T Cell Epitopes of the Malaria CS Proteins

描述(由申请人提供)：含有恶性疟原虫环子孢子虫(CS)蛋白T和B细胞表位的疟疾疫苗正在开发中，以努力阻止红细胞前寄生虫阶段的建立，并防止世界各地发生的2-3亿感染。合成多肽疫苗的I期研究表明，恶性疟原虫CS蛋白的免疫应答既受第II类相关免疫机制的正向调节，也受第II类相关免疫机制的负向调节。由于其有限的复杂性，合成肽疫苗提供了独特的免疫原来剖析在调节疫苗诱导的反应中起作用的遗传和细胞机制。当先天免疫系统的树突状细胞(DC)的呈递能力可以影响初始的CD4+T细胞分化为辅助T细胞(Th)以增强体液和细胞免疫，或影响下调免疫反应的CD4+T调节(Tr)细胞时，疫苗所引发的抗原特异性反应与感染性病原体一样被启动。具体目标1将重点放在先天免疫反应和获得性免疫反应之间的初始细胞相互作用，这对CS特异性的CD4T辅助反应是重要的。将检测来自人类志愿者和近交系小鼠的DC，以确定R和NR中的DC，并检查疫苗配置/佐剂配方通过调节DC功能来克服低反应性的效果。具体目标2将检查在CS多肽疫苗无反应者中是否存在下调抗体的CD4+Tr细胞和CD4+T辅助细胞。目的3利用表达恶性疟原虫CS重复序列(PfPb)的转基因伯氏疟原虫子孢子，研究恶性疟原虫疫苗诱导抗体和细胞免疫的效果。这一独特的PfPb子孢子/小鼠杂交模型的可获得性将有助于(1)临床前筛选恶性疟原虫疫苗引发的体液和细胞免疫，以及(2)评估疟疾疫苗免疫的人类志愿者诱导的抗P，恶性疟重复免疫反应。

DESCRIPTION (provided by the applicant): Malaria vaccines containing T and B cell epitopes of the Plasmodium falciparum circumsporozoite (CS) protein are being developed in an effort to block establishment of the pre-erythrocytic parasite stages and prevent the 200-300 million infections that occur world-wide. Phase I studies (carried out by the PI) of synthetic peptide vaccines indicate that the immune response to P. falciparum CS protein is both positively and negatively regulated by class II associated immune mechanisms. Due to their limited complexity, synthetic peptide vaccines provide unique immunogens for dissecting the genetic and cellular mechanisms that function in regulation of vaccine-induced responses. Antigen specific responses elicited by vaccines, as welt as by infectious pathogens, are initiated when dendritic cells (DC) of the innate immune system presenting capacity of DC can affect the differentiation of naive CD4+ T ceils into T helper (Th) cells that enhance humoral and cellular immunity, or CD4+ T regulatory (Tr) ceils that downregulate immune responses. Specific Aim 1 will focus on the initial cellular interactions between the innate and adaptive immune responses that are important for CS-specific CD4 T helper responses. DC from human volunteers and inbred strains of mice will be examined to determine DC from R and NR and also to examine the effect of vaccine configuration/adjuvant formulations overcome hypo-responsiveness by modulating DC function. Specific Aim 2 will examine whether CD4+ Tr cells that downregulate antibody and CD4+ T helper cells are present in non-responders to CS peptide vaccines. Specific Aim 3 will investigate protective efficacy of P. falciparum vaccine induced antibody and cellular responses using transgenic P. berghei sporozoites genetically modified to express P. falciparum CS repeats (PfPb). The availability of this unique hybrid PfPb sporozoite/murine model will facilitate (1) pre-clinical screening of humoral and cellular immunity elicited by P. falciparum vaccines and (2) evaluation of anti-P, falciparum repeat immune responses elicited in human volunteers immunized with malaria vaccines.