VLP-based Vaccines for Targeting Bacterial Virulence

描述（由申请人提供）：病毒样颗粒（vlp）是一种灵活的疫苗接种平台，用于靶向它们来自的病毒或用于以多价格式显示几乎任何表位。VLPs诱导强烈的抗体反应，因为其衣壳结构的周期性使抗原表位成为密集的、高度重复的阵列，有力地刺激B淋巴细胞。虽然vlp已被用于宿主防御病毒感染，但它们在预防细菌感染方面的应用有限。耐甲氧西林金黄色葡萄球菌（MRSA）已成为一种主要的公共卫生威胁，在美国和至少9个其他国家，与危及生命的感染相关的单克隆（USA300）的出现使人们重新关注预防这种感染的疫苗。由于大多数侵袭性MRSA感染的毒力因子是由群体感应操纵子agr控制的，因此我们建议使用基于vlp的疫苗接种来诱导针对自诱导肽信息素（AIP）的中和抗体，AIP可以激活这种全局毒力调节因子。由于AIP的大小（8个氨基酸），除非与一个大的载体蛋白络合，否则它的免疫原性很差。因此，在VLP上以密集阵列的形式显示AIP代表了诱导高亲和力抗体来中和其生物学功能的潜在策略。本探索性R21的目的是验证VLPs可以作为疫苗平台诱导针对金黄色葡萄球菌毒力的适应性免疫的假设。为了验证这一假设，我们将追求两个特定的目标：1)确定携带金黄色葡萄球菌毒力肽的VLPs是否可以诱导正常和免疫缺陷小鼠的保护性免疫。2)确定携带金黄色葡萄球菌毒力肽的VLPs是否能诱导定植正常和免疫缺陷小鼠的保护性免疫。

DESCRIPTION (provided by applicant): Virus-like particles (VLPs) are a flexible vaccination platform for targeting either the virus from which they were or for use in displaying practically any epitope in a multivalent format. VLPs induce strong antibody responses because the periodicity of their capsid structure presents antigenic epitopes as dense, highly repetitive arrays that robustly stimulate B lymphocytes. While VLPs have been pursued for host defense against viral infections, their use for prevention of bacterial infection has been limited. Methicillin resistant Staphylococcus aureus (MRSA) has emerged as a major public health threat and the emergence of a single clone (USA300) associated with life threatening infections in the US and at least 9 other countries has re-focused interest in vaccines to prevent this infection. Because the virulence factors most identified with invasive MRSA infection are controlled by a quorum sensing operon, agr, we propose to use VLP-based vaccination to induce neutralizing antibodies against the autoinducing peptide pheromone (AIP) that activates this global regulator of virulence. Because of its size (8 amino acids) AIP is poorly immunogenic unless complexed to a large carrier protein. Therefore, display of AIP as a dense array on a VLP represents a potential strategy for the induction of high affinity antibody for the neutralization of its biologic function. The goal of this exploratory R21 is to test the hypothesis that VLPs can be used as a vaccine platform to induce adaptive immunity targeting S. aureus virulence. To test this hypothesis, we will pursue two specific aims: 1) To determine if VLPs bearing S. aureus virulence peptides can induce protective immunity in normal and immunodeficient mice. 2) To determine if VLPs bearing S. aureus virulence peptides can induce protective immunity in colonized normal and immunodeficient mice. PUBLIC HEALTH RELEVANCE: Antibiotic resistant Staphylococcus aureus infections are emerging as a major public health threat. No vaccines are currently available to prevent these infections and the most recent vaccine clinical trials have not been successful. Because of this, there is interest in developing novel vaccination strategies to protect people most susceptible to these potentially lethal infections. We are proposing to use virus-like particles that express peptide pheromones that this bacterial pathogen uses to promote secretion of toxins and other products that cause invasive disease. This approach has not been attempted previously for S. aureus.