Development of sG as a human vaccine against Nipah/Hendra

开发 sG 作为针对尼帕/亨德拉的人类疫苗

• 批准号: 8268865
• 负责人: Antony S. Dimitrov
• 金额: $ 130.64万
• 依托单位: PROFECTUS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268865
• 关键词: Adjuvant; Adverse event; Aerosols; Agonist; Animal Model; Animals; Antigens; Area; Australia; Bangladesh; Biological; Biological Assay; Biological Products; Categories; Cell Line; Centers for Disease Control and Prevention (U.S.); Cercopithecus pygerythrus; Cessation of life; Characteristics; Clinical; Clinical Research; Clinical Trials; Consult; Cyclic GMP; Data; Development; Disease; Disease Outbreaks; Dose; Drug Formulations; Encephalitis; Environment; Equus caballus; Evaluation; Family; Fatality rate; Felis catus; Ferrets; Frequencies; Funding; Future; Hendra Virus; Henipavirus; Human; Immune response; Immunization; Immunology; India; Infection; Laboratories; Lead; Livestock; Lung diseases; Malaysia; Mammals; Marketing; Modeling; Morbidity - disease rate; Nipah Virus; Oryctolagus cuniculus; Outcome; Paramyxoviridae; Paramyxovirus; Persons; Phase; Preclinical Testing; Preparation; Process; Production; Proteins; Public Health; Qualifying; RNA Viruses; Reagent; Recombinants; Reporting; Research; Safety; Seeds; Specific qualifier value; Subunit Vaccines; Testing; Therapeutic; Toxicology; Tropism; United States National Institutes of Health; Vaccination; Vaccines; Viral; Virus; Virus Diseases; Zoonoses; aluminum sulfate; animal efficacy; attachment protein G; base; biothreat; cell bank; clinical lot; design; glycoprotein G; immunogenicity; improved; meetings; mortality; nonhuman primate; prevent; product development; prophylactic; research clinical testing; research study; transmission process

DESCRIPTION (provided by applicant): Nipah virus (NiV) and Hendra virus (HeV) are closely related viral zoonoses that form the genus Henipavirus in the family Paramyxoviridae. They are enveloped, negative-sense RNA viruses that cause a systemic and fatal disease in a variety of animal hosts and in humans. In some outbreaks, the death toll has reached as high as 75%. They are classified as biological safety level-4 (BSL4) viruses and possess several characteristics that justify their listing as Category C biothreat agents by the NIH and CDC including the ability to be transmitted via aerosol. There is currently no approved vaccine or therapeutic against either NiV or HeV. Annual outbreaks of NiV human infections in Bangladesh and other areas justify the benefit of a prophylactic vaccine for improving public health as well as reducing their potential as a biothreat. Immunization and challenge studies performed in cats, ferrets, and nonhuman primates using recombinant HeV soluble attachment protein G, HeV-sG, have demonstrated that a HeV-sG subunit vaccine can be completely effective against both HeV and NiV. In fact, HeV-sG subunit is currently being evaluated in Australia as an equine vaccine. Our objective here is to produce 1 gram of HeV-sG that will be suitable to perform IND-supportive toxicology and efficacy studies as necessary steps to support the evaluation of HeV-sG as a human vaccine against NiV and HeV. We will do so through the following specific aims: 1) Optimize HeV-sG immunogen/adjuvant formulation; 2) Identify release assays for HeV-sG; 3) Manufacture 1 g of HeV-sG; 4) Perform IND supportive animal studies. By the end of the funding period, we will have (i) identified an adjuvant suitable for further clinical development; ii) prepared a characterized research-grade "pre-seed" for use to manufacture a HeV-sG Master Cell Bank; (iii) optimized a development-scale process suitable for the manufacturing of cGMP clinical trial materials under future proposals; (iv) manufactured at least 1 g of development-grade vaccine to perform IND supportive toxicology and efficacy studies, and (v) executed said animal studies. Subsequent applications will pursue cGMP manufacture of 1) a master cell bank and 2) clinical lots of HeV-sG vaccine for Phase 1 clinical evaluation. PUBLIC HEALTH RELEVANCE: Nipah virus (NiV) and Hendra virus (HeV) are closely related viral zoonoses that are associated with significant morbidity and mortality in both animals and humans. Outbreaks of HeV and NiV lead to death in 75% of the cases. HeV and NiV can be easily grown to large amounts in cell lines under general laboratory conditions, and can be transmitted via aerosol justifying their listing as Category C biothreat agents by the NIH and CDC. There are currently no approved products that prevent or treat NiV or HeV infections. A recombinant subunit vaccine immunogen derived from the HeV attachment G glycoprotein has demonstrated complete protection in four different animal species, one of which is non-human primate. With this application we intend to perform IND-enabling preclinical testing for safety in rabbits and efficacy in ferrets and African green monkeys to support eventual phase 1 clinical evaluation in humans.

描述（由申请方提供）：尼帕病毒（NiV）和亨德拉病毒（HeV）是形成副粘病毒科亨帕病毒属的密切相关的病毒性人畜共患病。它们是有包膜的负义RNA病毒，在多种动物宿主和人类中引起全身性和致命性疾病。在一些疫情中，死亡人数已高达75%。它们被归类为生物安全4级（BSL 4）病毒，并具有几个特征，证明其被NIH和CDC列为C类生物威胁剂，包括通过气溶胶传播的能力。目前还没有针对NiV或HeV的批准的疫苗或治疗剂。孟加拉国和其他地区每年爆发的人类感染NiV的情况证明了预防性疫苗对改善公共卫生以及减少其作为生物威胁的潜力的好处。使用重组HeV可溶性附着蛋白G（HeV-sG）在猫、雪貂和非人灵长类动物中进行的免疫和攻击研究已经证明HeV-sG亚单位疫苗可以完全有效地对抗HeV和NiV。事实上，HeV-sG亚单位目前正在澳大利亚作为马疫苗进行评估。我们的目的是生产1 g HeV-sG，其将适合于进行IND支持性毒理学和有效性研究，作为支持HeV-sG作为抗NiV和HeV的人用疫苗的评价的必要步骤。我们将通过以下具体目标来实现：1）优化HeV-sG免疫原/佐剂制剂; 2）确定HeV-sG的放行试验; 3）生产1 g HeV-sG; 4）进行IND支持性动物研究。到资助期结束时，我们将（i）确定适合进一步临床开发的佐剂; ii）制备用于生产HeV-sG主细胞库的表征研究级“预种子”;（iii）优化适合生产未来提案中cGMP临床试验材料的开发规模工艺;（iv）制造至少Ig开发级疫苗以进行IND支持性毒理学和功效研究，以及（v）执行所述动物研究。后续申请将继续进行cGMP生产，1）主细胞库和2）临床批次的HeV-sG疫苗，用于1期临床评价。 公共卫生相关性：尼帕病毒（NiV）和亨德拉病毒（HeV）是密切相关的病毒性人畜共患病，与动物和人类的严重发病率和死亡率相关。HeV和NiV的爆发导致75%的病例死亡。HeV和NiV可以在一般实验室条件下容易地在细胞系中大量生长，并且可以通过气溶胶传播，从而证明它们被NIH和CDC列为C类生物威胁剂。目前还没有批准的产品可以预防或治疗NiV或HeV感染。来自HeV附着G糖蛋白的重组亚单位疫苗免疫原已经在四种不同的动物物种中表现出完全的保护作用，其中之一是非人灵长类动物。通过该申请，我们打算在家兔中进行IND使能临床前试验，以确定其安全性以及在雪貂和非洲绿色猴中的有效性，以支持最终的人体I期临床评价。