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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=717207
• 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.

Prion病是一种致命性的感染性神经退行性疾病，由细胞内的PrPC转变为病理亚型PrPSc而引起。鹿慢性消耗病(CWD)和牛疯牛病(BSE)是危害加拿大经济、生态以及动物和人类健康的一种动物普恩病毒病。慢性萎缩性胃病是传染性最强的普恩病毒疾病，影响自由放牧和饲养的鹿、麋鹿、驼鹿和驯鹿。加拿大的发病率和分布正在扩大，现在艾伯塔省猎鹿的发病率达到6%。CWD通过尿液、粪便和唾液大量排放到环境中，再加上多年的持久性，是CWD传播的驱动力。由于这种在野生动物中的有效水平传播和发生，疾病的控制极具挑战性。 我所在团队的主要研究问题是了解普里恩生物学，并将其用于开发治疗和预防反普鲁恩的策略。我们在这里的长期目标是开发CWD疫苗。免疫系统介导的针对普恩病毒疾病的方法的问题是，它们不会引发免疫反应，因为新产生的普恩病毒是自我蛋白质。我们的方法是独特的，因为它针对大脑外部的PrPC，使用易于聚集的重组PrP来克服自我耐受。这一策略导致产生与PrPC结合的自身抗体，干扰PrPC蛋白的转换。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可靠的概念验证，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到的体液和细胞免疫反应，而没有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中的工作将集中在Pron脱落上。我们的疫苗方法是否减少Pron的脱落是非常重要的问题，因为增加孵化时间但不减少脱落的方法将导致CWD在环境中的传染性全面增加。我们的单位已经开发出创新的PrP敲入小鼠，它可以有效地排出CWD普恩病毒，并且可以很好地被口服感染。我们将使用它们来评估疫苗接种对脱落的影响，使用超灵敏的普恩转换分析和共住作为读数。目标2中的工作将基于通过增加抗原稳定性可以克服耐受性的概念，解决如何优化疫苗设计。目标3将重点放在口服抗原传递上，使用纳米球共包裹免疫原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、记忆力和牛奶和体液中抗体的分泌问题。我们预计，该项目的工作将产生一些工具，从长远来看，这些工具有助于减少CWD的传播，降低加拿大人口的人畜共患病风险，并保护加拿大鹿群。