Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), a respiratory infection for which no specific vaccine is currently available. Studies show that individuals who have recovered from COVID-19 have SARS-CoV-2-specific T cell memory and T cell dysfunction, and hence T cells can play a pivotal role in mounting a robust immune response against COVID-19.
Both CD4+ and CD8+ T cells have been shown to have a role in COVID-19 with CD4+ T cells responsible for the secretion of cytokines interferon-gamma (IFN-g), interleukin-2 (IL-2), and tumor necrosis factor (TNF), and CD8+ T cells affecting direct target cell lysis by the secretion of perforin and granzymes, apart from secreting TNF and IFN-g. Cross-reactive T cells between SARS-CoV-2 and other human coronaviruses have been previously identified, suggesting the possibility of T cell cross-protection in COVID-19.
The potential link between BCG vaccination and protection against severe COVID-19
Several epidemiological studies suggest that the Bacillus Calmette-Guérin (BCG) vaccine may offer protection against COVID-19. BCG vaccine contains live attenuated Mycobacterium bovis, and is typically used as a vaccination against tuberculosis (TB). Like other vaccines, BCG can induce cross-protection against other pathogens as well. This cross-protective effect has been shown to reduce respiratory tract infections in adults and all-cause mortality in children.
However, the mechanism by which the BCG vaccine elicits a SARS-CoV-2-specific T cell response is not clear. Currently, there are over 15 clinical trials in progress to determine if BCG vaccination can help reduce or prevent the severity of COVID-19 disease.
Investigating the ability of BCG vaccine to produce cross-reactive T cells specific to SARS-CoV-2
Recently, researchers from the Monash University and Monash Medical Centre, Clayton, Victoria, Australia, investigated whether peptide sensitization using BCG can produce cross-reactive T cells specific to SARS-CoV-2. Their study is published on the preprint server, medRxiv*.
In this work, the researchers identified 8 BCG-derived peptides in silico with considerable sequence homology to either SARS-CoV-2 NSP3 or NSP13-derived peptides. They used an in vitro co-culture system and showed that human CD4+ and CD8+ T cells primed with a BCG-derived peptide developed high reactivity to its corresponding SARS-CoV-2-derived peptide.
BCG peptides helped enhance T cell reactivity to SARS-CoV-2 peptides
Owing to the human leukocyte antigen (HLA) differences between individuals, not all persons developed immune responses to all 8 BCG-derived peptides. Nevertheless, all 20 individuals primed with BCG-derived peptides developed improved T cell reactivity to 7 of 8 SARS-CoV-2-derived peptides.
TNF IFNγ proportions of responder individuals. BCG-primed individuals who responded to SARS-CoV-2-peptide restimulation mostly exhibited a strong IFNγ signature with a lower proportion of TNF, although some individuals showed a dominant TNF response. Across individuals and peptide pairs, a variable proportion of IFNγ SP, TNF SP and IFNγ, TNF DP was observed. A selection of 6 individuals CD4+ and CD8+ responses (of N = 20 tested) against 5 peptide pairs (PP) of 8 peptide pairs tested. IFNγ single positive (SP) – proportion of cells producing IFNγ and not TNF. TNF SP – proportion of cells producing TNF and not IFNγ. IFNγ TNF double positive (DP) – proportion of cells producing TNF and not IFNγ.
Cytokine production patterns varied between individuals and peptide pairs, as is clear from the complex pattern of T cell cytokine expression and phenotypes that BCG vaccination produces. The IFN-g and TNF response was mixed, as some individuals produced either IFN-g or TNF in response to a particular peptide pair, and others produced both. These observations agree with previously reported responses in COVID-19.
The researchers also observed that CD8+ T cells primed with BCG-derived peptides showed an enhanced perforin expression upon SARS-CoV-2 restimulation compared to the control primed cells.
“Cross-reactive perforin expression in responders was significantly increased across all 8 peptide pairs with a mean fold increase ranging from 1.9-fold (PP1) to 47.2-fold (PP4).”
Findings support epidemiological observations suggesting BCG vaccination protects COVID-19
The main objective of this study was to show that the observed benefits of BCG vaccination in reducing the severity of COVID-19 can be ascribed to T cell cross-reactivity. Overall, the study results suggest that CD4+ and CD8+ T cells specific for BCG-derived peptides are cross-reactive to SARS-CoV-2-derived peptides. These findings offer a mechanistic explanation for the epidemiologic observation that BCG vaccination protects COVID-19.
Based on the results, the authors endorse the use of BCG vaccination to trigger cross-reactive SARS-CoV-2-specific T cell response. They also support the continuation of ongoing clinical trials across the world, especially in individuals at high-risk of contracting SARS-CoV-2.
“These data provide a mechanistic explanation for the observed negative epidemiological associations between BCG vaccinations and COVID-19 severity and mortality and support the continuation of clinical trials around the world, particularly in people at high risk of contracting SARS-CoV-2.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.