Coadministration of capsid modified adenovirus for malaria vaccine development

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，间日疟原虫更广泛的地理分布是由这种寄生虫独特的生物学特征解释的。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，但抗药性寄生虫的出现和传播日益令人关切。因此，开发控制该疾病的新工具是全球优先事项。该建议将建立在我们开发嵌合重组蛋白和重组腺病毒载体的经验基础上，以开发结合这两种疫苗平台的联合施用疫苗接种方案。这项研究提案的总体目标是通过减少定期加强免疫的需要来简化免疫接种计划。我们将通过在衣壳结构内插入混杂T细胞表位来修饰现有的腺病毒载体，所述腺病毒载体表达疟原虫多阶段保护性抗原作为转基因。我们推测，通过衣壳掺入展示的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应答。然后将优化的衣壳修饰的载体用于与表达为重组蛋白的多阶段保护性抗原共同施用。具体目标是：1.表征并比较衣壳内T细胞表位插入对重组腺病毒载体免疫原性的影响。2.使用约氏疟原虫模型确定联合给药方案的免疫原性和保护效力。3.评估针对间日疟原虫定制的联合给药方案的免疫原性。我们将使用腺病毒血清型5（Ad 5）和嵌合Ad 5/3载体进行衣壳修饰。活载体将用于小鼠中的比较实验。啮齿类疟原虫的比较原理验证实验的成功结果将指导新型间日疟原虫疫苗接种方案的设计。我们设想我们的研究将提供有价值的数据，以提高基于蛋白质的疫苗诱导的保护性免疫应答。 公共卫生相关性：由间日疟原虫引起的疟疾是世界范围内的一个主要公共卫生问题，每年感染人数估计在1.32亿至3.91亿之间。间日疟原虫耐药菌株的出现和传播使得人们越来越重视对控制这种感染的替代预防和治疗策略的需求。我们的目标是开发一种有效的疫苗，能够诱导长期持久的保护使用简化的免疫接种计划。

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. PUBLIC HEALTH RELEVANCE: Malaria caused by Plasmodium vivax is a major public health problem worldwide with the number of annual infections estimated to be between 132 and 391 million. The emergence and spread of P. vivax drug resistant strains has brought increased emphasis to the need for alternative prophylactic and therapeutic strategies to control this infection. We aim to develop an effective vaccine able to induce long lasting protection using a simplified immunization schedule.