TESTING A NOVEL APPROACH TOWARD A MULTIVALENT CHIKUNGUNYA/DENGUE VACCINE

 描述（由申请人提供）：由蚊子传播的两种病毒持续传播，导致严重的人类疾病，导致广泛的发病率和死亡率，这是一个重大的公共卫生问题。这些病毒是基孔肯雅病毒（CHIKV，一种甲病毒）和登革热病毒（DENV，一种黄病毒）。这些病毒由相同的蚊子传播，现在在旧世界和新世界广泛传播。目前还没有疫苗可用于预防DENV或CHIKV感染。我们已经开发了一种嵌合的减毒活疫苗载体，该载体基于缺失其表面糖蛋白基因（G）的缺陷型水泡性口炎病毒（VSV），并且代之以表达CHIKV包膜蛋白。这种VSVΔG-CHIKV载体可以在组织培养物中容易地生长并诱导高水平的CHIKV中和抗体。它还提供单剂量保护免受CHIKV感染，但缺乏所有致病性，包括神经毒性。该项目的目标是测试表达来自所有四种DENV血清型的适当抗原的该载体的免疫原性和安全性，以确定其是否可能是针对CHIKV和所有四种DENV血清型的候选多价疫苗。基于减毒活病毒的疫苗载体通常非常有效，但在临床试验之前还需要进行广泛的安全性测试。因此，如果可以开发用于CHIKV和DENV两者的单一安全且有效的活疫苗载体，则将极大地简化监管批准和临床试验过程。 这也将有助于限制在两种病毒都在传播的地区生活或工作的人所需的疫苗接种数量。

 DESCRIPTION (provided by applicant): There is major public health concern about the continuing spread of two viruses transmitted by mosquitoes that cause serious human diseases leading to extensive morbidity and mortality. These viruses are chikungunya virus (CHIKV, an alphavirus) and dengue virus (DENV, a flavivirus). These viruses are transmitted by the same mosquito vectors and are now co-circulating extensively in both the old and new worlds. There are currently no vaccines available to protect against either DENV or CHIKV infection. We have developed a chimeric, live attenuated vaccine vector based on a defective vesicular stomatitis virus (VSV) deleted for its surface glycoprotein gene (G), and instead expressing the CHIKV envelope proteins. This VSVΔG-CHIKV vector can be grown readily in tissue culture and induces high levels of CHIKV neutralizing antibodies. It also provides single-dose protection from CHIKV infection but lacks all pathogenicity including neurotoxicity. The goal of this project is to test the immunogenicity and safety of this vector expressing appropriate antigens from all four DENV serotypes to determine if it might be a candidate multivalent vaccine protecting against both CHIKV and all four DENV serotypes. Vaccine vectors based on live attenuated viruses are typically highly effective, but they also require extensive safety testing prior to clinical trials. Thus if a single safe and effective live vaccine vector for both CHIKV and DENV could be developed, it would greatly simplify the regulatory approval and clinical trial processes. It would also help limit the number of vaccinations required for people living or working in areas where both viruses are circulating.