DNA Prime / Subunit 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使其成为一种吸引人的方法， 研制出一种通用的流感疫苗。不幸的是，对通用流感抗原的免疫反应 在过去，人类的DNA疫苗接种一直令人失望。为了克服这些和 开发有效、实用和真正通用的流感疫苗的其他障碍，我们打算提供 我们的疫苗使用DNA初免/蛋白质加强方案，并采用源自以下的新免疫原 三种保守的甲型流感抗原：1）血凝素（HA）的干区; 2）基质2蛋白 胞外域（M2 e）;和，3）核蛋白（NP）。我们相信，这些抗原将共同唤起 免疫广度是预防季节性和潜在大流行所必需 流感病毒株我们还将使用一种有效的DNA佐剂组合，以最大限度地提高免疫原性， 对Th 1表型的反应。最后，我们将利用重组蛋白加强，以扩大体液 免疫反应，并增加其耐久性。在第一阶段SBIR中，我们将构建和表达我们的流感病毒， 一种免疫原，并验证其免疫原性和小鼠保护效力，以确定疫苗是否 提供了广泛的保护，免受不同的季节性和大流行性甲型流感病毒株。如果我们 在第一阶段的概念验证研究中取得成功后，我们将继续在猕猴挑战中测试我们的疫苗 该模型处于II期申请阶段，并开始开发B型流感疫苗，可能还有C型流感疫苗。

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 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 in the past, DNA vaccination of humans has been disappointing. To overcome these and other obstacles to developing an effective, practical, and truly universal influenza vaccine, we intend to deliver our vaccine using a DNA prime / protein boost regimen and employ novel immunogens derived from the following three conserved influenza A antigens: 1) the stem region of hemagglutinin (HA); 2) the matrix 2 protein ectodomain (M2e); and, 3) the nucleoprotein (NP). We believe that together, these antigens will evoke the immunological breadth necessary to protect against a broad range of both seasonal and potential pandemic influenza strains. We will also use a potent DNA adjuvant combination to maximize immunogenicity and to tune the responses toward a Th1 phenotype. Finally, we will utilize a recombinant protein boost to amplify the humoral immune responses and increase their durability. In this Phase I SBIR, we will construct and express our influenza A immunogens and verify their immunogenicity and protective efficacy in mice to determine if the vaccine provides a wide breadth of protection from divergent seasonal and pandemic influenza A strains. If we are successful in this Phase I proof-of-concept study, we will move on to test our vaccine in a macaque challenge model under a Phase II application and begin development on influenza B, and possibly type C, immunogens.