Optimization of chimeric multi-stage immunogens for malaria vaccine development

描述（由申请人提供）：疟疾是传播最广泛的传染病之一，在全球100多个国家流行。一半的人口生活在有传播风险的地区。间日疟原虫是非洲以外最流行的人类疟疾寄生虫，估计80%的病例发生在南亚和东南亚，70%发生在美洲。据世界卫生组织统计，疟疾寄生虫造成的寿命损失占全球寿命损失的3%以上。经济影响也是巨大的，据估计，高输电地区的年经济增长率平均损失为1.3%。开发有效的疫苗、抗疟疾药物和实施抗病媒措施是控制该疾病的全球卫生优先事项。这项研究计划的总体目标是开发一种有效的多阶段间日疟原虫疫苗。我们最近的研究表明，通过遗传融合红细胞前期和红细胞期成分设计的杂交蛋白疫苗在非常敏感的啮齿动物系统中诱导了强大的保护性免疫反应。需要功能性抗体和CD4+ T细胞进行保护。我们还使用了一种新的嵌合腺病毒载体来传递这种保护性抗原，并证实了异源免疫方案增强了疫苗的效力。间日疟原虫中相应的同源序列也被表达为嵌合重组蛋白。间日疟原虫的一个关键生物学特征是在肝脏中形成休眠形式，导致随后的血液感染，即复发。我们假设这里提出的多阶段间日疟原虫疫苗将对疟疾复发产生重大影响。为了验证这一假设，我们将对cynomolgi疟原虫进行体外和体内研究，这是一种复制人类间日疟原虫生物学和临床特征的类人猿疟疾寄生虫。这些研究主要包括：(1)构建多期食蟹假体实验疫苗；(2)在恒河猴中评估食蟹假体多期构建疫苗的安全性、免疫原性和有效性；(3)优化间日假体多期候选疫苗并评估其在非人灵长类动物（猴猴）中的有效性。这项使用两种独特且互补的非人类灵长类动物模型的严格测试将确定该方法是否有希望，并将为后续临床途径开发提供潜力。鉴于间日疟原虫的广泛传播和严重性质日益引起人们的关注，疟疾的巨大影响以及迫切需要新的控制措施，我们的建议既重要又及时。

DESCRIPTION (provided by applicant): Malaria is one of the most widespread infectious diseases, prevalent in over 100 countries worldwide. Half of the human population is living in areas with risk of transmission. Plasmodium vivax is the most prevalent of the human malaria parasites outside Africa with an estimated 80% of the cases in South and Southeast Asia and 70% in the Americas. According to the World Health Organization malaria parasites are responsible for over 3% of the years of life lost. The economic impact is also enormous with an estimated average loss of 1.3% of annual economic growth in high transmission areas. The development of effective vaccines, anti-malaria drugs and the implementation of anti-vector measures are global health priorities to control the disease. The overall goal of this research proposal is to develop an effective multi-stage P. vivax vaccine. We have recently shown that a hybrid protein vaccine designed by genetic fusion of pre-erythrocytic and erythrocytic stage components induced a robust protective immune response in a very sensitive rodent system. Functional antibodies and CD4+ T cells are required for protection. We have also used a novel chimeric adenovirus vector to deliver such protective antigen and have confirmed that heterologous immunization regimens enhanced vaccine potency. The corresponding orthologous sequences in P. vivax have also been expressed as chimeric recombinant proteins. A critical biological feature of P. vivax is the development of dormant forms in the liver that cause subsequent blood infections known as relapses. We hypothesize that the multi-stage P. vivax vaccine proposed here will have a significant impact on malaria relapses. To test this hypothesis, we will conduct in vitro and in vivo studies with P. cynomolgi, a simian malaria parasite that reproduces the biological and clinical features of the human parasite P. vivax. The studies proposed are aimed at: (1) developing multi-stage P. cynomolgi experimental vaccine constructs, (2) assessing the safety, immunogenicity and efficacy of the P. cynomolgi multi-stage constructs in rhesus macaques and (3) optimizing a P. vivax multi-stage vaccine candidate and evaluating efficacy in non-human primates (Saimiri boliviensis). This rigorous testing, using two unique and complementary non-human primate models, will determine if the approach is promising and will offer the potential for subsequent clinical pathway development. Given the dramatic impact of malaria with increasing attention on the widespread and severe nature of P. vivax and the urgent need of novel control measures, our proposal is both significant and timely.