Sanofi Pasteur, Discovery US, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):13103-8. doi: 10.1073/pnas.1306245110. Epub 2013 Jul 15.
Tick-borne encephalitis (TBE) virus is the most important human pathogen transmitted by ticks in Eurasia. Inactivated vaccines are available but require multiple doses and frequent boosters to induce and maintain immunity. Thus far, the goal of developing a safe, live attenuated vaccine effective after a single dose has remained elusive. Here we used a replication-defective (single-cycle) flavivirus platform, RepliVax, to generate a safe, single-dose TBE vaccine. Several RepliVax-TBE candidates attenuated by a deletion in the capsid gene were constructed using different flavivirus backbones containing the envelope genes of TBE virus. RepliVax-TBE based on a West Nile virus backbone (RV-WN/TBE) grew more efficiently in helper cells than candidates based on Langat E5, TBE, and yellow fever 17D backbones, and was found to be highly immunogenic and efficacious in mice. Live chimeric yellow fever 17D/TBE, Dengue 2/TBE, and Langat E5/TBE candidates were also constructed but were found to be underattenuated. RV-WN/TBE was demonstrated to be highly immunogenic in Rhesus macaques after a single dose, inducing a significantly more durable humoral immune response compared with three doses of a licensed, adjuvanted human inactivated vaccine. Its immunogenicity was not significantly affected by preexisting immunity against WN. Immunized monkeys were protected from a stringent surrogate challenge. These results support the identification of a single-cycle TBE vaccine with a superior product profile to existing inactivated vaccines, which could lead to improved vaccine coverage and control of the disease.
蜱传脑炎（TBE）病毒是欧亚大陆蜱传播的最重要的人类病原体。已有的灭活疫苗虽然可用，但需要多次接种和频繁加强，以诱导和维持免疫。迄今为止，开发一种安全、单剂有效、减毒活疫苗的目标仍难以实现。在此，我们利用复制缺陷（单周期）黄病毒平台 RepliVax 来开发一种安全、单剂量 TBE 疫苗。使用不同的黄病毒骨架构建了几种缺失衣壳基因的 RepliVax-TBE 候选物，这些骨架包含 TBE 病毒的包膜基因。基于西尼罗河病毒骨架的 RepliVax-TBE（RV-WN/TBE）在辅助细胞中的生长效率高于基于 Langat E5、TBE 和黄热 17D 骨架的候选物，并且在小鼠中被发现具有高度的免疫原性和效力。还构建了活嵌合黄热 17D/TBE、登革热 2/TBE 和 Langat E5/TBE 候选物，但发现它们减毒不足。在恒河猴中，单剂 RV-WN/TBE 被证明具有高度的免疫原性，与三剂许可的、佐剂的人类灭活疫苗相比，诱导了更持久的体液免疫反应。WN 预先存在的免疫对其免疫原性没有显著影响。免疫的猴子受到严格的替代挑战的保护。这些结果支持了一种单周期 TBE 疫苗的鉴定，该疫苗具有优于现有灭活疫苗的产品特性，这可能会提高疫苗覆盖率并控制疾病。
