NOVEL GROUP A STREPTOCOCCUS HUMAN VACCINE CANDIDATES

描述(由申请人提供)： 这项研究旨在鉴定一种或多种保守的A组链球菌(GAS)蛋白，适合在全球范围内用作安全有效的人类疫苗。这项拟议研究的主要目标是使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，这些蛋白将显著保护猴子免受由表达异源M蛋白血清型的菌株引起的咽炎的攻击。保守的估计时间表是，到5年研究期结束时，抗原(S)将在开始第一阶段人体试验之前准备好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调查小组提出了以下研究路线，涉及“反向疫苗学”战略： 目的：用两种侵袭性GAS小鼠模型证实新的候选GAS抗原对表达异源M蛋白血清型的GAS株攻击的免疫小鼠有显著的保护作用。 目的2：确定满足上述目的(1)中描述的小鼠筛选标准的蛋白质是否在GAS的自然种群中保守，在遗传多样性的GAS菌株的细胞表面表达，并在不同类型的人类感染(咽炎、侵袭性感染等)中在体内表达。 目的3：使用最近描述的模仿人类咽炎的猴子模型来确定我们在AIM(1)和(2)中确定的一个或多个候选疫苗抗原是否显著预防由表达异源M蛋白血清型的GAS菌株引起的咽炎。

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.