BCG activation of trained immunity is associated with induction of cross reactive COVID-19 antibodies in a BCG vaccinated population

Background During the current COVID-19 pandemic, the rate of morbidity and mortality was considerably lower in BCG vaccinated countries like Pakistan. BCG has been shown to provide cross protection to both disseminated TB as well as non related viral infections in BCG vaccinated children which is consistent with COVID-19 morbidity in the younger age group. Recently, this cross protection was attributed to trained immunity (TI) associated with BCG recall responses in the innate arm of the immune system. Little is known about the longevity of BCG Trained Immunity (TI) beyond early childhood. Objective To assess the BCG-induced recall responses in healthy individuals by cytokines secreted from the TI network and its potential role in providing cross-protection against COVID-19 and other viral infections. Study Design In this cross-sectional study, healthy young adults and adolescents (n=20) were recruited from 16–40 years of age, with no prior history of TB treatment, autoimmune, or chronic inflammatory condition. Methods BCG-induced cytokine responses were assessed using prototypic markers for cells of the TI network {macrophages [M1 (TNFα, IFNγ), M2 (IL10)], NK (IL2), Gamma delta (γδ) T (IL17, IL4)} and SARS CoV2 IgG antibodies against RBD using short-term (12 hrs.) cultures assay. Results Significant differences were observed in the magnitude of recall responses to BCG with macrophage cytokines showing the highest mean levels of TNFα (9148 pg/ml) followed by IL10 (488 pg/ml) and IFNγ (355 pg/ml). The ratio of unstimulated vs.BCG-stimulated cytokines was 132 fold higher for TNFα, 40 fold for IL10, and 27 fold for IFNγ. Furthermore, SARS-CoV-2 antibodies were also detected in unstimulated plasma which showed cross reactivity with BCG. Conclusion The presence of cross reactive antibodies to SARS-CoV-2 and the relative ratio of pro-and anti-inflammatory cytokines secreted by activated TI cellular network may play a pivotal role in protection in the early stages of infection as observed during the COVID-19 pandemic in the younger age groups resulting in lower morbidity and mortality. ### Competing Interest Statement The authors have declared no competing interest.