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.
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.
Lancet Infect Dis. 2024 Mar;24(3):285-296. doi: 10.1016/S1473-3099(23)00501-7. Epub 2023 Nov 25.
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.
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-γ ELISpot response to antigen 85A (day 63 [geometric mean] and days 0-224 [area under the curve; AUC).
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-γ 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).
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.
UK Research and Innovations and Medical Research Council.
For the Swahili and Luganda translations of the abstract see Supplementary Materials section.
卡介苗（BCG）可提供针对肺结核的保护作用，但保护效果因人而异。目前需要开发更有效的疫苗。我们评估了候选疫苗 ChAdOx1 85A-MVA85A 与 BCG 复种在乌干达青少年中的安全性和免疫原性。
在 ChAdOx1 85A 剂量递增和年龄递减后，我们在乌干达恩德培市进行了一项随机、开放性、2a 期临床试验，纳入了 12-17 岁的健康青少年，他们在出生时接种了卡介苗，没有明显的结核接触史。参与者按 1:1 随机分组（使用 6 个的分组大小），分别接受 ChAdOx1 85A 加 MVA85A（第 56 天）或 BCG（莫斯科株）接种。实验室工作人员对分组情况不知情。主要终点是接种后 28 天内的不良事件（AE）和严重不良事件（SAE），以及接种后第 63 天（几何均数）和第 0-224 天（曲线下面积；AUC）时针对抗原 85A 的 IFN-γ ELISpot 反应。
ChAdOx1 85A 单剂递增和年龄递减研究（2019 年 7 月至 8 月）纳入 6 名成人（第 1 组，n=3；第 2 组，n=3）和 6 名青少年（第 3 组，n=3；第 4 组，n=3）。2a 期试验纳入 60 名青少年，随机分为 ChAdOx1 85A-MVA85A 组（第 5 组，n=30）或 BCG 组（第 6 组，n=30；2019 年 12 月至 2020 年 10 月）。第 5 组（ChAdOx1 85A-MVA85A）和第 6 组（BCG 复种）各有 30 名参与者中的 28 名和 29 名被纳入免疫原性结果分析。在随机试验中，30 名接受 ChAdOx1 85A-MVA85A 接种的参与者中有 23 名（77%）报告了 60 种 AE，31 种为全身性 AE，其中 1 种在 MVA85A 加强针后发生的严重事件迅速自限。BCG 复种组的 30 名参与者均报告了至少 1 种轻至中度的局部 AE。没有出现任何严重不良事件。在 ChAdOx1 85A-MVA85A 组，Ag85A 特异性 IFN-γ ELISpot 反应在接种后第 63 天达到峰值，且高于 BCG 复种组（几何均数比值 30·59 [95% CI 17·46-53·59]，p<0·0001，第 63 天；AUC 平均差异 57091 [95% CI 40524-73658]，p<0·0001，第 0-224 天）。
ChAdOx1 85A-MVA85A 方案安全，并且诱导的 Ag85A 特异性反应强于 BCG 复种。我们的研究结果支持进一步开发结核病加强疫苗。
英国研究与创新署和医学研究理事会。
