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

• Published in: Frontiers in immunology Vol. 12; p. 801799
• Main Authors: White, Andrew D, Sibley, Laura, Sarfas, Charlotte, Morrison, Alexandra L, Bewley, Kevin, Churchward, Colin, Fotheringham, Susan, Gkolfinos, Konstantinos, Gooch, Karen, Handley, Alastair, Humphries, Holly E, Hunter, Laura, Kennard, Chelsea, Longet, Stephanie, Mabbutt, Adam, Moffatt, Miriam, Rayner, Emma, Tipton, Tom, Watson, Robert, Hall, Yper, Bodman-Smith, Mark, Gleeson, Fergus, Dennis, Mike, Salguero, Francisco J, Carroll, Miles, McShane, Helen, Cookson, William, Hopkin, Julian, Sharpe, Sally
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 09-02-2022
• Subjects: Adaptive Immunity; Aerosol BCG vaccination; Aerosols; Animals; BCG Vaccine - immunology; COVID-19; COVID-19 - immunology; Cross Reactions; cross-protection; Disease Models, Animal; DNA, Viral - analysis; Humans; Immunity, Heterologous; Immunity, Innate; Immunology; Immunomodulation; Lymphocyte Activation; Macaca mulatta; macaque; non-specific; Receptors, Antigen, T-Cell, gamma-delta - metabolism; SARS-CoV-2; SARS-CoV-2 - physiology; T-Lymphocytes - immunology; Vaccination; COVID-19; macaque; non-specific; SARS-CoV-2; Aerosol BCG vaccination; trained immunity; cross-protection
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.801799

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.