Ramanathan Mathura P, Kuo Yuan-Chia, Selling Bernard H, Li Qianjun, Sardesai Niranjan Y, Kim J Joseph, Weiner David B
VGX Pharmaceuticals, Inc., 450 Sentry Parkway, Blue Bell, PA 19422, United States.
Vaccine. 2009 Oct 30;27(46):6444-53. doi: 10.1016/j.vaccine.2009.06.061. Epub 2009 Jul 4.
The increased transmission and geographic spread of dengue fever (DF) and its most severe presentations, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), make it one of the most important mosquito-borne viral disease of humans. Four distinct serotypes of dengue viruses are transmitted to humans through the bites of the mosquitoes. Currently there is no vaccine or antiviral drug against DV infections. Cross-protection between dengue virus serotypes is limited and antibody dependent enhancement (ADE) contributes significantly to the severity of the disease. The major challenge is to induce a broad durable immune response against all four serotypes of dengue virus simultaneously while avoiding the possible exacerbation of risk of developing the severe forms of disease through incomplete or modified responses. In order to address this worldwide concern, we present a synthetic consensus (SynCon) human codon optimized DNA vaccine that elicits immunity against all four dengue serotypes. We cloned consensus DIII domain of E protein from all serotypes and expressed them as a single open reading frame in a mammalian expression vector, called pDV-U-DIII (dengue-vaccine universal). In mice, this dengue-universal construct elicits significant level of anti-DIII antibody that neutralizes all four dengue subtypes and prevents cell death induced by dengue infection. This is the first SynCon DNA vaccine that provides tetravalent immunity against all four serotypes of dengue virus.
登革热（DF）及其最严重的表现形式登革出血热（DHF）和登革休克综合征（DSS）的传播增加和地理扩散，使其成为人类最重要的蚊媒病毒疾病之一。四种不同血清型的登革病毒通过蚊子叮咬传播给人类。目前尚无针对登革病毒感染的疫苗或抗病毒药物。登革病毒血清型之间的交叉保护有限，抗体依赖性增强（ADE）对疾病的严重程度有显著影响。主要挑战是同时诱导针对所有四种登革病毒血清型的广泛持久免疫反应，同时避免因不完全或改变的反应而可能加剧发展为严重疾病形式的风险。为了解决这一全球关注的问题，我们提出了一种合成共识（SynCon）人密码子优化DNA疫苗，该疫苗可引发针对所有四种登革热血清型的免疫反应。我们从所有血清型中克隆了E蛋白的共识DIII结构域，并将它们作为一个单一的开放阅读框在一个哺乳动物表达载体中表达，称为pDV-U-DIII（登革热疫苗通用型）。在小鼠中，这种登革热通用构建体引发了显著水平的抗DIII抗体，该抗体可中和所有四种登革热亚型并防止登革热感染诱导的细胞死亡。这是第一种针对所有四种登革病毒血清型提供四价免疫的SynCon DNA疫苗。
