HMGB1-Derived Peptides As Vaccine Adjuvants

描述（由申请人提供）：目前，铝化合物和最近的MPL是FDA批准用于美国人类的唯一佐剂。由于其对某些抗原无效并且不能增强细胞介导的免疫应答，仍然需要发现用于人类疫苗接种的新的、更有效的和更安全的佐剂。树突状细胞在指导适应性免疫的发展中发挥核心作用。由于它们的内在特性，利用树突状细胞进行疫苗接种可能会导致更强大的免疫应答。我们已经证明，高迁移率族蛋白1（HMGB 1）及其片段可以作为人类和小鼠树突状细胞的有效成熟刺激，因此是有前途的候选佐剂。本项目的总体目标是研究HMGB 1衍生肽Hp 91作为单纯疱疹病毒2型感染的疫苗佐剂在小鼠和豚鼠模型中的有效性并开发其。在目的1中，我们将评估Hp 91佐剂与3种HSV-2抗原组合用于保护免受病毒攻击的功效，并鉴定最有效的肽形式和制剂。在目标2中，我们将确定最有效的疫苗形式在模拟人类生殖器疾病的豚鼠模型中提供HSV-2保护的程度。在目标3中，我们将评估疫苗的安全性。在目标4中，我们将确定肽诱导免疫应答的机制。我们将进行结构功能研究，以确定关键氨基酸和调查受体参与。总之，这些研究将确定HMGB 1衍生肽Hp 91在何种程度上作为佐剂引发对HSV-2的保护性免疫应答。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.