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

• Published in: Frontiers in immunology Vol. 13; p. 985938
• Main Authors: Rakshit, Srabanti, Adiga, Vasista, Ahmed, Asma, Parthiban, Chaitra, Chetan Kumar, Nirutha, Dwarkanath, Pratibha, Shivalingaiah, Sudarshan, Rao, Srishti, D'Souza, George, Dias, Mary, Maguire, Thomas J A, Doores, Katie J, Zoodsma, Martijn, Geckin, Busranur, Dasgupta, Prokar, Babji, Sudhir, van Meijgaarden, Krista E, Joosten, Simone A, Ottenhoff, Tom H M, Li, Yang, Netea, Mihai G, Stuart, Kenneth D, De Rosa, Stephen C, McElrath, M Juliana, Vyakarnam, Annapurna
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 04.10.2022
• Subjects: Adjuvants, Immunologic; antibodies; BCG; BCG Vaccine; Chromatin; COVID-19 - prevention & control; COVID-19 Vaccines - immunology; Humans; Immunity; Immunology; Interleukin-2; SARS-CoV-2; T cell; trained immunity; Tumor Necrosis Factor-alpha; Vaccination; Young Adult; SARS-CoV-2; antibodies; trained immunity; T cell; BCG
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.985938

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™, an efficacious and the most widely distributed vaccine in India. We compared COVISHIELD™ 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™ 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™ booster, including distinct CD4+IFN-γ+ and CD4+IFN-γ- effector memory (EM) subsets co-expressing IL-2, TNF-α and activation induced markers (AIM) CD154/CD137 as well as CD8+IFN-γ+ EM,TEMRA (T cell EM expressing RA) subset combinations co-expressing TNF-α 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-1β and TNF-α 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™ 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.