Battelle Memorial Institute, Columbus, OH, United States.
Bavarian Nordic GmbH, Martinsried, Germany.
Front Immunol. 2021 Jan 19;11:598847. doi: 10.3389/fimmu.2020.598847. eCollection 2020.
Venezuelan, eastern and western equine encephalitis viruses (EEV) can cause severe disease of the central nervous system in humans, potentially leading to permanent damage or death. Yet, no licensed vaccine for human use is available to protect against these mosquito-borne pathogens, which can be aerosolized and therefore pose a bioterror threat in addition to the risk of natural outbreaks. Using the mouse aerosol challenge model, we evaluated the immunogenicity and efficacy of EEV vaccines that are based on the modified vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccine platform: three monovalent vaccines expressing the envelope polyproteins E3-E2-6K-E1 of the respective EEV virus, a mixture of these three monovalent EEV vaccines (Triple-Mix) as a first approach to generate a multivalent vaccine, and a true multivalent alphavirus vaccine (MVA-WEV, Trivalent) encoding the polyproteins of all three EEVs in a single non-replicating MVA viral vector. BALB/c mice were vaccinated twice in a four-week interval and samples were assessed for humoral and cellular immunogenicity. Two weeks after the second immunization, animals were exposed to aerosolized EEV. The majority of vaccinated animals exhibited VEEV, WEEV, and EEEV neutralizing antibodies two weeks post-second administration, whereby the average VEEV neutralizing antibodies induced by the monovalent and Trivalent vaccine were significantly higher compared to the Triple-Mix vaccine. The same statistical difference was observed for VEEV E1 specific T cell responses. However, all vaccinated mice developed comparable interferon gamma T cell responses to the VEEV E2 peptide pools. Complete protective efficacy as evaluated by the prevention of mortality and morbidity, lack of clinical signs and viremia, was demonstrated for the respective monovalent MVA-EEV vaccines, the Triple-Mix and the Trivalent single vector vaccine not only in the homologous VEEV Trinidad Donkey challenge model, but also against heterologous VEEV INH-9813, WEEV Fleming, and EEEV V105-00210 inhalational exposures. These EEV vaccines, based on the safe MVA vector platform, therefore represent promising human vaccine candidates. The trivalent MVA-WEV construct, which encodes antigens of all three EEVs in a single vector and can potentially protect against all three encephalitic viruses, is currently being evaluated in a human Phase 1 trial.
委内瑞拉东部马脑炎病毒、委内瑞拉西部马脑炎病毒和西部马脑炎病毒(EEV)可引起人类中枢神经系统严重疾病,可能导致永久性损伤或死亡。然而,目前尚无可用的人类用许可疫苗来预防这些通过蚊子传播的病原体,这些病原体可以气溶胶化,因此除了自然爆发的风险外,还构成生物恐怖威胁。我们使用小鼠气溶胶挑战模型评估了基于改良安卡拉牛痘病毒-巴伐利亚北欧株(MVA-BN)疫苗平台的 EEV 疫苗的免疫原性和功效:三种单价疫苗分别表达相应 EEV 病毒的包膜多蛋白 E3-E2-6K-E1,三种单价 EEV 疫苗的混合物(Triple-Mix)作为产生多价疫苗的初步方法,以及真正的多价甲病毒疫苗(MVA-WEV,三价)在单个非复制的 MVA 病毒载体中编码三种 EEV 的多蛋白。BALB/c 小鼠在四周间隔内进行两次接种,并评估体液和细胞免疫原性。第二次免疫后两周,动物暴露于气溶胶化的 EEV。大多数接种疫苗的动物在第二次给药后两周内表现出 VEEV、WEEV 和 EEEV 中和抗体,其中单价和三价疫苗诱导的 VEEV 中和抗体明显高于 Triple-Mix 疫苗。对于 VEEV E1 特异性 T 细胞反应也观察到了相同的统计学差异。然而,所有接种疫苗的小鼠对 VEEV E2 肽池产生了可比的干扰素γ T 细胞反应。在同源 VEEV Trinidad Donkey 挑战模型中,以及针对异源 VEEV INH-9813、WEEV Fleming 和 EEEV V105-00210 吸入暴露,分别通过预防死亡率和发病率、缺乏临床症状和病毒血症来评估完全保护效力,证明单价 MVA-EEV 疫苗、Triple-Mix 和三价单载体疫苗具有保护作用。这些基于安全的 MVA 载体平台的 EEV 疫苗因此代表了有前途的人类候选疫苗。三价 MVA-WEV 构建体,其在单个载体中编码三种 EEV 的抗原,并且有潜力预防所有三种脑炎病毒,目前正在一项人类 I 期临床试验中进行评估。
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