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Identification of Transmission blocking epitopes on P. vivax 48/45 protein

间日疟原虫 48/45 蛋白上传播阻断表位的鉴定

基本信息

批准号：
8986156
负责人：
Nirbhay Kumar
金额：
$ 7.53万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-15 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8986156
关键词：
Affinity Antibodies Antigens Area Binding Biological Assay Biological Process Biology Blocking Antibodies Cessation of life Clinical Complement Culicidae Data Development Disease Epitopes Exhibits Female Fertility Fertilization Future Generations Genetic Polymorphism Germ Cells Goals Grant Health Homologous Protein Human Hybridomas Immunofluorescence Immunologic In Vitro Infection Knowledge Malaria Membrane Membrane Proteins Methods Modeling Monoclonal Antibodies Mus Outcome Parasites Plasmodium Plasmodium falciparum Plasmodium vivax Population Property Protein Fragment Proteins Reagent Recombinant Proteins Recombinants Research Research Personnel Risk Role Severity of illness Specificity Sporozoites Staging Surface Antigens Symptoms System Tertiary Protein Structure Testing Time Transgenic Organisms Vaccines Vivax Malaria Work base cross reactivity feeding immunogenic immunogenicity in vivo innovation malaria transmission male mortality mouse model prevent protein expression success transmission process transmission-blocking vaccine vaccine candidate vaccine development zygote

项目摘要

DESCRIPTION (provided by applicant): Pfs48/45, a protein important for male gamete fertility, is in advanced stages of development as a Plasmodium falciparum transmission blocking vaccine. The Plasmodium vivax counterpart Pvs 48/45 is likewise expected to be an important vaccine candidate. In spite of significant sequence identify and presumed conserved biological function not much is known about the transmission blocking efficacy of antibodies against Pvs48/45 and if it will be similar to functional antibodies against Pfs48/45 as no cross-blocking reactivity has been observed. Several impediments to developing a transmission blocking vaccine for P. vivax malaria have delayed progress for this long term goal. These have included availability of conformationally suitable recombinant protein, lack of an in vivo challenge model and the inability to produce P. vivax gametocytes in the lab to test biological function of antibodies. In this application, we propose to develop certain much needed reagents to move the field forward capitalizing on success with Pfs48/45 in the co-investigator's lab. In Aim 1 we propose to generate monoclonal antibodies directed against Pvs48/45 and characterize their binding parameters and functionality through in vitro membrane feeding assays. Aim 2 will focus on examining the polymorphisms of Pvs48/45 in natural isolates and identification of epitopes recognized by antibodies elicited by natural infection. The third aim will determine the functional domains in Pvs48/45 using fragments of the protein to identify protein domains involved in forming conformational epitopes of relevance to transmission. The development of the mAb reagents against Pvs48/45 will greatly aid in understanding the biology of the protein and assist in the development of a transmission blocking vaccine based on Pvs48/45 for P. vivax malaria. While the objectives of the proposed work may appear routine, the generation of these reagents and characterization of epitopes are critical for more significant gains as discussed above as well as use of mAbs with transmission blocking potential in developing and establishing a murine model based on transgenic parasites (which is outside the scope of this application).

描述（由申请人提供）：Pfs48/45 是一种对雄性配子生育力很重要的蛋白质，作为恶性疟原虫传播阻断疫苗，正处于开发的后期阶段。间日疟原虫对应的 Pvs 48/45 同样有望成为重要的候选疫苗。尽管具有显着的序列鉴定和推测的保守生物学功能，但对于针对 Pvs48/45 的抗体的传播阻断功效以及其是否与针对 Pfs48/45 的功能性抗体相似还知之甚少，因为尚未观察到交叉阻断反应性。开发间日疟原虫疟疾传播阻断疫苗的几个障碍推迟了这一长期目标的进展。这些问题包括构象合适的重组蛋白的可用性、缺乏体内攻击模型以及无法在实验室中产生间日疟原虫配子体来测试抗体的生物学功能。在此应用中，我们建议利用联合研究人员实验室中 Pfs48/45 的成功，开发某些急需的试剂，以推动该领域向前发展。在目标 1 中，我们建议生成针对 Pvs48/45 的单克隆抗体，并通过体外膜喂养测定来表征其结合参数和功能。目标 2 将重点检查自然分离株中 Pvs48/45 的多态性，并鉴定自然感染引起的抗体识别的表位。第三个目标将确定功能使用蛋白质片段识别 Pvs48/45 中的结构域来识别参与形成与传输相关的构象表位的蛋白质结构域。针对 Pvs48/45 的 mAb 试剂的开发将极大地有助于了解该蛋白质的生物学特性，并有助于开发基于 Pvs48/45 的间日疟原虫传播阻断疫苗。虽然拟议工作的目标可能看起来很常规，但这些试剂的生成和表位的表征对于如上所述的更显着的收益以及在开发和建立基于转基因寄生虫的小鼠模型（这超出了本申请的范围）中使用具有传播阻断潜力的单克隆抗体至关重要。