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

基本信息

批准号：
8991471
负责人：
M Javad Aman
金额：
$ 77.94万
依托单位：
INTEGRATED BIOTHERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
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/8991471
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 Epitopes Family Formulation Foundations Future Goals Government Growth HLA-DR4 Antigen Health 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 vaccine 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 antibody libraries base clinically relevant cohort cytokine design group competition humanized mouse immunogenicity leukotoxin methicillin resistant Staphylococcus aureus mouse model mutant neutralizing antibody novel novel vaccines pathogen pre-clinical preclinical efficacy prevent programs prospective protective efficacy resistant strain response screening septic vaccine candidate vaccine development

项目摘要

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）是对公共卫生的主要威胁，没有可用于人类使用的疫苗。目前，大量的SA临床分离株是甲氧西林耐药（MRSA），这使得葡萄球菌疫苗的开发是紧迫的公共健康需求。 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靶向免疫细胞或引起组织破坏的毒素，使病原体能够在远处的器官中散发和种子。为金黄色葡萄球菌开发疫苗的几项先前尝试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导致侵袭性疾病的能力。先前使用表面蛋白或多糖（CLFA，SDRG，ISDB，CP5和CP8）开发SA疫苗的努力的重点是通过opsonopsopypytic机制实现无菌免疫（全部预防感染），一种成功应用于其他主要病原体的方法例如肺炎链球菌。然而，这些疫苗（NABI，MECK，Biosynexus）的临床试验结果质疑肠孢子抗体可以介导针对金黄色葡萄球菌的无菌免疫力的观念。无法诱导有效的Opsonic抗体反应可能与金黄色葡萄球菌的蛋白A表达有关。该提案通过制定一种策略来诱导关键金黄色葡萄球菌毒素的抗体，目的是防止侵入性疾病的并发症（临床保护 - 此类），提供了一种替代方法。作为预防败血症）而不是无菌免疫。该提案基于一组针对三类葡萄球菌毒素的结构设计的疫苗候选物，即单个成分α溶血素（HLA），双足体白细胞素以及上植物。拟议研究的进一步基础是一项前瞻性临床研究，证明了与所选毒素的抗体滴度与败血症的概率之间存在很强的反相关性，而在免疫能力的成年人与金黄色葡萄球菌菌血症中的概率有很强的相关性。当前的建议旨在证明多价配方在金黄色葡萄球菌感染的动物模型中的功效，从而导致临床前多价疫苗候选。该提案将进一步探讨通过对康复患者代表的中和表位的系统分析所允许的赋予免疫力的机制和相关性。该提案以四个特定的目的设计：在AIM 1中，我们将开发出双重或三价形成的孔形成毒素疫苗配方，对HLA进行广泛的中和活性，而白细胞素的家族将在小鼠和兔子中进行测试。在AIM 2中，将使用三种超抗原毒素开发三价疫苗配方，并在表达HLA-DR4的新型人源性小鼠模型中证明了功效。根据NIAID支持计划（VTEU），该疫苗（Stebvax）的一个组成部分已经在I期临床试验中。在AIM 3中，将开发最终的五价配方，包括孔形成和超抗原毒素，并在Hla-dr4小鼠和兔子的几种感染模型中进行了测试。在AIM 4中，使用大量的康复和化粪池患者患有金黄色葡萄球菌菌血症患者，我们试图确定HLA和白细胞素的特定表位的保护与特定表位的保护之间的关系。总而言之，该项目完成了美国政府支持的十年的工作，预计将为金黄色葡萄球菌提供新颖的疫苗，以及用于指导临床发展的免疫力的潜在相关性。该提案汇集了三个高技能的团队：综合的生物治疗学，在毒素疫苗方面具有广泛的专业知识； 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（U Toronto）是噬菌体领先的实验室，显示了人类抗体库。