Preclinical development of a chimeric tetravalent dengue vaccine

嵌合四价登革热疫苗的临床前开发

• 批准号: 7681592
• 负责人: Dan Thomas Stinchcomb
• 金额: $ 48.76万
• 依托单位: INVIRAGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-26 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681592
• 关键词: Academia; Adult; Adverse event; Africa; Amino Acids; Animal Model; Animals; Antibody Formation; Attenuated; Attenuated Live Virus Vaccine; Australia; Biological Assay; Biotechnology; Caribbean region; Cell Culture Techniques; Centers for Disease Control and Prevention (U.S.); Central Asia; Child; Chimera organism; Clinical; Clinical Trials; Collaborations; Complex; Country; Culicidae; Data; Dengue; Dengue Virus; Development; Dose; Drug Formulations; Ensure; Excipients; Functional RNA; Future; Genetic; Genetic screening method; Genome; Goals; Government; Health; Histopathology; Human; Immune response; Immunity; Immunization; Industry; Infection; Institution; International; Kinetics; Lead; Licensing; Life; Liquid substance; Macaca fascicularis; Manufactured Materials; Manufacturer Name; Measures; Modeling; Monitor; Monkeys; Mus; Mutation; Mycoplasma; Newborn Infant; Organ; Oryctolagus cuniculus; Pacific Islands; Parents; Phase; Phase I Clinical Trials; Polymers; Population; Positioning Attribute; Preparation; Principal Investigator; Procedures; Process; Property; Public Health; Qualifying; Quality Control; RNA; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Safety; Salts; Seeds; Serotyping; South America; Specialist; Staging; Sterility; Structural Genes; Techniques; Temperature; Testing; Thailand; Time; Toxic effect; Toxicity Tests; Transcript; Travel; Universities; Ursidae Family; Vaccines; Vero Cells; Vertebral column; Viral; Viremia; Virus; Work; assay development; attenuation; base; controlled release; immunogenic; immunogenicity; in vivo; meetings; mouse model; neurovirulence; neutralizing antibody; nonhuman primate; pre-clinical; preclinical evaluation; preclinical safety; programs; safety testing; sugar; vaccine candidate; vaccine delivery; vaccine development; vaccine efficacy; vaccine evaluation; vector

DESCRIPTION (provided by applicant): Dengue virus is endemic throughout tropical regions of the world and threatens over half of the world's population. A vaccine that can protect against infection by all four of the dengue viruses (serotypes DEN-1 through DEN-4) is a critical global health need. The attenuated DEN-2 virus has been shown to be safe, potent and effective, generating long-lasting neutralizing antibody responses in human clinical trials. The mutations that weaken the virus have been characterized and lie outside the DEN-2 structural genes. The attenuated virus has been used as a backbone to express the structural genes of DEN-1, DEN-3 and DEN-4. Each "chimeric" virus bears the distinctive attenuation markers of the original DEN-2 parent and is safe and effective in animal models. Mixing the parent attenuated DEN-2 virus with the three chimeric viruses generates a tetravalent vaccine that can induce immune responses against all four dengue serotypes. We propose to complete the preclinical development of this unique vaccine. We will generate and characterize viral seed stocks required for manufacture of the vaccine. We will undertake formulation studies to optimize the activity of the vaccine. We will test the final, formulated vaccine in critical dengue models. We will develop both industry standard and unique assays to assure the safety, identity and potency of our vaccine. Finally, we will manufacture sufficient quantities of the vaccine to initiate human clinical trials. To achieve these goals, we have formed an international consortium of vaccine and dengue specialists from biotechnology, academia, and government institutions. To facilitate delivery of this vaccine to those that need it most, our unique collaboration includes an Indian manufacturer that globally supplies WHO-approved vaccines. Development of an affordable, safe and effective dengue vaccine will protect those that live in or travel to Asia, Central and South America, the Caribbean, the Pacific Islands, and parts of Africa and Australia.

描述（由申请人提供）：登革热病毒在世界的热带地区是地方性的，并威胁到世界一半以上的人口。可以防止所有四种登革热病毒（血清型DEN-1至DEN-4）预防感染的疫苗是全球健康需求。已证明减毒的DEN-2病毒是安全，有效和有效的，在人类临床试验中产生了持久的中和抗体反应。削弱病毒的突变已被表征并位于DEN-2结构基因之外。衰减病毒已被用作表达DEN-1，DEN-3和DEN-4的结构基因的骨架。每种“嵌合”病毒都带有原始DEN-2父母的独特衰减标记，并且在动物模型中是安全有效的。将母体减弱的DEN-2病毒与三种嵌合病毒混合在一起会产生一种四含量的疫苗，可针对所有四种登革热血清型诱导免疫反应。我们建议完成这种独特的疫苗的临床前开发。我们将生成并表征生产疫苗所需的病毒种子库存。我们将进行配方研究以优化疫苗的活性。我们将在关键登革热模型中测试最终制定的疫苗。我们将开发行业标准和独特的测定法，以确保疫苗的安全性，身份和效力。最后，我们将生产足够数量的疫苗来启动人类临床试验。为了实现这些目标，我们成立了来自生物技术，学术界和政府机构的疫苗和登革热专家的国际财团。为了促进该疫苗向最需要的疫苗传递，我们独特的合作包括全球供应谁批准疫苗的印度制造商。负担得起，安全有效的登革热疫苗的开发将保护人们居住或前往亚洲，中部和南美，加勒比海，太平洋岛屿以及非洲和澳大利亚部分地区的人。

项目成果

Immunogenicity and efficacy of chimeric dengue vaccine (DENVax) formulations in interferon-deficient AG129 mice.

• DOI: 10.1016/j.vaccine.2011.11.072
• 发表时间: 2012-02-14
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Brewoo JN;Kinney RM;Powell TD;Arguello JJ;Silengo SJ;Partidos CD;Huang CY;Stinchcomb DT;Osorio JE
• 通讯作者: Osorio JE