Immunogenicity of Synthetic Peptide Malaria Vaccines

合成肽疟疾疫苗的免疫原性

• 批准号: 7686245
• 负责人: Elizabeth H Nardin
• 金额: $ 48.72万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686245
• 关键词: Animal Model; Antibodies; Antibody Formation; Artemisinins; Attenuated; B-Lymphocyte Epitopes; Biological Assay; Blood; Cells; Combination Drug Therapy; Complex; Core Protein; Development; Epitopes; Erythrocytes; Goals; Gold; Grant; HIV; Hepatitis B; Hepatitis B Core Antigen; Hepatitis B Virus; Human; Human Volunteers; Humoral Immunities; Immune; Immune response; Immunity; Immunization; In Vitro; Insecticides; Interferons; Knowledge; Life Cycle Stages; Malaria; Malaria Vaccines; Mediating; Minor; Modeling; Modification; Monkeys; Morbidity - disease rate; Mus; Parasites; Peptide Vaccines; Peptides; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Plasmodium; Plasmodium falciparum; Population; Public Health; Radiation; Recombinants; Resistance; Risk; Scheme; Specificity; Sporozoites; Staging; Sterility; Subunit Vaccines; Surface Antigens; T-Lymphocyte; Testing; Th1 Cells; Transgenic Organisms; Vaccine Design; Vaccines; Viral; Virus-like particle; artemisinine; base; circumsporozoite; circumsporozoite protein; cost; cytokine; extracellular; immunogenic; immunogenicity; in vivo; mortality; pathogen; pre-clinical; protective efficacy; response; synthetic peptide; vaccine development; vaccine efficacy; vaccine-induced immunity; virus core; volunteer

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（由申请人提供）：疟原虫寄生虫导致超过40%的世界人口的疟疾发病率和死亡率。尽管寄生虫的生命周期复杂，但用辐照过的子孢子免疫可以在小鼠、猴子和人类中引发无菌免疫，为红细胞前期疟疾疫苗提供了金标准。由于子孢子不能在体外产生，因此努力集中于开发引发与辐照子孢子相当的免疫应答的亚单位疫苗。在过去的资助期内，我们已经证明合成肽和含有最少恶性疟原虫CS蛋白表位的B型肝炎病毒核心蛋白病毒样颗粒（VLP）在临床前和I期试验中是安全的和免疫原性的。在当前的授权中，将检查在用ICC-1132免疫的志愿者中引发的抗体和细胞的精细特异性和功能，ICC-1132是表达恶性疟原虫CS重复序列和通用T* Th表位的VLP（具体目标1）。将比较该VLP和线性肽疫苗的保护效力，并使用表达恶性疟原虫CS表位的转基因寄生虫定义保护的免疫机制（特异性目的2）。为了优化体液和细胞应答，将截短的T和B细胞表位作为肽疫苗进行检测（特异性目标2），并将使用VLP和肽测定异源初免：加强免疫策略的保护效力（特异性目标3）。恶性疟原虫疫苗II期试验的一个主要限制是无法剖析人类志愿者的免疫应答以定义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* 表位的伯氏疟原虫转基因，以建立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的小动物模型（具体目标4）。从这些研究中获得的信息将适用于开发针对疟疾血液期寄生虫以及需要强体液应答以获得保护性免疫的病毒和细菌病原体的疫苗。

项目成果

Sporozoite neutralizing antibodies elicited in mice and rhesus macaques immunized with a Plasmodium falciparum repeat peptide conjugated to meningococcal outer membrane protein complex.

使用与脑膜炎球菌外膜蛋白复合物缀合的恶性疟原虫重复肽进行免疫的小鼠和恒河猴中引发子孢子中和抗体。

• DOI: 10.3389/fcimb.2012.00146
• 发表时间: 2012
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Przysiecki,Craig;Lucas,Bob;Mitchell,Robert;Carapau,Daniel;Wen,Zhiyun;Xu,Hui;Wang,Xin-Min;Nahas,Debbie;Wu,Chengwei;Hepler,Robert;Ottinger,Elizabeth;TerMeulen,Jan;Kaslow,David;Shiver,John;Nardin,Elizabeth
• 通讯作者: Nardin,Elizabeth