DEVELOPMENT OF A LIPOPEPTIDE-BASED THERAPEUTIC VACCINE TO TREAT CHRONIC HBV INFECTION .1. INDUCTION OF A PRIMARY CYTOTOXIC T-LYMPHOCYTE RESPONSE IN HUMANS
DEVELOPMENT OF A LIPOPEPTIDE-BASED THERAPEUTIC VACCINE TO TREAT CHRONIC HBV INFECTION .1. INDUCTION OF A PRIMARY CYTOTOXIC T-LYMPHOCYTE RESPONSE IN HUMANS
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DOI：
10.1172/jci117662
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发表时间：
1995-01-01
影响因子：
15.9
通讯作者：
CHESNUT, RW
中科院分区：
文献类型：
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作者：
VITIELLO, A;ISHIOKA, G;CHESNUT, RW
我们的目标是利用由细胞毒性T淋巴细胞（CTL）识别的肽表位作为免疫原，用于开发以慢性肝炎B病毒（HBV）感染为第一治疗靶点的预防性和治疗性疫苗。由于大多数CTL肽表位是不良的免疫原，我们通过共价连接两个额外的组分：T辅助肽表位和两个脂质分子来特异性地修饰它们。使用鼠流感病毒CTL表位NP 147-155作为模型系统，我们发现该构建体是高度免疫原性的，并且单次注射导致持续> 1年的记忆性CTL诱导。基于动物研究，设计并测试了疫苗的安全性及其在正常受试者中诱导初次CTL应答的能力。三种疫苗组分包括作为CTL表位的HBV核心抗原肽18-27、作为T辅助肽的破伤风环状肽830-843和作为脂质的两种棕榈酸分子。在26名正常受试者中进行的剂量递增试验（5、50和500 μ g）表明，该疫苗是安全的，并且能够诱导原发性HBV特异性CTL应答。观察到剂量-反应曲线，五分之五的受试者对500 μ g剂量有反应。
Our goal is to use peptide epitopes that are recognized by cytotoxic T lymphocytes (CTL) as immunogens for the development of prophylactic and therapeutic vaccines with chronic hepatitis B virus (HBV) infection being our first therapeutic target. Because most CTL peptide epitopes are poor immunogens, we specifically modified them by covalently attaching two additional components: a T helper peptide epitope and two lipid molecules. Using the murine influenza virus CTL epitope NP 147-155 as a model system, we found this construct to be highly immunogenic, and a single injection resulted in memory CTL induction that persisted for > 1 yr. Based on the animal studies, a vaccine was designed and tested for both safety and its ability to induce a primary CTL response in normal subjects. The three vaccine components included HBV core antigen peptide 18-27 as the CTL epitope, tetanus toroid peptide 830-843 as the T helper peptide, and two palmitic acid molecules as the lipids. A dose escalation trial (5, 50, and 500 mu g) carried out in 26 normal subjects showed that the vaccine was safe and able to induce a primary HBV-specific CTL response. A dose-response curve was observed and five out of five subjects responded to the 500-mu g dose.