Chronic wasting disease vaccine: inducing auto-antibodies for interfering in CWD infection and prion shedding

慢性消耗性疾病疫苗：诱导自身抗体干扰 CWD 感染和朊病毒脱落

• 批准号: RGPIN-2020-04581
• 负责人: Schaetzl, Hermann
• 金额: $ 3.06万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=740052
• 关键词: Chronic; wasting; disease; vaccine; inducing

Prion diseases are fatal infectious neurodegenerative disorders in animals and humans caused by conversion of the cellular prion protein (PrPC) into the pathologic isoform PrPSc. Chronic wasting disease (CWD) in cervids and BSE in cattle are animal prion diseases which negatively affect economy, ecology as well as animal and possibly human health in Canada. CWD is the most contagious prion disease and affects both free-ranging and farmed deer, elk, moose and reindeer. Incidence and distribution in Canada are expanding, reaching now 6% in hunted deer in Alberta. The substantial shedding of CWD infectivity via urine, feces and saliva into the environment, combined with persistence for many years, are driving forces for CWD transmission. Due to this effective horizontal transmission and occurrence in wildlife control of disease is extremely challenging. The main research question in my group is to understand prion biology and to use this for developing therapeutic and prophylactic anti-prion strategies. Our long-term goal here is to develop a CWD vaccine. The problem with immune system-mediated approaches against prion diseases is that they do not elicit an immune response as newly generated prions are self-proteins. Our approach is unique, as it targets PrPC outside the brain, using aggregation-prone recombinant PrP for overcoming self-tolerance. This strategy results in generation of self-antibodies binding to PrPC which interfere in prion conversion. My group pioneered this concept and established a solid proof-of-concept in rodent and reindeer models that tolerance to PrP can be overcome, resulting in detectable humoral and cellular immune responses without adverse side effects and protection in CWD challenge models. The proposed work program will optimize our CWD vaccine candidates. Work in Objective 1 will focus on prion shedding. The question whether our vaccine approach reduces prion shedding is very important, as an approach which increases incubation time but does not reduce shedding would result in an overall increase of CWD infectivity in the environment. Our unit has developed innovative PrP knock-in mice which shed CWD prions efficiently and can be well infected orally. We will use them to assess the effect of vaccination on shedding, using ultra-sensitive prion conversion assays and co-housing as read-outs. Work in Objective 2 will address how vaccine design can be optimized, based on the concept that tolerance can be overcome by increasing antigen stability. Objective 3 will focus on oral antigen delivery, using nanosphere co-encapsulation of immunogens and plant-based expression systems. Work in Objective 4 will extend studies in reindeer, addressing side effects, memory and antibody secretion in milk and body fluids. We expect that work in this program will result in tools which, in the long term, help to reduce the spread of CWD, lower the zoonotic risk for the Canadian population, and protect the Canadian cervid populations.

朊病毒病是由细胞朊病毒蛋白（PrPC）转化为病理同种型PrPSc引起的动物和人类致命的传染性神经退行性疾病。鹿的慢性消耗性疾病（CWD）和牛的BSE是动物朊病毒疾病，对加拿大的经济、生态以及动物和可能的人类健康产生负面影响。慢性消耗病是最具传染性的朊病毒疾病，影响自由放养和养殖的鹿、麋鹿、驼鹿和驯鹿。加拿大的发病率和分布正在扩大，在阿尔伯塔的猎鹿中现在达到6%。慢性消耗病的传染性通过尿液、粪便和唾液大量散发到环境中，加上多年的持续存在，是慢性消耗病传播的驱动力。由于这种有效的横向传播和发生在野生动物中，疾病的控制极具挑战性。 我们小组的主要研究问题是了解朊病毒的生物学，并利用它来开发治疗性和预防性的抗朊病毒策略。我们的长期目标是开发CWD疫苗。免疫系统介导的对抗朊病毒疾病的方法的问题在于，它们不会引起免疫应答，因为新产生的朊病毒是自身蛋白。我们的方法是独特的，因为它靶向脑外的PrPC，使用易于聚集的重组PrP克服自身耐受性。这种策略导致产生与PrPC结合的自身抗体，其干扰朊病毒转化。我的团队率先提出了这一概念，并在啮齿动物和驯鹿模型中建立了一个坚实的概念验证，即可以克服对PrP的耐受性，从而在CWD挑战模型中产生可检测的体液和细胞免疫反应，而不会产生不良副作用和保护作用。 拟议的工作计划将优化我们的CWD候选疫苗。目标1的工作重点是朊病毒脱落。我们的疫苗方法是否减少朊病毒脱落的问题非常重要，因为增加孵育时间但不减少脱落的方法将导致环境中CWD感染性的总体增加。我们的单位已经开发出创新的PrP基因敲入小鼠，有效地摆脱慢性消耗病朊病毒，可以很好地口服感染。我们将使用它们来评估疫苗接种对脱落的影响，使用超灵敏的朊病毒转化试验和共同住房作为读数。目标2中的工作将基于耐受性可以通过增加抗原稳定性来克服的概念来解决如何优化疫苗设计。目标3将集中于口服抗原递送，使用免疫原的纳米球共包封和基于植物的表达系统。目标4的工作将扩大对驯鹿的研究，解决副作用、记忆和乳汁和体液中的抗体分泌。我们期望，这项计划的工作将导致工具，从长远来看，有助于减少慢性消耗病的传播，降低加拿大人口的人畜共患病风险，并保护加拿大鹿科动物种群。