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Rational vaccine design through the use ofmolecular adjuvants

机译：通过使用分子佐剂进行合理的疫苗设计

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Nucleic acid immunization is an important vaccination strategy which delivers DNA constructs encoding for a specific immunogen into the host. These expression cassettes transfect the host cells, which become the in vivo protein source for the production of antigen. This antigen then is the focus of the resulting immune response. This vaccination technique is being explored as an immunization strategy against a variety of infectious diseases as well as cancer. The first generation DNA immunization experiments have shown that the DNA vaccines’ ability to elicit humoral and cellular responses in vivo in a safe and well-tolerated manner in various model systems, including humans. As we explore the next generation of DNA vaccines, our goal is to refine the current strategy to elicit more clinically efficacious immune responses. A more clinically effective vaccine may need to elicit a more specific immune response against the targeted pathogen. It would be a distinct advantage to design immunization strategies which can be “focused” according to the correlates of protection known for the particular pathogen.In order to focus the immune responses induced from DNA immunization, we have investigated the co-delivery of genes for immunologically important molecules, such as costimulatory molecules and cytokines which play critical regulatory and signaling roles in immunity. We and others have shown that the use of these molecular adjuvants could enhance and modulate immune responses induced by DNA immunogens. Co-administration of costimulatory molecules (CD80 and CD86), proinflammatory cytokines (IL-1 , TNF- , and TNF- ), Th1 cytokines (IL-2, IL-12, IL-15, and IL-18), Th2 cytokine (IL-4, IL-5 and IL-10), and GM-CSF with DNA vaccine constructs led to modulation of the magnitude and direction (humoral or cellular) of the immune responses. These studies demonstrate the potential utility of molecular adjuvant strategy as an important tool for the development of more rationally designed vaccines.
机译：核酸免疫是一种重要的疫苗接种策略，它将编码特定免疫原的DNA构建体传递到宿主中。这些表达盒转染宿主细胞，宿主细胞成为体内产生抗原的蛋白质来源。然后，该抗原是所得免疫反应的焦点。这种疫苗接种技术正在作为一种针对多种传染病和癌症的免疫策略进行探索。第一代DNA免疫实验表明，DNA疫苗能够在包括人类在内的各种模型系统中以安全且耐受良好的方式在体内引发体液和细胞反应。在探索下一代DNA疫苗时，我们的目标是完善当前策略，以引发更具临床效果的免疫反应。临床上更有效的疫苗可能需要引发针对靶病原体的更特异性的免疫反应。根据特定病原体已知的保护相关性设计可以“集中”的免疫策略将是一个明显的优势。为了集中DNA免疫诱导的免疫反应，我们研究了基因的共同传递具有免疫学意义的重要分子，例如共刺激分子和细胞因子，它们在免疫中起着关键的调节和信号传导作用。我们和其他人已经表明，使用这些分子佐剂可以增强和调节DNA免疫原诱导的免疫应答。共刺激分子（CD80和CD86），促炎细胞因子（IL-1，TNF-和TNF-），Th1细胞因子（IL-2，IL-12，IL-15和IL-18），Th2细胞因子的共同给药（IL-4，IL-5和IL-10），以及带有DNA疫苗构建体的GM-CSF导致免疫应答的大小和方向（体液或细胞）的调节。这些研究证明了分子佐剂策略作为开发更合理设计的疫苗的重要工具的潜在实用性。

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