Preclinical development of a chimeric tetravalent dengue vaccine

描述（由申请人提供）：登革热病毒在世界热带地区流行，威胁着世界一半以上的人口。一种能够预防所有四种登革热病毒（DEN-1至DEN-4血清型）感染的疫苗是一项关键的全球卫生需求。减毒DEN-2病毒已被证明是安全、强效和有效的，在人体临床试验中产生持久的中和抗体反应。削弱病毒的突变已经被确定，并且位于DEN-2结构基因之外。该减毒病毒已被用作表达DEN-1、DEN-3和DEN-4结构基因的主干。每种“嵌合”病毒都具有原始DEN-2亲本的独特衰减标记，在动物模型中是安全有效的。将亲本减毒DEN-2病毒与三种嵌合病毒混合可产生一种四价疫苗，可诱导针对所有四种登革热血清型的免疫应答。我们建议完成这种独特疫苗的临床前开发。我们将产生和鉴定制造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。我们将在关键的登革热模型中测试最终配制的疫苗。我们将开发行业标准和独特的检测方法，以确保我们疫苗的安全性、特性和效力。最后，我们将生产足够数量的疫苗，以启动人体临床试验。为了实现这些目标，我们组建了一个由来自生物技术、学术界和政府机构的疫苗和登革热专家组成的国际联盟。为了促进向最需要的人提供这种疫苗，我们的独特合作包括一家在全球供应世卫组织批准的疫苗的印度制造商。开发一种负担得起、安全有效的登革热疫苗将保护那些生活在或前往亚洲、中美洲和南美洲、加勒比、太平洋岛屿以及非洲和澳大利亚部分地区的人。

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.