Evaluation of the time needed for BCG to be alive to protect against tuberculosis in intravenously BCG vaccinated SIV plus macaques

Abstract Effective means of improving Bacille Calmette-Guérin (BCG) immunogenicity to protect against pulmonary tuberculosis (TB) is needed, especially among people living with HIV. Intravenous (IV) administration of BCG previously showed significant enhancement of immune responses and conferred ~75% protection against TB. Using our SIV/M. tuberculosis (Mtb) coinfection model (to mimic HIV/Mtb coinfection) in Mauritius cynomolgus macaques (MCM), we evaluated the length of time necessary for live BCG to elicit a protective immune responses by varying the timing of anti-BCG drug (isoniazid, rifampicin, and ethambutol: HRE) initiation. MCM were infected with SIVmac239 and randomly assigned into 4 different vaccination groups 16 weeks after SIV infection: intradermal BCG (BCG ID No HRE), BCG IV with HRE started 1 week post BCG (BCG IV 1wk HRE), BCG IV with HRE started 3 weeks post BCG (BCG IV 3wks HRE), and BCG IV without HRE treatment (BCG IV No HRE). The HRE treatment lasted for 8 weeks. Airways samples were collected by bronchoalveolar lavage (BAL), whereas lung tissue and lymph node were harvested at necropsy in a subset of BCG ID and BCG IV 3wks vaccinated MCM 20 weeks after BCG but before (Mtb) challenge. The remaining MCM were challenged with Mtb Erdman strain (~15 CFU). CD4 and CD8 T cell levels increased in BAL in all IV vaccinated MCM. CD4 T cells producing IFNg, IL-2, IL-17, and TNF peaked after BCG and were maintained until necropsy. There were increased tissue-resident T cells and cytokine production in lungs of IV vaccinated MCM compared to BCG ID. No signs of BCG dissemination were apparent in any IV vaccinated MCM. We are currently evaluating protection against infection and disease in the SIV+ MCM in each vaccination group. Supported by grant NIH (R01 AI155345)