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 是美国 FDA 批准用于人类的唯一佐剂。由于其对某些抗原无效且无法增强细胞介导的免疫反应，因此仍然需要发现用于人类疫苗接种的新的、更有效和更安全的佐剂。树突状细胞在指导适应性免疫的发展中发挥着核心作用。由于树突状细胞的内在特性，利用树突状细胞进行疫苗接种可能会产生更强大的免疫反应。我们已经证明，高迁移率族盒蛋白 1 (HMGB1) 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物，因此是有希望的佐剂候选者。该项目的总体目标是研究和开发 HMGB1 衍生肽 Hp91 作为小鼠和豚鼠模型中单纯疱疹病毒 2 感染的疫苗佐剂的功效。在目标 1 中，我们将评估 Hp91 佐剂与 3 种 HSV-2 抗原组合对抗病毒攻击的功效，并确定最有效的肽形式和配方。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多大程度的 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研究受体参与。总的来说，这些研究将确定 HMGB1 衍生肽 Hp91 在多大程度上充当佐剂，引发针对 HSV-2 的保护性免疫反应。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.