A single dose, BCG-adjuvanted COVID-19 vaccine provides sterilizing immunity against SARS-CoV-2 infection in mice

Counoupas, Claudio; Johansen, Matt D.; Stella, Alberto O.; Nguyen, Duc H.; Ferguson, Angela L.; Aggarwal, Anupriya; Bhattacharyya, Nayan D.; Grey, Alice; Patel, Karishma; Siddiquee, Rezwan; Stewart, Erica L.; Feng, Carl G.; Hansbro, Nicole G.; Palendira, Umaimainthan; Steain, Megan C.; Saunders, Bernadette M.; Low, Jason K. K.; Mackay, Joel P.; Kelleher, Anthony D.; Britton, Warwick J.; Turville, Stuart G; Hansbro, Philip M.; Triccas, James A.

Global control of COVID-19 requires broadly accessible vaccines that are effective against SARS-CoV-2 variants. In this report, we exploit the immunostimulatory properties of bacille Calmette-Guérin (BCG), the existing tuberculosis vaccine, to deliver a vaccination regimen with potent SARS-CoV-2-specific protective immunity. Combination of BCG with a stabilized, trimeric form of SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the blood of vaccinated mice, that was further augmented by the addition of alum. This vaccine formulation, BCG:CoVac, induced high-titre SARS-CoV-2 neutralizing antibodies (NAbs) and Th1-biased cytokine release by vaccine-specific T cells, which correlated with the early emergence of T follicular helper cells in local lymph nodes and heightened levels of antigen-specific plasma B cells after vaccination. Vaccination of K18-hACE2 mice with a single dose of BCG:CoVac almost completely abrogated disease after SARS-CoV-2 challenge, with minimal inflammation and no detectable virus in the lungs of infected animals. Boosting BCG:CoVac-primed mice with a heterologous vaccine further increased SARS-CoV-2-specific antibody responses, which effectively neutralized B.1.1.7 and B.1.351 SARS-CoV-2 variants of concern. These findings demonstrate the potential for BCG-based vaccination to protect against major SARS-CoV-2 variants circulating globally.