Oral Immunization Against Malaria with Recombinant Adenoviruses

用重组腺病毒口服免疫疟疾

基本信息

批准号：
7654740
负责人：
Gary W Ketner
金额：
$ 58.36万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7654740
关键词：
Address Adenovirus hexon capsid protein Adenoviruses Africa Animal Model Antigens Aotus primate Area Biological Models Capsid Capsid Proteins Cebidae Cessation of life Child Clinical Clinical Trials Developed Countries Developing Countries Dose Economic Burden Economic Development Engineering Enteral Epitopes Erythrocytes Evaluation Fiber Foundations Gene Expression Genes Genetic Goals Growth Human Human Adenoviruses Immunity Immunization In Vitro Individual Infection Laboratories Licensing Life Liver Malaria Malaria Vaccines Methods Modeling Monkeys Morbidity - disease rate Mus Oral Oral Administration Oral cavity Peptides Plasmodium falciparum Primates Production Property Proteins Public Health Recombinant Vaccines Recombinants Resources Simulate Sporozoites Staging Surface System Tablets Testing Ursidae Family Vaccination Vaccines Viral Work base capsule cell mediated immune response circumsporozoite protein design economic cost immunogenic immunogenicity killings mortality mutant neutralizing antibody novel oral vaccine particle research study vaccine candidate

项目摘要

Malaria kills over one million people each year. Most malaria deaths occur in Africa and most of the victims are children under five. An effective, affordable vaccine would greatly reduce the morbidity, mortality, and economic burden imposed by malaria. Work proposed here will investigate an approach to malaria immunization modeled on oral vaccines against human adenoviruses that have been used safely and effectively in millions of people for over three decades. The goals of the proposal are live recombinant adenovirus vaccines that are administered orally, protective in one dose, and inexpensive to produce, properties that would make them ideal for use in the resource-poor areas where most malaria deaths occur. Recombinant vaccine candidates will express pre-erythrocytic Plasmodium falciparum antigens that induce protective immunity in primates: circumsporozoite protein (PfCSP) and liver stage antigen 3 (PfLSA3). Antigens will be produced either as fusions with major viral capsid proteins designed to display antigenic epitopes on the surface of the recombinant particles (capsid display recombinants), by a novel system developed in this laboratory for high-level expression of genes inserted into the adenovirus major late transcriptional unit (MLTU recombinants), or both (compound recombinants). Both methods of antigen expression have been used successfully in viable recombinants in this laboratory. Recombinants will be characterized in vitro for antigen production and growth properties and selected recombinants will be evaluated for the ability to induce humoral and cell-mediated immune responses in Aotus, a primate model permissive for replication of recombinants. Aotus are also susceptible to infection by P. falciparum sporozoites and will be used to determine ability of recombinants to protect against experimental malaria challenge. These studies will address the feasibility and efficacy of enteric immunization with live adenovirus recombinants and will provide information essential in considering clinical trials of oral recombinant malaria vaccines.

疟疾每年夺去超过一百万人的生命。大多数疟疾死亡发生在非洲，大多数受害者是五岁以下的儿童。一种有效、负担得起的疫苗将大大降低疟疾的发病率、死亡率和经济负担。这里提出的工作将研究一种以人类腺病毒口服疫苗为模型的疟疾免疫方法，该疫苗已在数百万人中安全有效地使用了三十多年。该提案的目标是生产口服重组腺病毒活疫苗，一剂即可提供保护，且生产成本低廉，这些特性使其非常适合在大多数疟疾死亡发生的资源匮乏地区使用。重组候选疫苗将表达红细胞前恶性疟原虫抗原，可在灵长类动物中诱导保护性免疫：环子孢子蛋白 (PfCSP) 和肝期抗原 3 (PfLSA3)。抗原将通过与主要病毒衣壳蛋白的融合来产生，该病毒衣壳蛋白设计用于在重组颗粒表面展示抗原表位（衣壳展示重组体），通过本实验室开发的新系统，用于插入腺病毒主要基因的高水平表达晚期转录单位（MLTU 重组体），或两者（复合重组体）。两种抗原表达方法均已在本实验室成功用于可行的重组体中。将在体外表征重组体的抗原产生和生长特性，并将评估所选重组体在 Aotus（允许重组体复制的灵长类动物模型）中诱导体液和细胞介导的免疫应答的能力。 Aotus 也容易受到恶性疟原虫子孢子的感染，并将用于确定重组体抵御实验性疟疾挑战的能力。这些研究将探讨活腺病毒重组体肠道免疫的可行性和有效性，并将提供考虑口服重组疟疾疫苗临床试验所必需的信息。