MULTIVALENT VACCINE FOR LYMPHATIC FILARIASIS

淋巴丝虫病多价疫苗

• 批准号: 7470563
• 负责人: RAMASWAMY KALYANASUNDARAM
• 金额: $ 37.47万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470563
• 关键词: Active Immunization; Adult; Affect; Africa; Allergens; Animal Model; Animals; Antibodies; Antigens; Area; Blood; Blood specimen; Brugia malayi; Cells; Characteristics; Chimeric Proteins; Collagen; Complement; Data; Disease; Drug Formulations; Exposure to; Expression Library; Filaria bancrofti; Filarial Elephantiases; Filariasis; Genes; Genetic Polymorphism; Geographic Locations; Homologous Gene; Human; Immune; Immune response; Immunization; In Vitro; Incubated; India; Individual; Infection; Investigation; Jird; Knowledge; Laboratories; Laboratory Animal Models; Larva; Lymphatic; Malaria; Modeling; Molecular Weight; Monkeys; Mus; Nature; Parasites; Personal Satisfaction; Phage Display; Plant Leaves; Plasma; Primates; Property; Protocols documentation; Publishing; Recombinant Fusion Proteins; Recombinant Proteins; Reporting; Research Personnel; Role; Screening procedure; Serum; Solid; South America; Specimen; Staging; Testing; Transcript; Treatment Protocols; Vaccination; Vaccine Antigen; Vaccines; Venoms; Wasp Venoms; Work; base; cDNA Expression; cDNA Library; chemotherapy; cross reactivity; experience; gerbil/jird; hybrid gene; information gathering; killings; mouse model; pressure; programs; response; vaccine development; vaccine-induced immunity; vector

DESCRIPTION (provided by applicant): Lymphatic filariasis due to Brugia malayi and Wucheraria bancrofti is a debilitating disease that affects more than 200 million people worldwide. Mass chemotherapy is effective in reducing infection intensity in some endemic areas, suggesting that control against this infection is feasible. In endemic areas a group of individuals broadly defined as endemic normal (EN), remain refractive to infection despite frequent exposure to the infection. These individuals carry circulating protective antibodies that could kill infective larvae (L3) of B. malayi and W. bancrofti in vitro. Mechanism of this immune killing is not known. Nevertheless, these findings show that active immunization against lymphatic filariasis is possible, provided the antigens that generated the protective immune responses could be identified. Using an interative screening of a phage display expression library of B. malayi L3 with EN sera, we identified three antigens (BmALT-2, BmVAH and BmCol-4) that are specifically responsible for generating the protective immune responses. Homologues of all three antigens were subsequently cloned from W. bancrofti and show significant cross-reactivity. Preliminary immunization studies showed that significant protection (40-72%) could be achieved in mice and jird models following a prime (DNA) boost (recombinant protein) approach using all three antigens. Experiences from vaccine development against malaria suggest that a multivalent vaccine confer significantly higher protection than a single antigen alone. Therefore, in this application we are proposing to develop a multivalent vaccine comprising the three protective antigens (ALT-2, VAH and BmCol-4). There are four specific aims to this proposal. Since antigenic poly morphism has been reported in filariasis, Aim 1 will first determine whether there is any antigenic polymorphism in the three candidate vaccine antigens isolated from wild collected parasites. Preliminary studies show that both cells and antibodies are important in the protective responses in EN individuals. Therefore, Aim 2 will identify the characteristics of the protective immune responses to the vaccine constructs in human. Based on the information gathered from aims 1 and 2, Aim 3 will construct a multivalent vaccine consisting of hybrid gene of the three candid antigens in pVAX vector and fusion protein for boosting. Aim 4 will then evaluate and optimize the multivalent vaccine in animal models and determine the optimum protocol for human vaccination. The proposed studies are based on solid preliminary data and are hypotheses driven. Results from these studies, we believe will advance our knowledge towards developing a defined vaccine against lymphatic filariasis in the human.

描述（由申请人提供）：由于Brugia Malayi和Wucheraria Bancrofti引起的淋巴丝虫病是一种令人衰弱的疾病，影响了全球超过2亿人。质量化学疗法可有效降低某些流行区域的感染强度，这表明对这种感染的控制是可行的。在地方性地区，尽管经常暴露于感染，但一组广泛定义为流行正常（EN）的个体仍会折射感染。这些人携带循环的保护性抗体，可以在体外杀死Malayi和W. Bancrofti的感染性幼虫（L3）。这种免疫杀戮的机制尚不清楚。然而，这些发现表明，只要可以鉴定出产生保护性免疫反应的抗原，对淋巴丝虫病的主动免疫是可能的。使用与EN Sera的B. Malayi L3的噬菌体显示表达式库相时筛选，我们确定了三种抗原（BMALT-2，BMVAH和BMCOL-4），这些抗原专门负责产生保护性免疫反应。随后将所有三种抗原的同源物从W. bancrofti克隆并显示出明显的交叉反应性。初步免疫研究表明，使用所有三种抗原的素数（DNA）增强（重组蛋白）方法，可以在小鼠和JIRD模型中实现明显的保护（40-72％）。疫苗发育反对疟疾的经验表明，多价疫苗比单独的抗原具有明显更高的保护。因此，在此应用中，我们提议开发包括三种保护性抗原（Alt-2，VAH和BMCOL-4）的多价疫苗。该提案有四个具体的目标。由于已经在丝虫病中报道了抗原性多态性，因此AIM 1将首先确定从野生收集的寄生虫分离的三种候选疫苗抗原中是否存在任何抗原性多态性。初步研究表明，细胞和抗体在EN个体的保护反应中都很重要。因此，AIM 2将确定对人类疫苗构建的保护性免疫反应的特征。基于从目标1和2收集的信息，AIM 3将构建一种由PVAX载体中三种念珠菌抗原和融合蛋白的杂种基因组成的多价疫苗。然后，AIM 4将评估和优化动物模型中的多价疫苗，并确定人类疫苗接种的最佳方案。拟议的研究基于固体初步数据，是由假设驱动的。这些研究的结果，我们认为将我们的知识促进人类中针对淋巴丝虫病的定义疫苗。