Hou Jue, Shrivastava Shubham, Loo Hooi Linn, Wong Lan Hiong, Ooi Eng Eong, Chen Jianzhu
Interdisciplinary Research Group in Infectious Diseases, Singapore-MIT Alliance for Research and Technology (SMART), Singapore, Singapore.
Emerging Infectious Diseases Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
NPJ Vaccines. 2020 Jul 24;5(1):68. doi: 10.1038/s41541-020-00216-0. eCollection 2020.
A major challenge in dengue vaccine development is the need to induce immunity against four dengue (DENV) serotypes. Dengvaxia®, the only licensed dengue vaccine, consists of four variant dengue antigens, one for each serotype. Three doses of immunization with the tetravalent vaccine induced only suboptimal protection against DENV1 and DENV2. Furthermore, vaccination paradoxically and adversely primes dengue naïve subjects to more severe dengue. Here, we have tested whether sequential immunization induces stronger and broader immunity against four DENV serotypes than tetravalent-formulated immunization. Mice were immunized with four DNA plasmids, each encoding the pre-membrane and envelope from one DENV serotype, either sequentially or simultaneously. The sequential immunization induced significantly higher levels of interferon (IFN)γ- or tumor necrosis factor (TNF)α-expressing CD4 and CD8 T cells to both serotype-specific and conserved epitopes than tetravalent immunization. Moreover, sequential immunization induced higher levels of neutralizing antibodies to all four DENV serotypes than tetravalent vaccination. Consistently, sequential immunization resulted in more diversified immunoglobulin repertoire, including increased complementarity determining region 3 (CDR3) length and more robust germinal center reactions. These results show that sequential immunization offers a simple approach to potentially overcome the current challenges encountered with tetravalent-formulated dengue vaccines.
登革热疫苗研发中的一个主要挑战是需要诱导针对四种登革热（DENV）血清型的免疫。唯一获得许可的登革热疫苗Dengvaxia®由四种变异的登革热抗原组成，每种血清型一种。用四价疫苗进行三剂免疫仅诱导了对DENV1和DENV2的次优保护。此外，疫苗接种反常地且不利地使初次感染登革热的受试者更容易患上更严重的登革热。在此，我们测试了序贯免疫是否比四价配方免疫诱导更强、更广泛的针对四种DENV血清型的免疫。用四种DNA质粒免疫小鼠，每种质粒编码一种DENV血清型的前膜和包膜，采用序贯或同时免疫的方式。与四价免疫相比，序贯免疫诱导表达干扰素（IFN）γ或肿瘤坏死因子（TNF）α的CD4和CD8 T细胞针对血清型特异性和保守表位的水平显著更高。此外，序贯免疫诱导针对所有四种DENV血清型的中和抗体水平高于四价疫苗接种。一致地，序贯免疫导致免疫球蛋白库更加多样化，包括互补决定区3（CDR3）长度增加和生发中心反应更强。这些结果表明，序贯免疫提供了一种简单的方法，有可能克服目前四价配方登革热疫苗所面临的挑战。
