Viral and Rickettsial Diseases Department, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Drive, Bethesda, MD 20817, USA.
Viral and Rickettsial Diseases Department, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
Vaccine. 2020 Apr 9;38(17):3313-3320. doi: 10.1016/j.vaccine.2020.03.008. Epub 2020 Mar 14.
Dengue fever, caused by dengue viruses (DENV 1-4) is a leading cause of illness and death in the tropics and subtropics. Therefore, an effective vaccine is urgently needed. Currently, the only available licensed dengue vaccine is a chimeric live attenuated vaccine that shows varying efficacy depending on serotype, age and baseline DENV serostatus. Accordingly, a dengue vaccine that is effective in seronegative adults, children of all ages and in immunocompromised individuals is still needed. We are currently researching the use of psoralen to develop an inactivated tetravalent dengue vaccine. Unlike traditional formalin inactivation, psoralen inactivates pathogens at the nucleic acid level, potentially preserving envelope protein epitopes important for protective anti-dengue immune responses. We prepared highly purified monovalent vaccine lots of formalin- and psoralen-inactivated DENV 1-4, using Capto DeVirS and Capto Core 700 resin based column chromatography. Tetravalent psoralen-inactivated vaccines (PsIV) and formalin-inactivated vaccines (FIV) were prepared by combining the four monovalent vaccines. Mice were immunized with either a low or high dose of PsIV or FIV to evaluate the immunogenicity of monovalent as well as tetravalent formulations of each inactivation method. In general, the monovalent and tetravalent PsIVs elicited equivalent or higher titers of neutralizing antibodies to DENV than the FIV dengue vaccines and this response was dose dependent. The immunogenicity of tetravalent dengue PsIVs and FIVs were also evaluated in nonhuman primates (NHPs). Consistent with what was observed in mice, significantly higher neutralizing antibody titers for each dengue serotype were observed in the NHPs vaccinated with the tetravalent dengue PsIV compared to those vaccinated with the tetravalent dengue FIV, indicative of the importance of envelope protein epitope preservation during psoralen inactivation of DENV.
登革热是由登革病毒（DENV1-4）引起的，是热带和亚热带地区发病和死亡的主要原因。因此，急需一种有效的疫苗。目前，唯一可用的许可登革热疫苗是一种嵌合减毒活疫苗，其效果因血清型、年龄和基线登革热血清状态而异。因此，仍然需要一种对血清阴性的成年人、所有年龄段的儿童和免疫功能低下的个体有效的登革热疫苗。我们目前正在研究使用补骨脂素开发一种灭活四价登革热疫苗。与传统的福尔马林灭活不同，补骨脂素在核酸水平上灭活病原体，可能保留对保护性抗登革热免疫反应至关重要的包膜蛋白表位。我们使用 Capto DeVirS 和 Capto Core 700 基于树脂的柱层析法，制备了高度纯化的单价疫苗。使用四价福尔马林和补骨脂素灭活的 DENV1-4 疫苗（PsIV 和 FIV）通过组合四种单价疫苗制备。用低或高剂量的 PsIV 或 FIV 免疫小鼠，以评估单价和每种灭活方法的四价制剂的免疫原性。一般来说，单价和四价 PsIV 比 FIV 登革热疫苗诱导产生更高滴度的中和抗体，且这种反应呈剂量依赖性。还在非人类灵长类动物（NHPs）中评估了四价登革热 PsIV 和 FIV 的免疫原性。与在小鼠中观察到的一致，接种四价登革热 PsIV 的 NHPs 对每种登革热血清型的中和抗体滴度明显高于接种四价登革热 FIV 的 NHPs，表明补骨脂素灭活 DENV 时包膜蛋白表位的保存非常重要。
