Carrero Longlax Santiago, Koster Kent J, Kamat Ashish M, Lozano Marisa, Lerner Seth P, Hannigan Rebecca, Nishiguchi Tomoki, Sheikh Daanish, Ladki Malik, Portillo Alexandra, Koirala Amrit, Patel Tajhal D, Spieler Zoe, Benjamin Aaron B, Lebedev Maxim, Ofili Theresa U, Hutchison Robert W, Udeani George, Opperman Lynne A, Neal Gabriel, Mandalakas Anna M, Netea Mihai G, Arditi Moshe, Avalos Pablo, Grimm Sandra L, Coarfa Cristian, Cirillo Jeffrey D, DiNardo Andrew R
Global Tuberculosis Program, William T. Shearer Center for Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
Center for Airborne Pathogen Research and Imaging, Texas A&M School of Medicine, Bryan, Texas, USA.
Open Forum Infect Dis. 2025 Jan 16;12(1):ofaf007. doi: 10.1093/ofid/ofaf007. eCollection 2025 Jan.
The BCG vaccine induces trained immunity, an epigenetic-mediated increase in innate immune responsiveness. Therefore, this clinical trial evaluated if BCG-induced trained immunity could decrease coronavirus disease 2019 (COVID-19)-related frequency or severity.
A double-blind, placebo-controlled clinical trial of healthcare workers randomized participants to vaccination with BCG TICE or placebo (saline). Enrollment included 529 healthcare workers randomized to receive BCG or placebo. Primary analysis evaluated COVID-19 disease frequency, while secondary analysis evaluated coronavirus immunity in a subset of participants. Study enrollment ceased early in December 2020 following introduction of COVID-19-specific vaccines.
Study enrollment was halted early, prior to reaching the targeted recruitment, and was not powered to detect a decrease in COVID-19 frequency. Symptomatic COVID-19 occurred in 21 of 263 and 10 of 266 participants in the BCG and placebo arms, respectively ( = .50, Fisher exact test). Participants vaccinated with BCG, but uninfected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrated increased coronavirus vaccine immunity (increase spike-inducible levels of tumor necrosis factor, interleukin 6, and interleukin 1β) 12 months after BCG vaccination compared to participants receiving placebo. Immune responsiveness to SARS-CoV-2 antigens correlated with BCG-induced DNA methylation changes.
Due to early study closure, the study was not powered to evaluate COVID-19 frequency. Secondary analysis demonstrated that 12 months following vaccination, BCG increased coronavirus vaccine immunity compared to those who did not receive BCG. This increase in COVID-19 vaccine immunity correlated with BCG-induced DNA methylation changes.
卡介苗可诱导训练性免疫，即一种由表观遗传介导的先天免疫反应性增加。因此，本临床试验评估了卡介苗诱导的训练性免疫是否能降低2019冠状病毒病（COVID-19）的发病频率或严重程度。
一项针对医护人员的双盲、安慰剂对照临床试验，将参与者随机分为接种卡介苗TICE或安慰剂（生理盐水）组。入组的529名医护人员被随机分配接受卡介苗或安慰剂。主要分析评估COVID-19的发病频率，次要分析评估部分参与者的冠状病毒免疫力。在2020年12月引入COVID-19特异性疫苗后，研究提前终止入组。
在达到目标招募人数之前，研究提前停止入组，且没有足够的效力来检测COVID-19发病频率的降低。卡介苗组和安慰剂组中，分别有263名参与者中的21名和266名参与者中的10名出现有症状的COVID-19（P = 0.50，Fisher精确检验）。接种卡介苗但未感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的参与者，与接受安慰剂的参与者相比，在接种卡介苗12个月后表现出更高的冠状病毒疫苗免疫力（肿瘤坏死因子、白细胞介素6和白细胞介素1β的刺突诱导水平增加）。对SARS-CoV-2抗原的免疫反应性与卡介苗诱导的DNA甲基化变化相关。
由于研究提前结束，该研究没有足够的效力来评估COVID-19的发病频率。次要分析表明，接种疫苗12个月后，与未接种卡介苗的人相比，卡介苗增强了冠状病毒疫苗免疫力。这种COVID-19疫苗免疫力的增强与卡介苗诱导的DNA甲基化变化相关。
