Review 4: "A "suicide" BCG Strain provides Enhanced Immunogenicity and Robust Protection against Mycobacterium Tuberculosis in Macaques"

RR:C19 Evidence Scale rating by reviewer:

• Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

The manuscript entitled “A suicide BCG strain provides enhanced immunogenicity and robust protection against Mycobacterium tuberculosis in macaques” by Smith et al. is an exciting and innovative study describing a promising new TB vaccine candidate. This group utilizes a regulated promoter to induce two different lysin genes from the mycobacteriophages D29 and L5. The expression is regulated by anhydrotetracycline-regulated repressor, which this group pioneered. They elegantly demonstrate the expression of these lysins leads to rapid lysis and killing of BCG. Utilizing intravenous immunization with this suicide BCG in mice they show better protection than subcutaneous BCG in mice and macaques. The experimental design is well-controlled, and the collected data is compelling. The paper is superbly written and suggests that even if IV BCG is not used immediately for TB vaccination, it could be readily used to treat bladder cancer as the strain would be significantly safer than wild-type BCG. I recommend acceptance as is.