Development of a Global GBS Vaccine

全球 GBS 疫苗的开发

• 批准号: 7107941
• 负责人: LAWRENCE C PAOLETTI
• 金额: $ 65.06万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7107941
• 关键词: Streptococcus agalactiae; Streptococcus vaccine; bacterial antigens; biotechnology; clinical research; cooperative study; drug design /synthesis /production; drug screening /evaluation; enzyme linked immunosorbent assay; human tissue; laboratory mouse; laboratory rabbit; nonhuman therapy evaluation; protein purification; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): Group B Streptococcus (GBS) is an important human pathogen. At-risk populations include babies born to colonized mothers, peripartum women, diabetics, and the elderly with underlying illnesses. Vaccines to prevent GBS disease have been developed by coupling capsular polysaccharide (CPS) antigens of GBS to immunogenic protein carriers. Glycoconjugate vaccines against all nine GBS serotypes have been synthesized and shown to be immunogenic in animals in preclinical trials. Healthy adults have safely received conjugate vaccines prepared with GBS types la, Ib, II, III, and V CPSs in phase 1/2 clinical trials. These vaccines elicited CPS-specific antibody that opsonized GBS for in vitro killing by human blood leukocytes in the presence of complement. Despite these advances, a GBS vaccine for public use has not been developed due to the number of components required and the shifting pattern of serotypes in the population. Advances in vaccine development has been accelerated by the sequencing of the GBS genome and new protein antigens have been revealed using reverse vaccinology. This proven approach to vaccine development promises to be applicable to GBS vaccines. In this application, we propose to develop a combination vaccine composed of 3 to 4 recently identified protective proteins combined with GBS glycoconjugates representing the three major disease causing serotypes which will be effective against the large majority of GBS variants of all GBS serotypes. A systematic approach will: a) identify, express and purify GBS proteins, b) assess the conservation of these proteins among GBS strains, c) synthesize and test conjugate vaccines in animals using the new GBS antigens as carrier proteins, d) formulate and determine the efficacy of a multivalent GBS vaccine. Successful completion of these objectives will provide the rationale for: e) preparation of a multivalent GBS vaccine made under cGMP, and f) phase 1/2 clinical trials of a multivalent GBS vaccine in healthy nonpregnant (18 to 65 years of age) and elderly (>65 years of age) adults. This work will lead to a vaccine effective in preventing GBS diseases worldwide.

描述（由申请人提供）： B 族链球菌 (GBS) 是一种重要的人类病原体。高危人群包括殖民母亲所生的婴儿、围产期妇女、糖尿病患者和患有潜在疾病的老年人。通过将 GBS 荚膜多糖 (CPS) 抗原与免疫原性蛋白载体偶联，开发出预防 GBS 疾病的疫苗。针对所有九种 GBS 血清型的糖复合疫苗已被合成，并在临床前试验中显示在动物中具有免疫原性。 健康成年人已在 1/2 期临床试验中安全地接受了用 GBS la、Ib、II、III 和 V 型 CPS 制备的结合疫苗。这些疫苗引发了 CPS 特异性抗体，在补体存在的情况下，该抗体可以调理 GBS，从而在体外被人血液白细胞杀死。尽管取得了这些进展，但由于所需成分的数量以及人群中血清型的变化模式，尚未开发出供公众使用的 GBS 疫苗。 GBS 基因组测序加速了疫苗开发的进展 使用反向疫苗学揭示了新的蛋白质抗原。这种经过验证的疫苗开发方法有望适用于 GBS 疫苗。 在本申请中，我们建议最近开发一种由3至4种成分组成的组合疫苗 确定了与 GBS 糖复合物结合的保护性蛋白，代表了三种主要的 致病血清型，对所有 GBS 血清型中的绝大多数 GBS 变种有效。系统方法将：a) 鉴定、表达和纯化 GBS 蛋白，b) 评估这些蛋白在 GBS 菌株中的保守性，c) 使用新的 GBS 抗原作为载体蛋白在动物体内合成和测试结合疫苗，d) 制定和确定多价 GBS 疫苗的功效。成功完成这些目标将为以下工作提供依据：e) 根据 cGMP 制备多价 GBS 疫苗，以及 f) 在健康非妊娠者（18 至 65 岁）和老年人中进行多价 GBS 疫苗的 1/2 期临床试验（>65 岁）成人。这项工作将研制出一种可有效预防全球 GBS 疾病的疫苗。