HMGB1-Derived Peptides As Vaccine Adjuvants

描述(申请人提供)：目前，铝化合物和最近的MPL是美国FDA批准用于人类的唯一佐剂。由于它对某些抗原无效，无法增强细胞介导的免疫反应，仍然需要发现新的、更有效和更安全的人类疫苗佐剂。树突状细胞在引导获得性免疫的发展中起着核心作用。由于树突状细胞的固有特性，利用树突状细胞进行疫苗接种可能会导致更强大的免疫反应。我们已经证明高迁移率族蛋白1(HMGB1)及其片段可以作为人和小鼠树突状细胞的强大成熟刺激因子，因此是很有希望的佐剂候选分子。本项目的总体目标是研究和开发HMGB1衍生多肽Hp91作为疫苗佐剂在小鼠和豚鼠模型中治疗单纯疱疹病毒2型感染。在目标1中，我们将评估Hp91佐剂与3种HSV-2抗原联合使用对病毒攻击的保护作用，并确定最有效的多肽形式和配方。在目标2中，我们将确定在模仿人类生殖器疾病的豚鼠模型中，最有效的疫苗形式在多大程度上提供HSV-2保护。在目标3中，我们将评估疫苗的安全性。在目标4中，我们将确定多肽诱导免疫反应的机制。我们将进行结构功能研究，以确定关键氨基酸并调查受体参与。总体而言，这些研究将确定HMGB1衍生的多肽Hp91在多大程度上充当针对HSV-2的保护性免疫反应的佐剂。这些研究将为测试其对其他临床相关抗原的广泛适用性提供基础。

DESCRIPTION (provided by applicant): Currently, aluminum compounds and more recently MPL are the only adjuvants approved by the FDA for use in humans in the U.S. Because of its ineffectiveness for some antigens and inability to augment cell mediated immune responses, there is still a need to discover new, more potent, and safer adjuvants for human vaccination. Dendritic cells play a central role in guiding the development of adaptive immunity. Due to their intrinsic properties, harnessing dendritic cells for vaccination will likely result in a more robust immune response. We have demonstrated that high mobility group box protein 1 (HMGB1) and its fragments can act as potent maturation stimuli for human and mouse dendritic cells and are therefore promising candidates for adjuvants. The overall goal of this project is to investigate the efficacy of and develop the HMGB1-derived peptide Hp91 as vaccine adjuvant for herpes simplex virus 2 infections in mouse and guinea pig models. In Aim 1 we will assess the efficacy of the Hp91 adjuvant in combination with 3 HSV-2 antigens for protection against virus challenge and identify the most potent peptide format and formulation. In Aim 2 we will determine to what extent the most potent vaccine format provides HSV-2 protection in the guinea pig model that mimics human genital disease. In Aim 3 we will evaluate the safety profile of the vaccine. In Aim 4 we will determine the mechanism by which the peptide induces immune responses. We will perform structure function studies to determine critical amino acids and investigate receptor involvement. Overall these studies will determine to what extent the HMGB1-derived peptide Hp91 act as adjuvants in eliciting protective immune responses to HSV-2. These studies will provide the basis for testing its broad applicability to other clinically relevant antigens.