Luabeya Angelique Kany Kany, Rozot Virginie, Imbratta Claire, Ratangee Frances, Shenje Justin, Tameris Michele, Mendelsohn Simon C, Geldenhuys Hennie, Fisher Michelle, Musvosvi Munyaradzi, Young Carly, Mulenga Humphrey, Bilek Nicole, Mabwe Simbarashe, Jelsbak Ingrid Murillo, Rodríguez Esteban, Puentes Eugenia, Doce Juana, Aguilo Nacho, Martin Carlos, Pillay Cadwill, Tait Dereck, Russell Marisa, Van Der Merve Arrie, Rutkowski Kathryn, Hunt Devin, Ginsberg Ann, Scriba Thomas J, Hatherill Mark
South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa.
Biofabri, Porriño (Pontevedra), Spain.
Lancet Glob Health. 2025 Jun;13(6):e1030-e1042. doi: 10.1016/S2214-109X(25)00046-4. Epub 2025 Apr 15.
An effective adult vaccine is needed to control tuberculosis. We evaluated the safety and immunogenicity of a live-attenuated Mycobacterium tuberculosis vaccine (MTBVAC).
This single-centre, phase 1b-2a, double-blind, dose-escalation, randomised controlled trial (NCT02933281) enrolled South African adults previously vaccinated with BCG, who were HIV negative and aged 18-50 years, with or without M tuberculosis sensitisation assessed by QuantiFERON-tuberculosis Gold-Plus assay (QFT). Participants were recruited from the local community and randomly allocated (2:1) to receive MTBVAC (5 × 10, 5 × 10, 5 × 10, or 5 × 10 colony-forming unit [CFU] doses) or BCG revaccination (5 × 10 CFU dose). The primary outcomes were the occurrence of systemic solicited adverse events within 7 days and unsolicited adverse events within 28 days after vaccination, the occurrence of solicited and unsolicited injection-site reactions within 84 days after vaccination, and the occurrence of serious adverse events (SAEs) until the end of study, 365 days after vaccination. Data were analysed per modified intention to treat. The trial is now complete and closed.
Between Jan 15, 2019, and Sept 7, 2020, 485 participants provided consent and were screened. 144 participants were enrolled and 143 (99%) were vaccinated. BCG was administrated to 47 (33%) of 143 and MTBVAC to 96 (67%) of 143. 12 participants with QFT-negative results and 12 with QFT-positive results were randomly allocated to receive each dose of MTBVAC and 24 participants with QFT-negative results and 24 with QFT-positive results were randomly allocated to receive BCG revaccination. Injection-site pain, discharge, erythema, and swelling increased with MTBVAC dose level. MTBVAC 5 × 10 CFU recipients reported a similar proportion of related adverse events (23 [96%] of 24) as BCG recipients (45 [96%] of 47). MTBVAC recipients who were QFT positive reported more injection-site reactions (46 [96%] of 48; 95% CI 85·7-99·5) than MTBVAC recipients who were QFT negative (32 [67%] of 48; 51·6-79·6). No vaccine-related SAEs were reported. All doses of MTBVAC were immunogenic; vaccine-induced antigen-specific CD4 T-cell responses peaked 28 days after vaccination. The MTBVAC 5 × 10 and 5 × 10 CFU doses induced T-helper-cell-1 cytokine-expressing CD4 T-cell responses that exceeded BCG-induced responses in participants who were QFT negative and QFT positive.
MTBVAC at the 5 × 10 dose showed similar safety and reactogenicity and greater immunogenicity when compared to BCG. These results suggest that the 5 × 10 dose of MTBVAC could be selected for a subsequent efficacy evaluation.
Congressionally Directed Medical Research Programmes and US National Institutes of Health.
需要一种有效的成人疫苗来控制结核病。我们评估了减毒活结核分枝杆菌疫苗（MTBVAC）的安全性和免疫原性。
这项单中心、1b-2a期、双盲、剂量递增、随机对照试验（NCT02933281）招募了先前接种过卡介苗的南非成年人，他们HIV阴性，年龄在18至50岁之间，通过结核菌素γ干扰素释放试验（QFT）评估有无结核分枝杆菌致敏。参与者从当地社区招募，并随机分配（2:1）接受MTBVAC（5×10、5×10、5×10或5×10菌落形成单位[CFU]剂量）或卡介苗复种（5×10 CFU剂量）。主要结局为接种后7天内全身性预期不良事件的发生情况、28天内非预期不良事件的发生情况、接种后84天内预期和非预期注射部位反应的发生情况，以及直至研究结束（接种后365天）严重不良事件（SAE）的发生情况。数据按意向性分析进行分析。该试验现已完成并结束。
在2019年1月15日至2020年9月7日期间，485名参与者提供了知情同意并接受了筛查。144名参与者入组，143名（99%）接种了疫苗。143名参与者中，47名（33%）接种了卡介苗，96名（67%）接种了MTBVAC。12名QFT结果阴性的参与者和12名QFT结果阳性的参与者被随机分配接受每剂MTBVAC，24名QFT结果阴性的参与者和24名QFT结果阳性的参与者被随机分配接受卡介苗复种。注射部位疼痛、渗液、红斑和肿胀随MTBVAC剂量水平增加。接受5×10 CFU MTBVAC的参与者报告的相关不良事件比例（24名中的23名[96%]）与接受卡介苗的参与者（47名中的45名[96%]）相似。QFT阳性的MTBVAC接受者报告的注射部位反应（48名中的46名[96%]；95%CI 85.7-99.5）多于QFT阴性的MTBVAC接受者（48名中的32名[67%]；51.6-79.6）。未报告与疫苗相关的严重不良事件。所有剂量的MTBVAC均具有免疫原性；疫苗诱导的抗原特异性CD4 T细胞反应在接种后28天达到峰值。MTBVAC 5×10和5×10 CFU剂量在QFT阴性和QFT阳性的参与者中诱导的表达辅助性T细胞1细胞因子的CD4 T细胞反应超过了卡介苗诱导的反应。
与卡介苗相比，5×10剂量的MTBVAC显示出相似的安全性和反应原性以及更强的免疫原性。这些结果表明，可以选择5×10剂量的MTBVAC进行后续疗效评估。
国会指导的医学研究计划和美国国立卫生研究院。
