Adjunct rhIL-12 enhance THI response to viral vaccine?

辅助 rhIL-12 增强 THI 对病毒疫苗的反应？

• 批准号: 6623575
• 负责人: MARK A JACOBSON
• 金额: $ 29.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623575
• 关键词: HIV infections; Herpes simplex disease; antiviral antibody; cellular immunity; clinical research; clinical trial phase I; cytomegalovirus; cytotoxic T lymphocyte; dosage; flow cytometry; helper T lymphocyte; human subject; human therapy evaluation; immunization; immunomodulators; immunotherapy; interferon gamma; interleukin 12; neutralizing antibody; patient oriented research; recombinant proteins; viral vaccines

DESCRIPTION: (Provided by Applicant) Currently, there is no effective vaccine to prevent several clinically important chronic viral infections, including cytomegalovirus (CMV), herpes simplex virus (HSV) and human immunodeficiency virus (HIV) infection. The primary goal of this proposal is to determine whether co-administration of adjuvant recombinant human interleukin-I 2 (rhIL-12) with a live, attenuated viral vaccine of known immunogenicity to healthy, uninfected adults can safely enhance their virus-specific CD8+ cytotoxic T lymphocyte (CTL) and T helper lymphocyte type 1 (TH1)-type immune responses, as well as their virus-specific neutralizing antibody responses. An important secondary objective will focus on determining the optimally safe and effective dose of adjuvant rhIL-12. We propose to accomplish these aims by combining a live, attenuated CMV vaccine (Towne strain) with rhIL-12. CMV is an important cause of morbidity and mortality in newborn children and in immunocompromised individuals. We will use cytokine flow cytometry CFC) and neutralizing antibody assays to measure CMV-specific immunologic responses in CMV-uninfected volunteers who are randomized to receive the Towne human CMV strain vaccine with or without rhIL-12. To quantify CMV-specific CTL's, a novel method of stimulating PBMC's short-term with short overlapping peptides of a dominant, antigen target for CMV-specific CTL's will be employed with CFC to quantify CMV-specific, CD8+/IFNg+T lymphocytes. The proposed work involves a Phase I, randomized, double-blind, placebo-controlled, dose-escalation study design. Up to 48 medically stable, healthy, CMV-seronegative adults (age range 18-45 years old) will receive 1 x 10E3.47 pfu of the Towne CMV vaccine as a subcutaneous (SC) injection. The range of rhIL-12 doses to be explored will be 0.5, 1.0, 2.0 and 4.0 mg. At each rhIL-12 dose level, 12 subjects will be randomly assigned in a 3:1 manner to receive either active rhIL-12 or matching placebo as a SC injection simultaneously with Towne vaccine. If no more than one subject has had a Grade 3 or higher adverse event at a given dose level, then enrollment of the next, higher rhIL-12 dose group will begin. If adjuvant rhIL-12 is safe and does enhance in vitro anti-CMV immune responses to this vaccine, then further studies will be indicated to determine if combined viral vaccine/adjuvant rhIL-12 vaccination strategies can enhance protective efficacy in preventing serious chronic viral infections for which cell-mediated immune response (and CTL in particular) is key to protective immunity and for which effective vaccines do not exist (e.g. CMV, HSV and HIV).

描述：（申请人提供）目前尚无有效疫苗 预防几种临床上重要的慢性病毒感染，包括 巨细胞病毒 (CMV)、单纯疱疹病毒 (HSV) 和人类免疫缺陷 病毒（HIV）感染。该提案的主要目标是确定 是否联合给予重组人白细胞介素-I 2佐剂 (rhIL-12) 与已知免疫原性的活减毒病毒疫苗 健康、未感染的成年人可以安全地增强其病毒特异性 CD8+ 细胞毒性 T 淋巴细胞 (CTL) 和 1 型辅助 T 淋巴细胞 (TH1) 型免疫 反应，以及病毒特异性中和抗体反应。一个 重要的次要目标将集中于确定最佳安全和 佐剂rhIL-12的有效剂量。我们建议通过以下方式实现这些目标 将活的减毒 CMV 疫苗（Towne 株）与 rhIL-12 相结合。巨细胞病毒是一种 是新生儿和儿童发病和死亡的重要原因 免疫功能低下的个体。我们将使用细胞因子流式细胞术（CFC）和 中和抗体测定法测量 CMV 特异性免疫反应 未感染 CMV 的志愿者被随机分配接受 Towne 人类 CMV 含有或不含 rhIL-12 的菌株疫苗。为了量化 CMV 特异性 CTL，一种新颖的 用短重叠肽刺激 PBMC 的短期方法 CMV 特异性 CTL 的显性抗原靶标将与 CFC 一起使用， 量化 CMV 特异性 CD8+/IFNg+T 淋巴细胞。拟议的工作涉及 I 期、随机、双盲、安慰剂对照、剂量递增研究 设计。最多 48 名病情稳定、健康、CMV 血清阴性的成年人（年龄范围 18-45 岁）将接受 1 x 10E3.47 pfu Towne CMV 疫苗作为 皮下（SC）注射。待探索的 rhIL-12 剂量范围将是 0.5、1.0、2.0 和 4.0 毫克。在每个 rhIL-12 剂量水平，将有 12 名受试者 以 3:1 的方式随机分配接受活性 rhIL-12 或匹配的 安慰剂与 Towne 疫苗同时皮下注射。如果不超过 一名受试者在给定剂量水平下发生过 3 级或更高级别的不良事件， 然后将开始招募下一个更高的 rhIL-12 剂量组。如果是佐剂 rhIL-12 是安全的，并且确实能增强对此的体外抗 CMV 免疫反应 疫苗，然后将进行进一步的研究以确定是否联合病毒 疫苗/佐剂 rhIL-12 疫苗接种策略可增强保护功效 预防严重的慢性病毒感染，细胞介导的免疫 反应（尤其是 CTL）是保护性免疫的关键，为此 不存在有效的疫苗（例如 CMV、HSV 和 HIV）。