Multivalent Toxoid Vaccine for Prevention of S. aureus Invasive Diseases

描述(申请人提供)：金黄色葡萄球菌(SA)是对公众健康的主要威胁，没有疫苗可供人类使用。目前，大量的金黄色葡萄球菌临床分离株对甲氧西林耐药(MRSA)，使得研制葡萄球菌疫苗成为迫切的公共卫生需求。沙门氏菌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，以及针对免疫细胞或导致组织破坏的毒素，使病原体能够在遥远的器官中传播和播种。之前开发金黄色葡萄球菌疫苗的几次尝试都忽视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，从而导致侵袭性疾病。以前使用表面蛋白或多糖(ClfA、SdrG、ISDB、CP5和CP8)开发SA疫苗的失败努力集中在通过吞噬细胞机制实现无菌免疫(完全预防感染)，这一方法成功地应用于其他主要病原体，如肺炎链球菌。然而，这些疫苗(NaBi、Meck、Biastexx)的临床试验结果质疑噬液细胞抗体可以介导对金黄色葡萄球菌的不育免疫的观点。金黄色葡萄球菌不能诱导有效的调理抗体应答可能与其表达蛋白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，目的是预防侵袭性疾病的并发症(临床保护等 作为预防败血症)，而不是无菌免疫。这项建议是基于一套针对三种葡萄球菌毒素的结构设计的候选疫苗，即单组分α溶血素(Hla)、双组分杀白素以及超抗原。这项拟议研究的另一个基础是一项前瞻性的临床研究，该研究表明，先前存在的针对所选毒素的抗体效价与免疫功能正常的金黄色葡萄球菌菌血症患者发生败血症的可能性之间存在强烈的负相关。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有效性，从而导致临床前多价疫苗候选。该提案将通过对恢复期患者所代表的中和表位的系统分析，进一步探讨授予免疫的机制和相关性。在目标1中，我们将开发一种对人类白细胞抗原和杀白素家族具有广泛中和活性的二价或三价成孔类毒素疫苗配方，并将在小鼠和兔身上进行疗效测试。在目标2中，将开发一种使用三种超抗原类毒素的三价疫苗配方，并将在表达人类白细胞抗原-DR4的新的人源化小鼠模型中证明其有效性。这种疫苗的一种成分(STEBVax)已经在NIAID支持的计划(VTEU)下进行第一阶段临床试验。在目标3中，将开发一种最终的五价制剂，包括造孔和超抗原类毒素，并在几种感染模型中进行测试，包括在HL A-DR4小鼠和兔身上。在目标4中，利用一大批金黄色葡萄球菌菌血症的恢复期和败血症患者，我们试图确定对败血症的保护与针对人类白细胞抗原和杀白素的特定表位抗体的存在之间的关系。综上所述，该项目完成了美国政府支持的十多年的工作，有望产生一种新的金黄色葡萄球菌疫苗，以及潜在的免疫相关性，以指导临床开发。该提案汇集了三个高技能的团队：在毒素疫苗方面拥有丰富专业知识的集成生物疗法团队；金黄色葡萄球菌感染兔模型的先驱Diep实验室(UCSF)；以及Sidhu的实验室(U Toronto)，一个展示噬菌体人类抗体库的领先实验室。

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.