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

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).

摘要 疟疾疫苗RTS，S是抗击疟疾的一个历史性里程碑。然而，我们需要继续探索新的 抗原和新的方法来对抗疟疾，因为RTS，S的保护率约为37%。的 难以研制出最佳保护的疟疾疫苗表明缺乏合适的疟疾疫苗 抗原由于疟疾的感染和传播涉及两种宿主， 是疟原虫完成其生命周期的必要条件复杂的疟疾生命周期使我们能够 开发针对蚊子阶段疟疾传播的疫苗。我们发现蚊子 纤维蛋白原相关蛋白1（FREP 1），促进疟原虫传播给蚊子。FREP 1定位 在中肠围食基质中;因此，它很容易被血液摄入的抗体接近。序列 通过序列比对，在按蚊中发现了一个高度保守的C-末端纤维蛋白原相关结构域（FBG 直向同源物，并且该结构域可以结合寄生虫。值得注意的是，针对FBG的抗体显著抑制了细胞的增殖。 多个疟原虫物种（伯氏疟原虫、恶性疟原虫和间日疟原虫）传播给不同物种的 按蚊（Anopheles）gambiae和An. dirus）。此外，针对某些特定抗原表位的单克隆抗体， FBG在阻断疟疾传播方面比多克隆抗体更活跃，这表明靶向特异性 FBG上的表位将更有效地阻断疟疾传播。我们还开发了一种新的分子 刺激强烈的体液和细胞免疫反应的佐剂。我们假设 将来自FBG和我们的新分子佐剂的Anoesthesia特异性表位整合到一种疫苗中， 免疫反应阻断疟疾传播。我们将识别这些可用于治疗的特定表位 有效阻断FBG传播疟疾，并将表位与我们的分子佐剂融合，产生 纳米颗粒用于疫苗接种。我们的长期目标是提高疟疾疫苗保护率， 短期目标是研制一种有效的阻断疟疾传播的疫苗。