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NOVEL GROUP A STREPTOCOCCUS HUMAN VACCINE CANDIDATES

新型 A 组链球菌人类疫苗候选者

基本信息

批准号：
7493506
负责人：
James MALLORY Musser
金额：
$ 68.67万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7493506
关键词：
Acute Antigens Area Arts Biology Cell surface Childhood Data Development Disease Drug Industry Genome Glomerulonephritis Goals Gram-Positive Bacteria Guanosine Monophosphate Health Heart Diseases Human Industry Collaborators Infection Infectious Skin Diseases International Invasive Investigation Macaca Macaca fascicularis Methods Modeling Monkeys Mus Necrotizing fasciitis Neisseria meningitidis Organism Outcome Pathogenesis Pharyngitis Phase Phenocopy Population Group Proteins Research Research Design Rheumatic Fever Rheumatic Heart Disease Scarlet Fever Screening procedure Serotyping Sore Throat Streptococcus Streptococcus pyogenes Streptococcus vaccine Syndrome TimeLine Tonsillitis Toxic Shock Syndrome Toxicity Tests United States Vaccine Antigen Vaccines base design extracellular human disease in vivo mouse model multiple myeloma M Protein novel pathogen pre-clinical research study vaccinology

项目摘要

DESCRIPTION (provided by applicant): This study is designed to identify one or more conserved group A Streptococcus (GAS) proteins suitable for use as a safe and efficacious human vaccine worldwide. The key goal of the proposed research is to use genome-wide methods of contemporary vaccinology to identify one or more conserved GAS proteins that will significantly protect monkeys from pharyngitis caused by challenge with a strain expressing a heterologous M protein serotype. A conservative estimated timeline is that by the end of the 5-year research period, the antigen(s) will be ready for detailed toxicity testing prior to beginning phase I human trials. The international investigative team composed of academic and pharmaceutical industry collaborators proposes the following line of research involving a "reverse vaccinology" strategy: Aim 1: Use two mouse models of invasive GAS disease to confirm extensive preliminary data that novel candidate GAS antigens significantly protect immunized mice challenged with a GAS strain expressing a heterologous M protein serotype. Aim 2: Determine if the proteins satisfying the mouse screen criteria described in aim (1) above are conserved in natural populations of GAS, expressed on the cell surface of genetically diverse GAS strains, and expressed in vivo during diverse types of human infections (pharyngitis, invasive infections, etc). Aim 3: Use a recently-described monkey model that mimics human pharyngitis to determine if one or more of the candidate vaccine antigens we identify in aim (1) and (2) significantly protects against pharyngitis caused by a GAS strain expressing a heterologous M protein serotype.

描述（由申请人提供）：本研究旨在鉴定一种或多种保守的 A 族链球菌 (GAS) 蛋白，适合在全球范围内用作安全有效的人类疫苗。拟议研究的主要目标是利用当代疫苗学的全基因组方法来鉴定一种或多种保守的 GAS 蛋白，这些蛋白将显着保护猴子免受表达异源 M 蛋白血清型的菌株攻击引起的咽炎。保守估计的时间表是，在 5 年研究期结束时，抗原将准备好在开始第一阶段人体试验之前进行详细的毒性测试。由学术界和制药业合作者组成的国际研究小组提出了以下涉及“反向疫苗学”策略的研究路线：目标 1：使用侵袭性 GAS 疾病的两种小鼠模型来确认大量初步数据，即新的候选 GAS 抗原可显着保护受到表达异源 M 蛋白血清型的 GAS 菌株攻击的免疫小鼠。目标 2：确定满足上述目标 (1) 中描述的小鼠筛选标准的蛋白质是否在 GAS 自然群体中保守，在遗传多样性 GAS 菌株的细胞表面上表达，并在不同类型的人类感染（咽炎、侵袭性感染等）期间体内表达。目标 3：使用最近描述的模拟人类咽炎的猴子模型来确定我们在目标 (1) 和 (2) 中鉴定的一种或多种候选疫苗抗原是否能够显着预防由表达异源 M 蛋白血清型的 GAS 菌株引起的咽炎。