Homerton University Hospital, Homerton Row, London, UK.
Institute of Medical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
BMC Infect Dis. 2023 Feb 24;23(1):120. doi: 10.1186/s12879-023-08092-4.
BACKGROUND: Tuberculosis (TB) remains a leading cause of death worldwide, with 98% of cases occurring in low- and middle-income countries (LMICs). The only vaccine licenced for the prevention of TB has limited protection for adolescents, adults and vulnerable populations. A safe and effective vaccine for all populations at risk is imperative to achieve global elimination of TB. We aimed to systematically review the efficacy and safety of TB vaccine candidates in late-phase clinical trials conducted in LMICs. METHODS: Medline, Embase, CENTRAL, PubMed, Clinicaltrials.gov and Greylit.org were searched in June 2021 to identify phase 2 or later clinical randomised controlled trials that report the efficacy or safety (adverse events) of TB vaccine candidates with participants of any age living in an LMIC. TB vaccine candidates listed in the 2020 WHO Global TB Report were eligible for inclusion aside from BCG revaccination. Trials were excluded if all participants had active TB at baseline. Two reviewers independently assessed papers for eligibility, and for bias and quality using the Risk of Bias 2 tool and GRADE guidelines, respectively. We report efficacy rates and frequencies of adverse events from each included trial where available and qualitatively synthesise the findings. RESULTS: Thirteen papers representing eleven trials met our inclusion criteria. Seven vaccine candidates were reviewed across seven countries: M72/AS01, RUTI, VPM1002, H56:IC31, MTBVAC, DAR-901 and ID93 + GLA-SE. Two trials reported on efficacy: an efficacy rate of 54% (95% CI 11.5, 76.2) was reported for M72/AS01 in adults with latent TB and 3% (95% CI -13.9, 17.7) for DAR-901 in healthy adolescents. However, the latter trial was underpowered. All vaccine candidates had comparable occurrences of adverse events between treatment arms and demonstrated acceptable safety profiles; though, RUTI resulted in one serious complication in a person living with HIV. M72/AS01 was the only vaccine considered safe across a diverse group of people including people living with HIV or latent TB and healthy infants and adolescents. CONCLUSION: Further efficacy trials for M72/AS01 are warranted to include additional populations at risk where safety has been demonstrated. Further safety trials are needed for the remaining vaccine candidates to confirm safety in vulnerable populations.
背景：结核病（TB）仍然是全球主要的死亡原因，98%的病例发生在低收入和中等收入国家（LMICs）。唯一获准用于预防结核病的疫苗对青少年、成人和弱势群体的保护作用有限。为了实现全球消除结核病，迫切需要为所有高危人群提供安全有效的疫苗。我们旨在系统地审查在 LMICs 进行的后期临床研究中结核病候选疫苗的疗效和安全性。
方法：2021 年 6 月，检索了 Medline、Embase、CENTRAL、PubMed、Clinicaltrials.gov 和 Greylit.org，以确定报告了任何年龄居住在 LMIC 中的参与者的结核病候选疫苗的疗效或安全性（不良事件）的 2 期或后期临床随机对照试验。除 BCG 再接种外，2020 年世卫组织全球结核病报告中列出的结核病候选疫苗有资格入选。如果所有参与者在基线时均患有活动性结核病，则试验将被排除在外。两名评审员分别使用风险偏倚 2 工具和 GRADE 指南独立评估论文的入选标准和偏倚质量。我们报告了每个纳入试验中可用的疗效率和不良事件频率，并进行了定性综合分析。
结果：符合纳入标准的有 13 篇论文，涉及 11 项试验。在七个国家评估了七种疫苗候选物：M72/AS01、RUTI、VPM1002、H56:IC31、MTBVAC、DAR-901 和 ID93+GLA-SE。两项试验报告了疗效：M72/AS01 在潜伏性结核病的成年人中的疗效为 54%（95%CI 11.5，76.2），DAR-901 在健康青少年中的疗效为 3%（95%CI-13.9，17.7）。然而，后者试验的效能不足。所有疫苗候选物在治疗组之间的不良事件发生率相当，表现出可接受的安全性；然而，RUTI 导致一名 HIV 感染者出现严重并发症。M72/AS01 是唯一一种在包括 HIV 感染者或潜伏性结核病患者以及健康婴儿和青少年在内的不同人群中被认为安全的疫苗。
结论：需要进一步的疗效试验来包括安全性已得到证实的其他高危人群。需要进一步的安全性试验来确认其余疫苗候选物在弱势群体中的安全性。
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