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: 8463115
• 负责人: Antony S. Dimitrov
• 金额: $ 99.07万
• 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/8463115
• 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.

描述（由申请人提供）：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，构成副粘病毒科亨尼帕病毒属。它们是包膜的负义RNA病毒，可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，死亡人数高达75%。它们被列为生物安全4级（BSL4）病毒，并具有一些特征，有理由将其列为国家卫生研究院和疾病预防控制中心的C类生物威胁剂，包括通过气溶胶传播的能力。目前尚无批准的针对NiV或HeV的疫苗或治疗方法。孟加拉国和其他地区每年爆发的NiV人间感染证明了预防性疫苗在改善公共卫生和减少其作为生物威胁的潜力方面的好处。利用重组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激发研究表明，HeV- sg亚单位疫苗可以完全有效地对抗HeV和NiV。事实上，HeV-sG亚基目前正在澳大利亚作为马疫苗进行评估。我们的目标是生产1克HeV- sg，用于开展支持ind的毒理学和功效研究，作为支持评估HeV- sg作为抗NiV和HeV的人用疫苗的必要步骤。我们将通过以下具体目标：1)优化HeV-sG免疫原/佐剂配方；2)确定HeV-sG的释放法；3)制造HeV-sG 1 g；4)开展IND支持性动物研究。在资助期结束时，我们将(i)确定适合进一步临床开发的佐剂；ii)制备表征的研究级“预种子”，用于制造HeV-sG主细胞库；（iii）优化了适合未来建议生产cGMP临床试验材料的开发规模工艺；（iv）生产至少1g开发级疫苗以进行IND支持毒理学和功效研究，以及(v)进行上述动物研究。随后的申请将寻求cGMP生产1)主细胞库和2)HeV-sG疫苗的临床批次，用于1期临床评估。