# Viral control is required for intravenous BCG-mediated protection against tuberculosis in simian immunodeficiency virus-infected macaques

## TL;DR

This study shows that controlling SIV is essential for IV-BCG to protect against TB in SIV-infected macaques, regardless of whether BCG is eliminated with drugs.

## Contribution

The study demonstrates that SIV control, not BCG persistence, is critical for vaccine-induced TB protection in SIV-infected macaques.

## Key findings

- IV-BCG protection against TB was retained even when BCG was eliminated with drugs.
- Non-controllers with high SIV viremia had reduced protection compared to controllers.
- SIV control is necessary for full IV-BCG-mediated TB protection in SIV-infected macaques.

## Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a major global health challenge, especially for people living with HIV (PLWH) not on antiretroviral therapy. We previously showed that intravenous Bacillus Calmette-Guérin (IV-BCG) provides robust protection in SIV+ Mauritian cynomolgus macaques (MCM). Here, we evaluate whether the immunogenicity and efficacy of IV-BCG in SIV+ MCM was impaired by eliminating BCG with drugs. SIV+ macaques were treated with an anti-BCG regimen of isoniazid, rifampicin, and ethambutol (HRE), starting either 1- or 3-weeks post-BCG vaccination. Five months post-vaccination, macaques were challenged with Mtb for 12 weeks. Protection conferred by IV-BCG was significant regardless of HRE timing. However, non-controllers, characterized by high viremia and reduced CD4+ T cells in the lungs, were significantly less protected than controllers. Thus, the robust efficacy of IV-BCG in SIV+ MCM is retained regardless of anti-BCG drug treatment, indicating that BCG does not need to survive long to provide protection. In contrast, SIV control was necessary for full protection induced by IV-BCG. Thus, our results support that viral control is critical for vaccine-elicited protection from TB in PLWH.