Department of Internal Medicine, Radboud University Medical Centre, Geert Grooteplein-Zuid 10, 6525GA, Nijmegen, The Netherlands.
Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark.
Eur J Clin Microbiol Infect Dis. 2019 Mar;38(3):449-456. doi: 10.1007/s10096-018-03449-z. Epub 2019 Feb 5.
Vaccines such as Vaccinia or BCG have non-specific effects conferring protection against other diseases than their target infection, which are likely partly mediated through induction of innate immune memory (trained immunity). MVA85A, a recombinant strain of modified Vaccinia Ankara (MVA), has been suggested as an alternative vaccine against tuberculosis, but its capacity to induce positive or negative non-specific immune effects has not been studied. This study assesses whether Vaccinia and MVA are able to induce trained innate immunity in monocytes. Human primary monocytes were primed in an in vitro model with Vaccinia or MVA for 1 day, after which the stimulus was washed off and the cells were rechallenged with unrelated microbial ligands after 1 week. Heterologous cytokine responses were assessed and the capacity of MVA to induce epigenetic changes at the level of cytokine genes was investigated using chromatin immunoprecipitation and pharmacological inhibitors. Monocytes trained with Vaccinia showed significantly increased IL-6 and TNF-α production to stimulation with non-related stimuli, compared to non-trained monocytes. In contrast, monocytes primed with MVA showed significant decreased heterologous IL-6 and TNF-α responses, an effect which was abrogated by the addition of a histone methyltransferase inhibitor. No effects on H3K4me3 were observed after priming with MVA. It can be thus concluded that Vaccinia induces trained immunity in vitro, whereas MVA induces innate immune tolerance. This suggests the induction of trained immunity as an immunological mechanism involved in the non-specific effects of Vaccinia vaccination and points to a possible explanation for the lack of effect of MVA85A against tuberculosis.
疫苗，如牛痘或卡介苗，具有针对目标感染以外的其他疾病的非特异性保护作用，其机制可能部分是通过诱导先天免疫记忆（训练性免疫）实现的。MVA85A 是一种改良安卡拉牛痘病毒（MVA）的重组株，已被提议作为一种替代结核病疫苗，但它是否具有诱导正向或负向非特异性免疫作用的能力尚未得到研究。本研究评估了牛痘和 MVA 是否能够在单核细胞中诱导训练性先天免疫。人类原代单核细胞在体外模型中用牛痘或 MVA 孵育 1 天，然后用无关的微生物配体孵育 1 周后再次刺激细胞。评估异源细胞因子反应，并使用染色质免疫沉淀和药理学抑制剂研究 MVA 在细胞因子基因水平诱导表观遗传变化的能力。与未经训练的单核细胞相比，用牛痘训练的单核细胞对非相关刺激物的 IL-6 和 TNF-α 产生明显增加。相比之下，用 MVA 孵育的单核细胞显示出明显降低的异源 IL-6 和 TNF-α 反应，而加入组蛋白甲基转移酶抑制剂可消除这种反应。用 MVA 孵育后未观察到 H3K4me3 的变化。因此可以得出结论，牛痘在体外诱导训练性免疫，而 MVA 诱导先天免疫耐受。这表明诱导训练性免疫是牛痘疫苗非特异性作用的一种免疫机制，并为 MVA85A 对结核病无效提供了一种可能的解释。
