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、耐药菌株的流行而造成疟疾发病率的沉重负担，最重要的是，间日疟原虫感染导致严重的临床综合征，占非洲和非洲获得的感染的 12.4%。由于对现役军人或归国士兵的耐药性不断增强，目前亚洲和美洲报告的疟原虫感染病例比任何其他疟疾病例都要多。 Pv、Pv 的致命病例和复发行为，Pv 疫苗的开发是军事传染病研究计划的一个主要优先事项，其中一种主要的 Pv 疫苗候选物是间日疟原虫 Duffy 结合蛋白区域 II (PvDBPII)。寄生虫的细胞表面并结合宿主红细胞的达菲抗原（Fy），促进红细胞入侵。其他人类疟疾，如恶性疟原虫，有几种不同的特征。 Duffy 结合蛋白样基因促进裂殖子入侵的替代受体的使用，然而 PvDBPII 和 Duffy 抗原几乎完全依赖于 Pv 入侵红细胞，这是一个关键弱点，这使得 Pv DBP 配体成为疫苗开发的理想目标。 PvDBPII 仍被用作疫苗，包括其高度的多态性、弱的免疫原性以及对产生疫苗的分子的特定部分缺乏了解该建议建立在我们当前项目的观察基础上，首先，我们已经确定了流行地区的一部分个体获得了上述高滴度的功能性抗体，这些抗体可阻止与多种 PvDBPII 变体的结合。其次，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相对保守的抗体。 PvDBPII 的子结构域可以促进疫苗的开发第三，我们已经证明了 Fy（Fyb¿）的主要多态性。 Fya、Asp42Gly）与 PvDBPII 结合减少和人类临床 Pv 风险降低相关。我们发现，与 Fyb 红细胞相比，自然获得的和人工诱导的针对 PvDBPII 的抗体更能有效地阻断其与 Fya 的结合，这表明宿主。 Fy 基因型可能是重要的疫苗功效。 目标 1. 鉴定 PvDBPII 上可被菌株超越的中和抗体识别的表位。开发疫苗方法来引发针对 PvDBPII 的超越菌株阻断/侵袭抑制抗体。 目标 3. 确定 Duffy Fya 与 Fyb 表型在体外和体内 PvDBPII 功能性免疫反应中的作用。