A noninvasive BCG skin challenge model for assessing tuberculosis vaccine efficacy
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
We report here on the characterisation in mice of a noninvasive bacille Calmette-Guérin (BCG) skin challenge model for assessing tuberculosis (TB) vaccine efficacy. Controlled human infection models (CHIMs) are valuable tools for assessing the relevant biological activity of vaccine candidates, with the potential to accelerate TB vaccine development into the clinic. TB infection poses significant constraints on the design of a CHIM using the causative agent Mycobacterium tuberculosis (Mtb). A safer alternative is a challenge model using the attenuated vaccine agent Mycobacterium bovis BCG as a surrogate for Mtb, and intradermal (skin) challenge as an alternative to pulmonary infection. We have developed a unique noninvasive imaging system based on fluorescent reporters (FluorBCG) to quantitatively measure bacterial load over time, thereby determining a relevant biological vaccine effect. We assessed the utility of this model to measure the effectiveness of 2 TB vaccines: the currently licenced BCG and a novel subunit vaccine candidate. To assess the efficacy of the skin challenge model, a nonlinear mixed-effects models was built describing the decline of fluorescence over time. The model-based analysis identified that BCG vaccination reduced the fluorescence readout of both fluorophores compared to unvaccinated mice (p < 0.001). However, vaccination with the novel subunit candidate did not alter the fluorescence decline compared to unvaccinated mice (p > 0.05). BCG-vaccinated mice that showed the reduced fluorescent readout also had a reduced bacterial burden in the lungs when challenged with Mtb. This supports the fluorescence activity in the skin as a reflection of vaccine induced functional pulmonary immune responses. This novel noninvasive approach allows for repeated measurements from the challenge site, providing a dynamic readout of vaccine induced responses over time. This BCG skin challenge model represents an important contribution to the ongoing development of controlled challenge models for TB.
Date Issued
2024-08
Date Acceptance
2024-07-25
Citation
PLoS Biology, 2024, 22 (8)
ISSN
1544-9173
Publisher
Public Library of Science (PLoS)
Journal / Book Title
PLoS Biology
Volume
22
Issue
8
Copyright Statement
© 2024 Krishnan et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39159267
Subjects
Animals
Bacterial Load
BCG Vaccine
Disease Models, Animal
Female
Humans
Mice
Mice, Inbred C57BL
Mycobacterium bovis
Mycobacterium tuberculosis
Skin
Tuberculosis
Tuberculosis Vaccines
Vaccination
Vaccine Efficacy
Publication Status
Published
Coverage Spatial
United States
Article Number
e3002766
Date Publish Online
2024-08-19