Evidence for the heterologous benefits of prior BCG vaccination on COVISHIELD (TM) vaccine-induced immune responses in SARS-CoV-2 seronegative young Indian adults

This proof-of-concept study tested if prior BCG revaccination can qualitatively and quantitively enhance antibody and T-cell responses induced by Oxford/AstraZeneca ChAdOx1nCoV-19 or COVISHIELD (TM), an efficacious and the most widely distributed vaccine in India. We compared COVISHIELD (TM) induced longitudinal immune responses in 21 BCG re-vaccinees (BCG-RV) and 13 BCG-non-revaccinees (BCG-NRV), all of whom were BCG vaccinated at birth; latent tuberculosis negative and SARS-CoV-2 seronegative prior to COVISHIELD (TM) vaccination. Compared to BCG-NRV, BCG-RV displayed significantly higher and persistent spike-specific neutralizing (n) Ab titers and polyfunctional CD4+ and CD8+ T-cells for eight months post COVISHIELD (TM) booster, including distinct CD4+IFN-gamma+ and CD4+IFN-gamma- effector memory (EM) subsets co-expressing IL-2, TNF-alpha and activation induced markers (AIM) CD154/CD137 as well as CD8+IFN-gamma+ EM,TEMRA (T cell EM expressing RA) subset combinations co-expressing TNF-alpha and AIM CD137/CD69. Additionally, elevated nAb and T-cell responses to the Delta mutant in BCG-RV highlighted greater immune response breadth. Mechanistically, these BCG adjuvant effects were associated with elevated markers of trained immunity, including higher IL-1 beta and TNF-alpha expression in CD14+HLA-DR+monocytes and changes in chromatin accessibility highlighting BCG-induced epigenetic changes. This study provides first in-depth analysis of both antibody and memory T-cell responses induced by COVISHIELD (TM) in SARS-CoV-2 seronegative young adults in India with strong evidence of a BCG-induced booster effect and therefore a rational basis to validate BCG, a low-cost and globally available vaccine, as an adjuvant to enhance heterologous adaptive immune responses to current and emerging COVID-19 vaccines.