VLP-based Vaccines for Targeting Staphylococcus aureus Secreted Virulence Factors

 描述（申请人提供）：迄今为止，没有预防金黄色葡萄球菌感染的疫苗在III期临床试验中获得成功。与此同时，对疫苗的需求继续升级，这种病原体获得抗生素耐药性的能力也在升级。我们的目标是证明病毒样颗粒（VLP）作为一种创新的广谱平台生产抗链球菌疫苗的有效性。金黄色葡萄球菌分泌毒力因子。VLP是设计靶向细菌感染的疫苗的新方法，并且基于VLP的疫苗靶向分泌型S.金黄色葡萄球菌毒素诱导保护性免疫应答的研究尚未进行。因此，本提案的目的是检验毒素肽在VLP上的呈递可用于诱导靶向主要S.金黄色葡萄球菌分泌毒力因子。具体目标#1：确定展示结构上选择的Hla和双组分白细胞毒素肽的VLP在幼稚和S.金黄色葡萄球菌定殖小鼠。具体目标#2：为了确定展示代表Hla和双组分白细胞毒素的毒素肽组的10聚体肽的VLP在幼稚和S.金黄色葡萄球菌定殖小鼠。重要的是，与其他平台和实验佐剂不同，VLP目前用于FDA批准的疫苗（如目前的HPV疫苗）。因此，如果使用VLP的实验方法在动物模型中得到证实，它们可能很容易转化为人体试验。

 DESCRIPTION (provided by applicant): To date, no vaccine to prevent Staphylococcus aureus infection has succeeded in Phase III clinical trials. Meanwhile, the need for a vaccine continues to escalate as does the ability of this pathogen to acquire antibiotic resistance. Our goal is to demonstrate the effectiveness of virus-like particles (VLPs) as an innovative broad- spectrum platform for production of vaccines against S. aureus secreted virulence factors. VLPs are a novel approach to the design of vaccines targeting bacterial infection and the ability of VLP-based vaccines targeting secreted S. aureus toxins to induce a protective immune response has not been investigated. Therefore, the goal of this proposal is to test the hypothesis that presentation of toxin peptides on VLPs can be used to induce adaptive immunity targeting major S. aureus secreted virulence factors. To test this hypothesis we will pursue the following specific aims: Specific Aim #1: To determine the immunogenicity and efficacy of VLPs displaying structurally selected Hla and bi-component leukotoxin peptides in naïve and S. aureus colonized mice. Specific Aim #2: To determine the immunogenicity and efficacy of VLPs displaying 10-mer peptides representing the toxin peptidome of Hla and bi-component leukotoxins in naïve and S. aureus colonized mice. Importantly, unlike other platforms and experimental adjuvants, VLPs are currently used in FDA-approved vaccines (like the current HPV vaccines). Therefore, if experimental approaches using VLPs are confirmed in animal models, they can potentially translate into human trials fairly readily.