Review 2: "Therapeutic DNA Vaccine Targeting Mycobacterium Tuberculosis Persisters Shortens Curative Tuberculosis Treatment"

Andrea Cooper

doi:doi:10.1162/2e3983f5.f5f0e8eb

Therapeutic DNA Vaccine Targeting Mycobacterium tuberculosis Persisters Shortens Curative Tuberculosis Treatment

by Styliani Karanika, Tianyin Wang, Addis Yilma, Jennie Ruelas Castillo, James T. Gordy, Hannah Bailey, Darla Quijada, Kaitlyn Fessler, Rokeya Tasneen, Elisa M. Rouse Salcido, Harley T. Harris, Rowan E. Bates, Heemee Ton, Jacob Meza, Yangchen Li, Alannah D. Taylor, Jean J. Zheng, Jiaqi Zhang, J David Peske, Theodoros Karantanos, Amanda R. Maxwell, Eric Nuermberger, Richard B. Markham, and Petros C. Karakousis

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Published on Sep 07, 2024
www.biorxiv.org

Description

Abstract Mycobacterium tuberculosis (Mtb) is one of the leading infectious causes of death worldwide. There is no available licensed therapeutic vaccine that shortens active tuberculosis (TB) disease drug treatment and prevents relapse, despite the World Health Organization’s calls. Here, we show that an intranasal DNA vaccine containing a fusion of the stringent response relMtb gene with the gene encoding the immature dendritic cell-targeting chemokine, MIP-3α/CCL20, shortens the duration of curative TB treatment in immunocompetent mice. Compared to the first-line regimen for drug-susceptible TB alone, our novel adjunctive vaccine induced greater RelMtb-specific T-cell responses associated with optimal TB control in spleen, blood, lungs, mediastinal lymph nodes, and bronchoalveolar lavage (BAL) fluid. These responses were sustained, if not augmented, over time. It also triggered more effective dendritic cell recruitment, activation, and colocalization with T cells, implying enhanced crosstalk between innate and adaptive immunity. Moreover, it potentiated a 6-month TB drug-resistant regimen, rendering it effective across treatment regimens, and also showed promising results in CD4+ knockout mice, perhaps due to enhanced Rel-specific CD8+ T-cell responses. Notably, our novel fusion vaccine was also immunogenic in nonhuman primates, the gold standard animal model for TB vaccine studies, eliciting antigen-specific T-cell responses in blood and BAL fluid analogous to those observed in protected mice. Our findings have critical implications for therapeutic TB vaccine clinical development in immunocompetent and immunocompromised populations and may serve as a model for defining immunological correlates of therapeutic vaccine-induced protection.One sentence summary A TB vaccine shortens curative drug treatment in mice by eliciting strong TB-protective immune responses and induces similar responses in macaques.

RR\ID Evidence Scale rating by reviewer:

Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: This preprint has some strong data supporting the ability of a specifically designed vaccine to improve bacterial clearance during conventional drug treatment in an aerosol model of TB. Importantly the vaccine also leads to absence of relapse once drug treatment is removed.

A causal connection between the immunological measures and the reduction in bacterial burden is not robust as yet. There are some intriguing immunological measurements indicating strong induction of cytokine-producing antigen-specific T cells (CD4 and CD8) in the mice receiving the vaccine. The impact of the inclusion of the chemokine MIP-3a into the vaccine is shown by increased accumulation of myeloid cells of varying phenotypes (dendritic cells). The improved reduction in bacterial burden seen in the vaccinated mice can be seen in mice lacking CD4 T cells suggesting that the protective effect may be mediated by cells other than classical CD4 T cell responses. In future work, it would be good to identify the causal connection between the vaccine-induced response that specifically mediate the reduced bacterial burden.

There is data to show that the intranasal delivery of the vaccine can induce antigen-specific T cells in the PBMC of a nonhuman primate model. In future work, it will be good to see whether this regimen is as effective at reducing bacterial burden and disease in this model as seen in mice.

The number of mice and the number of repeated experiments with the same protocol is not definitively represented in the figure legends - addition of these details along with a precise description of the experiment for each figure legend would be helpful. The figures could be clearer with specific labelling of the axes. Additionally, there is a mistake in fig 6 in the legend - I am presuming that the green triangle should read BPal.

Review 2: "Therapeutic DNA Vaccine Targeting Mycobacterium Tuberculosis Persisters Shortens Curative Tuberculosis Treatment"

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