Vaccine potential of the proline-rich domain of pneumococcal surface protein A

肺炎球菌表面蛋白 A 富含脯氨酸结构域的疫苗潜力

基本信息

批准号：
9265801
负责人：
David E Briles
金额：
$ 36.75万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2015-05-06 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265801
关键词：
Address Antibodies Antigens Bacteremia Binding Binding Proteins Biological Assay Blood Cessation of life Childhood Choline Clinical Complement Data Deposition Development Diphtheria Toxoid Disease Elderly Environment Epitopes FDA approved Goals Human Immunity In Vitro Infant Infection Inflammation Knowledge Liquid substance Lung Mammals Membrane Proteins Meningitis Modeling Modernization Molecular Conformation Monoclonal Antibodies Mouse Protein Mus N-terminal NON Mouse Natural Immunity Nose Oryctolagus cuniculus Otitis Media Peptides Phase Phase I Clinical Trials Pneumococcal Infections Pneumococcal vaccine Pneumonia Polysaccharides Proline-Rich Domain Property Proteins Repetitive Sequence Safety Sepsis Signal Transduction Site Sterility Streptococcus pneumoniae Structure Surface Symptoms Tertiary Protein Structure Testing Vaccines Variant Virulence Virulent bactericide capsule cost cross reactivity efficacy trial high risk immunogenic improved in vitro Assay killings pathogen pneumococcal surface protein A prevent public health relevance virtual

项目摘要

DESCRIPTION (provided by applicant): Protection against otitis media, non-complicated pneumonia, and meningitis requires a vaccine solution that is not capsular type-specific. The pneumococcal surface protein PspA elicits protection in mice against pneumonia, bacteremia, colonization, and fatal sepsis. PspA was in FDA-approved safety (phase 1) trials (1998, 2002, 2010, and 2012-14). These trials revealed no safety problems, and the human antibody (Ab) elicited to PspA protected mice from fatal sepsis. The human trials of purified rPspA (1998, 2002, and 2010) examined protection elicited by the ~300 aa a-helical domain (aHD) at the N-terminal end of PspA. The aHD is variable; up to three different aHD may be required in a vaccine to cover the diversity of PspA in all Sp. We have recently shown that the ~80 aa proline-rich domain (PRD) also elicits protection against sepsis. The PRD domain is found in all PspAs. Each PRD contains 1 to 5 different 6-10 AA repeat sequences. We have protective monoclonal antibody (mAb) to one of these short repeat sequences and to a conserved 22 aa non-proline block (NBP) sequence, present in ~50% of PRD. However, a PRD lacking either of these epitopes could still elicit cross-protection, indicating the existence of additional protective epitopes. We have already found Ab to four of the PRD repeat sequences in human sera. We will create broadly cross-reactive rPRD by including all of its common protection-eliciting epitopes. Developing a highly cross-protective PRD immunogen is important because some of the delay in moving PspA into phase 3 efficacy trials is due to concern that variability in the aHD structure may allow Sp to evolve around a PspA aHD vaccine. The PRD will provide a second set of epitopes with which to cover all PspAs. We will determine the degree to which rPRD can replace, or augment, the cross-protection elicited by the aHD against Sp strains of all relevant capsular types. Aim1. Identify major protection-eliciting repeats in PRD that are immunogenic in mice, rabbits, and humans and use this information to construct candidate rPRD expected to be broadly cross-protective. Aim2. Evaluate cross- protection elicited by the rPRD immunogens constructed in Aim 1 in mouse sepsis, focal pneumonia, and colonization models. Compare the ability of PRD, aHD, and PRD+aHD to elicit protection against diverse Sp. Variations in PspA structure are not genetically or functionally related to capsule type. Thus, it has long been assumed that the protection observed against the few mouse-virulent capsule types with Ab to PspA would hold for Sp of non-mouse virulent capsular types. To examine protection against invasive strains of all relevant capsular types we will: 1) use our in vitro functional assay, 2) ue focal pneumonia which is caused in the mouse by many more capsular types than sepsis, and 3) use host inflammation-associated molecules to temporarily enhance the virulence of invasive clinical IPD isolates of capsular types that are not normally mouse-virulent. Aim3. Determine whether Ab to PRD can enhance C' deposition on Sp and enhance the killing of Sp by bactericidal peptides. Ab to the aHD of PspA functions by both of these mechanisms.

描述（由申请人提供）：预防中耳炎、非复杂性肺炎和脑膜炎需要非荚膜类型特异性的疫苗溶液。肺炎球菌表面蛋白 PspA 可在小鼠中引起针对肺炎、菌血症、定植和致命性败血症的保护。 PspA 正在进行 FDA 批准的安全性（1 期）试验（1998 年、2002 年、2010 年和2012-14）。这些试验没有发现安全问题，并且 PspA 引起的人类抗体（Ab）可以保护小鼠免受致命性败血症。纯化的 rPspA 的人体试验（1998 年、2002 年和 2010 年）检查了约 300 个氨基酸引起的保护作用。 PspA N 末端的 a-螺旋结构域 (aHD) 是可变的；疫苗中可能需要多达三个不同的 aHD。涵盖所有 Sp 中 PspA 的多样性。我们最近发现，约 80 个氨基酸富含脯氨酸的结构域 (PRD) 也能引发针对败血症的保护。每个 PRD 包含 1 至 5 个不同的 6-10。 AA 重复序列。我们拥有针对这些短重复序列之一和保守的 22 个氨基酸非脯氨酸块 (NBP) 序列的保护性单克隆抗体 (mAb)，该序列存在于约 50% 的序列中。然而，缺乏这些表位中的任何一个的 PRD 仍然可以引起交叉保护，这表明我们已经在人类血清中发现了针对四个 PRD 重复序列的抗体。开发一种高度交叉保护的 PRD 免疫原非常重要，因为 PspA 进入 3 期疗效试验的一些延迟是由于担心 PspA 的变异性。高清结构可能允许 Sp 围绕 PspA aHD 疫苗进化，PRD 将提供覆盖所有 PspA 的第二组表位。我们将确定 rPRD 可以替代或增强 aHD 引起的交叉保护的程度。针对所有相关荚膜类型的 Sp 菌株，鉴定在小鼠、兔子和人类中具有免疫原性的 PRD 中主要的保护诱导重复序列，并使用该信息构建预期广泛应用的候选 rPRD。目的 2. 评估目的 1 中构建的 rPRD 免疫原在小鼠败血症、局灶性肺炎和定植模型中引起的交叉保护作用。 PspA 结构在遗传或功能上与胶囊类型无关，因此，长期以来人们一直认为，用 PspA 抗体观察到的针对少数小鼠毒性胶囊类型的保护作用也适用于 Sp。为了检查对所有相关荚膜类型的侵袭性菌株的保护作用，我们将：1）使用我们的体外功能测定，2）在小鼠中由比败血症更多的荚膜类型引起的局灶性肺炎， 3) 使用宿主炎症相关分子暂时增强通常对小鼠无毒力的荚膜型侵入性临床 IPD 分离株的毒力。通过这两种机制增强 C' 在 Sp 上的沉积并增强杀菌肽对 PspA 的 aHD 的杀伤作用。