. [ABSTRACT FROM AUTHOR]

Published
2021
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19. Immune Profiling Enables Stratification of Patients With Active Tuberculosis Disease or Mycobacterium tuberculosis Infection.

Author

Duffy, Darragh, Nemes, Elisa, Llibre, Alba, Rouilly, Vincent, Musvosvi, Munyaradzi, Smith, Nikaïa, Filander, Elizabeth, Africa, Hadn, Mabwe, Simbarashe, Jaxa, Lungisa, Charbit, Bruno, Mulenga, Humphrey, Tameris, Michele, Walzl, Gerhard, Malherbe, Stephanus, Thomas, Stephanie, Hatherill, Mark, Bilek, Nicole, Scriba, Thomas J, and Albert, Matthew L

Subjects
MYCOBACTERIAL disease diagnosis, ANTIGEN analysis, BLOOD testing, PROTEIN analysis, TUBERCULOSIS diagnosis, INTERFERON gamma release tests, CYTOKINES, BIOMARKERS, PREDICTIVE tests, BACILLUS (Bacteria), IMMUNOPHENOTYPING, ENZYME-linked immunosorbent assay
Abstract

Background Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and is a major public health problem. Clinical challenges include the lack of a blood-based test for active disease. Current blood-based tests, such as QuantiFERON (QFT) do not distinguish active TB disease from asymptomatic Mtb infection. Methods We hypothesized that TruCulture, an immunomonitoring method for whole-blood stimulation, could discriminate active disease from latent Mtb infection (LTBI). We stimulated whole blood from patients with active TB and compared with LTBI donors. Mtb -specific antigens and live bacillus Calmette-Guérin (BCG) were used as stimuli, with direct comparison to QFT. Protein analyses were performed using conventional and digital enzyme-linked immunosorbent assay (ELISA), as well as Luminex. Results TruCulture showed discrimination of active TB cases from LTBI (P <.0001, AUC =.81) compared with QFT (P =.45, AUC =.56), based on an interferon γ (IFNγ) readout after Mtb antigen (Ag) stimulation. This result was replicated in an independent cohort (AUC =.89). In exploratory analyses, TB stratification could be further improved by the Mtb antigen to BCG IFNγ ratio (P <.0001, AUC =.91). Finally, the combination of digital ELISA and transcriptional analysis showed that LTBI donors with high IFNγ clustered with patients with TB, suggesting the possibility to identify subclinical disease. Conclusions TruCulture offers a next-generation solution for whole-blood stimulation and immunomonitoring with the possibility to discriminate active and latent infection. [ABSTRACT FROM AUTHOR]

Published
2021
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20. Noninvasive Detection of Tuberculosis by Oral Swab Analysis

Author

Luabeya, Angelique K., Wood, Rachel C., Shenje, Justin, Filander, Elizabeth, Ontong, Cynthia, Mabwe, Simbarashe, Africa, Hadn, Nguyen, Felicia K., Olson, Alaina, Weigel, Kris M., Jones-Engel, Lisa, Hatherill, Mark, and Cangelosi, Gerard A.

Subjects
Adult, Diagnostic Tests, Routine, GeneXpert MTB/RIF, Sputum, food and beverages, oral swab, Mycobacteriology and Aerobic Actinomycetes, Mycobacterium tuberculosis, Sensitivity and Specificity, point of care, respiratory tract diseases, fluids and secretions, PCR, tuberculosis, molecular diagnosis, Humans, Tuberculosis, Pulmonary, nonsputum sampling, POC
Abstract

Diagnostic tests for tuberculosis (TB) usually require collection of sputum, a viscous material derived from human airways. Sputum can be difficult and hazardous to collect and challenging to process in the laboratory., Diagnostic tests for tuberculosis (TB) usually require collection of sputum, a viscous material derived from human airways. Sputum can be difficult and hazardous to collect and challenging to process in the laboratory. Oral swabs have been proposed as alternative sample types that are noninvasive and easy to collect. This study evaluated the biological feasibility of oral swab analysis (OSA) for the diagnosis of TB. Swabs were tested from South African adult subjects, including sputum GeneXpert MTB/RIF (GeneXpert)-confirmed TB patients (n = 138), sputum GeneXpert-negative but culture-positive TB patients (n = 10), ill non-TB patients (n = 37), and QuantiFERON-negative controls (n = 34). Swabs were analyzed by using a manual, nonnested quantitative PCR (qPCR) targeting IS6110. Two swab brands and three sites within the oral cavity were compared. Tongue swabbing yielded significantly stronger signals than cheek or gum swabbing. A flocked swab performed better than a more expensive paper swab. In a two-phase study, tongue swabs (two per subject) exhibited a combined sensitivity of 92.8% relative to sputum GeneXpert. Relative to all laboratory-diagnosed TB, the diagnostic yields of sputum GeneXpert (1 sample per subject) and OSA (2 samples per subject) were identical at 49/59 (83.1%) each. The specificity of the OSA was 91.5%. An analysis of “air swabs” suggested that most false-positive results were due to contamination of manual PCRs. With the development of appropriate automated methods, oral swabs could facilitate TB diagnosis in clinical settings and patient populations that are limited by the physical or logistical challenges of sputum collection.

Published
2019

21. Diagnostic performance of an optimized transcriptomic signature of risk of tuberculosis in cryopreserved peripheral blood mononuclear cells

Author

Matiwane, Sindile, Jaxa, Lungisa, Xoyana, Noncedo, Schreuder, Constance, Botes, Janelle, Africa, Hadn, Makhethe, Lebohang, Steyn, Marcia, Darboe, Fatoumatta, Mbandi, Stanley Kimbung, Thompson, Ethan G., Fisher, Michelle, Rodo, Miguel, van Rooyen, Michele, Filander, Elizabeth, Bilek, Nicole, Mabwe, Simbarashe, Hatherill, Mark, Zak, Daniel E., Penn-Nicholson, Adam, and Scriba, Thomas J.

Published
2018
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22. Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial

Author

Tameris, Michele, primary, Mearns, Helen, additional, Penn-Nicholson, Adam, additional, Gregg, Yolande, additional, Bilek, Nicole, additional, Mabwe, Simbarashe, additional, Geldenhuys, Hennie, additional, Shenje, Justin, additional, Luabeya, Angelique Kany Kany, additional, Murillo, Ingrid, additional, Doce, Juana, additional, Aguilo, Nacho, additional, Marinova, Dessislava, additional, Puentes, Eugenia, additional, Rodríguez, Esteban, additional, Gonzalo-Asensio, Jesús, additional, Fritzell, Bernard, additional, Thole, Jelle, additional, Martin, Carlos, additional, Scriba, Thomas J, additional, Hatherill, Mark, additional, Africa, Hadn, additional, Arendsen, Denis, additional, Botes, Natasja, additional, Cloete, Yolundi, additional, De Kock, Marwou, additional, Erasmus, Margaret, additional, Jack, Lungisa, additional, Kafaar, Fazlin, additional, Kalepu, Xoliswa, additional, Khomba, Nondumiso Gloria, additional, Kruger, Sandra, additional, Leopeng, Thelma, additional, Makhethe, Lebohang, additional, Mouton, Angelique, additional, Mulenga, Humphrey, additional, Musvosvi, Munyaradzi, additional, Noble, Julia, additional, Opperman, Fajwa, additional, Reid, Tim, additional, Rossouw, Susan, additional, Schreuder, Constance, additional, Smit, Erica, additional, Steyn, Marcia, additional, Tyambethu, Petrus, additional, Van Rooyen, Elma, additional, and Veldsman, Ashley, additional

Published
2019
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23. Dose Optimization of H56:IC31 Vaccine for Tuberculosis-Endemic Populations. A Double-Blind, Placebo-controlled, Dose-Selection Trial

Author

Suliman, Sara, primary, Luabeya, Angelique Kany Kany, additional, Geldenhuys, Hennie, additional, Tameris, Michele, additional, Hoff, Soren T., additional, Shi, Zhongkai, additional, Tait, Dereck, additional, Kromann, Ingrid, additional, Ruhwald, Morten, additional, Rutkowski, Kathryn Tucker, additional, Shepherd, Barbara, additional, Hokey, David, additional, Ginsberg, Ann M., additional, Hanekom, Willem A., additional, Andersen, Peter, additional, Scriba, Thomas J., additional, Hatherill, Mark, additional, Oelofse, Rachel Elizabeth, additional, Stone, Lynnett, additional, Swarts, Anne Marie, additional, Onrust, Raida, additional, Jacobs, Gail, additional, Coetzee, Lorraine, additional, Khomba, Gloria, additional, Diamond, Bongani, additional, Companie, Alessandro, additional, Veldsman, Ashley, additional, Mulenga, Humphrey, additional, Cloete, Yolundi, additional, Steyn, Marcia, additional, Africa, Hadn, additional, Nkantsu, Lungisa, additional, Smit, Erica, additional, Botes, Janelle, additional, Bilek, Nicole, additional, and Mabwe, Simbarashe, additional

Published
2019
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24. Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination

Author

Nemes, Elisa, primary, Geldenhuys, Hennie, additional, Rozot, Virginie, additional, Rutkowski, Kathryn T., additional, Ratangee, Frances, additional, Bilek, Nicole, additional, Mabwe, Simbarashe, additional, Makhethe, Lebohang, additional, Erasmus, Mzwandile, additional, Toefy, Asma, additional, Mulenga, Humphrey, additional, Hanekom, Willem A., additional, Self, Steven G., additional, Bekker, Linda-Gail, additional, Ryall, Robert, additional, Gurunathan, Sanjay, additional, DiazGranados, Carlos A., additional, Andersen, Peter, additional, Kromann, Ingrid, additional, Evans, Thomas, additional, Ellis, Ruth D., additional, Landry, Bernard, additional, Hokey, David A., additional, Hopkins, Robert, additional, Ginsberg, Ann M., additional, Scriba, Thomas J., additional, and Hatherill, Mark, additional

Published
2018
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25. T-cell biomarkers for diagnosis of tuberculosis: candidate evaluation by a simple whole blood assay for clinical translation

Author

Musvosvi, Munyaradzi, primary, Duffy, Darragh, additional, Filander, Elizabeth, additional, Africa, Hadn, additional, Mabwe, Simbarashe, additional, Jaxa, Lungisa, additional, Bilek, Nicole, additional, Llibre, Alba, additional, Rouilly, Vincent, additional, Hatherill, Mark, additional, Albert, Matthew, additional, Scriba, Thomas J., additional, and Nemes, Elisa, additional

Published
2018
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26. Diagnostic performance of an optimized transcriptomic signature of risk of tuberculosis in cryopreserved peripheral blood mononuclear cells

Author

Darboe, Fatoumatta, primary, Mbandi, Stanley Kimbung, additional, Thompson, Ethan G., additional, Fisher, Michelle, additional, Rodo, Miguel, additional, van Rooyen, Michele, additional, Filander, Elizabeth, additional, Bilek, Nicole, additional, Mabwe, Simbarashe, additional, Hatherill, Mark, additional, Zak, Daniel E., additional, Penn-Nicholson, Adam, additional, Scriba, Thomas J., additional, Matiwane, Sindile, additional, Jaxa, Lungisa, additional, Xoyana, Noncedo, additional, Schreuder, Constance, additional, Botes, Janelle, additional, Africa, Hadn, additional, Makhethe, Lebohang, additional, and Steyn, Marcia, additional

Published
2018
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27. Detection of Tuberculosis Recurrence, Diagnosis and Treatment Response by a Blood Transcriptomic Risk Signature in HIV-Infected Persons on Antiretroviral Therapy.

Author

Darboe, Fatoumatta, Mbandi, Stanley Kimbung, Naidoo, Kogieleum, Yende-Zuma, Nonhlanhla, Lewis, Lara, Thompson, Ethan G., Duffy, Fergal J., Fisher, Michelle, Filander, Elizabeth, van Rooyen, Michele, Bilek, Nicole, Mabwe, Simbarashe, McKinnon, Lyle R., Chegou, Novel, Loxton, Andre, Walzl, Gerhard, Tromp, Gerard, Padayatchi, Nesri, Govender, Dhineshree, and Hatherill, Mark

Subjects
HIV-positive persons, THERAPEUTICS, HIV, TUBERCULOSIS, MYCOBACTERIUM tuberculosis, TUBERCULOSIS diagnosis, VIRAL load
Abstract

HIV-infected individuals are at high risk of tuberculosis disease and those with prior tuberculosis episodes are at even higher risk of disease recurrence. A non-sputum biomarker that identifies individuals at highest tuberculosis risk would allow targeted microbiological testing and appropriate treatment and also guide need for prolonged therapy. We determined the utility of a previously developed whole blood transcriptomic correlate of risk (COR) signature for (1) predicting incident recurrent tuberculosis, (2) tuberculosis diagnosis and (3) its potential utility for tuberculosis treatment monitoring in HIV-infected individuals. We retrieved cryopreserved blood specimens from three previously completed clinical studies and measured the COR signature by quantitative microfluidic real-time-PCR. The signature differentiated recurrent tuberculosis progressors from non-progressors within 3 months of diagnosis with an area under the Receiver-operating characteristic (ROC) curve (AUC) of 0.72 (95% confidence interval (CI), 0.58–0.85) amongst HIV-infected individuals on antiretroviral therapy (ART). Twenty-five of 43 progressors (58%) were asymptomatic at microbiological diagnosis and thus had subclinical disease. The signature showed excellent diagnostic discrimination between HIV-uninfected tuberculosis cases and controls (AUC 0.97; 95%CI 0.94–1). Performance was lower in HIV-infected individuals (AUC 0.83; 95%CI 0.81–0.96) and signature scores were directly associated with HIV viral loads. Tuberculosis treatment response in HIV-infected individuals on ART with a new recurrent tuberculosis diagnosis was also assessed. Signature scores decreased significantly during treatment. However, pre-treatment scores could not differentiate between those who became sputum negative before and after 2 months. Direct application of the unmodified blood transcriptomic COR signature detected subclinical and active tuberculosis by blind validation in HIV-infected individuals. However, prognostic performance for recurrent tuberculosis, and performance as diagnostic and as treatment monitoring tool in HIV-infected persons was inferior to published results from HIV-negative cohorts. Our results suggest that performance of transcriptomic signatures comprising interferon stimulated genes are negatively affected in HIV-infected individuals, especially in those with incompletely suppressed viral loads. [ABSTRACT FROM AUTHOR]

Published
2019
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28. Live-attenuated Mycobacterium tuberculosisvaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial

Author

Tameris, Michele, Mearns, Helen, Penn-Nicholson, Adam, Gregg, Yolande, Bilek, Nicole, Mabwe, Simbarashe, Geldenhuys, Hennie, Shenje, Justin, Luabeya, Angelique Kany Kany, Murillo, Ingrid, Doce, Juana, Aguilo, Nacho, Marinova, Dessislava, Puentes, Eugenia, Rodríguez, Esteban, Gonzalo-Asensio, Jesús, Fritzell, Bernard, Thole, Jelle, Martin, Carlos, Scriba, Thomas J, Hatherill, Mark, Africa, Hadn, Arendsen, Denis, Botes, Natasja, Cloete, Yolundi, De Kock, Marwou, Erasmus, Margaret, Jack, Lungisa, Kafaar, Fazlin, Kalepu, Xoliswa, Khomba, Nondumiso Gloria, Kruger, Sandra, Leopeng, Thelma, Makhethe, Lebohang, Mouton, Angelique, Mulenga, Humphrey, Musvosvi, Munyaradzi, Noble, Julia, Opperman, Fajwa, Reid, Tim, Rossouw, Susan, Schreuder, Constance, Smit, Erica, Steyn, Marcia, Tyambethu, Petrus, Van Rooyen, Elma, and Veldsman, Ashley

Abstract

Infants are a key target population for new tuberculosis vaccines. We assessed the safety and immunogenicity of the live-attenuated Mycobacterium tuberculosisvaccine candidate MTBVAC in adults and infants in a region where transmission of tuberculosis is very high.

Published
2019
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29. Multidimensional analyses reveal modulation of adaptive and innate immune subsets by tuberculosis vaccines.

Author

Rozot, Virginie, Nemes, Elisa, Geldenhuys, Hennie, Musvosvi, Munyaradzi, Toefy, Asma, Rantangee, Frances, Makhethe, Lebohang, Erasmus, Mzwandile, Bilek, Nicole, Mabwe, Simbarashe, Finak, Greg, Fulp, William, Ginsberg, Ann M., Hokey, David A., Shey, Muki, Gurunathan, Sanjay, DiazGranados, Carlos, Bekker, Linda-Gail, Hatherill, Mark, and Scriba, Thomas J.

Subjects
NATURAL immunity, TUBERCULOSIS vaccines, IMMUNE response, DRUG efficacy, CD4 antigen
Abstract

We characterize the breadth, function and phenotype of innate and adaptive cellular responses in a prevention of Mycobacterium tuberculosis infection trial. Responses are measured by whole blood intracellular cytokine staining at baseline and 70 days after vaccination with H4:IC31 (subunit vaccine containing Ag85B and TB10.4), Bacille Calmette-Guerin (BCG, a live attenuated vaccine) or placebo (n = ~30 per group). H4:IC31 vaccination induces Ag85B and TB10.4-specific CD4 T cells, and an unexpected NKTlike subset, that expresses IFN-γ, TNF and/or IL-2. BCG revaccination increases frequencies of CD4 T cell subsets that either express Th1 cytokines or IL-22, and modestly increases IFNγ-producing NK cells. In vitro BCG re-stimulation also triggers responses by donor-unrestricted T cells, which may contribute to host responses against mycobacteria. BCG, which demonstrated efficacy against sustained Mycobacterium tuberculosis infection, modulates multiple immune cell subsets, in particular conventional Th1 and Th22 cells, which should be investigated in discovery studies of correlates of protection. Virginie Rozot and Elisa Nemes et al. report comprehensive profiling of immune responses from participants in a recent clinical trial of the H4:IC31 and BCG vaccines against Mycobacterium tuberculosis infection. Using a novel analysis platform, they uncover complex vaccine-induced modulation of different immune cell subsets. [ABSTRACT FROM AUTHOR]

Published
2020
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30. Noninvasive Detection of Tuberculosis by Oral Swab Analysis

Author

Luabeya, Angelique K., Wood, Rachel C., Shenje, Justin, Filander, Elizabeth, Ontong, Cynthia, Mabwe, Simbarashe, Africa, Hadn, Nguyen, Felicia K., Olson, Alaina, Weigel, Kris M., Jones-Engel, Lisa, Hatherill, Mark, and Cangelosi, Gerard A.

Abstract

Diagnostic tests for tuberculosis (TB) usually require collection of sputum, a viscous material derived from human airways. Sputum can be difficult and hazardous to collect and challenging to process in the laboratory.

Published
2018
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31. Diagnostic Accuracy of Early Secretory Antigenic Target-6-Free Interferon-gamma Release Assay Compared to QuantiFERON-TB Gold In-tube.

Author

Nemes E, Abrahams D, Scriba TJ, Ratangee F, Keyser A, Makhethe L, Erasmus M, Mabwe S, Bilek N, Rozot V, Geldenhuys H, Hatherill M, Lempicki MD, Holm LL, Bogardus L, Ginsberg AM, Blauenfeldt T, Smith B, Ellis RD, Loxton AG, Walzl G, Andersen P, and Ruhwald M

Subjects
Adolescent, Antigens, Bacterial immunology, Bacterial Proteins immunology, Child, Cohort Studies, Female, Humans, Male, Mycobacterium tuberculosis immunology, ROC Curve, Reproducibility of Results, Tuberculosis blood, Tuberculosis immunology, Tuberculosis Vaccines administration & dosage, Tuberculosis Vaccines immunology, Interferon-gamma blood, Interferon-gamma Release Tests, Reagent Kits, Diagnostic, Tuberculosis diagnosis
Abstract

Background: Early secretory antigenic target-6 (ESAT-6) is an immunodominant Mycobacterium tuberculosis (M.tb) antigen included in novel vaccines against tuberculosis (TB) and in interferon-gamma (IFN-γ) release assays (IGRAs). Therefore, the availability of an ESAT-6-free IGRA is essential to determine M.tb infection status following vaccination with ESAT-6-containing vaccines. We aimed to qualify a recently developed ESAT-6-free IGRA and to assess its diagnostic performance in comparison to QuantiFERON-TB Gold In-tube (QFT)., Methods: Participants with different levels of M.tb exposure and TB disease were enrolled to determine the ESAT-6-free IGRA cutoff, test assay performance in independent cohorts compared to standard QFT, and perform a technical qualification of antigen-coated blood collection tubes., Results: ESAT-6-free IGRA antigen recognition was evaluated in QFT-positive and QFT-negative South African adolescents. The ESAT-6-free IGRA cutoff was established at 0.61 IU/mL, based on receiver operating characteristic analysis in M.tb-unexposed controls and microbiologically confirmed pulmonary TB patients. In an independent cohort of healthy adolescents, levels of IFN-γ released in QFT and ESAT-6-free IGRA were highly correlated (P < .0001, r = 0.83) and yielded comparable positivity rates, 41.5% and 43.5%, respectively, with 91% concordance between the tests (kappa = 0.82; 95% confidence interval, 0.74-0.90; McNemar test P = .48). ESAT-6-free IGRA blood collection tubes had acceptable lot-to-lot variability, precision, and stability., Conclusions: The novel ESAT-6-free IGRA had diagnostic accuracy comparable to QFT and is suitable for use in clinical trials to assess efficacy of candidate TB vaccines to prevent established M.tb infection., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Published
2019
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32. Functional, Antigen-Specific Stem Cell Memory (T SCM ) CD4 + T Cells Are Induced by Human Mycobacterium tuberculosis Infection.

Author

Mpande CAM, Dintwe OB, Musvosvi M, Mabwe S, Bilek N, Hatherill M, Nemes E, and Scriba TJ

Subjects
Adolescent, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Cell Proliferation, Cross-Sectional Studies, Cytokines immunology, Female, Humans, Male, Receptors, Chemokine immunology, Th1 Cells pathology, Th17 Cells pathology, Tuberculosis pathology, Antigens, Bacterial immunology, Immunologic Memory, Mycobacterium bovis immunology, Mycobacterium tuberculosis immunology, Th1 Cells immunology, Th17 Cells immunology, Tuberculosis immunology
Abstract

Background: Maintenance of long-lasting immunity is thought to depend on stem cell memory T cells (T SCM ), which have superior self-renewing capacity, longevity and proliferative potential compared with central memory (T CM ) or effector (T EFF ) T cells. Our knowledge of T SCM derives primarily from studies of virus-specific CD8 + T SCM . We aimed to determine if infection with Mycobacterium tuberculosis ( M. tb ), the etiological agent of tuberculosis, generates antigen-specific CD4 + T SCM and to characterize their functional ontology., Methods: We studied T cell responses to natural M. tb infection in a longitudinal adolescent cohort of recent QuantiFERON-TB Gold (QFT) converters and three cross-sectional QFT + adult cohorts; and to bacillus Calmette-Guerin (BCG) vaccination in infants. M. tb and/or BCG-specific CD4 T cells were detected by flow cytometry using major histocompatibility complex class II tetramers bearing Ag85, CFP-10, or ESAT-6 peptides, or by intracellular cytokine staining. Transcriptomic analyses of M. tb -specific tetramer + CD4 + T SCM (CD45RA + CCR7 + CD27 + ) were performed by microfluidic qRT-PCR, and functional and phenotypic characteristics were confirmed by measuring expression of chemokine receptors, cytotoxic molecules and cytokines using flow cytometry., Results: M. tb -specific T SCM were not detected in QFT-negative persons. After QFT conversion frequencies of T SCM increased to measurable levels and remained detectable thereafter, suggesting that primary M. tb infection induces T SCM cells. Gene expression (GE) profiling of tetramer + T SCM showed that these cells were distinct from bulk CD4 + naïve T cells (T N ) and shared features of bulk T SCM and M. tb -specific tetramer + T CM and T EFF cells. These T SCM were predominantly CD95 + and CXCR3 + , markers typical of CD8 + T SCM . Tetramer + T SCM expressed significantly higher protein levels of CCR5, CCR6, CXCR3, granzyme A, granzyme K, and granulysin than bulk T N and T SCM cells. M. tb -specific T SCM were also functional, producing IL-2, IFN-γ, and TNF-α upon antigen stimulation, and their frequencies correlated positively with long-term BCG-specific CD4 + T cell proliferative potential after infant vaccination., Conclusion: Human infection with M. tb induced distinct, antigen-specific CD4 + T SCM cells endowed with effector functions, including expression of cytotoxic molecules and Th1 cytokines, and displayed chemokine receptor profiles consistent with memory Th1/17 cells. Induction of CD4 + T SCM should be considered for vaccination approaches that aim to generate long-lived memory T cells against M. tb .

Published
2018
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