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：
7847631
负责人：
Gary W Ketner
金额：
$ 56.64万
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 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847631
关键词：
Address Adenovirus hexon capsid protein Adenoviruses Africa Animals Antigens Aotus primate Area Capsid Capsid Proteins Cebidae Cessation of life Child Clinical Trials Developing Countries Dose Economic Burden Economic Development Engineering Enteral Epitopes Erythrocytes Evaluation Fiber Foundations Gene Expression Genes Genetic Goals Growth Human Human Adenoviruses Immune response 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 Plasmodium falciparum Primates Production Property Proteins Public Health Recombinant Vaccines Recombinants Resources Route Simulate Sporozoites Staging Surface System Tablets Testing 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.

疟疾每年杀死100万人。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。一种有效的，负担得起的疫苗将大大减轻疟疾施加的发病率，死亡率和经济负担。这里提出的工作将调查一种以口服疫苗对人类腺病毒进行建模的疟疾免疫接种方法，这些腺病毒已在数百万人中安全有效地使用了三十多年。该提案的目标是现场重组腺病毒疫苗，这些腺病毒疫苗被口服服用，一剂量保护和廉价生产的特性，这些特性将使它们非常适合在大多数疟疾死亡发生的资源贫乏地区使用。重组疫苗的候选物将表达诱导灵长类动物保护性免疫的恶性疟原虫抗原：外孢子虫蛋白（PFCSP）和肝脏阶段抗原3（PFLSA3）（PFLSA3）。抗原将作为与主要病毒capsID蛋白的融合作用，该蛋白设计用于在重组颗粒表面上显示抗原表位（CapsID显示重组者），这是该实验室在该实验室中开发的，用于高级基因的高级表达，插入了腺病毒后期转录的主要单位（MLTTU重新组合）（MLTUBIMBINANT），或者两者（两者）。两种抗原表达方法均已成功地用于该实验室中的可行重组。重组将在体外表征抗原生产和生长特性，并评估选定的重组者的体外重组，以诱导AOTUS中的体液和细胞介导的免疫反应的能力，AOTUS（一种灵长类动物模型允许复制重组者。 AOTUS还易受恶性疟原虫孢子菌感染的感染，并将用于确定重组者防止实验性疟疾挑战的能力。这些研究将解决用实时腺病毒重组剂肠性免疫的可行性和功效，并为考虑口服重组疟疾疫苗的临床试验提供必不可少的信息。