Adjunct rhIL-12 enhance THI response to viral vaccine?

说明：（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病毒感染。本提案的主要目标是确定 是否联合给予佐剂重组人白细胞介素-I2 （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提高他们的病毒特异性CD 8 + 细胞毒性T淋巴细胞（CTL）和辅助性T淋巴细胞1型（TH 1）型免疫 反应，以及它们的病毒特异性中和抗体反应。一个 重要的次要目标将集中在确定最佳安全性和 佐剂rhIL-12的有效剂量。我们建议以下列方法达致这些目标： 将活的减毒CMV疫苗（Towne株）与rhIL-12组合。CMV是一种 新生儿和幼儿发病率和死亡率重要原因 免疫力低下的人。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特异性免疫应答， 随机接受Towne人CMV的未感染CMV的志愿者 有或没有rhIL-12的菌株疫苗。为了定量CMV特异性CTL， 用短的重叠肽刺激PBMC的短期的方法 CMV特异性CTL的抗原靶将与CFC一起使用， 定量CMV特异性CD 8 +/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血清阴性成人（年龄范围 18-45岁）将接受1 x 10E3.47 pfu的Towne CMV疫苗， 皮下（SC）注射。将探索rhIL-12剂量范围， 0.5、1.0、2.0和4.0 mg。在每个rhIL-12剂量水平下，将有12名受试者接受治疗。 以3：1的方式随机分配，接受活性rhIL-12或匹配 与Towne疫苗同时皮下注射安慰剂。如果不超过 一名受试者在给定剂量水平下具有3级或更高的不良事件， 则开始招募下一个更高rhIL-12剂量组。如果佐剂 rhIL-12是安全的，并且确实增强了体外抗CMV免疫应答。 疫苗，然后进一步的研究将表明，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效力 在预防严重的慢性病毒感染方面， 应答（特别是CTL）是保护性免疫的关键， 没有有效的疫苗（如CMV、HSV和HIV）。

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).