T Cell Epitopes of the Malaria CS Proteins

描述（由申请人提供）：正在开发含有恶性疟原虫环孢子子（CS）蛋白T和B细胞表位的疟疾疫苗，以阻止红细胞前寄生虫阶段的建立，并预防全世界发生的2 -3亿例感染。合成肽疫苗的I期研究（由PI进行）表明，对恶性疟原虫CS蛋白的免疫反应受到II类相关免疫机制的积极和消极调节。由于其有限的复杂性，合成肽疫苗提供了独特的免疫原，用于解剖在疫苗诱导反应调节中起作用的遗传和细胞机制。当具有DC能力的先天免疫系统的树突状细胞（DC）能够影响幼稚CD4+ T细胞分化为增强体液和细胞免疫的T辅助细胞（Th）或下调免疫反应的CD4+ T调节细胞（Tr）时，疫苗和感染性病原体就会引发抗原特异性应答。特异性目标1将关注先天免疫反应和适应性免疫反应之间的初始细胞相互作用，这对cs特异性CD4 T辅助反应很重要。将检查来自人类志愿者和近交系小鼠的DC，以确定来自R和NR的DC，并检查疫苗配置/佐剂配方通过调节DC功能克服低反应性的效果。特异性目的2将检查CD4+ Tr细胞下调抗体和CD4+ T辅助细胞是否存在于对CS肽疫苗无反应的细胞中。特异性目的3将研究恶性疟原虫疫苗诱导抗体的保护效果和利用转基因表达恶性疟原虫CS重复序列（PfPb）的贝格黑氏孢子子的细胞反应。这种独特的PfPb孢子虫/小鼠杂交模型的可用性将有助于(1)临床前筛选恶性疟原虫疫苗引起的体液和细胞免疫，(2)评估接种疟疾疫苗的人类志愿者引起的抗恶性疟原虫重复免疫反应。

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.