Assessing vaccine-mediated protection in an ultra-low dose Mycobacterium tuberculosis murine model.

Autor: Plumlee, Courtney R., Barrett, Holly W., Shao, Danica E., Lien, Katie A., Cross, Lauren M., Cohen, Sara B., Edlefsen, Paul T., Urdahl, Kevin B.
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Zdroj: PLoS Pathogens; 11/27/2023, Vol. 19 Issue 11, p1-18, 18p
Abstrakt: Despite widespread immunization with Bacille-Calmette-Guerin (BCG), the only currently licensed tuberculosis (TB) vaccine, TB remains a leading cause of mortality globally. There are many TB vaccine candidates in the developmental pipeline, but the lack of a robust animal model to assess vaccine efficacy has hindered our ability to prioritize candidates for human clinical trials. Here we use a murine ultra-low dose (ULD) Mycobacterium tuberculosis (Mtb) challenge model to assess protection conferred by BCG vaccination. We show that BCG confers a reduction in lung bacterial burdens that is more durable than that observed after conventional dose challenge, curbs Mtb dissemination to the contralateral lung, and, in a small percentage of mice, prevents detectable infection. These findings are consistent with the ability of human BCG vaccination to mediate protection, particularly against disseminated disease, in specific human populations and clinical settings. Overall, our findings demonstrate that the ultra-low dose Mtb infection model can measure distinct parameters of immune protection that cannot be assessed in conventional dose murine infection models and could provide an improved platform for TB vaccine testing. Author summary: Despite over 100 years of vaccination with the current tuberculosis (TB) vaccine, Bacille Calmette-Guérin (BCG), TB remains the world's leading infectious killer. Although BCG is effective in some settings, it has been overmatched as a tool to curb the global TB pandemic; a better vaccine is needed. Many TB vaccine candidates are being developed, but human TB vaccine trials are costly and take years to complete. The most promising candidates must be identified and prioritized, but existing animal models for TB vaccine testing poorly predict efficacy in humans. Recently we described an improved mouse TB model that uses an ultra-low dose (ULD) challenge of 1–3 Mycobacterium tuberculosis (Mtb) bacteria, which more closely reflects a human inoculum. Here we use the ULD model to examine protection provided by BCG vaccination. Compared to conventional dose Mtb infection, we show that BCG vaccination in the ULD model leads to longer lasting protection, blocks dissemination from one lung to the other, and prevents detectable infection in a small percentage of mice. Overall, we show that the ULD model can measure unique aspects of protection that cannot be assessed in existing models and could provide an improved platform for prioritizing TB vaccine candidates. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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