Optimization of chimeric multi-stage immunogens for malaria vaccine development

用于疟疾疫苗开发的嵌合多阶段免疫原的优化

• 批准号: 8880440
• 负责人: Alberto Moreno
• 金额: $ 84.38万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-16 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8880440
• 关键词: Adenovirus Vector; Africa; Americas; Antibodies; Antigens; Area; Attention; Autologous; Biochemical; Biological; Biological Assay; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cebidae; Child; Chimeric Proteins; Clinical; Clinical Pathways; Communicable Diseases; Country; Data; Development; Drug resistance; Economics; Epidemiology; Epitopes; Equilibrium; Erythrocytes; Experimental Animal Model; Generations; Genetic; Geographic Distribution; Goals; Growth; Health; Health Priorities; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immune system; Immunity; Immunization; In Vitro; Individual; Infection; Infection Control; Life; Life Cycle Stages; Link; Liver; Macaca mulatta; Malaria; Malaria Vaccines; Measures; Mediating; Modeling; Multicenter Trials; Mus; Nature; Outcome; Parasites; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Plasmodium falciparum; Plasmodium vivax; Plasmodium vivax vaccine; Population; Proteins; Reagent; Recombinant Proteins; Recombinants; Regimen; Relapse; Research Proposals; Resistance; Risk; Rodent; Safety; Saimiri; Sampling; Serum; Southeastern Asia; Splenectomy; Sporozoites; Staging; Subunit Vaccines; Synthetic Genes; System; T cell response; Testing; Therapeutic; Time; Translations; Vaccination; Vaccine Design; Vaccines; Viral Vector; Vivax Malaria; Work; World Health Organization; aged; base; design; design and construction; disorder control; economic impact; efficacy testing; experience; global health; hybrid protein; immunogenicity; improved; in vitro testing; in vivo; insight; nonhuman primate; novel; pre-clinical; prophylactic; protective efficacy; research clinical testing; resistant strain; safety testing; success; transmission process; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vector; years of life lost

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.

描述（由申请人提供）：疟疾是最广泛的传染病之一，在全世界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。根据世界卫生组织的数据，疟疾寄生虫造成了超过3%的寿命损失。经济影响也是巨大的，在高传输地区，估计平均每年经济增长损失1.3%。研制有效的疫苗、抗疟疾药物和执行抗病媒措施是控制这一疾病的全球卫生优先事项。本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。我们最近已经表明，通过红细胞前和红细胞期组分的基因融合设计的杂合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应答。需要功能性抗体和CD4+ T细胞来保护。我们还使用了一种新的嵌合腺病毒载体来递送这种保护性抗原，并证实了异源免疫方案增强了疫苗效力。间日疟原虫中相应的正向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肝脏中休眠形式的发展，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，我们将对食蟹猴疟原虫进行体外和体内研究，食蟹猴疟原虫是一种复制人类寄生虫间日疟原虫的生物学和临床特征的猿类疟疾寄生虫。所提出的研究旨在：（1）开发多阶段食蟹猴疟原虫实验疫苗构建体，（2）评估食蟹猴疟原虫多阶段构建体在恒河猴中的安全性、免疫原性和功效，以及（3）优化间日疟原虫多阶段疫苗候选物并评估在非人灵长类动物（Saimiri boliviensis）中的功效。使用两种独特且互补的非人灵长类动物模型进行的严格测试将确定该方法是否有前途，并将为后续的临床路径开发提供潜力。鉴于疟疾的巨大影响以及对间日疟原虫广泛和严重性质的日益关注以及对新控制措施的迫切需要，我们的建议既重要又及时。