5179e766b5c04e39108d4c0b28ef9e3b pmc_9961649.pdf b44680e711ea570de146a53fde4edb39bef6395e pmc_9961649.pdf 9063ec722faf1361e69006149ff52f11345ce88981f9c062bd8b831b69ec1eeb pmc_9961649.pdf Title: Surveillance of Daughter Micronodule Formation Is a Key Factor for Vaccine Evaluation Using Experimental Infection Models of Tuberculosis in Macaques Subject: Tuberculosis (TB) is still a major worldwide health problem and models using non-human primates (NHP) provide the most relevant approach for vaccine testing. In this study, we analysed CT images collected from cynomolgus and rhesus macaques following exposure to ultra-low dose Mycobacterium tuberculosis (Mtb) aerosols, and monitored them for 16 weeks to evaluate the impact of prior intradermal or inhaled BCG vaccination on the progression of lung disease. All lesions found (2553) were classified according to their size and we subclassified small micronodules (<4.4 mm) as ‘isolated’, or as ‘daughter’, when they were in contact with consolidation (described as lesions 4.5 mm). Our data link the higher capacity to contain Mtb infection in cynomolgus with the reduced incidence of daughter micronodules, thus avoiding the development of consolidated lesions and their consequent enlargement and evolution to cavitation. In the case of rhesus, intradermal vaccination has a higher capacity to reduce the formation of daughter micronodules. This study supports the ‘Bubble Model’ defined with the C3HBe/FeJ mice and proposes a new method to evaluate outcomes in experimental models of TB in NHP based on CT images, which would fit a future machine learning approach to evaluate new vaccines. Keywords: tuberculosis; BCG vaccine; aerosol vaccination; non-human primate; macaque; bubble model; computed tomography scanner Author: Isabel Nogueira, Martí Català, Andrew D. White, Sally A Sharpe, Jordi Bechini, Clara Prats, Cristina Vilaplana and Pere-Joan Cardona Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Feb 2 08:06:50 2023 CET ModDate: Thu Feb 2 08:09:47 2023 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 21 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 7168906 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- PYPZKK+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 KORLVE+VnURWPalladioL Type 1 Custom yes yes no 15 0 KXYZGR+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 OUZVMM+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 SQLIRU+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 DJQPZW+CMSY10 Type 1 Builtin yes yes no 32 0 UXHOAG+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 51 0 OQIVQT+EURM10 Type 1 Builtin yes yes no 76 0 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KLDCNB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 278 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-07-08 02:36:03 CEST RepresentationInformation: pmc_9961649.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-02 02:17:18 CET Size: 7168906 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 588 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Animals Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Experimental Groups Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: CT Images Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: TB Lung Lesions Analysis from CT Images Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Statistical Assessment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Children: Item: Title: Preliminary Images’ Assessment and Anatomy Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Mtb-Induced Disease Is Worse in Rhesus Macaques Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: BCG Vaccination in Rhesus Macaques Reduces the Number of Lesions, Although Intradermal Vaccination Better Controls Daughter Micronodules Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Cavitation Is More Probable in Larger Lesions and Contact with Pleura Appear to Impact on TB Progression Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Info: Title: Surveillance of Daughter Micronodule Formation Is a Key Factor for Vaccine Evaluation Using Experimental Infection Models of Tuberculosis in Macaques Author: Isabel Nogueira, Martí Català, Andrew D. White, Sally A Sharpe, Jordi Bechini, Clara Prats, Cristina Vilaplana and Pere-Joan Cardona Subject: Tuberculosis (TB) is still a major worldwide health problem and models using non-human primates (NHP) provide the most relevant approach for vaccine testing. In this study, we analysed CT images collected from cynomolgus and rhesus macaques following exposure to ultra-low dose Mycobacterium tuberculosis (Mtb) aerosols, and monitored them for 16 weeks to evaluate the impact of prior intradermal or inhaled BCG vaccination on the progression of lung disease. All lesions found (2553) were classified according to their size and we subclassified small micronodules (<4.4 mm) as ‘isolated’, or as ‘daughter’, when they were in contact with consolidation (described as lesions 4.5 mm). Our data link the higher capacity to contain Mtb infection in cynomolgus with the reduced incidence of daughter micronodules, thus avoiding the development of consolidated lesions and their consequent enlargement and evolution to cavitation. In the case of rhesus, intradermal vaccination has a higher capacity to reduce the formation of daughter micronodules. This study supports the ‘Bubble Model’ defined with the C3HBe/FeJ mice and proposes a new method to evaluate outcomes in experimental models of TB in NHP based on CT images, which would fit a future machine learning approach to evaluate new vaccines. 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