Intracellular-acting antibodies for the prevention of malaria liver stage infection

用于预防疟疾肝期感染的细胞内作用抗体

• 批准号: 10571407
• 负责人: Brandon Keith Wilder
• 金额: $ 26.95万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-04 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10571407
• 关键词: Anopheles Genus; Antibodies; Antibody titer measurement; Antigens; Antimalarials; Area; Autophagocytosis; Back; Binding; Blood; Cessation of life; Characteristics; Child; Communicable Diseases; Complex; Culicidae; Cytoplasm; Data; Dermis; Disease; Dose; Epitopes; Erythrocytes; Fab Immunoglobulins; Future; Goals; Hepatocyte; Human; Immunity; Infection; Infection prevention; Interruption; Intervention; Kinetics; Knockout Mice; Life Cycle Stages; Liver; Location; Malaria; Malaria Vaccines; Malaria prevention; Mediating; Membrane Proteins; Monoclonal Antibodies; Morbidity - disease rate; Parasites; Passive Transfer of Immunity; Plasmodium; Predisposition; Protein Secretion; Proteins; Publications; Recording of previous events; Regimen; Role; Skin; Sporozoites; Sterility; Subunit Vaccines; Surface; Testing; Therapeutic; Time; Vaccines; Visualization; circumsporozoite protein; extracellular; in vivo; liver infection; mortality; novel; pathogen; polyclonal antibody; prevent; rational design; synergism; transmission process; vaccine candidate; vaccine development; vaccine evaluation; vaccine-induced antibodies; vector

Abstract Malaria, caused by infection with Plasmodium spp., is one of the oldest and most lethal diseases in human history. It continues to be a leading cause of morbidity and mortality, especially amongst children under five. Despite over a decade of progress in reducing the burden of malaria, the last four years have seen a stagnation due to recalcitrance in highly endemic areas and interruptions in eradication efforts. As for any infectious disease, sustained progress will require an effective vaccine. For malaria, antibodies have been shown particularly potent in stopping the “sporozoite” form of Plasmodium during its ~30 minute journey from the mosquito, into the skin and then into a liver hepatocyte. Here, the parasite completes the asymptomatic “pre-erythrocytic” (PE) stages over ~1 week before emerging back into the blood for the erythrocytic stage, where it infects red blood cells and causes all morbidity, mortality and transmission. Stopping the parasite at the PE stage (i.e. sterile protection) is the ultimate goal of a malaria vaccine. Unfortunately, antibody-based vaccine candidates targeting the major surface protein (circumsporozoite protein, CSP) exposed at the sporozoite surface have failed to provide the long-lasting sterile protection needed for sustained control and elimination as this requires extremely high titers of antibodies which can only be maintained over short periods or with frequent boosting. One strategy to enhance CSP-based vaccines is to target additional antigens. However, demonstration that non-CSP targeting antibodies which can function on their own or in concert with CSP has been lacking. Current efforts have focused on surface/secreted proteins exposed during the extracellular sporozoite stage in line with dogma that once the parasite is within the hepatocyte, it is no longer accessible to antibodies. Surprisingly, we have found that antibodies targeting a liver stage-specific protein, UIS3, can efficiently kill the parasite during the intracellular hepatocyte stage. Furthermore, a low dose of these antibodies can synergize with a low dose of anti-CSP antibodies to raise sterile protection from 0% with each antibody alone to 64% in combination. These data not only add to the small number of bona fide PE antibody targets, but also open an entirely new parasite stage for antibody discovery and are the first demonstration of synergy between multiple antigens at the PE stage. While such intracellularly targeted antibodies (iAbs) have been described for other pathogens, their mechanisms of action are not well understood. Here, we aim to use monoclonal antibodies to define the basic functional characteristics of anti-UIS3 antibodies and to identify the core mechanisms of anti-UIS3 iAb action. These data will support the rational design of superior CSP-based vaccines and monoclonal antibody regimens with an iAb component, with the goal that these Ab-based interventions can achieve the high levels of long- lasting sterile protection to drive malaria to elimination.

抽象的 由疟原虫感染引起的疟疾是人类最古老，最致命的疾病之一 历史。它仍然是发病率和死亡率的主要原因，尤其是在五岁以下的儿童中。 尽管在减少了疟疾的伯恩伯恩（Burnen of Malaria）方面的进展已有十多年了，但过去四年来 由于高度内在区域的顽固性和根除努力的中断而导致的停滞。至于任何 传染病，持续进展将需要有效的疫苗。对于疟疾，抗体已经 在约30分钟的旅程中，在停止“孢子虫”形式的“孢子虫”形式的可能性特别有潜力 蚊子进入皮肤，然后进入肝肝细胞。在这里，寄生虫完成渐近 在大约1周内，“芽孢细胞前”（PE）阶段，然后恢复到血液中的血液阶段， 它感染了红细胞并引起所有发病率，死亡率和传播。停止寄生虫 PE阶段（即无菌保护）是疟疾疫苗的最终目标。不幸的是，基于抗体 靶向主要表面蛋白（外表蛋白蛋白，CSP）的疫苗候选物暴露于 孢子岩表面未能提供持续控制所需的持久无菌保护和 消除，因为这需要极高的抗体滴度，只能在短期内维持 或经常提高。增强基于CSP的疫苗的一种策略是靶向其他抗原。 但是，证明可以自行起作或与之共同起作用的非CSP靶向抗体 CSP缺乏。当前的努力集中在表面/分泌的蛋白质上 细胞外孢子岩阶段与寄生虫在肝细胞内的教条一致，不再是 抗体可访问。令人惊讶的是，我们发现针对肝脏特异性的抗体 蛋白质UIS3可以在细胞内肝细胞阶段有效地杀死寄生虫。此外， 低剂量的这些抗体可以与低剂量的抗CSP抗体协同作用以提高无菌性 仅使用每种抗体的0％保护到组合64％。这些数据不仅添加到 少量的真正的PE抗体靶标，但也打开了一个全新的寄生虫阶段 抗体发现，是PE上多种抗原之间协同作用的首次证明 阶段。尽管已经描述了其他病原体的细胞内靶向抗体（IAB） 作用机制尚不清楚。在这里，我们旨在使用单克隆抗体来定义基本 抗UIS3抗体的功能特征，并确定抗UIS3 IAB作用的核心机制。 这些数据将支持基于CSP的疫苗和单克隆抗体方案的合理设计 使用IAB成分，目标是这些基于AB的干预措施可以实现高水平的长期长期 持久的无菌保护以驱动疟疾消除。