Membrane-cloaked nanoparticles as mucosal vaccines against giardiasis

膜包裹纳米粒子作为贾第鞭毛虫病粘膜疫苗

基本信息

批准号：
10495210
负责人：
LARS ECKMANN
金额：
$ 19.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10495210
关键词：
Adjuvant Adverse effects Animal Model Animals Antigen-Presenting Cells Antigenic Variation Antigens B-Lymphocytes Biological Assay CD4 Positive T Lymphocytes Canis familiaris Category B pathogen Centers for Disease Control and Prevention (U.S.)Characteristics Chemicals Child Clinical Cyst Day center care Diarrhea Disease Disease Outbreaks Effector Cell Endotoxins Epigastric Epithelial Felis catus Formulation Gene Targeting Gerbils Giardia Giardia lamblia Giardiasis Glycolates Health Human Immune Immunization Immunize Immunoglobulin A Immunologics In Vitro Individual Infection Ingestion Malabsorption Syndromes Malnutrition Mechanics Mediating Medical Membrane Microbe Military Personnel Modeling Mucous Membrane Mus Nanotechnology Nausea and Vomiting Pain Parasites Parasitic Diseases Play Prevalence Prevention Preventive Process Proteins Quality Control Reagent Regimen Resources Role Safety Series Small Intestines Solvents Sonication Sterility Surface Surface Antigens Surrogate Markers System Testing United States Vaccination Vaccine Design Vaccines Viral Water Supply adaptive immunity attenuation base biodegradable polymer clinical development controlled release diarrheal disease enteric infection enteric pathogen evaporation gut colonization immunogenicity improved in vivo innovation insight long-term sequelae mouse model mucosal vaccination mucosal vaccine nanoformulation nanoparticle nanovaccine neglect non-Native novel pathogen preclinical development preclinical study uptake vaccination strategy vaccine candidate vaccine development vaccine efficacy vaccine platform vaccine-induced immunity

项目摘要

Project Summary Giardia lamblia, a protozoan CDC category B priority pathogen, is an important cause of diarrheal disease with hundreds of millions of annual cases worldwide. In the United States, G. lamblia is one of the two most common causes of outbreaks of parasitic disease, with prevalence rates of 1-7%. Symptomatic giardiasis is characterized by diarrhea, epigastric pain, nausea, vomiting, malabsorption and malnutrition, especially in children. Long-term sequelae are common and can persist despite apparently successful treatment. Importantly, infection can be initiated by ingestion of fewer than ten cysts, demonstrating that G. lamblia is highly contagious and a credible threat to the safety of public water supplies and health. Trophozoites, the disease-causing forms of the parasite, colonize the lumen of the small intestine and attach to the epithelium. Infection is typically self-limiting, indicating that effective immune defenses exist. Despite the clinical importance of G. lamblia, no preventive medical strategies are available. Prior preclinical studies have shown that immunization with individual surface antigens can confer partial protection against G. lamblia infection in mice and gerbils, but protection is not as effective as prior infection with the parasite, suggesting that single antigens may not be sufficient to induce optimal protection. Multi-antigen immunizations can be done with live pathogen vaccines, but the necessary attenuation has not been achieved for G. lamblia and may not be possible due to the predictably compromised ability to colonize the intestine. As an alternative, we propose a nanoparticle-based vaccine, constructed from the membranes of G. lamblia strains, which enables effective multi-antigen mucosal immunization without concerns about adverse effects due to live microbe exposure. The resulting nanoparticle vaccines offer several distinct advantages: i) delivery of multi-antigenic material present on the pathogen surface, ii) stability and homogeneous sizing for effective transport in vivo and efficient uptake into antigen-presenting cells, and iii) tunable immunological biasing by loading the core with suitable adjuvants for controlled release. Therefore, our overall objective is to develop G. lamblia membrane- coated nanoparticles as a novel mucosal vaccination strategy against giardiasis. We will systematically fabricate different nanovaccine formulations with native pathogen membranes and test them for immunogenicity and protective capacity in relevant animal models of giardiasis. This project brings new ideas and approaches from the field of nanotechnology to the prevention of giardiasis, a highly contagious and clinically important but largely neglected diarrheal disease. Importantly, our innovative strategy overcomes the challenges associated with identifying single protective antigens or with using non-native, chemically modified forms of the target pathogen, thereby greatly improving induction of adaptive immunity to multiple native proteins found on the live parasite surface. The new strategy has broad implications for vaccine design for other mucosal pathogens, including not only protozoan, but also bacterial and viral agents.

项目摘要贾第鞭毛虫（Giardia Lamblia）是一种原生动物CDC类别B优先病原体，是腹泻病的重要原因全球有数亿个年度案件。在美国，G。Lamblia是最重要的之一寄生疾病爆发的常见原因，患病率为1-7％。有症状的贾第鞭毛病是以腹泻，上腹疼痛，恶心，呕吐，吸收不良和营养不良为特征，尤其是在孩子们。长期后遗症很常见，尽管显然成功地进行了治疗，也可以持续存在。重要的是，可以通过摄入少于十个囊肿来引发感染，这表明G. lamblia是对公共供水和健康安全的高度传染性和可靠的威胁。滋养体，寄生虫引起疾病的形式，定居小肠的腔，并附着在上皮上。感染通常是自限制的，表明存在有效的免疫防御能力。尽管有临床 G. lamblia的重要性，没有预防性医疗策略。先前的临床前研究表明用单个表面抗原免疫可以赋予G. lamblia感染的部分保护小鼠和沙鼠，但保护不如先前感染寄生虫，这表明单身抗原可能不足以诱导最佳保护。可以实时进行多抗原免疫接种病原体疫苗，但是G. lamblia尚未实现必要的衰减，可能不是由于可以预见的殖民肠道的能力，因此可能导致。作为替代方案，我们建议基于纳米颗粒的疫苗，由G. lamblia菌株的膜建造，可有效多抗原粘膜免疫，而无需担心由于微生物暴露而产生的不良影响。由此产生的纳米颗粒疫苗提供了几个不同的优势：i）多食材料的递送存在于病原体表面，ii）稳定性和均匀尺寸，可在体内有效运输和有效摄取抗原呈递细胞，以及通过将核心加载的可调免疫偏见合适的佐剂可控制释放。因此，我们的总体目标是发展G. lamblia膜 - 涂层纳米颗粒是针对贾第鞭毛疾病的新型粘膜疫苗接种策略。我们将系统地用天然病原体膜制造不同的纳米酮配方，并测试贾第鞭毛疾病相关动物模型中的免疫原性和保护能力。这个项目带来了新的想法以及从纳米技术领域到预防贾第鞭毛病的方法，这是一种高度传染性的和临床上重要但在很大程度上被忽视的腹泻病。重要的是，我们的创新策略克服了挑战与识别单一保护抗原或使用非本地化学修改有关的挑战靶病原体的形式，从而大大提高了对多种天然的自适应免疫的诱导在活寄生虫表面发现的蛋白质。新策略对疫苗设计具有广泛的影响其他粘膜病原体，不仅包括原生动物，还包括细菌和病毒剂。