A Protective Tetravalent Vaccine Candidate for Dengue Fever Virus

登革热病毒的保护性四价候选疫苗

基本信息

批准号：
8832942
负责人：
ROBERT E. JOHNSTON
金额：
$ 53.28万
依托单位：
ALTRAVAX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-15 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8832942
关键词：
129/Sv Mouse Adjuvant Adolescent Adoption Adult Animal Model Antibodies Antibody Response Antigens Antiviral Therapy Arboviruses Attenuated Live Virus Vaccine Cells Cellular Immunity Centers for Disease Control and Prevention (U.S.)Clinical Trials Code Confidence Intervals Country Dengue Dengue Hemorrhagic Fever Dengue Shock Syndrome Dengue Virus Development Disease Drug Formulations E protein Economics Epitopes Fever Florida Genes Goals Hawaii Health Human Humoral Immunities Immune response Immunity Immunocompetent In Vitro Indigenous Individual Infant Infection Licensing Low income Maternal antibody Measures Mediating Mus Names Nonstructural Protein Palliative Care Particulate Persons Phase Placebos Population Proteins Puerto Rico Replicon Risk Schools Serotyping Serum Small Business Technology Transfer Research South Texas Staging System T cell response T-Lymphocyte Technology Testing Vaccinated Vaccination Vaccines Venezuelan Equine Encephalitis Virus Virion Virus Virus Diseases Work aluminum sulfate arm bone cohort congenic demographics economic cost immunogenicity improved in vivo mouse model neutralizing antibody novel pandemic disease particle pre-clinical preclinical study prevent protective efficacy research study response single molecule vaccine candidate vaccine development

项目摘要

DESCRIPTION (provided by applicant): There are approximately 390 million cases of dengue fever each year, with 2.5 billion people at risk, mostly in low income countries. There are four serotypes of dengue fever virus (DENV), and in its uncomplicated form, the disease is worthy of its indigenous name, "break-bone fever". An individual may suffer sequential infections with multiple DENV serotypes, and a second infection is associated with increased risk of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), a much more serious and potentially fatal disease. Altravax, Inc. (AVI), has developed a particulate, single molecule, tetravalent immunogen capable of inducing neutralizing antibodies directed against all four serotypes of DENV. Global Vaccines, Inc. (GVI), a not-for-profit vaccine company, has developed a novel adjuvant, which is not only capable of promoting neutralizing antibody responses induced by other DENV immunogens, but also catalyzing the induction of cell mediated immunity. As recent evidence suggests that both arms of the immune response contribute to protection against DENV, these two companies will collaborate to determine the effect of combining their respective technologies in an improved DENV vaccine. The AVI immunogen will be tested in two forms. First, the protein immunogen will be produced in 293F cells and purified. It then will be administered to 129/Sv mice, either alone, with the GVI adjuvant or with alum as a positive adjuvant control. In a second approach, the gene for the AVI immunogen will be cloned into a Venezuelan equine encephalitis virus replicon particle (VRP), and the VRP will be administered to 129/Sv mice for in vivo expression of the immunogen. These formulations will be evaluated for induction of neutralizing antibodies and T cells to each of the four DENV serotypes. The polyclonal sera also will be evaluated to determine whether the antibodies induced by the AVI tetravalent immunogen are directed to serotype specific neutralizing epitopes or to a neutralizing epitope(s) that is (are) conserved in each of the four serotypes. The best of the formulations will be used to immunize 129/Sv mice. Serum, T cells or a mixture of the two from the fully immunocompetent 129/Sv mice will be transferred to naïve AG129 mice, a congenic DENV sensitive mouse model, to assess the ability of the induced immune responses to protect against challenge with each of the four DENV serotypes. These experiments are the first to combine these two promising vaccine technologies, and represent an important step in the preclinical development of a safe DENV vaccine candidate which induces both protective humoral and cellular responses and is appropriately inexpensive for the majority of persons at risk.

描述（通过申请证明）：每年大约有3.9亿例登革热病例，有2.5 BITH 2.5个收入国家。发烧”。第二种感染与登革热大量发烧/登革热综合征（DHF/DSS）的风险增加有关，这是一种更严重且严重的致命疾病。诱导针对Denv。GlobalAglob疫苗的所有四种血清型的中和抗体的BLE。（GVI）是一家非供应疫苗公司，已经开发了一种新型佐剂，这不仅是促进抗体反应的ER DENV免疫原子，而且还可以催化细胞介导的免疫。免疫反应的臂有助于保护DENV，这两个公司将确定将其各自的技术组合起来的效果。然后将其纯化为129/SVITHER，将AVI免疫原将克隆到委内瑞拉马脑炎病毒复制品颗粒（VRP）中，并将VRP施用至129/SV小鼠，以用于免疫原体的体内exples。还将评估对四个DENV血清型中每一种的抗体和T细胞。血清型。用于免疫129/SV小鼠。在促疫苗的临床前开发中，该疫苗既可以诱导保护剂又有保护剂，并且对大多数处于危险中的人来说都是廉价的。