Multivalent Toxoid Vaccine for Prevention of S. aureus Invasive Diseases

描述（由申请人提供）：金黄色葡萄球菌（SA）是对公众健康的主要威胁，目前没有可供人类使用的疫苗。目前，大量SA临床分离株具有耐甲氧西林（MRSA），使得葡萄球菌疫苗的开发成为迫切的公共卫生需求。SA的致病性依赖于大量的毒力因子，包括细胞表面蛋白和多糖，以及靶向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传播和播种。之前几次开发金黄色葡萄球菌疫苗的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感染的能力，导致侵袭性疾病。先前使用表面蛋白或多糖（ClfA、SdrG、IsdB、CP5和CP8）开发SA疫苗的努力失败，主要是通过促噬细胞机制实现无菌免疫（完全预防感染），这种方法成功应用于其他主要病原体，如肺炎链球菌。然而，这些疫苗的临床试验结果（Nabi, Meck, Biosynexus）质疑调理噬细胞抗体可以介导针对金黄色葡萄球菌的无菌免疫的概念。无法诱导有效的偶声抗体反应可能与金黄色葡萄球菌表达蛋白A有关。这一建议提供了一种替代方法，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，以防止侵袭性疾病的并发症(临床保护-例如

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 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.