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

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.