Coadministration of capsid modified adenovirus for malaria vaccine development

描述(申请人提供)：间日疟原虫是分布最广的人类疟疾寄生虫，导致南亚和东南亚80%的临床病例以及美洲70%的病例。间日疟原虫独特的生物学特性解释了间日疟原虫较恶性疟原虫更广泛的地理分布。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日益令人担忧。因此，开发新的工具来控制这种疾病是全球的优先事项。这一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的基础上，以开发一种结合这两个疫苗平台的联合接种方案。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时间表。我们将通过在衣壳结构中插入一个混杂的T细胞表位来修改现有的表达疟原虫多阶段保护性抗原的腺病毒载体。我们推测，衣壳掺入所显示的高拷贝数的T细胞表位将显著增强对嵌合转基因产物的免疫应答。优化后的衣壳蛋白修饰载体将与表达为重组蛋白的多级保护性抗原共同给药。具体目的是：1.鉴定和比较衣壳内插入T细胞表位对重组腺病毒载体免疫原性的影响。2.利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果。3.评估针对间日疟原虫定制的联合用药方案的免疫原性。我们将使用腺病毒血清型5型(Ad5)和嵌合型Ad5/3载体进行衣壳修饰。可行的载体将用于在小鼠身上进行比较实验。对啮齿动物疟疾寄生虫进行的比较原则验证实验的成功结果将指导设计一种新的间日疟原虫疫苗接种方案。我们预计，我们的研究将为提高蛋白质疫苗诱导的保护性免疫反应提供有价值的数据。

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.