DNA prime / rVSV boost Multi-Antigen Universal Influenza Vaccine

摘要 如果有效地针对流感的保守区域，通用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 通常由DNA疫苗提供的加速产品开发和生产使其成为一种有吸引力的 开发这样一种通用流感疫苗的方法。不幸的是，对普遍流感的免疫反应 抗原通常很弱，早期对人类接种DNA疫苗的研究显示体液很差 免疫原性。然而，最近在疫苗递送和佐剂和病毒载体的使用方面的进展 改善了DNA疫苗接种的前景。克服障碍，开发出有效、实用和 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初始/病毒载体增强 疫苗方案，使用来自以下四种保守的甲型流感病毒的新免疫原 抗原：1)血凝素的干区(Stem)；2)基质2蛋白胞外区(M2e)；3) 核蛋白(NP)；以及4)基质1蛋白(M1)。我们的第一阶段结果表明，这些抗原加在一起 激发免疫广度和免疫反应类型，以针对广泛的 季节性和潜在的大流行流感病毒株并激发适当的抗病毒免疫反应 与这些流感病毒感染作斗争所必需的。我们的策略还使用了一种经过临床验证的DNA佐剂 这最大限度地提高了免疫原性，调整了对抗病毒Th1表型的反应，并提高了抗 病毒活动的体液免疫反应。在这个第二阶段的SBIR应用下，我们将测试一种病毒载体 增强DNA引发的免疫反应。我们还将确定我们的 在其他相关的临床前动物模型(雪貂和猕猴)中接种疫苗，并进行旨在 进一步定义疫苗的作用机制。 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