Allelic Diversity/Immune Correlates of Vaccine Protectio

抗原多样性为疟疾寄生虫提供了逃避宿主免疫系统的手段，并且是开发安全有效的疟疾疫苗的障碍。如果疫苗所提供的保护是等位基因特异性的，免疫接种可以选择寄生虫种群中这些基因的等位基因变体。寄生虫种群结构的这种变化可能极大地影响疫苗的效力。在迄今为止的大多数疫苗试验中，免疫原性研究的终点是抗体测量。通常认为抗体介导对包括AMA-1在内的血液阶段抗原的重要免疫应答，但这种疫苗和其他候选疫苗（如果有的话）引起的保护性免疫应答的性质尚不清楚。细胞免疫反应，无论是在血液或肝脏阶段的寄生虫，可能是重要的保护免受疟疾疾病和感染，抗体反应 在标准测定中检测到的可能不是对保护最重要的那些。最后，标准 免疫原性测量不提供关于疫苗诱导的免疫应答的持续时间或关于疫苗引发免疫力的能力的信息，所述免疫力保护免受与疫苗来源的菌株在遗传上不同的寄生虫的侵害。该项目将评估等位基因多样性在疫苗效力和免疫应答中的作用，并测量 AMA-1候选疫苗提供的异源保护的持续时间和程度 FMP2.1/AS 02A。这将通过对现有样本以及从横断面调查和项目1中描述的试验中获得的样本进行遗传学和免疫学分析来实现。此外，分子研究将为2B期试验中的毒株特异性疫苗有效性提供直接测量。

Antigenic diversity provides the malaria parasite the means to evade the host immune system, and represents an obstacle to developing a safe and effective malaria vaccine. If the protection conferred by a vaccine is allele-specific, immunization may select allelic variants of these genes in the parasite population. Such changes in the parasite population structure could greatly affect the efficacy of a vaccine. In most vaccine trials to date, the end point for the immunogenicity studies has been antibody measurements. It is generally assumed that antibodies mediate the important immune responses to bloodstage antigens including AMA-1, but the nature of the protective immune response elicited by this and other vaccine candidates, if any, is not known. A cellular immune response, whether in the blood or liver stages of the parasite, may be important for protection against malaria disease and infection, and antibody responses detected in standard assays may not be those most important for protection. Finally, standard immunogenicity measurements do not provide information about the duration of the vaccine-induced immune response or about the ability of a vaccine to elicit immunity that protects against parasites that are genetically different from the strain of vaccine origin. This project will assess the role of allelic diversity in vaccine efficacy and immune responses, and measure the duration and degree of heterologous protection provided by the AMA-1 vaccine candidate FMP2.1/AS02A. This will be accomplished though genetic and immunological analyses of existing samples and those obtained from a cross-sectional survey and from the trials described in Project 1. In addition, molecular studies will provide a direct measure of strain-specific vaccine efficacy in the Phase 2B trial.