Strain-specific Immunity to Plasmodium vivax malaria

对间日疟原虫疟疾的菌株特异性免疫

• 批准号: 8542980
• 负责人: Christopher L King
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542980
• 关键词: Accounting; Address; Affect; Afghanistan; Africa; Africa South of the Sahara; Americas; Animals; Antibodies; Antigens; Area; Asia; B-Lymphocytes; Behavior; Binding; Binding Proteins; Biological Assay; Blocking Antibodies; Blood; Brazil; Cell Separation; Cessation of life; Clinical; Conflict (Psychology); Data; Dependence; Development; Disease; Drug resistance; Epitope Mapping; Epitopes; Erythrocytes; Falciparum Malaria; Funding; Generations; Genes; Genetic Polymorphism; Genotype; Health Policy; Human; Immune response; Immunity; Immunoglobulins; In Vitro; Individual; Infection; Infectious Diseases Research; Iraq; Left; Ligands; Light; Liver; Malaria; Malaria Vaccines; Maps; Measures; Memory B-Lymphocyte; Military Personnel; Monoclonal Antibodies; Morbidity - disease rate; Mus; Nature; Parasites; Pathway interactions; Phenotype; Plasmodium falciparum; Plasmodium vivax; Population; Population Study; Prevalence; Protein Region; Proteins; Public Health; Relapse; Reporting; Risk; Role; Soldier; Staging; Surface; Syndrome; T-Lymphocyte Epitopes; Time; Transcend; Trefoil Motif; Vaccines; Variant; Vivax Malaria; acquired immunity; base; clinical risk; genetic variant; immunogenicity; in vitro Assay; in vivo; mortality; neutralizing antibody; neutralizing monoclonal antibodies; novel; polyclonal antibody; programs; public health relevance; receptor; resistant strain; response; vaccine candidate; vaccine development; vaccine efficacy

DESCRIPTION (provided by applicant): Plasmodium vivax malaria contributes to a large burden of malaria morbidity owing to its widespread global distribution, the increasing prevalence of drug-resistant strains and most importantly, infections with Pv cause severe clinical syndromes. Plasmodium vivax accounts for 12.4% of infections acquired in Africa and 70-90% of infections acquired in Asia and the Americas. More cases of Pv are now reported than any other malaria species for active duty or returning soldiers. Because of increasing drug resistance to Pv, lethal cases and replapsing behavior of Pv, development of Pv vaccine is a major priority of the Military Infectious Disease Research Program. One the leading Pv vaccine candidates is P. vivax Duffy binding protein region II (PvDBPII). This protein is expressed at the parasite's cellular surface and binds the host red cell's Duffy antigen (Fy) that facilitates erythrocyte invasion. Other human malaria such as P. falciparum, have several different Duffy Binding Protein-like genes that facilitate the use o alternative receptors for merozoite invasion, however the almost exclusive dependence of PvDBPII and Duffy antigen for Pv invasion of erythrocytes a critical weakness and makes the Pv DBP ligand an ideal target for vaccine development. Substantial challenges remain for use PvDBPII as a vaccine, including its high degree of polymorphism, its weak immunogenicity and a lack of understanding as regards to the specific portion of the molecule engendering the strongest blocking or protective responses. This proposal builds on observations from our current project. First, we have identified a subset of individuals in endemic areas who acquire high titers of functional antibodies described above that block binding to multiple PvDBPII variants. Mapping of the functional human Abs to specific regions of PvDBPII may help to identify a strain-transcending vaccine. Second, polyclonal and monoclonal antibodies generated in different animals that block binding of PvDBPII to Fy preferentially recognize a relatively conserved sub-domain of PvDBPII that could facilitate development of a vaccine. Third, we have shown that the major polymorphism in Fy (Fyb¿Fya, Asp42Gly) is associated with both diminished binding of PvDBPII and a reduced risk of clinical Pv in humans. We found that both naturally acquired and artificially induced Abs directed to PvDBPII more effectively blocked its binding to Fya as compared to Fyb erythrocytes, indicating host Fy genotype may be important vaccine efficacy. Aim 1. To identify epitopes on PvDBPII recognized by strain-transcending neutralizing antibodies. Aim 2. To develop vaccine approaches to elicit strain-transcending blocking/invasion inhibitory antibodies to PvDBPII. Aim 3. To determine the role of the Duffy Fya as compared to Fyb phenotype in functional immune responses to PvDBPII in vitro and in vivo.

描述（由申请人提供）： 疟原虫疟疾由于其宽度的全球分布，耐药菌株的患病率的增加，最重要的是，PV感染引起严重的临床综合征，导致了大量疟疾发病率燃烧。疟原虫占非洲感染的12.4％，在亚洲和美洲获得的感染中的70-90％。现在，据报道，与其他任何疟疾物种有关现役或返回士兵的疟疾病例更多。由于对PV的耐药性增加，致命病例和PV的复制行为，PV疫苗的开发是军事传染病研究计划的主要优先事项。领先的PV疫苗候选者之一是假子Duffy结合蛋白II（PVDBPII）。该蛋白在寄生虫的细胞表面表达，并结合宿主红细胞的达菲抗原（FY），促进红细胞的其他人类疟疾，例如恶性疟原虫，具有几种不同的Duffy结合蛋白样基因，这些基因几乎促进了Merozoite Invisigig and Indig Invife and perfuff infuff and PV的替代者，并具有PV的替代品，红细胞的关键弱点，使PV DBP配体成为疫苗发育的理想目标。将PVDBPII用作疫苗，包括其高度多态性，其免疫原性弱和缺乏理解作为对分子的特定部分的关注，从而产生强烈阻断或保护反应的问题。该提案建立在我们当前项目的观察基础上。首先，我们已经确定了内在区域中的一部分个体，这些个体获得了上面描述的高滴度的功能抗体，该功能抗体阻碍了与多个PVDBPII变体结合的。将功能性人类ABS映射到PVDBPII的特定区域可能有助于鉴定出菌株的疫苗。其次，在不同的动物中产生的多克隆和单克隆抗体，这些抗体阻止了PVDBPII对FY的结合，优先识别了一个相对构成的PVDBPII亚域，该域可能促进疫苗的发展。第三，我们已经表明，FY（FYB。fya，asp42gly）的主要多态性与PVDBPII的结合减少以及人类临床PV的降低有关。我们发现，与FYB红细胞相比，针对PVDBPII的自然获得和人为诱导的ABS更有效地阻断了其与FYA的结合，表明宿主FY FY基因型可能是重要的疫苗有效性。目的1。通过菌株转移中和抗体识别的PVDBPII的表位。目的2。开发疫苗方法以引起对PVDBPII的应变转移阻断/侵袭抑制性抗体。目的3。与FYB表型相比，在体外和体内确定Duffy FYA的作用。