Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health emergency, with >10 million cases and 1.6 million deaths annually. Lineage 2-Beijing Mtb (L2B) strains predominate in East Asia and are widespread globally. L2B strains are hypervirulent, multidrug resistant, and result in elevated rates of relapse post-treatment. In a case contact study in Indonesia, although the Bacillus Calmette-Guérin (BCG) vaccine protected against other Mtb strains as expected, there was no evidence of protection against L2B strains. In vitro, using a mycobacterial growth inhibition assay, we revealed BCG-trained alveolar macrophages are impaired in their killing of L2B strains, compared to Lineage 4-Mtb (L4) strains. To understand the mechanisms driving immune evasion by L2B strains, we developed an aerosol murine Mtb infection model using fluorescently tagged clinical L2B and L4 isolates. Flow cytometry, RNA-seq, and spatial transcriptomics were used to measure mucosal and peripheral immune responses. In BCG vaccinated mice, L2B strains actively suppressed immune pathways and upregulated genes associated with immune evasion. This study has identified pathways that are critical for the protective efficacy of BCG, which will inform rational design of improved vaccines.