BACKGROUND Certain vaccines, such as Bacille Calmette-Guérin (BCG), have nonspecific effects, which modulate innate immune responses and lead to protection against mortality from unrelated infections (trained immunity). In contrast, in spite of the disease-specific effects, an enhanced overall mortality has been described after diphtheria-tetanus-pertussis (DTP) vaccination in females. This randomized trial aimed to investigate the nonspecific immunological effects of BCG and DTP-containing vaccines on the immune response to unrelated pathogens. METHODS We randomized 75 healthy, female, adult volunteers to receive either BCG, followed by a booster dose of tetanus-diphtheria-pertussis inactivated polio vaccine (Tdap) 3 months later; BCG and Tdap combined; or Tdap followed by BCG 3 months later. Blood was collected before vaccination, as well as at 1 day, 4 days, 2 weeks, and 3 months after the first vaccination(s), plus 2 weeks after the second vaccination. Ex vivo leukocyte responses to unrelated stimuli and pathogens were assessed. RESULTS Tdap vaccination led to short-term potentiation and long-term repression of monocyte-derived cytokine responses, and short-term as well as long-term repression of T-cell reactivity to unrelated pathogens. BCG led to short-term and long-term potentiation of monocyte-derived cytokine responses. When given together with Tdap or after Tdap, BCG abrogated the immunosuppressive effects of Tdap vaccination. CONCLUSIONS Tdap induces immunotolerance to unrelated antigens, which is partially restored by concurrent or subsequent BCG vaccination. These data indicate that the modulation of heterologous immune responses is induced by vaccination with Tdap and BCG, and more studies are warranted to investigate whether this is involved in the nonspecific effects of vaccines on mortality. CLINICAL TRIALS REGISTRATION NCT02771782.

中文翻译：

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卡介苗和破伤风-白喉-百日咳灭活脊髓灰质炎疫苗的相互作用、非特异性、免疫学效应：一项探索性随机试验。

背景技术某些疫苗，例如卡介苗 (BCG)，具有非特异性作用，可调节先天免疫反应并防止无关感染导致的死亡（受过训练的免疫）。相比之下，尽管有疾病特异性影响，但女性接种白喉-破伤风-百日咳 (DTP) 疫苗后总体死亡率有所增加。该随机试验旨在研究含 BCG 和 DTP 的疫苗对无关病原体的免疫反应的非特异性免疫学影响。方法 我们将 75 名健康的女性成年志愿者随机分配接受 BCG，然后在 3 个月后接受加强剂量的破伤风-白喉-百日咳灭活脊髓灰质炎疫苗 (Tdap)；BCG 和 Tdap 结合；或 Tdap 然后是 3 个月后的 BCG。在接种疫苗前采集血液，以及在第一次疫苗接种后的 1 天、4 天、2 周和 3 个月，加上第二次疫苗接种后的 2 周。评估了对无关刺激和病原体的离体白细胞反应。结果 Tdap 疫苗接种导致单核细胞衍生的细胞因子反应的短期增强和长期抑制，以及 T 细胞对无关病原体的反应性的短期和长期抑制。BCG 导致单核细胞衍生的细胞因子反应的短期和长期增强。当与 Tdap 一起给药或在 Tdap 之后给药时，BCG 消除了 Tdap 疫苗接种的免疫抑制作用。结论 Tdap 诱导对无关抗原的免疫耐受性，通过同时或随后的 BCG 疫苗接种可部分恢复。这些数据表明异源免疫反应的调节是由接种 Tdap 和 BCG 诱导的，需要更多的研究来调查这是否与疫苗对死亡率的非特异性影响有关。临床试验注册 NCT02771782。