DNA prime / rVSV boost Multi-Antigen Universal Influenza Vaccine

DNA 初免 / rVSV 加强多抗原通用流感疫苗

基本信息

批准号：
9981388
负责人：
Kenneth C Bagley
金额：
$ 100万
依托单位：
ORLANCE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981388
关键词：
Adjuvant Animal Model Animals Antibodies Antibody Formation Antigens Antiviral Agents CD8-Positive T-Lymphocytes Clinical DNA DNA Vaccines DNA amplification Development Fc Receptor Ferrets Hemagglutinin Human Immune response Immunize Immunologics Individual Inflammatory Influenza Influenza A Virus, H5N1 Subtype Influenza A Virus, H7N9 Subtype Influenza A virus Interferon Type II Interleukin-12 Lung Macaca Mediating Mucous Membrane Mus Nucleoproteins Pathogenicity Phase Phenotype Population Pre-Clinical Model Production Proteins Publishing Reagent Recombinants Regimen Role Safety Small Business Innovation Research Grant T cell response T-Lymphocyte Subsets Testing Time Toxic effect Vaccinated Vaccination Vaccines Vesicular stomatitis Indiana virus Viral Pathogenesis Viral Physiology Viral Vector Virus Virus Diseases booster vaccine combat immunogenic immunogenicity improved nonhuman primate novel pandemic influenza pre-clinical product development protective effect protective efficacy response stem universal influenza vaccine vaccine delivery vector vector vaccine

项目摘要

Abstract A universal influenza vaccine is believed to be possible if conserved regions of influenza are effectively targeted and appropriate immune responses are generated against those targets. The enhanced safety, stability, and accelerated product development and production generally provided by DNA vaccination make it an appealing approach to develop such a universal influenza vaccine. Unfortunately, immune responses to universal influenza antigens are typically weak and earlier studies of DNA vaccination in humans showed poor humoral immunogenicity. However, recent advancements in vaccine delivery and use of adjuvants and viral vector boosts have improved the outlook of DNA vaccination. To overcome obstacles to developing an effective, practical, and truly universal influenza vaccine, we propose to further develop and test our DNA prime / viral-vectored boost vaccine regimen, which employs novel immunogens derived from the following four conserved influenza A antigens: 1) the stem region of hemagglutinin (Stem); 2) the matrix 2 protein ectodomain (M2e); 3) the nucleoprotein (NP); and 4) the matrix 1 protein (M1). Our phase I results indicate that together, these antigens evoke the immunological breadth and types of immune responses necessary to target a broad range of both seasonal and potential pandemic influenza strains and to evoke appropriate antiviral immune responses necessary to combat these influenza viral infections. Our strategy also uses a clinically proven DNA adjuvant that maximizes immunogenicity, tunes the responses toward an antiviral Th1 phenotype, and improves the anti- viral activities of the humoral immune response. Under this phase II SBIR application, we will test a viral-vectored boost for amplification of the DNA-raised immune responses. We will also determine the protective effects of our vaccine in other relevant preclinical animal models (ferrets and macaques) and perform studies intended to further define the vaccine's mechanisms of action. 3

抽象的如果有效地针对性地，普遍的流感疫苗被认为是可能的并针对这些目标产生适当的免疫反应。增强的安全性，稳定性和 DNA疫苗接种通常提供的加速产品开发和生产使其成为一种吸引人的开发这种普遍流感疫苗的方法。不幸的是，对普遍流感的免疫反应抗原通常很弱，对人类DNA疫苗接种的早期研究表现出较差的体液免疫原性。但是，疫苗输送和使用辅助和病毒载体的最新进展改善了DNA疫苗接种的前景。克服发展有效，实用和的障碍真正的通用流感疫苗，我们建议进一步开发和测试我们的DNA Prime / viral-vectored Boost 疫苗方案采用了以下四个保守流感A的新型免疫原样抗原：1）血凝素（茎）的茎区域； 2）基质2蛋白质域（M2E）; 3）核蛋白（NP）; 4）基质1蛋白（M1）。我们的第一阶段结果表明，这些抗原在一起唤起针对广泛的两者所需的免疫宽度和免疫反应的类型季节性和潜在的大流行性流感菌株，并引起适当的抗病毒免疫反应对抗这些流感病毒感染所必需的。我们的策略还使用临床证明的DNA辅助最大化免疫原性，调整对抗病毒TH1表型的反应，并改善抗病毒体液免疫反应的病毒活性。在此II阶段SBIR应用下，我们将测试一个病毒载体增强DNA提升的免疫反应的增强。我们还将确定我们的保护作用其他相关临床前动物模型（雪貂和猕猴）中的疫苗，并进行旨在的研究进一步定义了疫苗的作用机制。 3