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).

抽象的 疟疾疫苗 RTS,S 是抗击疟疾的历史里程碑。但我们还需要继续探索新的 抗原和对抗疟疾的新方法，因为 RTS,S 的保护率约为 37%。这 开发最佳保护疟疾疫苗的困难表明合适的疟疾疫苗的稀缺 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 开发一种针对蚊子阶段疟疾传播的疫苗。我们发现了蚊子 纤维蛋白原相关蛋白 1 (FREP1)，促进疟原虫传播给蚊子。 FREP1 本地化 在中肠周围营养基质中；因此，通过血液摄入的抗体很容易接触到它。顺序 比对鉴定出按蚊中高度保守的 C 端纤维蛋白原相关结构域 (FBG) 直向同源物，该结构域可以结合寄生虫。值得注意的是，针对 FBG 的抗体显着抑制 将多种疟原虫（伯氏疟原虫、恶性疟原虫和间日疟原虫）传播给不同种类的疟原虫 按蚊（冈比亚按蚊和迪鲁斯按蚊）。此外，针对某些特定表位的单克隆抗体 FBG 在阻断疟疾传播方面比多克隆抗体更活跃，这表明针对特定目标 FBG 上的表位将更有效地阻止疟疾传播。我们还开发了一种新的分子 刺激强烈体液和细胞免疫反应的佐剂。我们假设结合 来自 FBG 的按蚊特异性表位和我们的新分子佐剂融入一种疫苗将引发强大的免疫反应。 阻止疟疾传播的免疫反应。我们将鉴定这些可用于 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 用于疫苗接种的纳米颗粒。我们的长期目标是提高疟疾疫苗的保护率，同时我们的 短期目标是开发一种有效的阻断疟疾传播的疫苗（TBV）。