婴儿中MTBVAC疫苗的安全性、反应原性和免疫原性：在结核病流行地区开展的2a期随机、双盲、剂量确定试验。
Safety, reactogenicity, and immunogenicity of MTBVAC in infants: a phase 2a randomised, double-blind, dose-defining trial in a TB endemic setting.
作者信息
Tameris Michele, Rozot Virginie, Imbratta Claire, Geldenhuys Hennie, Mendelsohn Simon C, Kany Luabeya Angelique Kany, Shenje Justin, Tredoux Nicolette, Fisher Michelle, Mulenga Humphrey, Bilek Nicole, Young Carly, Veldsman Ashley, Botes Natasja, Thole Jelle, Fritzell Bernard, Mukherjee Rajat, Jelsbak Ingrid Murillo, Rodriguez Esteban, Puentes Eugenia, Doce Juana, Marinova Dessislava, Gonzalo-Asensio Jesús, Aguilo Nacho, Martin Carlos, Scriba Thomas J, Hatherill Mark
机构信息
South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease & Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
Biofabri, S.L.U, Porriño, Pontevedra, Spain.
出版信息
EBioMedicine. 2025 Apr;114:105628. doi: 10.1016/j.ebiom.2025.105628. Epub 2025 Mar 17.
BACKGROUND
Safer and more effective tuberculosis (TB) vaccines than Bacille Calmette Guérin (BCG) are needed. We evaluated the safety, reactogenicity, and immunogenicity of three dose levels of the live-attenuated Mycobacterium tuberculosis (Mtb) vaccine, MTBVAC, compared to BCG, in South African infants.
METHODS
Healthy, HIV-unexposed, BCG-naïve infants were randomised to receive a single intradermal dose of BCG (2.5 × 10 CFU, n = 24) or MTBVAC (2.5 × 10, 2.5 × 10, or 2.5 × 10 CFU, each n = 25). Safety endpoints were solicited systemic, solicited injection site, and unsolicited adverse events (AE), and serious AE (SAE). Immunogenicity was measured using interferon-γ release assay (IGRA) and whole blood intracellular cytokine staining assay. Follow-up was 12 months post-vaccination.
FINDINGS
Ninety-nine infants were enrolled between 18 February 2019 and 08 March 2021. Seventy-eight infants experienced reactogenicity AE (all mild except one grade 2 erythema). Induration, swelling, and erythema were more frequent as MTBVAC dose increased. All reactogenicity events were less frequent in infants receiving MTBVAC 2.5 × 10 CFU compared with BCG. Twelve infants (three BCG and nine MTBVAC recipients) experienced 14 vaccine-unrelated SAE, including one death due to bronchopneumonia (MTBVAC recipient). Eight infants were treated for unconfirmed pulmonary TB (four BCG and four MTBVAC 2.5 × 10 CFU recipients); one BCG recipient was treated for unconfirmed TB meningitis. MTBVAC was immunogenic at all 3 doses, inducing predominantly Th1-cytokine-expressing CD4 T cells, which peaked at Day 56. The 2.5 × 10 and 2.5 × 10 CFU MTBVAC doses induced similar response magnitudes and were more immunogenic than BCG. Day 56 IGRA conversion was observed in 61 (87.4%) infants receiving any MTBVAC dose, but only 28 (42.4%) remained positive by Day 365.
INTERPRETATION
MTBVAC appeared safe, well-tolerated, and immunogenic at doses between 2.5 × 10 and 2.5 × 10 CFU in South African infants. The 2.5 × 10 CFU MTBVAC dose, being less reactogenic and more immunogenic than BCG, was selected for a multi-centre, phase 3 trial.
FUNDING
This trial was funded by the European and Developing Countries Clinical Trials Partnership (EDCTP).
背景
需要比卡介苗（BCG）更安全、更有效的结核病（TB）疫苗。我们在南非婴儿中评估了三种剂量水平的减毒活结核分枝杆菌（Mtb）疫苗MTBVAC与卡介苗相比的安全性、反应原性和免疫原性。
方法
将健康、未感染HIV且未接种卡介苗的婴儿随机分为接受单剂量皮内注射卡介苗（2.5×10CFU，n = 24）或MTBVAC（2.5×10、2.5×10或2.5×10CFU，每组n = 25）。安全性终点包括主动报告的全身反应、主动报告的注射部位反应和非主动报告的不良事件（AE）以及严重不良事件（SAE）。使用干扰素-γ释放试验（IGRA）和全血细胞内细胞因子染色试验测量免疫原性。随访时间为接种疫苗后12个月。
研究结果
2019年2月18日至2021年3月8日期间共招募了99名婴儿。78名婴儿出现了反应原性AE（除1例2级红斑外均为轻度）。随着MTBVAC剂量增加，硬结、肿胀和红斑更频繁出现。与卡介苗相比，接受2.5×10CFU MTBVAC的婴儿中所有反应原性事件的发生频率更低。12名婴儿（3名卡介苗接种者和9名MTBVAC接种者）经历了14起与疫苗无关的SAE，包括1例因支气管肺炎死亡（MTBVAC接种者）。8名婴儿因未确诊的肺结核接受治疗（4名卡介苗接种者和4名2.5×10CFU MTBVAC接种者）；1名卡介苗接种者因未确诊的结核性脑膜炎接受治疗。MTBVAC在所有3个剂量下均具有免疫原性，主要诱导表达Th1细胞因子的CD4 T细胞，在第56天达到峰值。接受任何MTBVAC剂量的61名（87.4%）婴儿在第56天观察到IGRA转换，但到第365天只有28名（42.4%）仍为阳性。
解读
在南非婴儿中，MTBVAC在2.5×10至2.5×10CFU剂量之间似乎是安全、耐受性良好且具有免疫原性的。2.5×10CFU的MTBVAC剂量比卡介苗反应原性更低且免疫原性更强，因此被选用于多中心3期试验。
资金来源
本试验由欧洲和发展中国家临床试验合作组织（EDCTP）资助。
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