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Apr 25, 2020;12 (5):

Protective Efficacy of Inhaled BCG Vaccination Against Ultra-Low Dose Aerosol Challenge in Rhesus Macaques.

Andrew D White, Charlotte Sarfas, Laura S Sibley, Jennie Gullick, Simon Clark, Emma Rayner, Fergus Gleeson, Martí Català, Isabel Nogueira, Pere-Joan Cardona, Cristina Vilaplana, Mike J Dennis, Ann Williams, Sally A Sharpe
Author Information
  1. Andrew D White: Public Health England, National Infection Service, Porton Down, Salisbury SP4 0JG, UK. ORCID
  2. Charlotte Sarfas: Public Health England, National Infection Service, Porton Down, Salisbury SP4 0JG, UK.
  3. Laura S Sibley: Public Health England, National Infection Service, Porton Down, Salisbury SP4 0JG, UK.
  4. Jennie Gullick: Public Health England, National Infection Service, Porton Down, Salisbury SP4 0JG, UK.
  5. Simon Clark: Public Health England, National Infection Service, Porton Down, Salisbury SP4 0JG, UK.
  6. Emma Rayner: Public Health England, National Infection Service, Porton Down, Salisbury SP4 0JG, UK.
  7. Fergus Gleeson: The Churchill Hospital, Headington, Oxford OX3 7LE, UK.
  8. Martí Català: Comparative Medicine and Bioimage Centre of Catalonia (CMCiB), Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, 08916 Catalonia, Spain. ORCID
  9. Isabel Nogueira: Servei de Radiodiagnòstic, Hospital Universitari Germans Trias i Pujol, Badalona, 08916 Catalonia, Spain.
  10. Pere-Joan Cardona: Unitat de Tuberculosi Experimental, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, CIBERES, 28029 Madrid, Spain. ORCID
  11. Cristina Vilaplana: Unitat de Tuberculosi Experimental, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, CIBERES, 28029 Madrid, Spain.
  12. Mike J Dennis: Public Health England, National Infection Service, Porton Down, Salisbury SP4 0JG, UK.
  13. Ann Williams: Public Health England, National Infection Service, Porton Down, Salisbury SP4 0JG, UK.
  14. Sally A Sharpe: Public Health England, National Infection Service, Porton Down, Salisbury SP4 0JG, UK. ORCID
PMID: 32344890 DOI: 10.3390/pharmaceutics12050394

Abstract

Ten million cases of tuberculosis (TB) were reported in 2018 with a further 1.5 million deaths attributed to the disease. Improved vaccination strategies are urgently required to tackle the ongoing global TB epidemic. In the absence of a validated correlate of protection, highly characterised pre-clinical models are required to assess the protective efficacy of new vaccination strategies. In this study, we demonstrate the application of a rhesus macaque ultra-low dose (ULD) aerosol challenge model for the evaluation of TB vaccination strategies by directly comparing the immunogenicity and efficacy of intradermal (ID) and aerosol BCG vaccination delivered using a portable vibrating mesh nebulizer (VMN). Aerosol- and ID-delivered Bacille Calmette-Guérin (BCG) induced comparable frequencies of IFN-γ spot forming units (SFU) measured in peripheral blood mononuclear cells (PBMCs) by ELISpot, although the induction of IFN-γ SFU was significantly delayed following aerosol immunisation. This delayed response was also apparent in an array of secreted pro-inflammatory and chemokine markers, as well as in the frequency of antigen-specific cytokine producing CD4 and CD8 T-cells measured by multi-parameter flow cytometry. Interrogation of antigen-specific memory T-cell phenotypes revealed that vaccination-induced CD4 and CD8 T-cell populations primarily occupied the central memory (TCM) and transitional effector memory (TransEM) phenotype, and that the frequency of CD8 TCM and TransEM populations was significantly higher in aerosol BCG-vaccinated animals in the week prior to infection. The total and lung pathology measured following challenge was significantly lower in vaccinated animals relative to the unvaccinated control group and pathology measured in extra-pulmonary tissues was significantly reduced in aerosol BCG-vaccinated animals, relative to the ID-immunised group. Similarly, significantly fewer viable CFU were recovered from the extra-pulmonary tissues of aerosol BCG-vaccinated macaques relative to unvaccinated animals. In this study, a rhesus macaque ULD aerosol challenge model was applied as a refined and sensitive system for the evaluation of TB vaccine efficacy and to confirm that aerosol BCG vaccination delivered by portable VMN can confer a significant level of protection that is equivalent, and by some measures superior, to intradermal BCG vaccination.

Keywords

BCG T-cell memory aerosol vaccination immunogenicity macaque non-human primate tuberculosis vaccine

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