The HyVac4 subunit vaccine efficiently boosts BCG-primed anti-mycobacterial protective immunity.

Background: The current vaccine against tuberculosis (TB), BCG, has failed to control TB worldwide and the protective efficacy is moreover limited to 10–15 years. A vaccine that could efficiently boost a BCG-induced immune response and thus prolong protective immunity would therefore have a significant impact on the global TB-burden. Methods/Findings: In the present study we show that the fusion protein HyVac4 (H4), consisting of the mycobacterial antigens Ag85B and TB10.4, given in the adjuvant IC31H or DDA/MPL effectively boosted and prolonged immunity induced by BCG, leading to improved protection against infection with virulent M. tuberculosis (M.tb). Increased protection correlated with an increased percentage of TB10.4 specific IFNc/TNFa/IL-2 or TNFa/IL-2 producing CD4 T cells at the site of infection. Moreover, this vaccine strategy did not compromise the use of ESAT-6 as an accurate correlate of disease development/vaccine efficacy. Indeed both CD4 and CD8 ESAT-6 specific T cells showed significant correlation with bacterial levels. Conclusions/Significance: H4-IC31H can efficiently boost BCG-primed immunity leading to an increased protective antiM.tb immune response dominated by IFNc/TNFa/IL-2 or TNFa/IL2 producing CD4 T cells. H4 in the CD4 T cell inducing adjuvant IC31H is presently in clinical trials.