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.
Highlights
The emergence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), instigated a worldwide pandemic that has resulted in more than four million deaths to date [1]
The weight changes measured in aerosol BCGvaccinated macaques following SARS-CoV-2 challenge was not significantly different to the weight loss observed in unvaccinated animals as determined by comparison of area under the curve values calculated from the post-challenge phase of the experiment (p = 0.66)
The impressive pace at which these SARS-CoV-2-specific vaccines have become available has inevitably reduced the focus on Bacille Calmette-Guerin (BCG) as a deployable intervention or therapeutic to aid control of the COVID-19 pandemic
Summary
The emergence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), instigated a worldwide pandemic that has resulted in more than four million deaths to date [1]. BCG vaccination has been associated with non-specific protection against nontuberculous childhood diseases and has been linked to a reduction in the incidence of all-cause childhood mortality and morbidity [7–9]. These non-specific, cross-protective effects have been attributed to heterologous immune mechanisms such as trained innate immunity brought about by epigenetic reprogramming of monocyte and natural killer cell populations [10, 11], activation of non-conventional T-cells [12], and in the context of SARS-CoV-2, the induction of cross-reactive CD4+ and CD8+ T-cells responsive to homologous peptide sequences found in BCG and SARS-CoV-2 proteins [13]. The potential for BCG vaccination-induced cross-protection to influence the current and future pandemic situations has become a vibrant topic of debate [4, 15–17], and several clinical trials designed to determine the ability of ID BCG vaccination or revaccination to prevent SARS-COV-2 infection, or reduce the severity of COVID-19, are underway [18]
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