DNA prime / rVSV boost Multi-Antigen Universal Influenza Vaccine

摘要 如果流感的保守区域被有效地靶向，则通用流感疫苗被认为是可能的 并产生针对这些靶标的适当免疫应答。增强的安全性、稳定性和 通常由DNA疫苗接种提供的加速的产品开发和生产使其成为一种有吸引力的 这是一种开发通用流感疫苗的方法。不幸的是，对普遍性流感的免疫反应 抗原通常是弱的，早期的人类DNA疫苗研究显示， 免疫原性然而，最近在疫苗输送和佐剂及病毒载体的使用方面的进展 改善了DNA疫苗的前景。克服障碍，制定一个有效的，实用的， 真正通用的流感疫苗，我们建议进一步开发和测试我们的DNA初免/病毒载体加强 疫苗方案，其采用源自以下四种保守的甲型流感病毒的新型免疫原 抗原：1）血凝素的干区（Stem）; 2）基质2蛋白胞外域（M2 e）; 3）血凝素的胞外域（M2 e）。 核蛋白（NP）;和4）基质1蛋白（M1）。我们的第一阶段结果表明，这些抗原 激发免疫学的广度和类型的免疫反应，需要靶向广泛的 季节性和潜在的大流行性流感毒株，并引起适当的抗病毒免疫应答 对抗这些流感病毒感染所必需的。我们的策略还使用了临床证明的DNA佐剂 使免疫原性最大化，调整对抗病毒Th 1表型的应答，并提高抗- 体液免疫反应的病毒活动。在第二阶段SBIR应用中，我们将测试一个病毒载体 增强DNA引起的免疫反应的扩增。我们还将确定我们的保护作用， 在其他相关临床前动物模型（雪貂和猕猴）中接种疫苗，并进行旨在 进一步确定疫苗的作用机制。 3

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