Novel vaccine against Norovirus

针对诺如病毒的新型疫苗

• 批准号: 7941404
• 负责人: Xi Jiang
• 金额: $ 94.2万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941404
• 关键词: Acute; Address; Adjuvant; Affect; Age; Animal Model; Antigenic Variation; Antigens; Biological Assay; Bioreactors; Blood Group Antigens; Calicivirus; Capsid Proteins; Categories; Cell Culture System; Cell Culture Techniques; Chemicals; Clinical Trials; Consensus; Data; Developing Countries; Development; Disease; Disinfectants; Dose; Epitopes; Escherichia coli; Evaluation; Evolution; Family suidae; Fermentation; Food; Future; Gastroenteritis; Genetic; Genotype; Gnotobiotic; Human; Human Volunteers; Immunity; Immunization; Immunology; In Vitro; Infection; Institutes; Laboratories; Lead; Macaca mulatta; Medical center; Methods; Modeling; Molecular Virology; Monkeys; Mus; National Institute of Allergy and Infectious Disease; Nature; Norovirus; Pediatric Hospitals; Pharmacologic Substance; Phase I Clinical Trials; Physics; Principal Investigator; Procedures; Production; Property; Regimen; Research; Resistance; Resources; Route; Safety; Serotyping; Staging; Subunit Vaccines; Talents; Testing; Toxicology; Trefoil Motif; Universities; Vaccination; Vaccines; Viral; Virginia; Virus; Water; Yeasts; base; biodefense; burden of illness; commercialization; design; immunogenic; immunogenicity; innovation; meetings; novel vaccines; particle; pathogen; product development; programs; receptor; receptor binding; response; scale up; vaccine candidate; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): The Cincinnati Children's Hospital Medical Center (CCHMC), the Virginia Polytechnic Institute and State University (the Virginia Tech), and the LigoCyte Pharmaceuticals Inc. will team together for this application in response to RFA-AI-09-027, entitled "Partnerships for Biodefense Food- and Water-borne Diseases (R01). We propose to develop a vaccine against noroviruses (NVs), one of the NIAID Category B food- and water-borne priority pathogens, based on our newly discovered subviral particle, the P particle, of NVs. This P particle is spontaneously formed by 24 copies of the protrusion (P) domain of the viral capsid protein, in octahedral symmetry, with an authentic host receptor binding property, highly immunogenic, easily to produce in E. coli and yeast with extremely high yields and simple procedures for purification, and highly stable under a wide range of physic-chemical conditions, making it an excellent subunit vaccine for mucosal immunization. Four projects representing different early-to-middle product development stages will be performed to evaluate the P particle vaccine. In stage 1 we will perform in vitro and mouse immunization studies and compare different vaccination regimens of P particles by different routes with/without an adjuvant for a maximal safety and efficacy. We also will perform similar studies for proof-of-concept of the usefulness of P particle vaccine using the cell culture model of a newly discovered monkey calicivirus, the Tulane virus. In stage 2 we will characterize the antigenic variations of NVs representing different genotypes of NVs for developing a broadly reactive vaccine based on defined antigenic types (serotypes) with a cocktail or consensus vaccine approach. We also will perform genetic and antigenic analysis of the currently dominant GII-4 viruses to address a question about epochal evolution of NVs for future vaccine strategy against NVs. In stage 3 we will further characterize the safety, immunogenicity and broadness of the candidate vaccine in protection against various NVs using the gnotobiotic (Gn) pig challenge model of human NVs developed in our laboratories recently. In the last stage we will develop a fermentation bioreactor for scale up production of P particles for future evaluation of the vaccine by human volunteer challenge studies and clinical trials. NVs are genetically diverse and there is no suitable cell culture for NVs. Our cocktail/consensus vaccine approach and the procedures for evaluation of the vaccine by the surrogate "neutralization" assay and using the newly discovered Tulane virus and the Gn pig model are highly innovative. We are confident that a panel of lead candidates (vaccine strains) will be selected ready for future clinical trials by the conclusion of the studies in this application. Narrative/Relevance: Noroviruses (NVs) are an important cause of acute gastroenteritis, affecting people of all ages, in both developed and developing countries. The wide spread nature of NVs due to the low infection dose and the high stability and resistance to disinfectants makes NVs an easy agent for bioterrorist attack. In this study we propose to develop a vaccine against NVs based on our newly discovered subviral particle, the P particle, of NVs. This P particle is spontaneously formed by 24 copies of the protrusion (P) domain of the viral capsid protein, with an authentic host receptor binding property, highly immunogenic, ease to produce in E. coli and yeast with extremely high yields and simple procedures for purification. It is highly stable under a wide range of physic-chemical conditions making it an excellent subunit vaccine for mucosal immunization. NVs have been known to cause a brief protective immunity following a natural infection. In this study we will perform mouse immunization studies with different vaccination regimens and immunization routes of the P particle vaccine for the maximal efficacy and safety. NVs are also genetically diverse but our recent data showed that the receptor binding interfaces of NVs are highly conserved due to a convergent evolution selected by the human histo-blood group antigens. We will perform antigenic characterization of NVs representing different genotypes to design a cocktail/consensus vaccine based on defined antigenic types ("serotypes") using a surrogate neutralization assay (receptor blocking assay). NVs remain difficult to cultivate in vitro. We will take advantage of the cell culture system of our newly discovered rhesus monkey calicivirus, the Tulane virus, and the gnotobiotic (Gn) pig model of human NVs to prove concept and to further evaluate usefulness of the vaccine for future development in clinical trials. This project will be conducted by a research team with multidiscipline experts in molecular virology, immunology, vaccine development at the Cincinnati Children's Hospital Medical Center (CCHMC), the Virginia Polytechnic Institute and State University (Virginia Tech) and the LigoCyte Pharmaceuticals Inc. Our highly innovative approach of the unique P particles and the cocktail/consensus vaccine and the novel procedures for evaluation of the vaccine by the surrogate "neutralization" assay and using the newly discovered Tulane virus and the Gn pig model warrant that we will make a rapid progress leading to the next level of evaluation by the phase I clinical trials toward future commercialization.

描述(由申请人提供)：辛辛那提儿童医院医疗中心(CCHMC)、弗吉尼亚理工学院和州立大学(弗吉尼亚理工学院)和LigoCyte制药公司将联手申请这一申请，以响应RFA-AI-09-027，题为“生物防御食品和水传播疾病的伙伴关系(R01)”。我们建议开发一种针对诺如病毒(NVS)的疫苗，NVS是NIAID B类食物和水传播的优先病原体之一，基于我们新发现的NVS亚病毒颗粒，P颗粒。这种P颗粒由24个拷贝的病毒衣壳蛋白突起(P)结构域自发形成，呈八面体对称，具有真实的宿主受体结合性质，具有高度的免疫原性，易于在大肠杆菌和酵母中生产，产量极高，纯化步骤简单，在广泛的物理化学条件下高度稳定，使其成为一种优秀的粘膜免疫亚单位疫苗。将执行代表不同早中期产品开发阶段的四个项目来评估P颗粒疫苗。在第一阶段，我们将进行体外和小鼠免疫研究，并比较不同途径接种P颗粒的不同途径，是否有佐剂，以获得最大的安全性和有效性。我们还将使用一种新发现的猴子杯状病毒杜兰病毒的细胞培养模型进行类似的概念验证P粒子疫苗的有效性的研究。在第二阶段，我们将表征代表不同基因类型的NV的抗原变异，以鸡尾酒或共识疫苗方法开发基于定义的抗原类型(血清型)的广泛反应疫苗。我们还将对目前占主导地位的GII-4病毒进行遗传和抗原性分析，以解决有关新城疫病毒的划时代进化的问题，为未来针对新城疫病毒的疫苗战略提供参考。在第三阶段，我们将利用我们实验室最近建立的人新城疫的Gn-Biotic(Gn)猪攻击模型，进一步表征候选疫苗在预防各种新城疫方面的安全性、免疫原性和广泛性。在最后阶段，我们将开发一种发酵生物反应器，用于扩大P颗粒的生产，以供未来通过人类志愿者挑战研究和临床试验对疫苗进行评估。NV在基因上是多样化的，目前还没有适合NV的细胞培养。我们的鸡尾酒/共识疫苗方法和通过替代“中和”试验以及使用新发现的杜兰病毒和Gn猪模型对疫苗进行评估的程序具有很高的创新性。我们相信，在这项应用的研究结束后，将选出一组主要候选者(疫苗株)，为未来的临床试验做好准备。 叙述/相关性：诺如病毒(NV)是急性胃肠炎的一个重要原因，在发达国家和发展中国家影响所有年龄段的人。由于新城疫病毒的低感染剂量和高稳定性以及对消毒剂的抵抗力而具有广泛的传播特性，使得新城疫病毒很容易成为生物恐怖袭击的媒介。在这项研究中，我们建议开发一种基于我们新发现的NVS亚病毒颗粒--NVS的P颗粒--的疫苗。这种P颗粒是由24个拷贝的病毒衣壳蛋白的突起(P)结构域自发形成的，具有真实的宿主受体结合特性，具有高度的免疫原性，易于在大肠杆菌和酵母中生产，产量极高，纯化步骤简单。它在广泛的物理化学条件下高度稳定，是一种优秀的粘膜免疫亚单位疫苗。已知NVS在自然感染后会引起短暂的保护性免疫。在本研究中，我们将对P颗粒疫苗的不同接种方案和免疫途径进行小鼠免疫研究，以求获得最大的效果和安全性。NV在遗传上也是多样化的，但我们最近的数据表明，由于人类组织血型抗原选择的趋同进化，NV的受体结合界面是高度保守的。我们将对代表不同基因类型的NV进行抗原性鉴定，以使用代理中和试验(受体阻断试验)根据已定义的抗原类型(“血清型”)设计鸡尾酒/共识疫苗。NVS的体外培养仍然很困难。我们将利用我们新发现的恒河猴杯状病毒、杜兰病毒和人类新城疫的Gn生物(Gn)猪模型的细胞培养系统来验证疫苗的概念，并进一步评估疫苗在未来临床试验中的有效性。该项目将由辛辛那提儿童医院医学中心(CCHMC)、弗吉尼亚理工学院和州立大学(弗吉尼亚理工大学)和LigoCyte制药公司的多学科专家组成的研究团队进行。我们独特的P颗粒和鸡尾酒/共识疫苗的高度创新方法，以及通过代理“中和”分析和使用新发现的杜兰病毒和Gn PIG模型对疫苗进行评估的新程序，保证我们将取得快速进展，从而通过I阶段临床试验进入下一级别的评估，以实现未来的商业化。