Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America.
Department of Mathematics and Mathematical Statistics, Umeå University, Umeå, Sweden.
PLoS One. 2023 Aug 3;18(8):e0289358. doi: 10.1371/journal.pone.0289358. eCollection 2023.
Although BCG has been used for almost 100 years to immunize against Mycobacterium tuberculosis, TB remains a global public health threat. Numerous clinical trials are underway studying novel vaccine candidates and strategies to improve or replace BCG, but vaccine development still lacks a well-defined set of immune correlates to predict vaccine-induced protection against tuberculosis. This study aimed to address this gap by examining transcriptional responses to BCG vaccination in C57BL/6 inbred mice, coupled with protection studies using Diversity Outbred mice. We evaluated relative gene expression in blood obtained from vaccinated mice, because blood is easily accessible, and data can be translated to human studies. We first determined that the average peak time after vaccination is 14 days for gene expression of a small subset of immune-related genes in inbred mice. We then performed global transcriptomic analyses using whole blood samples obtained two weeks after mice were vaccinated with BCG. Using comparative bioinformatic analyses and qRT-PCR validation, we developed a working correlate panel of 18 genes that were highly correlated with administration of BCG but not heat-killed BCG. We then tested this gene panel using BCG-vaccinated Diversity Outbred mice and revealed associations between the expression of a subset of genes and disease outcomes after aerosol challenge with M. tuberculosis. These data therefore demonstrate that blood-based transcriptional immune correlates measured within a few weeks after vaccination can be derived to predict protection against M. tuberculosis, even in outbred populations.
虽然卡介苗（BCG）已经使用了近 100 年用于预防结核分枝杆菌，但结核病仍然是全球公共卫生威胁。目前正在进行许多临床试验，研究新型疫苗候选物和策略，以改善或替代卡介苗，但疫苗开发仍然缺乏明确的免疫相关性来预测卡介苗接种诱导的结核病保护。本研究旨在通过检查 C57BL/6 近交系小鼠接种卡介苗后的转录反应，并结合使用多样性杂交小鼠进行保护研究，来解决这一差距。我们评估了从接种疫苗的小鼠中获得的血液中的相对基因表达，因为血液容易获得，并且数据可以转化为人类研究。我们首先确定，在近交系小鼠中，一小部分免疫相关基因的表达在接种疫苗后的平均峰值时间为 14 天。然后，我们使用接种卡介苗两周后获得的全血样本进行了全转录组分析。使用比较生物信息学分析和 qRT-PCR 验证，我们开发了一个由 18 个基因组成的工作相关性面板，这些基因与卡介苗的给药高度相关，而与热灭活卡介苗无关。然后，我们使用接种卡介苗的多样性杂交小鼠测试了这个基因面板，并揭示了一组基因的表达与结核分枝杆菌气溶胶挑战后疾病结果之间的关联。因此，这些数据表明，在接种后几周内测量的基于血液的转录免疫相关性可以预测对结核分枝杆菌的保护，即使在杂交人群中也是如此。
