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

Reviewers suggested modifying the title to highlight safety and comparable protection, verifying statistical calculations, providing supplementary data, and conducting further experiments to support conclusions.

Published onJan 15, 2024
Review 4: "A "suicide" BCG Strain provides Enhanced Immunogenicity and Robust Protection against Mycobacterium Tuberculosis in Macaques"
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A “suicide” BCG strain provides enhanced immunogenicity and robust protection against Mycobacterium tuberculosis in macaques
A “suicide” BCG strain provides enhanced immunogenicity and robust protection against Mycobacterium tuberculosis in macaques
Description

Abstract Intravenous (IV) BCG delivery provides robust protection against Mycobacterium tuberculosis (Mtb) in macaques but poses safety challenges. Here, we constructed two BCG strains (BCG-TetON-DL and BCG-TetOFF-DL) in which tetracyclines regulate two phage lysin operons. Once the lysins are expressed, these strains are cleared in immunocompetent and immunocompromised mice, yet induced similar immune responses and provided similar protection against Mtb challenge as wild type BCG. Lysin induction resulted in release of intracellular BCG antigens and enhanced cytokine production by macrophages. In macaques, cessation of doxycycline administration resulted in rapid elimination of BCG-TetOFF-DL. However, IV BCG-TetOFF-DL induced increased pulmonary CD4 T cell responses compared to WT BCG and provided robust protection against Mtb challenge, with sterilizing immunity in 6 of 8 macaques, compared to 2 of 8 macaques immunized with WT BCG. Thus, a “suicide” BCG strain provides an additional measure of safety when delivered intravenously and robust protection against Mtb infection.

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.

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