Safety, Immunogenicity, and Efficacy of Therapeutic Mycobacterium Bovis BCG (BOOST)

The purpose of this study is to find out if the Mycobacterium bovis Bacillus Calmette Guerin (BCG) vaccine can be used safely to treat Mycobacterium avium complex (MAC) lung disease. Researchers will compare responses from patients with MAC lung disease after receiving an injection of BCG or placebo (a look-alike substance that contains no drug) Participants in the study: * Receive a BCG or placebo injection at UVA study center on Day 0 * Come to UVA study center on Day 60 * Come to UVA study center at the end of the study * Answer surveys and questionnaires about how you are doing * Have blood drawn 3 times, on injection day, day 60, and at end of study * Give the study team personal and demographic information * Discuss any new symptoms with the study team * Provide monthly sputum samples per usual care

Mycobacterium avium complex (MAC) lung disease (LD) is an increasingly prevalent condition in the United States. Treatment involves administration of multiple antibiotics for at least 12 months and many patients still fail, or infection recurs. New therapeutic strategies are needed. We hypothesize that Mycobacterium bovis Bacillus Calmette Guerin (BCG) will have microbiologic activity against MAC during lung disease, because of * Its mycobacterium antigens shared with MAC (1). * In vitro evidence that BCG stimulates MAC-specific immune responses in mice and humans (2, 3). * In vivo evidence that BCG reduces MAC in mice with established infection (4). Clinical evidence for BCG protection against MAC infection in HIV patients and in children (5, 6). Objectives: The primary objective is to determine the safety and immunogenicity of BCG against MAC lung disease after intradermal vaccination with BCG or placebo. The secondary objectives include: * the microbiologic efficacy of BCG compared to placebo. * to determine if BCG is superior to placebo in reducing all-cause respiratory illness requiring additional antibiotics, healthcare assessment, or admission. Endpoints: Primary endpoints: * Safety and tolerability of intradermal BCG (TICE®) in this patient population, compared to placebo, assessed by weekly questionnaire of adverse events over 12 weeks. * Serious adverse events related to the intradermal BCG over 12 months. * Immunogenicity of BCG as measured by the change in BCG-induced IFN-γ production in PBMCs 60 days after vaccination, compared to placebo. Secondary endpoints: * Proportion of monthly sputum cultures positive for MAC after BCG vaccine or placebo over 24 months. * Immunogenicity of BCG on MAC-specific IFN-γ responses. * Proportion of patients with MAC culture conversion and MAC recurrence within 24 months. * Rates of all-cause respiratory illness requiring additional antibiotics, healthcare assessment, or admission over 24 months. * Symptom scores using the Quality of Life- Bronchiectasis Respiratory (QOL-BR) questionnaire over 24 months. * Adverse Events of Special Interest (local/systemic M. bovis BCG infection) over 24 months. Exploratory endpoints: * Assess the efficacy of BCG versus placebo on chest imaging score. * While the study is not powered to detect differences among subgroups, we will enumerate whether above endpoints are modified among these patient subgroups: cavitary versus non-cavitary disease, age, gender, the species of MAC infection, and those with higher IFN-γ responses. * Assess PBMC cytokine responses beyond IFN-γ. * Assess durability of immune responses at 24 months. Study Population: We aim to enroll a total of 48 participants with MAC, of which 24 will be randomized to receive each of BCG and placebo.