Adjunct rhIL-12 enhance THI response to viral vaccine?

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、单纯疱疹病毒与人类免疫缺陷 病毒(HIV)感染。这项提案的主要目标是确定 辅助性重组人白介素I-2是否联合应用 (rhIL-12)与已知免疫原性的减毒活病毒疫苗 健康、未感染的成年人可以安全地增强他们的病毒特异性CD8 细胞毒性T淋巴细胞(CTL)和辅助性T淋巴细胞1型(TH1)免疫 以及它们的病毒特异性中和抗体反应。一个 重要的次要目标将侧重于确定最佳的安全和 佐剂rh IL-12的有效剂量。我们建议通过以下方式实现这些目标 将CMV减毒活疫苗(汤恩株)与重组人IL-12结合。CMV是一种 新生儿发病率和死亡率的重要原因 免疫功能受损的个体。我们将使用细胞因子流式细胞术(CFC)和 中和抗体试验检测鸡巨细胞病毒特异性免疫应答 未感染CMV的志愿者被随机接受Towne人CMV 使用或不使用重组人白介素12的菌株疫苗。量化CMV特异性CTL，一种新的 短重叠多肽短期刺激PBMC的方法 针对CMV特异性CTL的显性抗原靶点将与CFC一起使用 定量检测CMV特异性CD8/IFNG T淋巴细胞。拟议的工作涉及一个 第一阶段，随机、双盲、安慰剂对照、剂量递增研究 设计。多达48名医学上稳定、健康、CMV血清阴性的成年人(年龄范围 18-45岁)将接种1×10E3.47 pfu的Towne CMV疫苗作为 皮下注射。将探索的rhIL-12剂量范围将包括 0.5、1.0、2.0和4.0 mg。在每个rhIL-12剂量水平，12名受试者 以3：1的方式随机分配以接受活性的重组人白细胞介素12或匹配 安慰剂作为SC注射，与汤恩疫苗同时注射。如果不超过 一个受试者在给定的剂量水平上有3级或更高的不良事件， 然后，下一个更高剂量的rhIL-12组将开始招募。如果是佐剂 重组人IL-12是安全的，并在体外增强对此的抗CMV免疫反应 疫苗，然后将进行进一步的研究，以确定联合病毒 疫苗/佐剂rh IL-12疫苗接种策略可增强保护效力 在预防细胞免疫的严重慢性病毒感染方面 反应(特别是CTL)是保护性免疫的关键，因此 不存在有效的疫苗(例如巨细胞病毒、单纯疱疹病毒和艾滋病毒)。

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).