Tuberculosis (TB) continues to be a major global health burden and kills over a million people annually. New immunization strategies are required for the development of an efficacious TB vaccine that can potentially induce sterilizing immunity. In this study, we first confirmed that various strains of the IKEPLUS vaccine confer a higher survival benefit than BCG in a murine model of intravenous Mycobacterium tuberculosis (Mtb) infection. We have shown that there was a significant increase in the expression of the Rv0282 when IKEPLUS was grown in low zinc and iron containing Sauton medium. We confirmed on biofilm assays that zinc plays a vital role in the growth and formation of Mycobacterium smegmatis ( M. smegmatis ) biofilms. IKEPLUS grown in low zinc media led to better protection of mice after intravenous challenge with very high dosage of Mtb. We also showed that various variants of IKEPLUS induced apoptotic cell-death of infected macrophages at a higher rate than wild type M. smegmatis . We next attempted to determine if zinc containing ribosomal proteins such as rpmb2 could contribute to protective efficacy against Mtb infection. Since BCG has an established role in anti-mycobacterial efficacy, we boosted BCG vaccinated mice with rmpb2 but this did not lead to an increment in the protection mediated by BCG.