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）： 间日疟原虫疟疾由于其广泛的全球分布、耐药菌株的日益流行以及最重要的是，Pv感染导致严重的临床综合征，造成了疟疾发病率的巨大负担。间日疟原虫占非洲获得性感染的12.4%，占亚洲和美洲获得性感染的70-90%。现在报告的现役或返回的士兵中的Pv病例比任何其他疟疾种类都多。由于PV耐药性的增加、致死病例的增加和PV的再感染行为，PV疫苗的开发是军事传染病研究计划的主要优先事项。间日疟原虫Duffy结合蛋白区域II（PvDBPII）是一种主要的Pv疫苗候选物。这种蛋白质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），促进红细胞入侵。其他人疟疾如恶性疟原虫具有几种不同的Duffy结合蛋白样基因，其促进使用用于裂殖子侵入的替代受体，然而，Pv侵入红细胞几乎完全依赖于PvDBPII和Duffy抗原，这是一个关键的弱点，并使Pv DBP配体成为疫苗开发的理想靶标。 使用PvDBPII作为疫苗仍然存在巨大的挑战，包括其高度多态性，其弱免疫原性以及缺乏对产生最强阻断或保护性应答的分子的特定部分的理解。这一建议建立在我们目前项目的观察基础上。首先，我们已经鉴定了流行地区的一个个体子集，其获得高滴度的上述功能性抗体，其阻断与多种PvDBPII变体的结合。将功能性人抗体定位到PvDBPII的特定区域可能有助于鉴定菌株超越疫苗。第二，在不同动物中产生的阻断PvDBPII与Fy结合的多克隆和单克隆抗体优先识别PvDBPII的相对保守的亚结构域，其可以促进疫苗的开发。第三，我们已经表明，Fy的主要多态性（Fyb <$Fya，Asp 42 Gly）与PvDBPII结合减少和人类临床Pv风险降低有关。我们发现，与Fyb红细胞相比，天然获得的和人工诱导的针对PvDBPII的Ab更有效地阻断其与Fya的结合，表明宿主Fy基因型可能是重要的疫苗功效。目标1。鉴定PvDBPII上可被跨菌株中和抗体识别的表位。目标二。开发疫苗方法以引发针对PvDBPII的菌株超越阻断/侵袭抑制抗体。目标3。确定与Fyb表型相比，Duffy Fya在体外和体内对PvDBPII的功能性免疫反应中的作用。