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VACCINE RESEARCH

Establishment of an Aerosol Challenge Model of Tuberculosis in Rhesus Macaques and an Evaluation of Endpoints for Vaccine Testing

S. A. Sharpe, H. McShane, M. J. Dennis, R. J. Basaraba, F. Gleeson, G. Hall, A. McIntyre, K. Gooch, S. Clark, N. E. R. Beveridge, E. Nuth, A. White, A. Marriott, S. Dowall, A. V. S. Hill, A. Williams, P. D. Marsh
S. A. Sharpe
1Health Protection Agency, Centre for Emergency Preparedness and Response, Porton Down, Salisbury, United Kingdom
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  • For correspondence: sally.sharpe@hpa.org.uk
H. McShane
2 the Jenner Institute, University of Oxford, Oxford, United Kingdom
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M. J. Dennis
1Health Protection Agency, Centre for Emergency Preparedness and Response, Porton Down, Salisbury, United Kingdom
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R. J. Basaraba
3Colorado State University, Fort Collins, Colorado
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F. Gleeson
4Churchill Hospital, Headington, Oxford, United Kingdom
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G. Hall
1Health Protection Agency, Centre for Emergency Preparedness and Response, Porton Down, Salisbury, United Kingdom
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A. McIntyre
3Colorado State University, Fort Collins, Colorado
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K. Gooch
1Health Protection Agency, Centre for Emergency Preparedness and Response, Porton Down, Salisbury, United Kingdom
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S. Clark
1Health Protection Agency, Centre for Emergency Preparedness and Response, Porton Down, Salisbury, United Kingdom
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N. E. R. Beveridge
2 the Jenner Institute, University of Oxford, Oxford, United Kingdom
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E. Nuth
3Colorado State University, Fort Collins, Colorado
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A. White
1Health Protection Agency, Centre for Emergency Preparedness and Response, Porton Down, Salisbury, United Kingdom
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A. Marriott
1Health Protection Agency, Centre for Emergency Preparedness and Response, Porton Down, Salisbury, United Kingdom
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S. Dowall
1Health Protection Agency, Centre for Emergency Preparedness and Response, Porton Down, Salisbury, United Kingdom
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A. V. S. Hill
2 the Jenner Institute, University of Oxford, Oxford, United Kingdom
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A. Williams
1Health Protection Agency, Centre for Emergency Preparedness and Response, Porton Down, Salisbury, United Kingdom
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P. D. Marsh
1Health Protection Agency, Centre for Emergency Preparedness and Response, Porton Down, Salisbury, United Kingdom
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DOI: 10.1128/CVI.00079-10
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  • FIG. 1.
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    FIG. 1.

    Experimental study design. PM, postmortem.

  • FIG. 2.
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    FIG. 2.

    Immune response to vaccination. (A) Frequency of PPD-specific IFN-γ-secreting cells measured by ELISpot assay. (B) Frequency of Ag85A-specific IFN-γ-secreting cells measured by ELISpot assay. (C) Quantity of IFN-γ secreted by PBMC during 6 days of culture of PBMC with PPD measured by ELISA. (D) Frequency of CD3+ T cells that secreted IFN-γ following stimulation with PPD. Vaccination with BCG at week 0 is indicated by the dotted line, and vaccination with MVA85A indicated by the dashed line at week 12.

  • FIG. 3.
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    FIG. 3.

    Polyfunctional T-cell analysis after vaccination. (A to C) Responding CD4+ T-cell populations following stimulation with Ag85A peptide pools. (D to H) Responding CD4+ T-cell populations following stimulation with PPD. (I and J) Responding CD8+ T cells following stimulation with PPD.

  • FIG. 4.
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    FIG. 4.

    Kaplan-Meier plot of survival of vaccinated and unvaccinated NHPs after challenge with M. tuberculosis.

  • FIG. 5.
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    FIG. 5.

    Measures of tuberculosis-induced pulmonary and clinical disease burden. (A) Ratio of lung volume to lesion volume determined by MR stereology. (B) Number of lesions in the lung enumerated by serial sectioning and manual counting. (C) Total pathology score determined by using a qualitative scoring system. (D) Scores attributed to the pulmonary component as part of the total pathology score. (E) Score attributed to the chest radiogram on the day of euthanasia. (F) Percent weight loss from peak postchallenge weight on the day of euthanasia. (G) ESR on the day of euthanasia. (H) Bacterial load in the lung.

  • FIG. 6.
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    FIG. 6.

    Immune responses after aerosol challenge with M. tuberculosis. (A to C) Frequency of mycobacterium-specific IFN-γ-secreting cells after challenge measured by ELISpot assay. (A) ESAT6; (B) Ag85A; (C) PPD. (D) Profile of IFN-γ secretion by PPD-stimulated whole blood measured by ELISA.

Tables

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  • TABLE 1.

    Aerosol challenge doses of M. tuberculosis delivered to rhesus macaques

    Vaccine group (regimen)AnimalPresented dose (CFU)Estimated retained dose (CFU)
    A (BCG + MVA85A)K201,29360
    K6189840
    K651,27160
    K6985840
    K791,29960
    K8681240
    B (BCG)K431,26360
    K441,36865
    K5093245
    K521,27560
    K5988440
    K8081740
    C (no vaccine)K321,28660
    K471,23760
    K5482140
    K6282140
  • TABLE 2.

    Statistical analysis of the differences between test groups using different vaccine efficacy readoutsa

    ReadoutP value
    Unvaccinated vs BCGUnvaccinated vs BCG-MVA85ABCG vs BCG-MVA85A
    Ratio of lesion vol to lung vol0.011b0.011b0.631
    No. of lesions0.024c0.1990.337
    Total pathology score0.017b0.1980.33
    Lung pathology score0.0790.0830.466
    Chest X ray0.1740.2850.371
    Bacterial load (CFU/g)0.1360.5220.297
    % wt loss0.1990.0550.747
    ESR0.0870.1570.515
    • ↵ a Mann-Whitney test results are shown.

    • ↵ b Vaccinated significantly lower than unvaccinated (P < 0.05).

    • ↵ c Vaccinated significantly higher than unvaccinated (P < 0.05).

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Establishment of an Aerosol Challenge Model of Tuberculosis in Rhesus Macaques and an Evaluation of Endpoints for Vaccine Testing
S. A. Sharpe, H. McShane, M. J. Dennis, R. J. Basaraba, F. Gleeson, G. Hall, A. McIntyre, K. Gooch, S. Clark, N. E. R. Beveridge, E. Nuth, A. White, A. Marriott, S. Dowall, A. V. S. Hill, A. Williams, P. D. Marsh
Clinical and Vaccine Immunology Jul 2010, 17 (8) 1170-1182; DOI: 10.1128/CVI.00079-10

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Establishment of an Aerosol Challenge Model of Tuberculosis in Rhesus Macaques and an Evaluation of Endpoints for Vaccine Testing
S. A. Sharpe, H. McShane, M. J. Dennis, R. J. Basaraba, F. Gleeson, G. Hall, A. McIntyre, K. Gooch, S. Clark, N. E. R. Beveridge, E. Nuth, A. White, A. Marriott, S. Dowall, A. V. S. Hill, A. Williams, P. D. Marsh
Clinical and Vaccine Immunology Jul 2010, 17 (8) 1170-1182; DOI: 10.1128/CVI.00079-10
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    • ABSTRACT
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KEYWORDS

Aerosols
Disease Models, Animal
Inhalation
Mycobacterium tuberculosis
tuberculosis vaccines
Tuberculosis, Pulmonary

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