Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
Cell Rep. 2021 May 11;35(6):109107. doi: 10.1016/j.celrep.2021.109107.
As vaccine-induced non-neutralizing antibodies may cause antibody-dependent enhancement of Zika virus (ZIKV) infection, we test a vaccine that induces only specific cytotoxic T lymphocytes (CTLs) without specific antibodies. We construct a DNA vaccine expressing a ubiquitinated and rearranged ZIKV non-structural protein 3 (NS3). The protein is immediately degraded and processed in the proteasome for presentation via major histocompatibility complex (MHC) class I for CTL generation. We immunize Ifnar1 adult mice with the ubiquitin/NS3 vaccine, impregnate them, and challenge them with ZIKV. Our data show that the vaccine greatly reduces viral titers in reproductive organs and other tissues of adult mice. All mice immunized with the vaccine survived after ZIKV challenge. The vaccine remarkably reduces placenta damage and levels of pro-inflammatory cytokines, and it fully protects fetuses from damage. CD8 CTLs are essential in protection, as demonstrated via depletion experiments. Our study provides a strategy to develop safe and effective vaccines against viral infections.
由于疫苗诱导的非中和抗体可能导致寨卡病毒（ZIKV）感染的抗体依赖性增强，我们测试了一种仅诱导特异性细胞毒性 T 淋巴细胞（CTL）而不诱导特异性抗体的疫苗。我们构建了一种表达泛素化和重排的寨卡病毒非结构蛋白 3（NS3）的 DNA 疫苗。该蛋白在蛋白酶体中立即降解并加工，通过主要组织相容性复合体（MHC）I 类呈递以产生 CTL。我们用泛素/NS3 疫苗免疫 Ifnar1 成年小鼠，使它们受孕，并用 ZIKV 对它们进行挑战。我们的数据表明，该疫苗大大降低了成年小鼠生殖器官和其他组织中的病毒滴度。所有接种疫苗的小鼠在 ZIKV 挑战后均存活。该疫苗显著减轻了胎盘损伤和促炎细胞因子的水平，并完全保护了胎儿免受损伤。通过耗竭实验证明，CD8 CTLs 是保护的关键。我们的研究为开发针对病毒感染的安全有效的疫苗提供了一种策略。
