Immunogenicity of Synthetic Peptide Malaria Vaccines

描述（由申请人提供）：疟原虫引起的疟疾发病率和死亡率占世界人口的40%以上。尽管寄生虫的生命周期很复杂，但用辐照的孢子子免疫可以在小鼠、猴子和人类中引起不育免疫，为红细胞前期疟疾疫苗提供了金标准。由于孢子虫不能在体外产生，因此努力的重点是开发亚单位疫苗，以引起与辐照孢子虫相当的免疫反应。在过去的资助期，我们已经证明，在临床前和I期试验中，合成肽和含有最少恶性疟原虫CS蛋白表位的乙型肝炎病毒核心蛋白病毒样颗粒（VLP）是安全和免疫原性的。在目前的资助中，将检查在接种ICC-1132（表达恶性疟原虫CS重复序列和通用T* Th表位的VLP）的志愿者中引发的抗体和细胞的精细特异性和功能（Specific Aim 1）。将比较该VLP和线性肽疫苗的保护效果，并利用表达恶性疟原虫CS表位的转基因寄生虫确定保护的免疫机制（Specific Aim 2）。为了优化体液和细胞反应，截断的T和B细胞表位将作为肽疫苗（Specific Aim 2）进行测试，使用VLP和肽的异源prime:boost免疫策略将用于检测保护效果（Specific Aim 3）。恶性疟原虫疫苗II期试验的一个主要限制是无法解剖人类志愿者的免疫反应，以确定保护性免疫的相关因素。因此，我们将构建表达恶性疟原虫CS主要或次要重复序列或通用T*表位的伯黑氏疟原虫转基因，以建立小动物模型，用于分析恶性疟原虫CS亚单位疫苗引发的保护性免疫机制（Specific Aim 4）。从这些研究中获得的信息将适用于开发针对疟疾血期寄生虫以及需要强烈体液反应才能产生保护性免疫的病毒和细菌病原体的疫苗。

DESCRIPTION (provided by applicant): Plasmodium parasites cause malaria morbidity and mortality in over 40% of the worlds population. Despite a complex parasite life cycle, immunization with irradiated sporozoites can elicit sterile immunity in mice, monkeys and humans, providing a gold standard for a pre-erythrocytic stage malaria vaccine. Since sporozoites cannot be produced in vitro, efforts have focused on developing subunit vaccines that elicit immune responses comparable to irradiated sporozoites. Over the past grant period, we have shown that synthetic peptides and hepatitis B virus core protein virus-like particles (VLP) containing minimal P. falciparum CS protein epitopes, were safe and immunogenic in preclinical and Phase I trials. In the current grant, the fine specificity and function of antibody and cells elicited in volunteers immunized with ICC-1132, a VLP expressing P. falciparum CS repeats and the universal T* Th epitope, will be examined (Specific Aim 1). The protective efficacy of this VLP and linear peptide vaccines will be compared and the immune mechanisms of protection defined using transgenic parasites expressing P. falciparum CS epitopes (Specific Aim 2). In an effort to optimize humoral and cellular responses, truncated T and B cell epitopes will be tested as peptide vaccines (Specific Aim 2) and heterologous prime:boost immunization strategies, using VLP and peptides, will be assayed for protective efficacy (Specific Aim 3). A major limitation in P. falciparum vaccine Phase II trials is the inability to dissect immune responses of human volunteers to define correlates of protective immunity. We will therefore construct P. berghei transgenics expressing P. falciparum CS major or minor repeats, or the universal T* epitope, to establish small animal models for analysis of protective immune mechanisms elicited by P. falciparum CS subunit vaccines (Specific Aim 4). The information gained from these studies will be applicable to development of vaccines against malaria blood stage parasites, as well as viral and bacterial pathogens that require strong humoral responses for protective immunity.