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

Abstract

Next-generation vaccines that are safe, effective and with equitable access globally are required to prevent SARS-CoV-2 transmission at a population level. One strategy that has gained significant interest is to ‘repurpose’ existing licensed vaccines for use against COVID-19. In this report, we have exploited the immunostimulatory properties of bacille Calmette-Guérin (BCG), the vaccine for tuberculosis, to develop a SARS-CoV-2-specific and highly immunogenic vaccine candidate. Combination of BCG with a stabilized, trimeric form of the SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the sera of vaccinated mice, which could be further augmented by the addition of alum. This vaccine formulation, termed BCG:CoVac, induced a Th1-biased response both in terms of IgG antibody subclass and cytokine release by vaccine-specific CD4+ and CD8+ T cells. A single dose of BCG:CoVac was sufficient to induce high-titre SARS-CoV-2 neutralizing antibodies (NAbs) that were detectable as early as 2 weeks post-vaccination; NAb levels were greater than that seen in the sera of SARS-CoV-2-infected individuals. Boosting of BCG:CoVac-primed mice with a heterologous vaccine combination (spike protein plus alum) could further increase SARS-CoV-2 spike protein-specific antibody response. BCG:CoVac would be broadly applicable for all populations susceptible to SARS-CoV-2 infection and in particular could be readily incorporated into current vaccine schedules in countries where BCG is currently used.ImportanceEffective distribution of vaccine to low- and middle-income countries is critical for the control of the COVID-19 pandemic. To achieve this, vaccines must offer effective protective immunity yet should be cheap to manufacture and meet cold chain management requirements. This study describes a unique COVID-19 vaccine candidate, termed BCG:CoVac, that when delivered as a single dose induces potent SARS-CoV-2 specific immunity in mice, particularly through generation of high-titre, anti-viral neutralising antibodies. BCG:CoVac is built on safe and well-characterised vaccine components: 1) the BCG vaccine, used for control of tuberculosis since 1921 which also has remarkable ‘off target’ effects, protecting children and the elderly against diverse respiratory viral infections; 2) Alhydrogel adjuvant (Alum), a low cost, globally accessible vaccine adjuvant with an excellent safety record in humans (part of >20 licensed human vaccines and in use >70 years); 3) Stabilized, trimeric SARS-CoV-2 spike protein, which stimulates immune specificity for COVID-19. Further assessment in humans will determine if BCG:CoVac can impart protective immunity against not only SARS-CoV-2, but also other respiratory infections where BCG has known efficacy.

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

“…The COVID-19 outbreak has refocused interest in the crossprotective benefits of BCG in two ways. First, several clinical trials are designed to test if BCG, and indeed more widely available vaccines such as the Influenza, OPV, MMR, Varicella Zoster with reported cross protective benefits, can potentially reduce SARS-CoV-2 infection incidence and disease severity (19)(20)(21)(22)(23)(24), with the most compelling protective evidence for BCG emerging from murine live challenge studies (25,26). Emerging human controlled clinical trial data however, report variable efficacy of BCG vaccination in protecting against SARS-CoV-2 infection (27-30) with rhesus macaques live challenge studies showing no protective effect of BCG (31).…”

The BCG Vaccine for COVID-19: First Verdict and Future Directions

“…Such therapeutic vaccination strategy addresses the hypothesis that the induction of both innate and viral-specific immune responses might be beneficial during active SARS-CoV-2 antigenic exposure and provides further rationale for combining BCG-based vaccines with other approved vaccines. Recent preclinical evidence corroborated this notion: BCG:CoVac, a formulation combining BCG with a stabilized form of the spike (S) protein resulted in the stimulation of SARS-CoV-2-specific antibody and T-cell responses in mice at the levels equivalent to or exceeding responses elicited by current clinical-stage vaccines in the murine models (37). Further demonstrating complex interplay between innate and adaptive immunity, a randomized clinical trial of topical BCG in children having common warts caused by the human papillomavirus, showed 65% complete responses, with no response detected in the control group (38).…”

The COVID-19/Tuberculosis Syndemic and Potential Antibody Therapy for TB Based on the Lessons Learnt From the Pandemic

“…These findings may provide a fundamental platform to investigate BCG’s efficacy against COVID-19 elderly patients. Another important preclinical study investigated the combined therapeutic potentials of BCG and COVID-19 vaccines against the SARS-CoV-2 virus in vivo ( 101 ). It would be beneficial for the investigation to be expanded in clinical settings as the outcome would not only provide essential findings on protection against COVID-19 but most importantly on the dual protection during TB-COVID-19 coinfection which is crucial in high TB burden countries.…”