INSERM, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
Gastroenterology. 2011 Sep;141(3):890-899.e1-4. doi: 10.1053/j.gastro.2011.06.009. Epub 2011 Jun 13.
BACKGROUND & AIMS: Therapy for chronic hepatitis C (CHC) has limited efficacy, adverse effects, and high costs. Cohort and vaccine-based preclinical studies have indicated the importance of T-cell-based immunity in controlling viral infection. TG4040 is a recombinant poxvirus vaccine that expresses the hepatitis C virus (HCV) proteins NS3, NS4, and NS5B. We performed a phase I clinical trial to assess the safety, immunogenicity, and early antiviral efficacy of TG4040 in patients with CHC.
In an open-label, dose-escalating study, patients with mild CHC (genotype 1) were assigned to 3 groups of 3 patients each; they received subcutaneous injections of 10⁶, 10⁷, or 10⁸ plaque-forming units of TG4040 on study days 1, 8, and 15. Six additional patients were given the highest dose of vaccine (10⁸ plaque-forming units). Patients were followed for 6 months after the last injection. T-cell-based and antibody responses and levels of HCV RNA were measured.
All 3 doses of TG4040 were well tolerated, without serious adverse events. Vaccine-induced HCV-specific cellular immune responses were observed in 5 of the 15 patients (33%). A transient decrease in circulating levels of HCV RNA, from -0.52 log₁₀ to -1.24 log₁₀, was observed in 8 patients; in 5 patients, the lowest level of HCV RNA was observed on day 37, after the first injection. The most pronounced decrease in viral load occurred in 2 patients, who also had marked vaccine-induced T-cell responses.
In patients with CHC, the viral-vector-based vaccine TG4040 had a good safety profile, induced HCV-specific cellular immune responses, and reduced viral load. This vaccine should be investigated in further clinical studies, in combination with standard of care.
慢性丙型肝炎（CHC）的治疗疗效有限，不良反应多，费用高。基于队列和疫苗的临床前研究表明，T 细胞免疫在控制病毒感染方面具有重要意义。TG4040 是一种表达丙型肝炎病毒（HCV）蛋白 NS3、NS4 和 NS5B 的重组痘病毒疫苗。我们进行了一项 I 期临床试验，以评估 TG4040 在 CHC 患者中的安全性、免疫原性和早期抗病毒疗效。
在一项开放性、剂量递增研究中，将轻度 CHC（基因型 1）患者分为 3 组，每组 3 例；他们在研究第 1、8 和 15 天接受皮下注射 10⁶、10⁷或 10⁸ 噬菌斑形成单位的 TG4040。另外 6 例患者给予最高剂量的疫苗（10⁸ 噬菌斑形成单位）。最后一次注射后随访 6 个月。测量 T 细胞和抗体反应以及 HCV RNA 水平。
TG4040 的所有 3 个剂量均耐受良好，无严重不良事件。在 15 例患者中有 5 例（33%）观察到 HCV 特异性细胞免疫反应。在 8 例患者中观察到循环 HCV RNA 水平短暂下降，从-0.52 log₁₀降至-1.24 log₁₀；在 5 例患者中，最低 HCV RNA 水平出现在第 1 次注射后第 37 天。病毒载量下降最明显的发生在 2 例患者中，他们也有明显的疫苗诱导的 T 细胞反应。
在 CHC 患者中，基于病毒载体的疫苗 TG4040 具有良好的安全性，可诱导 HCV 特异性细胞免疫反应，并降低病毒载量。这种疫苗应在进一步的临床研究中与标准护理联合进行研究。
