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，用于靶向其来源的病毒或用于以多价形式展示几乎任何表位。VLP诱导强烈的抗体应答，因为其衣壳结构的周期性将抗原表位呈现为密集的、高度重复的阵列，其强烈刺激B淋巴细胞。虽然VLP已被用于宿主防御病毒感染，但其用于预防细菌感染的用途有限。 耐甲氧西林金黄色葡萄球菌（MRSA）已成为一个主要的公共卫生威胁，在美国和至少9个其他国家出现了与危及生命的感染相关的单一克隆（USA300），这使人们重新关注预防这种感染的疫苗。由于大多数确定与侵袭性MRSA感染的毒力因子控制的群体感应操纵子，agr，我们建议使用VLP为基础的疫苗接种，以诱导针对自诱导肽信息素（AIP），激活这一全球调节毒力的中和抗体。由于其大小（8个氨基酸），除非与大载体蛋白复合，否则AIP的免疫原性较差。因此，在VLP上展示AIP作为密集阵列代表了诱导高亲和力抗体以中和其生物学功能的潜在策略。该探索性R21的目的是检验VLP可用作疫苗平台以诱导靶向S的适应性免疫的假设。金黄色葡萄球菌毒力。为了验证这一假设，我们将追求两个具体目标：1）确定是否VLP轴承S。金黄色葡萄球菌毒力肽可诱导正常和免疫缺陷小鼠产生保护性免疫。2)以确定是否有VLP轴承S。金黄色葡萄球菌毒力肽可诱导定植正常和免疫缺陷小鼠的保护性免疫。 公共卫生相关性：耐抗生素金黄色葡萄球菌感染正在成为一个主要的公共卫生威胁。目前还没有疫苗可以预防这些感染，最近的疫苗临床试验也没有成功。正因为如此，人们有兴趣开发新的疫苗接种策略，以保护最容易受到这些潜在致命感染的人。我们建议使用表达肽信息素的病毒样颗粒，这种细菌病原体使用这些颗粒来促进毒素和其他导致侵入性疾病的产物的分泌。这种方法以前没有尝试过S。金黄色。

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.