Mucosal Vaccination Against Dengue Virus Infection

描述(申请人提供)：登革热病毒(DENV)引起登革热(DF)和登革出血热/登革休克综合征(DHF/DSS)，这是全球人类最常见的蚊媒病毒疾病。研究表明，在继发性DENV感染期间，DENV特异性抗体的亚中和浓度可能通过一种称为“抗体依赖增强(ADE)”的现象促进病毒复制和疾病严重程度。然而，由于缺乏合适的动物模型，ADE诱导的登革热的细胞和分子基础尚不清楚，DENV候选疫苗的安全性也不能完全评估。我们最近开发了一种ADE诱导的DENV疾病的小鼠模型，从而使我们能够开发和评估可能预防ADE的新DENV疫苗的安全性和有效性。在此，我们建议开发一种针对M细胞的新型DENV特异性黏膜疫苗候选方案，并验证黏膜免疫预防ADE诱导的严重DENV疾病，并提供比皮下免疫更好的预防DENV感染的假设。两个具体目标如下。首先，我们将确定粘膜疫苗接种是否对同源或异种DENV感染具有保护作用(目标1)。第二，我们将研究粘膜疫苗接种是否能预防DENV感染和疾病的ADE(目标2)。这些研究的完成将阐明抗DENV抗体反应的特征，从而产生对ADE的保护作用，并导致开发一种比传统非肠道疫苗更容易管理的新型有效疫苗。

DESCRIPTION (provided by applicant): Dengue virus (DENV) causes dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), the most prevalent mosquito-borne viral illnesses in humans worldwide. Studies suggest that sub-neutralizing concentrations of DENV-specific antibodies may contribute to viral replication and disease severity during secondary DENV infections via a phenomenon known as "antibody-dependent-enhancement (ADE)." However, due to the lack of an adequate animal model, the cellular and molecular bases of ADE- induced dengue disease are poorly understood, and the safety of DENV vaccine candidates cannot be fully evaluated. We have recently developed a mouse model of ADE-induced DENV disease, thereby allowing us to develop and evaluate the safety and efficacy of new DENV vaccines that are likely to prevent ADE. Herein, we propose to develop a novel DENV-specific mucosal vaccine candidate that targets M cells and test the hypothesis that mucosal immunization prevents ADE-induced severe DENV disease and affords better protection against DENV infections than subcutaneous immunization. The two specific aims are as follows. First, we will determine whether mucosal vaccination protects against homologous or heterologous DENV infection (Aim 1). Second, we will examine whether mucosal vaccination prevents ADE of DENV infection and disease (Aim 2). Completion of these studies should elucidate the feature of the anti-DENV antibody response that results in protection versus ADE and lead to the development a novel, effective vaccine that is easier to administer than conventional parenteral vaccines.