# Cross-species blood transcriptional correlates of BCG-mediated protection against tuberculosis include innate and adaptive immune processes

## TL;DR

This study identifies immune mechanisms linked to BCG vaccine protection against tuberculosis by comparing blood transcription data across species.

## Contribution

The study introduces a systems modeling approach to translate immune pathways from animal models to humans, improving vaccine outcome understanding.

## Key findings

- Innate and adaptive immune activation mechanisms are linked to BCG-mediated protection against TB.
- TransCompR identified human blood transcriptional variability predictive of TB outcomes in BCG-vaccinated NHPs.
- Publicly available infant data partially validated immune mechanisms associated with protection in humans.

## Abstract

The immune mechanisms induced by the Bacillus Calmette-Guérin (BCG) vaccine, and the subset of which that mediate protection against tuberculosis (TB), remain poorly understood. This is further complicated by difficulties in verifying vaccine-induced protection in humans. Although research in animal models, namely mice and nonhuman 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 that could predict Mycobacterium tuberculosis challenge outcomes in BCG-vaccinated NHPs. These protection-associated pathways included both innate and adaptive immune activation mechanisms, along with signaling via type I IFNs and antimycobacterial Th 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 2 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.

By translating insights from animal models, our work overcomes limitations in clinical data to identify human immune mechanisms associated with successful vaccine outcomes.