Anopheles FBG: a novel malaria transmission-blocking vaccine target

按蚊FBG：一种新型的阻断疟疾传播的疫苗靶点

• 批准号: 10575260
• 负责人: Jun Li
• 金额: $ 21.48万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-08 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10575260
• 关键词: Address; Adjuvant; Anopheles Genus; Antibodies; Antigens; Area; Binding; Biological Assay; Blood; C-terminal; Carrier Proteins; Chimeric Proteins; Clinical; Clinical Trials; Collaborations; Communities; Culicidae; Data; Drug resistance; Epitopes; Fibrinogen; Future; Genes; Goals; Immune response; Ingestion; Insecticide Resistance; Intervention; Invaded; Kenya; Life Cycle Stages; Link; Malaria; Malaria Vaccines; Membrane; Midgut; Molecular; Monoclonal Antibodies; Mus; Oocysts; Orthologous Gene; Oryctolagus cuniculus; Parasite resistance; Parasites; Parasitic infection; Patients; Peptides; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Predisposition; Proteins; Sequence Alignment; Site-Directed Mutagenesis; Techniques; Testing; Universities; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; feeding; fighting; improved; in vivo; industry partner; inhibiting antibody; insight; malaria infection; malaria transmission; malaria transmission-blocking vaccine; multidisciplinary; nanoparticle; new technology; novel; novel strategies; polyclonal antibody; protective efficacy; tool; transmission blocking; transmission process; transmission-blocking vaccine; vaccine development; Address; Adjuvant; Anopheles Genus; Antibodies; Antigens; Area; Binding; Biological Assay; Blood; C-terminal; Carrier Proteins; Chimeric Proteins; Clinical; Clinical Trials; Collaborations; Communities; Culicidae; Data; Drug resistance; Epitopes; Fibrinogen; Future; Genes; Goals; Immune response; Ingestion; Insecticide Resistance; Intervention; Invaded; Kenya; Life Cycle Stages; Link; Malaria; Malaria Vaccines; Membrane; Midgut; Molecular; Monoclonal Antibodies; Mus; Oocysts; Orthologous Gene; Oryctolagus cuniculus; Parasite resistance; Parasites; Parasitic infection; Patients; Peptides; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Predisposition; Proteins; Sequence Alignment; Site-Directed Mutagenesis; Techniques; Testing; Universities; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; feeding; fighting; improved; in vivo; industry partner; inhibiting antibody; insight; malaria infection; malaria transmission; malaria transmission-blocking vaccine; multidisciplinary; nanoparticle; new technology; novel; novel strategies; polyclonal antibody; protective efficacy; tool; transmission blocking; transmission process; transmission-blocking vaccine; vaccine development

ABSTRACT Malaria vaccine RTS,S is a historical milestone to fight malaria. However, we need to continue exploring new antigens and new approaches to fight against malaria because the protection rate of RTS,S is about 37%. The difficulty in developing optimal protection of a malaria vaccine indicates the scarcity of suitable malaria vaccine antigens. Since malaria infection and transmission involve two hosts, malaria transmission through mosquitoes is obligatory for a Plasmodium parasite to complete its life cycle. The complicated malaria life cycle allows us to develop a vaccine that targets malaria transmission at the mosquito stage. We identified mosquito fibrinogen-related protein 1 (FREP1) that facilitates Plasmodium transmission to mosquitoes. FREP1 localizes in the midgut peritrophic matrix; thus, it is easily accessible by antibodies ingested with blood. Sequence alignment identified a highly conserved C-terminal fibrinogen-related domain (FBG) among anopheline mosquito orthologs, and this domain can bind parasites. Notably, antibodies against FBG significantly inhibit the transmission of multiple Plasmodium species (P. berghei, P. falciparum, and P. vivax) to various species of Anopheles (An. gambiae and An. dirus). Moreover, monoclonal antibodies against some specific epitopes on FBG is more active in blocking malaria transmission than polyclonal antibodies, indicating that targeting specific epitopes on FBG will block malaria transmission more effectively. We have also developed a new molecular adjuvant that stimulates the strong humoral and cellular immune response. We hypothesize that combining Anopheles-specific epitopes from FBG and our new molecular adjuvant into one vaccine will trigger a robust immune response to block malaria transmission. We will identify these specific epitopes that can be used to efficiently block malaria transmission from FBG and fuse the epitopes with our molecular adjuvant to generate nanoparticles for vaccination. Our long-term goal is to improve the malaria vaccine protection rate, while our short-term goal is to develop an efficient malaria transmission-blocking vaccine (TBV).

抽象的 疟疾疫苗RTS，S是与疟疾作斗争的历史里程碑。但是，我们需要继续探索新的 抗原和对抗疟疾的新方法，因为RT的保护率约为37％。这 难以开发对疟疾疫苗的最佳保护表明合适的疟疾疫苗的稀缺性 抗原。由于疟疾感染和传播涉及两个宿主，因此疟疾通过蚊子传播 疟原虫必须完成其生命周期。复杂的疟疾生命周期使我们能够 开发一种靶向蚊子阶段疟疾传播的疫苗。我们确定了蚊子 纤维蛋白原相关的蛋白1（FREP1），促进疟原虫向蚊子传播。 FREP1本地化 在中肠营养基质中；因此，被血液摄入的抗体很容易获得。顺序 对齐鉴定了高度保守的C末端纤维蛋白原相关结构域（FBG） 直系同源物，该领域可以结合寄生虫。值得注意的是，针对FBG的抗体显着抑制 将多种疟原虫（P. berghei，falciparum和P. vivax）传播到各种物种 Anopheles（An。Gambiae和An。Dirus）。此外，针对某些特定表位的单克隆抗体 与多克隆抗体相比，FBG在阻断疟疾传播方面更为活跃，表明针对特定 FBG上的表位会更有效地阻断疟疾的传播。我们还开发了一个新的分子 辅助刺激强烈的体液和细胞免疫反应。我们假设结合 来自FBG和我们的新分子佐剂到一种疫苗的肛门特异性表位将触发可靠的 对阻断疟疾传播的免疫反应。我们将确定这些可以用来用于的特定表位 有效阻止疟疾从FBG传播，并将表位与我们的分子佐剂融合以产生 纳米颗粒进行疫苗接种。我们的长期目标是提高疟疾疫苗保护率，而我们 短期目标是开发有效的疟疾传播阻滞疫苗（TBV）。