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：（由申请人提供）目前没有有效的疫苗 为了防止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。该提议的主要目标是确定 辅助重组人白介素I 2是否共同给药2 （RHIL-12）具有已知免疫原性的活病毒疫苗， 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T辅助淋巴细胞1型（TH1） - 型免疫 反应及其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 有效剂量的辅助RHIL-12。我们建议通过 将活的，减弱的CMV疫苗（Towne Train）与Rhil-12结合使用。 CMV是一个 新生儿发病和死亡的重要原因以及 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 中和抗体测定以测量CMV特异性免疫反应 被随机接收Towne Human CMV的CMV未感染的志愿者 有或没有RHIL-12的疫苗过滤疫苗。要量化CMV特异性CTL的小说 用A的短期重叠肽刺激PBMC的短期方法 CMV特异性CTL的主要，抗原靶标将使用CFC进行 量化CMV特异性CD8+/IFNG+T淋巴细胞。提议的工作涉及 第一阶段，随机，双盲，安慰剂对照，剂量降低研究 设计。多达48位医学稳定，健康，CMV副副成年人（年龄范围 18-45岁）将获得1 x 10e3.47 PFU Towne CMV疫苗 皮下（SC）注射。 RHIL-12剂量的范围将是 0.5、1.0、2.0和4.0 mg。在每个RHIL-12剂量水平上，将有12个受试者 以3：1的方式随机分配以接收Active Rhil-12或匹配 安慰剂与Towne疫苗同时作为SC注射。如果不超过 一个受试者在给定剂量水平上有3级或更高的不良事件， 然后将开始入学下一个较高的RHIL-12剂量组。如果佐剂 RHIL-12是安全的，并且确实增强了对此的体外抗CMV免疫反应 疫苗，然后将表明进一步的研究以确定是否合并病毒 疫苗/辅助RHIL-12疫苗接种策略可以提高保护效果 在预防严重的慢性病毒感染中，细胞介导的免疫 反应（尤其是CTL）是保护性免疫的关键，并且 有效疫苗不存在（例如CMV，HSV和HIV）。