PMID- 38012890 OWN - NLM STAT- MEDLINE DCOM- 20240226 LR - 20240313 IS - 1474-4457 (Electronic) IS - 1473-3099 (Linking) VI - 24 IP - 3 DP - 2024 Mar TI - Safety and immunogenicity of ChAdOx1 85A prime followed by MVA85A boost compared with BCG revaccination among Ugandan adolescents who received BCG at birth: a randomised, open-label trial. PG - 285-296 LID - S1473-3099(23)00501-7 [pii] LID - 10.1016/S1473-3099(23)00501-7 [doi] AB - BACKGROUND: BCG confers reduced, variable protection against pulmonary tuberculosis. A more effective vaccine is needed. We evaluated the safety and immunogenicity of candidate regimen ChAdOx1 85A-MVA85A compared with BCG revaccination among Ugandan adolescents. METHODS: After ChAdOx1 85A dose escalation and age de-escalation, we did a randomised open-label phase 2a trial among healthy adolescents aged 12-17 years, who were BCG vaccinated at birth, without evident tuberculosis exposure, in Entebbe, Uganda. Participants were randomly assigned (1:1) using a block size of 6, to ChAdOx1 85A followed by MVA85A (on day 56) or BCG (Moscow strain). Laboratory staff were masked to group assignment. Primary outcomes were solicited and unsolicited adverse events (AEs) up to day 28 and serious adverse events (SAEs) throughout the trial; and IFN-gamma ELISpot response to antigen 85A (day 63 [geometric mean] and days 0-224 [area under the curve; AUC). FINDINGS: Six adults (group 1, n=3; group 2, n=3) and six adolescents (group 3, n=3; group 4, n=3) were enrolled in the ChAdOx1 85A-only dose-escalation and age de-escalation studies (July to August, 2019). In the phase 2a trial, 60 adolescents were randomly assigned to ChAdOx1 85A-MVA85A (group 5, n=30) or BCG (group 6, n=30; December, 2019, to October, 2020). All 60 participants from groups 5 and 6 were included in the safety analysis, with 28 of 30 from group 5 (ChAdOx1 85A-MVA85A) and 29 of 30 from group 6 (BCG revaccination) analysed for immunogenicity outcomes. In the randomised trial, 60 AEs were reported among 23 (77%) of 30 participants following ChAdOx1 85A-MVA85A, 31 were systemic, with one severe event that occurred after the MVA85A boost that was rapidly self-limiting. All 30 participants in the BCG revaccination group reported at least one mild to moderate solicited AE; most were local reactions. There were no SAEs in either group. Ag85A-specific IFN-gamma ELISpot responses peaked on day 63 in the ChAdOx1 85A-MVA85A group and were higher in the ChAdOx1 85A-MVA85A group compared with the BCG revaccination group (geometric mean ratio 30.59 [95% CI 17.46-53.59], p<0.0001, day 63; AUC mean difference 57 091 [95% CI 40 524-73 658], p<0.0001, days 0-224). INTERPRETATION: The ChAdOx1 85A-MVA85A regimen was safe and induced stronger Ag85A-specific responses than BCG revaccination. Our findings support further development of booster tuberculosis vaccines. FUNDING: UK Research and Innovations and Medical Research Council. TRANSLATIONS: For the Swahili and Luganda translations of the abstract see Supplementary Materials section. CI - Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved. FAU - Wajja, Anne AU - Wajja A AD - MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; Department of Global Health, Amsterdam University Medical Centers, Amsterdam, Netherlands; Amsterdam Institute for Global Health and Development, Amsterdam University Medical Centers, Amsterdam, Netherlands; Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, UK. FAU - Nassanga, Beatrice AU - Nassanga B AD - MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; The Jenner Institute, Old Road Campus Research Building, University of Oxford, Oxford, UK; Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda. Electronic address: beatrice.nassanga@gmail.com. FAU - Natukunda, Agnes AU - Natukunda A AD - MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda. FAU - Serubanja, Joel AU - Serubanja J AD - MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda. FAU - Tumusiime, Josephine AU - Tumusiime J AD - MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda. FAU - Akurut, Helen AU - Akurut H AD - MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda. FAU - Oduru, Gloria AU - Oduru G AD - MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda. FAU - Nassuuna, Jacent AU - Nassuuna J AD - MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda. FAU - Kabagenyi, Joyce AU - Kabagenyi J AD - MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda. FAU - Morrison, Hazel AU - Morrison H AD - The Jenner Institute, Old Road Campus Research Building, University of Oxford, Oxford, UK; Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford, Churchill Hospital, Oxford, UK. FAU - Scott, Hannah AU - Scott H AD - The Jenner Institute, Old Road Campus Research Building, University of Oxford, Oxford, UK. FAU - Doherty, Rebecca Powell AU - Doherty RP AD - The Jenner Institute, Old Road Campus Research Building, University of Oxford, Oxford, UK. FAU - Marshall, Julia L AU - Marshall JL AD - The Jenner Institute, Old Road Campus Research Building, University of Oxford, Oxford, UK. FAU - Puig, Ingrid Cabrera AU - Puig IC AD - The Jenner Institute, Old Road Campus Research Building, University of Oxford, Oxford, UK. FAU - Cose, Stephen AU - Cose S AD - MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, UK. FAU - Kaleebu, Pontiano AU - Kaleebu P AD - MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, UK. FAU - Webb, Emily L AU - Webb EL AD - Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK. FAU - Satti, Iman AU - Satti I AD - The Jenner Institute, Old Road Campus Research Building, University of Oxford, Oxford, UK. FAU - McShane, Helen AU - McShane H AD - The Jenner Institute, Old Road Campus Research Building, University of Oxford, Oxford, UK; Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford, Churchill Hospital, Oxford, UK. FAU - Elliott, Alison M AU - Elliott AM AD - MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, UK. CN - TB042 Study Team LA - eng GR - MC_UU_00027/5/MRC_/Medical Research Council/United Kingdom GR - MC_UU_00033/1/MRC_/Medical Research Council/United Kingdom GR - MR/K019708/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Randomized Controlled Trial DEP - 20231125 PL - United States TA - Lancet Infect Dis JT - The Lancet. Infectious diseases JID - 101130150 RN - 0 (MVA 85A) RN - 0 (BCG Vaccine) RN - 0 (Tuberculosis Vaccines) RN - 0 (Vaccines, DNA) SB - IM MH - Adult MH - Infant, Newborn MH - Humans MH - Adolescent MH - BCG Vaccine MH - Immunization, Secondary MH - Uganda MH - *Tuberculosis/prevention & control MH - *Tuberculosis Vaccines MH - Immunogenicity, Vaccine MH - *Vaccines, DNA COIS- Declaration of interests We declare no competing interests. FIR - Namutebi, Milly IR - Namutebi M FIR - Nakazibwe, Esther IR - Nakazibwe E FIR - Onen, Caroline IR - Onen C FIR - Apuule, Barbara IR - Apuule B FIR - Akello, Florence IR - Akello F FIR - Mukasa, Mike IR - Mukasa M FIR - Nnaluwooza, Marble IR - Nnaluwooza M FIR - Sewankambo, Moses IR - Sewankambo M FIR - Kiwanuka, Sam IR - Kiwanuka S FIR - Kiwudhu, Fred IR - Kiwudhu F FIR - Imede, Esther IR - Imede E FIR - Nkurunungi, Gyaviira IR - Nkurunungi G FIR - Nakawungu, Prossy Kabuubi IR - Nakawungu PK FIR - Kabami, Grace IR - Kabami G FIR - Nuwagaba, Emmanuel IR - Nuwagaba E FIR - Akello, Mirriam IR - Akello M EDAT- 2023/11/28 06:42 MHDA- 2024/02/26 06:45 CRDT- 2023/11/28 00:20 PHST- 2023/05/27 00:00 [received] PHST- 2023/07/21 00:00 [revised] PHST- 2023/07/31 00:00 [accepted] PHST- 2024/02/26 06:45 [medline] PHST- 2023/11/28 06:42 [pubmed] PHST- 2023/11/28 00:20 [entrez] AID - S1473-3099(23)00501-7 [pii] AID - 10.1016/S1473-3099(23)00501-7 [doi] PST - ppublish SO - Lancet Infect Dis. 2024 Mar;24(3):285-296. doi: 10.1016/S1473-3099(23)00501-7. Epub 2023 Nov 25.