Intravenous BCG protects SIV+ macaques from tuberculosis.
Erica C. Larson 1, Mark A. Rodgers 1, Amy L. Ellis 2, Cassaundra L. Ameel 1, Janelle L. Gleim 1, Abigail K. Gubernat 1, Alexis J. Balgeman 2, Ryan V. Moriarty 2, Tricia A. Darrah 3, Pauline A. Maiello 1, Mario Roederer 3, Robert A. Seder 3, Shelby O’Connor 2, Charles A. Scanga 1*.
1) Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA; 2) Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, WI; 3) Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
* Corresponding author
Tuberculosis is the most common cause of death due to infection in people living with HIV (PLHIV). BCG, a live attenuated Mycobacterium bovis strain given intradermally to infants, is the only licensed vaccine to prevent TB. However, intradermal BCG offers little protection from pulmonary TB in adults and safety concerns limit its use in PLHIV. Recently, intravenous (IV) BCG has been shown to provide striking protection from TB in rhesus macaques and was associated with a rapid and sustained increase in lung T cells. Given this dramatic success, we tested whether IV BCG could protect macaques with a pre-existing, chronic SIV infection using our established model of SIV/Mtb coinfection in Mauritian cynomolgus macaques (MCM). MCM were intrarectally infected with SIVmac239 and subsequently vaccinated with BCG at 8 x10^7 CFU delivered IV 5 months later. To prevent disseminated BCG disease, four weeks after IV vaccination animals were treated with an 8-week regimen of isoniazid/rifampin/ethambutol (HRE). Four weeks after cessation of the antibiotic regimen, animals were challenged with low-dose Mtb Erdman via bronchoscope. SIV+, unvaccinated MCM and SIV-naïve, IV BCG-vaccinated MCM were also infected with Mtb Erdman and served as controls. SIV+ MCM exhibited no signs of BCG disease before or after HRE treatment. Flow cytometry of BAL revealed a rapid and sustained increase in airway T cells following BCG vaccination in both SIV+ and SIV-naïve animals. Increased plasma antibody titers to Mtb lysate were detected by ELISA following IV BCG. Remarkably, PBMC responses to Mtb-specific stimuli by ELISpot indicated rapid and early clearance of Mtb in vaccinated animals regardless of SIV. Necropsy 12 weeks after Mtb challenge revealed all SIV-naïve (n=7) and 7 out of 10 SIV+, vaccinated animals to be free of TB and without culturable bacilli in their tissues. Flow cytometric analysis of tissues obtained at necropsy are underway. IV BCG is safe, immunogenic, and confers extraordinary protection in SIV+ macaques.