Serotype independent therapeutic vaccine for Streptococcus pneumoniae

在抗生素耐药性不断增长的时代，几种细菌病原体的危及生命的感染是导致 主要关注。批准的疫苗只针对少数细菌病原体。即使疫苗 由于缺乏血清型覆盖率，疫苗反应不良， 接种疫苗的人群，或者因为许多人根本没有接种疫苗。因此，需要创新概念， 科普这些挑战。目前的建议旨在开发一种新的暴露后治疗方法， 不依赖于血清型，可应用于多种革兰氏阳性菌。这种方法被称为感染 位点靶向通用桥接抗原（ISTUBA）利用了种特异性，但血清型- 独立的、噬菌体衍生的细菌细胞壁结合结构域（CBD），以靶向“ImmunoBridge”， 大多数人对细菌表面有抗体。《生物多样性公约》将重新引导现有的 免疫力对免疫桥对新的入侵病原体导致感染的清除。 在该提案中，将为肺炎链球菌（导致 社区获得性肺炎以及其他危及生命的感染。在初步研究中， 证明了基于减毒葡萄球菌肠毒素B疫苗（STEBVax）的ISTUBA作为 ImmunoBridge和S. pneumoniae特异性CBD可以指导S.金黄色葡萄球菌特异性抗体应答介导 S. pneumoniae菌株基于这些强有力的初步数据，我们将在目标1中测试 广泛的候选CBD，用于结合广泛的肺炎球菌血清型，以确定最佳的 CBD。具有高亲和力的广泛反应性CBD的短列表将用于在Aim 2中创建候选ISTuBA 不仅使用STEBVax，而且使用白喉类毒素（CRM 197）和破伤风类毒素作为免疫桥。的 候选ISTUBA将全面表征其生化和功能特性，包括 在抗ImmunoBridge抗体存在下的调理吞噬作用。将对两名最佳ISTUBA候选人进行测试 在小鼠鼻内S.目的3中肺炎感染。在第一阶段成功完成后，我们 预计第二阶段的项目，将重点放在优化的结构，广泛的功效测试，在这两个 肺炎和脓毒症模型、制剂、药代动力学和其他IND使能研究。

In the era of growing antibiotic resistance, life threatening infections with several bacterial pathogens are cause for major concern. Approved vaccines exist only for a handful of bacterial pathogens. Even when a vaccine is available invasive bacterial diseases can occur due to lack of serotype coverage, poor vaccine response among vaccinated populations, or because many simply don’t get vaccinated. Thus, innovative concepts are needed to cope with these challenges. The current proposal is aimed at developing a novel post exposure treatment that is serotype independent and can be applied to a variety of gram positive bacteria. The approach, termed Infection Site Targeted universal Bridging Antigen (ISTuBA) exploits the ability of species-specific, but serotype- independent, phage-derived bacterial cell wall binding domains (CBD) to target an “ImmunoBridge”, an antigen against which most people have antibodies, to the surface of bacteria. The CBD will redirect the pre-existing immunity against ImmunoBridge towards the new invading pathogen leading to clearance of infection. In this proposal prototype ISTuBAs will be created for Streptococcus pneumoniae, the leading cause of community acquired pneumonia as well other life-threatening infections. In preliminary studies we have demonstrated that ISTuBAs based on an attenuated staphylococcal enterotoxin B vaccine (STEBVax) as ImmunoBridge and S. pneumoniae specific CBDs can direct an S. aureus specific antibody response to mediate opsonophagocytosis of S. pneumoniae strains. Building upon these strong preliminary data, in Aim 1 we will test a wide range of candidate CBDs for binding against a broad panel of pneumococcal serotypes to identify the best CBDs. A short list of broadly reactive CBDs with high affinity will be used to create candidate ISTuBAs in Aim 2 using not only STEBVax but also diphtheria toxoid (CRM197) and Tetanus toxoid as ImmunoBridge. The candidate ISTuBAs will be thoroughly characterized for biochemical and functional properties including opsonophagocytosis in presence of anti-ImmunoBridge antibodies. Two best ISTuBA candidates will be tested in mouse intranasal model of S. pneumoniae infection in Aim 3. Upon successful completion of Phase I we anticipate a Phase II project that will focus on optimization of the constructs, extensive efficacy testing in both pneumonia and sepsis models, formulation, pharmacokinetics and other IND-enabling studies.