Anopheles FBG: a novel malaria transmission-blocking vaccine target

摘要 疟疾疫苗RTS，S是抗击疟疾的历史里程碑。然而，我们需要继续探索新的 抗原性和抗击疟疾的新方法因为RTS的保护率，S约为37%。这个 开发疟疾疫苗最佳保护的困难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，疟疾通过蚊子传播 是疟原虫完成其生命周期的必备条件。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。我们确认了蚊子 纤维蛋白原相关蛋白1(FREP1)，促进疟原虫向蚊子传播。FREP1本地化 在中肠周围的基质中；因此，它很容易被血液中的抗体摄取。数列 比对发现在按蚊中高度保守的纤维蛋白原C末端相关结构域 同源基因，这个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 多种疟原虫(伯氏疟原虫、恶性疟原虫和间日疟原虫)向不同物种的传播 按蚊(Anopheles(An.冈比亚亚纲和An.迪鲁斯)。此外，针对某些特定表位的单抗 FBG在阻断疟疾传播方面比多克隆抗体更活跃，这表明靶向特定的 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 刺激强烈的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整合为一种疫苗将引发强大的 阻断疟疾传播的免疫反应。我们将确定这些特定的表位，可以用来 有效阻断来自FBG的疟疾传播，并将表位与我们的分子佐剂融合产生 用于接种疫苗的纳米颗粒。我们的长期目标是提高疟疾疫苗的保护率，而我们的 短期目标是开发一种有效的疟疾传播阻断疫苗(TBV)。

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).