Oral Immunization Against Malaria with Recombinant Adenoviruses

用重组腺病毒口服免疫疟疾

• 批准号: 7648323
• 负责人: Gary W Ketner
• 金额: $ 62.28万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7648323
• 关键词: Adenovirus hexon capsid protein; Adenoviruses; Africa South of the Sahara; Animal Model; Animals; Antibodies; Antigens; Aotus primate; Biological Models; Canis familiaris; Capsid; Capsid Proteins; Cells; Cessation of life; Child; Condition; Dose; Economic Burden; Economic Development; Epitopes; Erythrocytes; Evaluation; Facility Construction Funding Category; Fiber; Foundations; Gene Expression; Genes; Genetic; Goals; Growth; Healthcare; Human; Human Adenoviruses; Human Papillomavirus; Immune response; Immunity; Immunization; Immunization Programs; In Vitro; Infection; Laboratories; Licensing; Life; Liver; Location; Macaca; Malaria; Malaria Vaccines; Measures; Mediating; Modeling; Monkeys; Morbidity - disease rate; Mus; Oral; Papillomavirus; Peptides; Plasmodium; Plasmodium falciparum; Primates; Production; Property; Proteins; Public Health; Range; Recombinant Vaccines; Recombinants; Research Infrastructure; Resources; Simulate; Sporozoites; Staging; Structure; Surface; System; Testing; Ursidae Family; Vaccines; Viral; base; cell mediated immune response; circumsporozoite protein; cost; design; experience; immunogenic; immunogenicity; killings; mortality; mutant; neutralizing antibody; novel; particle; research study; response; tissue culture

Malaria kills more than one million people each year. Most malaria deaths occur in sub-Saharan Africa and most of the victims are children under five. An effective, affordable vaccine could greatly reduce the morbidity, mortality, and economic burden imposed by malaria. This proposal will investigate one approach to such a vaccine. The immunization approach that we will explore is modeled on existing programs for immunization against human adenoviruses and will employ live recombinant derivatives of adenovirus vaccine strains that have been used safely and effectively for over three decades. These vaccines are administered orally, are protective in one dose, and are relatively inexpensive to produce, making them promising for use in resource-poor locations that lack strong health-care infrastructures. Recombinants will express two pre-erythrocytic Plasmodium falciparum antigens that induce immunity in animals: circumsporozoite protein (CSP) and liver stage antigen 3 (LSA-3). These antigens will be produced 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 in the form of fusions with major viral capsid proteins designed to display malaria antigenic determinants on the surface of the recombinant particles (capsid display recombinants). We have extensive experience with viable recombinants that abundantly express human and canine papillomavirus L1 genes from the MLTU and have prepared capsid display recombinants that bear antigenic epitopes of the P. falciparum CSP and HPV L2 proteins. The L1 protein produced by MLTU recombinants assembles into VLPs that induce antibodies in mice, and capsid display recombinant particles expressing CSP or HPV L2 induce neutralizing antibody to malaria sporozoites and HPV, respectively. We will prepare recombinants expressing CSP and LSA-3 that are analogous to existing L1 MLTU recombinants, and a range of CSP capsid display recombinants with varying structures. The recombinants will be characterized in vitro for antigen production and growth properties and then evaluated in two animal model systems for immunogenicity and protective efficacy. Capsid display mutants will first be examined in mice for their ability to induce antibody and protect against a sporozoite challenge and optimal constructs will be identified. Promising capsid display recombinants identified in mice and MLTU recombinants selected for desirable properties in tissue culture then will be assessed for the ability to induce humoral and cell-mediated immune responses in a permissive primate model. We will also attempt to develop a primate model in which protection from experimental challenge can be determined, and will measure protective efficacy if that effort is successful. These studies will provide information that can be used to prepare live recombinant vaccines that express malaria antigens for use in human trials.

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撒哈拉以南地区 非洲，大多数受害者是五岁以下的儿童。一种有效、负担得起的疫苗可以大大减少 疟疾造成的发病率、死亡率和经济负担。该提案将调查一项 开发这种疫苗的方法。我们将探索的免疫方法以现有的方法为蓝本 针对人类腺病毒的免疫计划，并将采用活的重组衍生物 腺病毒疫苗株已安全有效地使用了三十多年。这些 疫苗是口服给药，一剂即可发挥保护作用，而且生产成本相对较低， 使它们有望在缺乏强大医疗基础设施的资源匮乏地区使用。 重组体将表达两种前红细胞恶性疟原虫抗原，诱导 动物免疫：环子孢子蛋白（CSP）和肝期抗原3（LSA-3）。这些抗原会 由本实验室开发的新系统产生，用于插入基因的高水平表达 腺病毒主要晚期转录单位（MLTU重组体），或与主要病毒融合的形式 衣壳蛋白设计用于在重组体表面展示疟疾抗原决定簇 颗粒（衣壳展示重组体）。我们在可行的重组体方面拥有丰富的经验 从 MLTU 中大量表达人和犬乳头瘤病毒 L1 基因，并制备衣壳 展示带有恶性疟原虫 CSP 和 HPV L2 蛋白抗原表位的重组体。 L1 MLTU重组体产生的蛋白质组装成VLP，在小鼠中诱导抗体，衣壳 展示表达 CSP 或 HPV L2 的重组颗粒诱导抗疟疾中和抗体 分别是子孢子和HPV。我们将制备表达 CSP 和 LSA-3 的重组体 类似于现有的 L1 MLTU 重组体，以及一系列具有不同特性的 CSP 衣壳展示重组体 结构。重组体将在体外进行抗原产生和生长特性的表征， 然后在两个动物模型系统中评估免疫原性和保护功效。衣壳展示 首先将在小鼠中检查突变体诱导抗体和预防子孢子的能力 将确定挑战和最佳结构。在小鼠中鉴定出有前途的衣壳展示重组体 并在组织培养中选择具有所需特性的 MLTU 重组体，然后对其进行评估 在允许的灵长类动物模型中诱导体液和细胞介导的免疫反应的能力。我们也会 尝试开发一种灵长类动物模型，在该模型中可以确定免受实验挑战的保护，并且 如果该努力成功，将衡量保护效果。这些研究将提供可用于 用于制备表达疟疾抗原的重组活疫苗，用于人体试验。

项目成果

Origin of a High-Latitude Population of Aedes aegypti in Washington, DC.

华盛顿特区高纬度埃及伊蚊种群的起源。

• 发表时间: 2018-02
• 作者: Gloria;Lima, Andrew;Lovin, Diane D;Cunningham, Joanne M;Severson, David W;Powell, Jeffrey R
• 通讯作者: Powell, Jeffrey R

Adenovirus particles that display the Plasmodium falciparum circumsporozoite protein NANP repeat induce sporozoite-neutralizing antibodies in mice.

展示恶性疟原虫环子孢子蛋白 NANP 重复序列的腺病毒颗粒可在小鼠体内诱导子孢子中和抗体。

• 发表时间: 2011-02-11
• 影响因子: 5.5
• 作者: Palma, Christopher;Overstreet, Michael G.;Guedon, Jean-Marc;Hoiczyk, Egbert;Ward, Cameron;Karen, Kasey A.;Zavala, Fidel;Ketner, Gary
• 通讯作者: Ketner, Gary