VLP-based Vaccines for Targeting Bacterial Virulence

描述(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形式展示几乎任何表位。VLP诱导强烈的抗体反应是因为其衣壳结构的周期性将抗原表位呈现为密集、高度重复的阵列，从而有力地刺激B淋巴细胞。虽然VLP一直被用于宿主抵御病毒感染的防御，但它们在预防细菌感染方面的使用一直受到限制。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，在美国和至少其他9个国家出现了与危及生命的感染有关的单一克隆(USA300)，这重新引起了人们对预防这种感染的疫苗的兴趣。由于大多数侵袭性MRSA感染的毒力因子由群体感应操纵子AGR控制，我们建议使用基于VLP的疫苗来诱导针对自身诱导的多肽信息素(AIP)的中和抗体，AIP激活这种全球毒力调节因子。由于其大小(8个氨基酸)，AIP除非与一个大的载体蛋白复合，否则免疫原性很差。因此，在VLP上以密集排列的形式显示AIP是一种潜在的策略，可以诱导高亲和力抗体来中和其生物学功能。这一探索性R21的目的是检验VLP可作为疫苗平台诱导针对金黄色葡萄球菌毒力的获得性免疫的假设。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多肽的VLP是否能在正常和免疫缺陷小鼠中诱导保护性免疫。2)检测携带金黄色葡萄球菌毒力多肽的VLP能否诱导正常小鼠和免疫缺陷小鼠的保护性免疫。 公共卫生相关性：抗药性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。我们正在提议使用病毒样颗粒来表达多肽信息素，这种细菌病原体利用这些信息素来促进毒素和其他导致侵袭性疾病的产品的分泌。这种方法以前从未对金黄色葡萄球菌进行过尝试。

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.