Development of a Panton Valentine Leukocidin bivalent vaccine

潘顿·瓦伦丁杀白细胞素二价疫苗的开发

• 批准号: 8056021
• 负责人: M Javad Aman
• 金额: $ 30万
• 依托单位: INTEGRATED BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056021
• 关键词: Adjuvant; Advanced Development; Amino Acids; Animal Model; Animals; Antibiotic Resistance; Antibodies; Antibody Formation; Antigens; Attenuated; Biological Assay; Biological Response Modifier Therapy; Cells; Cholera Toxin Protomer B; Communities; Community Hospitals; Computer Simulation; Development; Drug Formulations; Effectiveness; Ensure; Evaluation; Exotoxins; Filovirus; Genes; Goals; Hospitals; Human; Immune; In Vitro; Inbred BALB C Mice; Infection; Measures; Modeling; Mus; Mutate; National Institute of Allergy and Infectious Disease; Panton-Valentine leukocidin; Phase; Phase I Clinical Trials; Play; Pneumonia; Point Mutation; Prevention; Production; Recombinants; Research; Role; Route; Safety; Schedule; Site; Site-Directed Mutagenesis; Small Business Innovation Research Grant; Staging; Staphylococcus aureus; Structure; Subunit Vaccines; Testing; Toxic effect; Toxin; Toxoids; Translational Research; Vaccinated; Vaccination; Vaccines; Virulence Factors; assay development; attenuation; base; cytotoxic; design; experience; immunogenicity; in vitro testing; in vivo; manufacturing process; manufacturing process development; methicillin resistant Staphylococcus aureus; mutant; neutrophil; novel; pathogen; pre-clinical; preclinical efficacy; programs; public health relevance; safety study; staphylococcal enterotoxin; subcutaneous; vaccine candidate

DESCRIPTION (provided by applicant): Staphylococcus aureus (S.aureus) is a formidable human pathogen responsible for severe infections in the hospitals and community. S. aureus produces a variety of virulence factors including a range of exotoxins with immune inhibitory, immunomodulatory, and cytotoxic activities. One of these toxins, the Panton Valentine Leukocidin (PVL), is a pore forming toxin associated with severe pneumonia cases of community acquired S. aureus infections. Current vaccine efforts targeting PVL are focused on single wild type subunits. However, this approach may pose serious safety concerns for human use. The overall goal of this research plan is to develop a recombinant, mutant (attenuated) and bivalent vaccine against PVL. The proposal is based on extensive structural analysis of the components of PVL and structure- based, rational design of potentially attenuated mutants. This Phase I SBIR is designed in two Specific Aims. In Aim 1 we will introduce point mutations into the genes encoding for the LukS and LukF subunits of PVL to abolish toxin oligomerization and the resulting pore formation, and characterize the integrity and activity of the mutant PVL subunits in vitro. The degree of attenuation of the vaccine candidates will be determined in vitro and in vivo. In Aim 2 we seek to further characterize and down-select mutant PVL subunits as vaccine candidate(s) based on efficacy studies using mouse challenge models of native PVL toxin and to perform preliminary evaluation in S. aureus infections in BALB/c mice using the MRSA clone USA300. The endpoint for the Phase I is the identification of one or two preclinical candidates. In Phase II of this SBIR we will complete the preclinical efficacy, formulation, and safety studies for the selected vaccine candidate(s). The ultimate goal is to develop a safe and effective PVL antigen that could be integrated into a multivalent S. aureus vaccine formulation that will include other toxins or cell- associated S. aureus antigens. PUBLIC HEALTH RELEVANCE: This proposal is aimed at development of a safe and effective vaccine for one the toxins produced by Staphylococcus aureus (SA), known as PVL. Antibiotic resistant SA infections have been on the rise in the past two decades both in the hospitals and in the community. There are currently no vaccine available against SA infections. PVL is known to play an important role in severe cases of pneumonia caused by community acquired MRSA. The vaccine produced under this program is expected to be a component of a multicomponent vaccine for prevention of SA infections.

描述（由申请人提供）：金黄色葡萄球菌（S.aureus）是一种可怕的人类病原体，可导致医院和社区的严重感染。S.金黄色葡萄球菌产生多种毒力因子，包括一系列具有免疫抑制、免疫调节和细胞毒性活性的外毒素。这些毒素之一，Panton Valentine杀白细胞素（PVL），是一种与社区获得性链球菌严重肺炎病例相关的成孔毒素。金黄色葡萄球菌感染目前靶向PVL的疫苗努力集中在单个野生型亚基上。然而，这种方法可能对人类使用造成严重的安全问题。本研究计划的总体目标是开发针对PVL的重组、突变（减毒）和双价疫苗。该提议基于对PVL组分的广泛结构分析和基于结构的潜在减毒突变体的合理设计。第一阶段SBIR的设计有两个具体目标。在目的1中，我们将引入点突变的基因编码的LukS和LukF亚基的PVL，以消除毒素寡聚化和由此产生的孔形成，并在体外表征的完整性和活性的突变PVL亚基。将在体外和体内测定候选疫苗的减毒程度。在目的2中，我们寻求基于使用天然PVL毒素的小鼠攻击模型的功效研究进一步表征和下调选择突变PVL亚基作为疫苗候选物，并在S.使用MRSA克隆USA 300在BALB/c小鼠中检测金黄色葡萄球菌感染。第一阶段的终点是确定一个或两个临床前候选人。在本SBIR的II期，我们将完成所选候选疫苗的临床前有效性、制剂和安全性研究。最终的目标是开发一种安全有效的PVL抗原，可以整合到多价的S。金黄色葡萄球菌疫苗制剂，将包括其他毒素或细胞相关的S。金黄色葡萄球菌抗原 公共卫生关系：该提案旨在开发一种安全有效的疫苗，用于金黄色葡萄球菌（SA）产生的毒素之一，称为PVL。在过去的二十年里，无论是在医院还是在社区，抗生素耐药性SA感染都呈上升趋势。目前还没有针对SA感染的疫苗。已知PVL在社区获得性MRSA引起的严重肺炎病例中起重要作用。根据该计划生产的疫苗预计将成为预防SA感染的多组分疫苗的组成部分。

项目成果

Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model.

• DOI: 10.1371/journal.pone.0065384
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Karauzum H;Adhikari RP;Sarwar J;Devi VS;Abaandou L;Haudenschild C;Mahmoudieh M;Boroun AR;Vu H;Nguyen T;Warfield KL;Shulenin S;Aman MJ
• 通讯作者: Aman MJ