Precision Medicine Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia.
Precision Medicine Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia; University of Applied Sciences Leiden, Zernikedreef 11, 2333 CK Leiden, the Netherlands.
Vaccine. 2022 Mar 8;40(11):1594-1605. doi: 10.1016/j.vaccine.2021.03.084. Epub 2021 Apr 22.
In addition to providing pathogen-specific immunity, vaccines can also confer nonspecific effects (NSEs) on mortality and morbidity unrelated to the targeted disease. Immunisation with live vaccines, such as the BCG vaccine, has generally been associated with significantly reduced all-cause infant mortality. In contrast, some inactivated vaccines, such as the diphtheria, tetanus, whole-cell pertussis (DTPw) vaccine, have been controversially associated with increased all-cause mortality especially in female infants in high-mortality settings. The NSEs associated with BCG have been attributed, in part, to the induction of trained immunity, an epigenetic and metabolic reprograming of innate immune cells, increasing their responsiveness to subsequent microbial encounters. Whether non-live vaccines such as DTPw induce trained immunity is currently poorly understood. Here, we report that immunisation of mice with DTPw induced a unique program of trained immunity in comparison to BCG immunised mice. Altered monocyte and DC cytokine responses were evident in DTPw immunised mice even months after vaccination. Furthermore, splenic cDCs from DTPw immunised mice had altered chromatin accessibility at loci involved in immunity and metabolism, suggesting that these changes were epigenetically mediated. Interestingly, changing the order in which the BCG and DTPw vaccines were co-administered to mice altered subsequent trained immune responses. Given these differences in trained immunity, we also assessed whether administration of these vaccines altered susceptibility to sepsis in two different mouse models. Immunisation with either BCG or a DTPw-containing vaccine prior to the induction of sepsis did not significantly alter survival. Further studies are now needed to more fully investigate the potential consequences of DTPw induced trained immunity in different contexts and to assess whether other non-live vaccines also induce similar changes.
除了提供针对病原体的免疫外，疫苗还可以对与目标疾病无关的死亡率和发病率产生非特异性效应（NSEs）。活疫苗（如卡介苗）的免疫接种通常与全因婴儿死亡率显著降低相关。相比之下，一些灭活疫苗（如白喉、破伤风、全细胞百日咳（DTPw）疫苗）在高死亡率环境中，特别是在女婴中，与全因死亡率增加有关，这一现象引起了争议。卡介苗相关的 NSEs 部分归因于训练有素的免疫的诱导，这是先天免疫细胞的表观遗传和代谢重编程，增加了它们对随后微生物接触的反应性。目前尚不清楚非活疫苗（如 DTPw）是否会诱导训练有素的免疫。在这里，我们报告说，与卡介苗免疫的小鼠相比，用 DTPw 免疫小鼠会诱导出独特的训练有素的免疫程序。即使在接种疫苗数月后，DTPw 免疫的小鼠中单核细胞和 DC 的细胞因子反应也发生了改变。此外，来自 DTPw 免疫的小鼠的脾脏 cDCs 在参与免疫和代谢的基因座处具有改变的染色质可及性，这表明这些变化是由表观遗传介导的。有趣的是，改变卡介苗和 DTPw 疫苗同时接种给小鼠的顺序改变了随后的训练有素的免疫反应。鉴于这些训练有素的免疫差异，我们还评估了在两种不同的小鼠模型中，这些疫苗的接种是否改变了对败血症的易感性。在诱导败血症之前，用卡介苗或含 DTPw 的疫苗免疫接种不会显著改变存活率。现在需要进一步研究以更全面地研究 DTPw 诱导的训练有素的免疫在不同情况下的潜在后果，并评估其他非活疫苗是否也会引起类似的变化。
