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Frontiers in immunology
2021;12 801799.

Influence of Aerosol Delivered BCG Vaccination on Immunological and Disease Parameters Following SARS-CoV-2 Challenge in Rhesus Macaques.

Andrew D White, Laura Sibley, Charlotte Sarfas, Alexandra L Morrison, Kevin Bewley, Colin Churchward, Susan Fotheringham, Konstantinos Gkolfinos, Karen Gooch, Alastair Handley, Holly E Humphries, Laura Hunter, Chelsea Kennard, Stephanie Longet, Adam Mabbutt, Miriam Moffatt, Emma Rayner, Tom Tipton, Robert Watson, Yper Hall, Mark Bodman-Smith, Fergus Gleeson, Mike Dennis, Francisco J Salguero, Miles Carroll, Helen McShane, William Cookson, Julian Hopkin, Sally Sharpe
Author Information
  1. Andrew D White: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  2. Laura Sibley: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  3. Charlotte Sarfas: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  4. Alexandra L Morrison: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  5. Kevin Bewley: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  6. Colin Churchward: National Heart and Lung Institute, Imperial College London, London, United Kingdom.
  7. Susan Fotheringham: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  8. Konstantinos Gkolfinos: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  9. Karen Gooch: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  10. Alastair Handley: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  11. Holly E Humphries: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  12. Laura Hunter: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  13. Chelsea Kennard: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  14. Stephanie Longet: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  15. Adam Mabbutt: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  16. Miriam Moffatt: National Heart and Lung Institute, Imperial College London, London, United Kingdom.
  17. Emma Rayner: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  18. Tom Tipton: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  19. Robert Watson: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  20. Yper Hall: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  21. Mark Bodman-Smith: Infection and Immunity Research Institute, St George's University of London, London, United Kingdom.
  22. Fergus Gleeson: Department of Oncology, Churchill Hospital, Oxford, United Kingdom.
  23. Mike Dennis: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  24. Francisco J Salguero: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  25. Miles Carroll: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
  26. Helen McShane: The Jenner Institute, University of Oxford, Oxford, United Kingdom.
  27. William Cookson: National Heart and Lung Institute, Imperial College London, London, United Kingdom.
  28. Julian Hopkin: College of Medicine, Institute of Life Science, Swansea University, Swansea, United Kingdom.
  29. Sally Sharpe: Research and Evaluation, United Kingdom Health Security Agency, Salisbury, United Kingdom.
PMID: 35222355 DOI: 10.3389/fimmu.2021.801799

Abstract

The tuberculosis vaccine, Bacille Calmette-Guerin (BCG), also affords protection against non-tuberculous diseases attributable to heterologous immune mechanisms such as trained innate immunity, activation of non-conventional T-cells, and cross-reactive adaptive immunity. Aerosol vaccine delivery can target immune responses toward the primary site of infection for a respiratory pathogen. Therefore, we hypothesised that aerosol delivery of BCG would enhance cross-protective action against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and be a deployable intervention against coronavirus disease 2019 (COVID-19). Immune parameters were monitored in vaccinated and unvaccinated rhesus macaques for 28 days following aerosol BCG vaccination. High-dose SARS-CoV-2 challenge was applied by intranasal and intrabronchial instillation and animals culled 6-8 days later for assessment of viral, disease, and immunological parameters. Mycobacteria-specific cell-mediated immune responses were detected following aerosol BCG vaccination, but SARS-CoV-2-specific cellular- and antibody-mediated immunity was only measured following challenge. Early secretion of cytokine and chemokine markers associated with the innate cellular and adaptive antiviral immune response was detected following SARS-CoV-2 challenge in vaccinated animals, at concentrations that exceeded titres measured in unvaccinated macaques. Classical CD14+ monocytes and Vδ2 γδ T-cells quantified by whole-blood immunophenotyping increased rapidly in vaccinated animals following SARS-CoV-2 challenge, indicating a priming of innate immune cells and non-conventional T-cell populations. However, viral RNA quantified in nasal and pharyngeal swabs, bronchoalveolar lavage (BAL), and tissue samples collected at necropsy was equivalent in vaccinated and unvaccinated animals, and in-life CT imaging and histopathology scoring applied to pulmonary tissue sections indicated that the disease induced by SARS-CoV-2 challenge was comparable between vaccinated and unvaccinated groups. Hence, aerosol BCG vaccination did not induce, or enhance the induction of, SARS-CoV-2 cross-reactive adaptive cellular or humoral immunity, although an influence of BCG vaccination on the subsequent immune response to SARS-CoV-2 challenge was apparent in immune signatures indicative of trained innate immune mechanisms and primed unconventional T-cell populations. Nevertheless, aerosol BCG vaccination did not enhance the initial clearance of virus, nor reduce the occurrence of early disease pathology after high dose SARS-CoV-2 challenge. However, the heterologous immune mechanisms primed by BCG vaccination could contribute to the moderation of COVID-19 disease severity in more susceptible species following natural infection.

Keywords

Aerosol BCG vaccination COVID-19 SARS-CoV-2 cross-protection macaque non-specific trained immunity

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MeSH Term

Adaptive Immunity
Aerosols
Animals
BCG Vaccine
COVID-19
Cross Reactions
DNA, Viral
Disease Models, Animal
Humans
Immunity, Heterologous
Immunity, Innate
Immunomodulation
Lymphocyte Activation
Macaca mulatta
Receptors, Antigen, T-Cell, gamma-delta
SARS-CoV-2
T-Lymphocytes
Vaccination

Chemicals

Aerosols
BCG Vaccine
DNA, Viral
Receptors, Antigen, T-Cell, gamma-delta
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 9

Word Cloud

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