Immune correlates of postexposure vaccine protection against Marburg virus

Postexposure immunization can prevent disease and reduce transmission following pathogen exposure. The rapid immunostimulatory properties of recombinant vesicular stomatitis virus (rVSV)-based vaccines make them suitable postexposure treatments against the filoviruses Ebola virus and Marburg virus (MARV); however, the mechanisms that drive this protection are undefined. Previously, we reported 60-75% survival of rhesus macaques treated with rVSV vectors expressing MARV glycoprotein (GP) 20-30 minutes after a low dose exposure to the most pathogenic variant of MARV, Angola. Survival in this model was linked to production of GP-specific antibodies and lower viral load. To confirm these results and potentially identify novel correlates of postexposure protection, we performed a similar experiment, but analyzed plasma cytokine levels, frequencies of immune cell subsets, and the transcriptional response to infection in peripheral blood. In surviving macaques (80-89%), we observed induction of genes mapping to antiviral and interferon-related pathways early after treatment and a higher percentage of T helper 1 (Th1) and NK cells. In contrast, the response of non-surviving macaques was characterized by hypercytokinemia; a T helper 2 signature; recruitment of low HLA-DR expressing monocytes and regulatory T-cells; and transcription of immune checkpoint (e.g. PD-1, LAG3) genes. These results suggest dysregulated immunoregulation is associated with poor prognosis, whereas early innate signaling and Th1-skewed immunity are important for survival.

病原体暴露后实施免疫接种，可预防疾病发生并降低传播风险。基于重组水疱性口炎病毒（recombinant vesicular stomatitis virus, rVSV）的疫苗凭借快速免疫刺激特性，成为针对丝状病毒埃博拉病毒（Ebola virus）与马尔堡病毒（Marburg virus, MARV）的适宜暴露后治疗手段；但介导该保护效应的具体分子机制仍未明确。此前我们曾报道，在以低剂量感染马尔堡病毒最强致病变异株安哥拉毒株（MARV Angola）后20~30分钟，给予表达马尔堡病毒糖蛋白（glycoprotein, GP）的重组水疱性口炎病毒载体处理的恒河猴，存活率可达60%~75%。该模型中的动物存活率与糖蛋白特异性抗体的产生及较低的病毒载量密切相关。为验证上述结果并潜在挖掘暴露后保护效应的新型关联标志物，我们开展了类似实验，额外对血浆细胞因子水平、免疫细胞亚群占比以及外周血感染应答的转录组特征进行了分析。在存活率达80%~89%的存活恒河猴体内，我们观察到给药早期即可诱导抗病毒及干扰素相关通路的基因表达上调，同时辅助性T细胞1（T helper 1, Th1）与自然杀伤细胞（natural killer cell, NK）的占比显著升高。与之相反，未存活的恒河猴则表现为高细胞因子血症、辅助性T细胞2型极化特征、低表达HLA-DR的单核细胞与调节性T细胞的招募，以及免疫检查点（如程序性死亡受体1（programmed cell death protein 1, PD-1）、淋巴细胞活化基因3（lymphocyte-activation gene 3, LAG3））相关基因的转录上调。上述结果表明，免疫调节失衡与不良预后密切相关，而早期先天信号通路激活与辅助性T细胞1极化的免疫应答对宿主存活至关重要。