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

Abstract

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.

Interim results from comparison of immune responses elicited by an inactivated and a vectored SARS-CoV-2 vaccine in seronegative and seropositive participants in India

“…Thirdly and in parallel to the antibody responses, in the earliest cohort (BBH), Covishield™ elicited a higher frequency of both CD4 and CD8 T cells while Covaxin ® elicited mainly CD4 T cell responses. The frequencies and quality of cytokine-expressing T cells that we report in the seronegative Covishield™ arm are broadly consistent with prior studies, though the dosing interval in those studies was only 4 weeks 14,15 . The poor CD8 responses from Covaxin ® is not unexpected given that TLR7/8 agonists need to be physically linked to the antigen in order to induce CD8 T cell responses in mice 16 , which is not the case with Covaxin ® .…”

BCG Vaccination of Health Care Workers Does Not Reduce SARS-CoV-2 Infections nor Infection Severity or Duration: a Randomized Placebo-Controlled Trial

“…This finding is not robust, because the number of participants with a SARS-CoV-2 infection in the first 3 months of the study was small and the overall anti-S1 antibody concentrations at month 3 were low. However, additional evidence for BCG potentially acting as an adjuvant comes from human challenge studies in which participants received BCG (re)vaccination followed by influenza or COVID-19 vaccination ( 7 , 28 ).…”

BCG vaccination of healthcare workers does not reduce SARS-CoV-2 infections nor infection severity or duration: a randomised placebo-controlled trial

“…However, additional evidence for BCG potentially acting as an adjuvant comes from human challenge studies in which participants received BCG (re)vaccination followed by influenza or COVID-19 vaccination. 7,32 Important strengths of this trial are the large number and comprehensive nature of the endpoints.…”