Bridges Kate, Awany Denis, Gela Anele, Mwanbene Temwa-Dango, Sassetti Christopher M, Scriba Thomas J, Lauffenburger Douglas A
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
bioRxiv. 2025 May 9:2025.05.05.652268. doi: 10.1101/2025.05.05.652268.
The immune mechanisms induced by the Bacillus Calmette-Guérin (BCG) vaccine, and the subset of which mediate protection against tuberculosis (TB), remain poorly understood. This is further complicated by difficulties to verify vaccine-induced protection in humans. Although research in animal models, namely mice and non-human primates (NHPs), has begun to close this knowledge gap, discrepancies in the relative importance of biological pathways across species limit the utility of animal model-derived biological insights in humans. To address these challenges, we applied a systems modeling framework, Translatable Components Regression (TransCompR), to identify human blood transcriptional variability which could predict challenge outcomes in BCG-vaccinated NHPs. These protection-associated pathways included both innate and adaptive immune activation mechanisms, along with signaling via type I interferons and anti-mycobacterial T helper cytokines. We further partially validated the associations between these mechanisms and protection in humans using publicly available microarray data collected from BCG-vaccinated infants who either developed TB or remained healthy during two years of follow-up. Overall, our work demonstrates how species translation modeling can leverage animal studies to generate hypotheses about the mechanisms that underlie human infectious disease and vaccination outcomes, which may be difficult or impossible to ascertain using human data alone.
卡介苗（BCG）疫苗所诱导的免疫机制，以及其中介导抗结核（TB）保护作用的亚群，仍未得到充分了解。由于难以在人体中验证疫苗诱导的保护作用，情况变得更加复杂。尽管在动物模型（即小鼠和非人类灵长类动物（NHPs））中的研究已开始填补这一知识空白，但跨物种生物途径相对重要性的差异限制了动物模型衍生的生物学见解在人类中的应用。为应对这些挑战，我们应用了一个系统建模框架——可翻译成分回归（TransCompR），以识别可预测卡介苗接种的非人类灵长类动物中感染结果的人类血液转录变异性。这些与保护相关的途径包括先天性和适应性免疫激活机制，以及通过I型干扰素和抗分枝杆菌辅助性T细胞细胞因子的信号传导。我们还利用从接种卡介苗的婴儿收集的公开可用微阵列数据，进一步部分验证了这些机制与人类保护之间的关联，这些婴儿在两年随访期间要么患了结核病，要么保持健康。总体而言，我们的工作展示了物种翻译建模如何利用动物研究来生成关于人类传染病和疫苗接种结果潜在机制的假设，而仅使用人类数据可能难以或无法确定这些假设。
