Multivalent Toxoid Vaccine for Prevention of S. aureus Invasive Diseases

用于预防金黄色葡萄球菌侵袭性疾病的多价类毒素疫苗

• 批准号: 8799801
• 负责人: M Javad Aman
• 金额: $ 41.19万
• 依托单位: INTEGRATED BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8799801
• 关键词: Adjuvant; Adult; Affinity; Animal Model; Antibiotics; Antibodies; Antibody Response; Antigens; Attenuated; Bacteremia; Binding; Biological Assay; Biological Response Modifier Therapy; Cell Surface Proteins; Cell surface; Cells; Cessation of life; Clinical; Clinical Research; Clinical Trials; Community Hospitals; Complement; Development; Disease; Distant; Drug Formulations; Epitopes; Family; Foundations; Future; Goals; Government; Growth; HLA-DR4 Antigen; Hemolysin; Hospitalization; Human; Immune; Immune Targeting; Immune response; Immunity; Immunocompetent; Individual; Infection; Infection Control; Infection prevention; Laboratories; Lead; Leucocidin; Libraries; MHC Class II Genes; Manuscripts; Mediating; Membrane Proteins; Methicillin Resistance; Modeling; Mus; National Institute of Allergy and Infectious Disease; Organ; Oryctolagus cuniculus; Panton-Valentine leukocidin; Pathogenicity; Patients; Phage Display; Phase I Clinical Trials; Pneumonia; Polysaccharides; Prevention; Preventive; Probability; Public Health; Seeds; Sepsis; Serological; Serum; Staphylococcal Enterotoxin B; Staphylococcal Protein A; Staphylococcal Vaccines; Staphylococcus aureus; Sterility; Streptococcus pneumoniae; Superantigens; Targeted Toxins; Testing; Tissues; Toxic Shock Syndrome; Toxic Shock Syndrome Toxin-1; Toxic effect; Toxin; Toxoids; Vaccination; Vaccines; Variant; Virulence Factors; Work; aluminum sulfate; base; clinically relevant; cohort; cytokine; design; group competition; immunogenicity; leukotoxin; methicillin resistant Staphylococcus aureus; mouse model; mutant; neutralizing antibody; novel; novel vaccines; pathogen; pre-clinical; preclinical efficacy; prevent; programs; prospective; protective efficacy; public health relevance; resistant strain; response; screening; septic; vaccine candidate; vaccine development

DESCRIPTION (provided by applicant): Staphylococcus aureus (SA) is a major threat to public health with no vaccines available for human use. Currently a large number of SA clinical isolates are methicillin resistant (MRSA) making the development of staphylococcal vaccines a pressing public health need. The pathogenicity of SA is dependent on a plethora of virulence factors including cell surface proteins and polysaccharides as well as toxins that target the immune cells or cause tissue destruction enabling the pathogen to disseminate and seed in distant organs. Several prior attempts to develop vaccines for S. aureus have ignored the importance of key toxins. The myriad of cytolytic and immune modulating toxins cripples the ability of the innate immune response to control the infection leading to invasive disease. Prior failed efforts for development of SA vaccines using surface proteins or polysaccharides (ClfA, SdrG, IsdB, CP5, and CP8) were focused on achieving sterile immunity (total prevention of infection) through an opsonophagocytic mechanism, an approach successfully applied to other major pathogens such as S. pneumoniae. However, the results of the clinical trials with these vaccines (Nabi, Meck, Biosynexus) question the notion that opsonophagocytic antibodies can mediate sterile immunity against S. aureus. Inability to induce effective opsonic antibody response may relate to expression of protein A by S. aureus. This proposal offers an alternative approach by devising a strategy to induce broadly neutralizing antibodies to key S. aureus toxins with the goal of preventing the complications of invasive disease (clinical protection- such as prevention of sepsis) rather than sterile immunity. The proposal is based on a set of structurally designed vaccine candidates for three classes of staphylococcal toxins, i.e. single component alpha hemolysin (Hla), bicomponent leukocidins, as well as superantigens. A further foundation of the proposed study is a prospective clinical study demonstrating a strong inverse correlation between pre-existing antibody titers to the selected toxins and the probability of sepsis in immunocompetent adults with S. aureus bacteremia. The current proposal is aimed at demonstration of efficacy of a multivalent formulation in animal models of S. aureus infection leading to a preclinical multivalent vaccine candidate. The proposal will further explore the mechanism and correlates of the conferred immunity informed by a systematic analysis of the neutralizing epitopes represented in convalescent patients. The proposal is designed in four Specific Aims: In Aim 1 we will develop a bi- or trivalent pore-forming toxoid vaccine formulation with broad neutralizing activity towards Hla and the family of leukocidins and efficacy will be tested in mice and rabbits. In Aim 2, a trivalent vaccine formulation will be developed using three superantigen toxoids and efficacy will be demonstrated in a novel humanized mouse model expressing HLA-DR4. One component of this vaccine (STEBVax) is already in Phase I clinical trial under an NIAID supported program (VTEU). In Aim 3 a final pentavalent formulation will be developed including pore-forming and superantigen toxoids and tested in several infection models in HLA- DR4 mice as well as rabbits. In Aim 4, using a large cohort of convalescent and septic patients with S. aureus bacteremia, we seek to determine the relationship between protection from sepsis and presence of antibodies to specific epitopes in Hla and leukocidins. In summary this project completes over a decade of work supported by US government and is expected to result in a novel vaccine for S. aureus as well as potential correlates of immunity to guide clinical development. The proposal brings together three highly skilled teams: Integrated Biotherapeutics with extensive expertise in toxoid vaccines; Diep's lab (UCSF) a pioneer in rabbit models of S. aureus infections, and Sidhu's lab (U Toronto) a leading laboratory in phage display human antibody libraries.

描述（由申请人提供）：金黄色葡萄球菌 (SA) 是对公共健康的主要威胁，目前尚无可供人类使用的疫苗。目前，大量 SA 临床分离株具有甲氧西林耐药性 (MRSA)，使得葡萄球菌疫苗的开发成为迫切的公共卫生需求。 SA 的致病性取决于多种毒力因子，包括细胞表面蛋白和多糖以及针对免疫细胞或导致组织破坏的毒素，使病原体能够在远处器官中传播和播种。先前开发金黄色葡萄球菌疫苗的几次尝试都忽略了关键毒素的重要性。无数的细胞溶解和免疫调节毒素削弱了先天免疫反应控制导致侵袭性疾病的感染的能力。之前使用表面蛋白或多糖（ClfA、SdrG、IsdB、CP5 和 CP8）开发 SA 疫苗的失败努力主要集中在通过调理吞噬机制实现无菌免疫（全面预防感染），这种方法成功应用于其他主要病原体，例如肺炎链球菌。然而，这些疫苗（Nabi、Meck、Biosynexus）的临床试验结果对调理吞噬抗体可以介导针对金黄色葡萄球菌的无菌免疫的概念提出了质疑。无法诱导有效的调理性抗体反应可能与金黄色葡萄球菌表达 A 蛋白有关。该提案提供了另一种方法，通过设计一种策略来诱导针对关键金黄色葡萄球菌毒素的广泛中和抗体，其目标是预防侵袭性疾病的并发症（临床保护-例如 作为预防败血症）而不是无菌免疫。该提案基于针对三类葡萄球菌毒素的一组结构设计的候选疫苗，即单组分α溶血素（Hla）、双组分杀白细胞素以及超抗原。拟议研究的进一步基础是一项前瞻性临床研究，证明针对选定毒素的预先存在的抗体滴度与患有金黄色葡萄球菌菌血症的免疫功能正常的成人败血症的可能性之间存在很强的负相关性。目前的提案旨在证明多价制剂在金黄色葡萄球菌感染动物模型中的功效，从而形成临床前多价候选疫苗。该提案将通过对恢复期患者中所代表的中和表位进行系统分析，进一步探讨赋予免疫力的机制和相关性。该提案有四个具体目标：在目标 1 中，我们将开发一种二价或三价成孔类毒素疫苗制剂，对 Hla 和杀白细胞素家族具有广泛的中和活性，并将在小鼠和兔子中测试功效。在目标 2 中，将使用三种超抗原类毒素开发三价疫苗制剂，并将在表达 HLA-DR4 的新型人源化小鼠模型中证明功效。该疫苗的一个成分 (STEBVax) 已在 NIAID 支持的计划 (VTEU) 下进行 I 期临床试验。在目标 3 中，将开发最终的五价制剂，包括成孔类毒素和超抗原类毒素，并在 HLA-DR4 小鼠和兔子的几种感染模型中进行测试。在目标 4 中，我们利用一大群患有金黄色葡萄球菌菌血症的恢复期和脓毒症患者，试图确定脓毒症的保护作用与 Hla 和杀白细胞素中特定表位的抗体的存在之间的关系。总之，该项目完成了美国政府支持的十多年的工作，预计将产生一种新型金黄色葡萄球菌疫苗以及指导临床开发的潜在免疫相关因素。该提案汇集了三个高技能团队：在类毒素疫苗方面拥有丰富专业知识的综合生物治疗团队； Diep 的实验室（UCSF）是金黄色葡萄球菌感染兔模型的先驱，Sidhu 的实验室（多伦多大学）是噬菌体展示人类抗体库的领先实验室。