VLP-based Vaccines for Targeting Bacterial Virulence

基于 VLP 的针对细菌毒力的疫苗

• 批准号: 7877135
• 负责人: Hattie D. Gresham
• 金额: $ 14.68万
• 依托单位: BIOMEDICAL RESEARCH INSTITUTE OF NEW MEX
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7877135
• 关键词: Amino Acids; Antibiotic Resistance; Antibodies; Antibody Affinity; Antibody Formation; B-Lymphocytes; Bacterial Infections; Bacteriophages; Binding; Capsid; Carrier Proteins; Complex; Country; Data; Disease; Epitopes; Goals; Hepatitis B; Host Defense; Human; Human Papillomavirus; Immune Sera; Immunity; Immunodeficient Mouse; Immunoglobulin G; Infection; Infection Control; Infection prevention; Life; Modeling; Operon; Outcome; Peptides; Periodicity; Pheromone; Prevention; Public Health; Research; Serum; Staphylococcus aureus; Structure; Testing; Toxin; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccines; Virulence; Virulence Factors; Virus; Virus Diseases; Virus-like particle; Wild Type Mouse; adaptive immunity; anthrax toxin; attenuation; base; density; flexibility; immunogenic; immunogenicity; in vitro activity; in vivo; interest; methicillin resistant Staphylococcus aureus; mutant; neutralizing antibody; novel; pathogen; public health relevance; quorum sensing; vaccination strategy

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.

描述（由申请人提供）：病毒样颗粒（VLP）是一个灵活的疫苗接种平台，用于靶向其所在的病毒或用于以多价格式显示任何表位的病毒。 VLP会引起强抗体反应，因为其衣壳结构的周期性将抗原表位作为密集的，高度重复的阵列，可刺激B淋巴细胞。虽然已追求VLP来防止宿主防御病毒感染，但它们用于预防细菌感染的使用受到限制。 耐甲氧西林金黄色葡萄球菌（MRSA）已成为主要的公共卫生威胁，并且与美国威胁生命的感染相关的单个克隆（USA300）的出现，至少其他9个国家对疫苗有重新关注的兴趣，以防止这种感染。由于侵入性MRSA感染最鉴定出的毒力因子由法定感应操纵子AGR控制，因此我们建议使用基于VLP的疫苗接种来诱导对自身诱导自身诱导肽信息素（AIP）的中和抗体，从而激活这种毒力性的全球调节剂。由于其大小（8个氨基酸）AIP的免疫原性较差，除非与大型载体蛋白复合。因此，在VLP上显示AIP作为密集阵列代表了诱导高亲和力抗体中和其生物学功能的潜在策略。该探索性R21的目的是检验以下假设：VLP可以用作诱导靶向金黄色葡萄球菌毒力的适应性免疫的疫苗平台。为了检验这一假设，我们将追求两个具体的目的：1）确定含有金黄色葡萄球菌毒力肽的VLP是否可以在正常和免疫缺陷的小鼠中诱导保护性免疫。 2）确定带有金黄色葡萄球菌毒力肽的VLP是否可以在定殖的正常和免疫缺陷的小鼠中诱导保护性免疫。 公共卫生相关性：抗生素抗生素金黄色葡萄球菌感染正在成为主要的公共卫生威胁。目前尚无疫苗来预防这些感染，最近的疫苗临床试验尚未成功。因此，人们有兴趣制定新的疫苗接种策略，以保护最容易受到这些潜在致命感染的人。我们建议使用这种细菌病原体用来促进毒素和其他引起侵入性疾病的产品的病毒样颗粒来表达肽的信息素。以前尚未尝试过这种方法为金黄色葡萄球菌。