Coadministration of capsid modified adenovirus for malaria vaccine development

衣壳修饰腺病毒联合给药用于疟疾疫苗开发

• 批准号: 8501354
• 负责人: Alberto Moreno
• 金额: $ 21.17万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501354
• 关键词: Adenovirus Vector; Adenoviruses; Africa South of the Sahara; Americas; Antigens; Area; Biological; CD4 Positive T Lymphocytes; Capsid; Chimeric Proteins; Clinical; Data; Development; Drug resistance; Engineering; Epitopes; Fiber; Geographic Distribution; Goals; Human; Hybrids; Immune response; Immunity; Immunization; Immunization Schedule; Infection; Infection Control; Investigation; Life Cycle Stages; Liver; Malaria; Malaria Vaccines; Measures; Merozoite Surface Protein 1; Modeling; Modification; Morbidity - disease rate; Multicenter Trials; Mus; Names; Outcome; Parasites; Phase; Phase III Clinical Trials; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Proteins; Public Health; Publishing; Recombinant Proteins; Recombinants; Regimen; Reporting; Research Proposals; Rodent; Serotyping; Site; South America; Southeastern Asia; Species Specificity; Sporozoites; Staging; Structure; Subunit Vaccines; Surface; T-Lymphocyte Epitopes; Testing; Therapeutic; Transgenes; Vaccination; Vaccines; Vivax Malaria; base; circumsporozoite protein; comparative; density; design; disorder control; experience; immunogenicity; improved; killings; mortality; novel; novel strategies; phase 2 study; prophylactic; protective efficacy; public health priorities; research study; resistant strain; tool; transmission process; vaccine candidate; vaccine development; vector

DESCRIPTION (provided by applicant): Plasmodium vivax is the most widely distributed human malaria parasite responsible for 80% of the clinical cases in South and Southeast Asia and 70% in the Americas. The wider geographic distribution of P. vivax in comparison to P. falciparum is explained by the unique biological features of this parasite. Although the implementation of transmission control measures has had a significant impact on morbidity and mortality, the emergence and spread of drug-resistant parasites is a growing concern. The development of novel tools to control the disease is therefore a global priority. This proposal wil build on our experience developing chimeric recombinant proteins and recombinant adenovirus vectors to develop a coadministration vaccination regimen that combines these two vaccine platforms. The overall goal of this research proposal is to simplify the immunization schedule by reducing the need for boosting at regular intervals. We will modify existing adenovirus vectors that express a Plasmodium multi-stage protective antigen as a transgene by insertion of a promiscuous T cell epitope within the capsid structure. We hypothesize that the high copy number of T cell epitopes displayed by capsid incorporation will significantly enhance the immune responses to the chimeric transgene product. The optimized capsid modified vectors will then be used for coadministration with the multi- stage protective antigen expressed as recombinant protein. The specific aims are to: 1. Characterize and compare the effect of the insertion of T cell epitopes within the capsid on the immunogenicity of recombinant adenovirus vectors. 2. Determine the immunogenicity and protective efficacy of a coadministration regimen using the P. yoelii model. 3. Assess the immunogenicity of a coadministration regimen tailored for P. vivax. We will use adenovirus serotype 5 (Ad5) and the chimeric Ad5/3 vectors for capsid modification. Viable vectors will be used for comparative experiments in mice. The successful outcome of comparative proof-of-principle experiments with the rodent malaria parasite will guide the design of a novel P. vivax vaccination regimen. We envision that our studies will provide valuable data to improve protective immune response induced by protein- based vaccines.

描述（由申请人提供）：间日疟原虫是分布最广泛的人类疟疾寄生虫，在南亚和东南亚占80%的临床病例，在美洲占70%。与恶性疟原虫相比，间日疟原虫的地理分布更广，这可以用这种寄生虫独特的生物学特征来解释。虽然传播控制措施的实施对发病率和死亡率产生了重大影响，但耐药寄生虫的出现和传播是一个日益令人关切的问题。因此，开发控制该疾病的新工具是全球的优先事项。该建议将基于我们开发嵌合重组蛋白和重组腺病毒载体的经验，开发一种结合这两种疫苗平台的联合接种方案。这项研究计划的总体目标是通过减少定期加强的需要来简化免疫计划。我们将通过在衣壳结构中插入一个混杂的T细胞表位来修饰现有的表达疟原虫多阶段保护性抗原的腺病毒载体作为转基因。我们推测衣壳结合所显示的T细胞表位的高拷贝数将显著增强对嵌合转基因产物的免疫反应。优化后的衣壳修饰载体将与表达为重组蛋白的多阶段保护性抗原共给药。具体目标是：1。表征并比较T细胞表位插入衣壳对重组腺病毒载体免疫原性的影响。2. 利用约氏假体模型确定联合给药方案的免疫原性和保护效果。3. 评估间日疟原虫联合给药方案的免疫原性。我们将使用5型腺病毒（Ad5）和嵌合Ad5/3载体进行衣壳修饰。活菌载体将用于小鼠的比较实验。啮齿动物疟疾寄生虫的比较原理验证实验的成功结果将指导新的间日疟原虫疫苗接种方案的设计。我们设想我们的研究将为改善基于蛋白质的疫苗诱导的保护性免疫反应提供有价值的数据。