Star-oddi传感器应用一种安全的昆虫源基登热疫苗在食蟹猴中可提供快速且持久的保护
Abstract
Eilat (EILV)/chikungunya virus (CHIKV), an insect-based chimeric alphavirus was previously reported to protect mice months after a single dose vaccination. The underlying mechanisms of host protection are not clearly defined. Here, we assessed the capacity of EILV/CHIKV to induce quick and durable protection in cynomolgus macaques. Both EILV/CHIKV and the live attenuated CHIKV 181/25 vaccine protected macaques from wild-type (WT) CHIKV infection 1 year after a single dose vaccination. Transcriptome and functional analyses reveal that EILV/CHIKV triggered T cell, memory B cell and antibody responses in a dose-dependent manner. EILV/CHIKV induced more robust, durable, and broader repertoire of CHIKV-specific T cell responses than CHIKV 181/25; whereas the latter group induced more durable memory B cells and comparable or higher CHIKV -specific neutralization and binding antibodies. EILV/CHIKV and an inactivated WT CHIKV protected macaques from WT CHIKV infection and CHIK fever (CHIKF) within 6 days post vaccination. Transcriptome analysis showed that the chimeric virus induced multiple innate immune pathways, including Toll-like receptor signaling, antigen presenting cell activation, and NK receptor signaling. EILV/CHIKV triggered quicker and more robust type I interferon and NK cell responses than the inactivated WT virus vaccine. Lastly, we developed a guinea pig sensitization model and demonstrated that the chimeric virus produced in insect cells, did not cause skin hypersensitivity reactions. Overall, EILV/CHIKV is safe, and confers rapid and long-lasting protection in cynomolgus macaques via preferential induction of robust innate immune signaling and superior T cell immunity.
摘要
埃拉特病毒（EILV）/基孔肯雅病毒（CHIKV）是一种基于昆虫的嵌合性甲型病毒，此前报道显示其单次接种后可为小鼠提供数月保护。宿主保护的潜在机制尚未明确。本研究评估了EILV/CHIKV在食蟹猴中诱导快速且持久保护的能力。单次接种后1年，EILV/CHIKV与减毒活疫苗CHIKV 181/25均能有效保护猴群免受野生型（WT）CHIKV感染。转录组与功能分析表明，EILV/CHIKV以剂量依赖方式诱发T细胞、记忆B细胞及抗体反应。相较于CHIKV 181/25疫苗，EILV/CHIKV诱导的CHIKV特异性T细胞反应更强烈、持久且谱系更广；而后者则能诱导更持久的记忆B细胞，并产生相当或更高的CHIKV特异性中和抗体及结合抗体。EILV/CHIKV和灭活的WT CHIKV保护猕猴在6小时内免受WT CHIKV感染和CHIK热（CHIKF） 接种疫苗后几天。转录组分析表明，嵌合病毒诱导了多种先天免疫途径，包括Toll样受体信号传导、抗原呈递细胞激活和NK受体信号传导。EILV/CHIKV引发的I型干扰素和NK细胞反应比灭活WT病毒疫苗更快、更强烈。最后，我们开发了一种豚鼠致敏模型，并证明昆虫细胞中产生的嵌合病毒不会引起皮肤超敏反应。总体而言，EILV/CHIKV是安全的，通过优先诱导强大的先天免疫信号和卓越的T细胞免疫，为食蟹猴提供快速持久的保护。
