Immunogenicity of Synthetic Peptide Malaria Vaccines

合成肽疟疾疫苗的免疫原性

• 批准号: 6985967
• 负责人: Elizabeth H Nardin
• 金额: $ 43.81万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6985967
• 关键词: Plasmodium falciparum; active immunization; antibody neutralization test; biotechnology; clinical research; clinical trials; enzyme linked immunosorbent assay; helper T lymphocyte; human subject; laboratory mouse; malaria; malaria vaccines; nonhuman therapy evaluation; synthetic vaccines; vaccine development; vaccine evaluation; viruslike particle

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.

描述(申请人提供)：疟疾寄生虫导致疟疾发病率和死亡率超过40%的世界人口。尽管寄生虫有一个复杂的生命周期，但用辐照过的子孢子免疫可以在小鼠、猴子和人类身上引起无菌免疫，为红细胞前期疟疾疫苗提供了黄金标准。由于子孢子不能在体外产生，因此努力的重点是开发亚单位疫苗，这种疫苗可以引起与受辐射的子孢子相当的免疫反应。在过去的资助期间，我们已经在临床前和I期试验中证明了含有最小恶性疟原虫CS蛋白表位的合成肽和乙肝病毒核心蛋白病毒样颗粒(VLP)是安全和免疫的。在目前的赠款中，将检测ICC-1132、表达恶性疟原虫CS重复序列的VLP和通用T*Th表位免疫志愿者所诱导的抗体和细胞的良好特异性和功能(特定目标1)。将比较这种VLP疫苗和线性多肽疫苗的保护效果，并使用表达恶性疟原虫CS表位的转基因寄生虫来确定保护的免疫机制(特定目标2)。为了优化体液和细胞反应，截短的T和B细胞表位将作为多肽疫苗进行测试(特定目标2)，并将测试使用VLP和多肽的异源PRIME免疫策略的保护效果(特定目标3)。恶性疟原虫疫苗第二阶段试验的一个主要限制是无法剖析人类志愿者的免疫反应，以确定保护性免疫的相关性。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*表位的转基因伯氏疟原虫，以建立用于分析恶性疟原虫CS亚单位疫苗诱导的保护性免疫机制的小动物模型(特定目标4)。从这些研究中获得的信息将适用于疟疾血液期寄生虫疫苗的开发，以及需要强烈体液反应以进行保护性免疫的病毒和细菌病原体的开发。