A Booster Vaccine Expressing a Latency-Associated Antigen Augments BCG Induced Immunity and Confers Enhanced Protection against Tuberculosis

Abstract

BackgroundIn spite of a consistent protection against tuberculosis (TB) in children, Mycobacterium bovis Bacille Calmette-Guerin (BCG) fails to provide adequate protection against the disease in adults as well as against reactivation of latent infections or exogenous reinfections. It has been speculated that failure to generate adequate memory T cell response, elicitation of inadequate immune response against latency-associated antigens and inability to impart long-term immunity against M. tuberculosis infections are some of the key factors responsible for the limited efficiency of BCG in controlling TB.Methods/Principal FindingsIn this study, we evaluated the ability of a DNA vaccine expressing α-crystallin- a key latency antigen of M. tuberculosis to boost the BCG induced immunity. ‘BCG prime – DNA boost’ regimen (B/D) confers robust protection in guinea pigs along with a reduced pathology in comparison to BCG vaccination (1.37 log10 and 1.96 log10 fewer bacilli in lungs and spleen, respectively; p<0.01). In addition, B/D regimen also confers enhanced protection in mice. Further, we show that B/D immunization in mice results in a heightened frequency of PPD and antigen specific multi-functional CD4 T cells (3+) simultaneously producing interferon (IFN)γ, tumor necrosis factor (TNF)α and interleukin (IL)2.Conclusions/SignificanceThese results clearly indicate the superiority of α-crystallin based B/D regimen over BCG. Our study, also demonstrates that protection against TB is predictable by an increased frequency of 3+ Th1 cells with superior effector functions. We anticipate that this study would significantly contribute towards the development of superior booster vaccines for BCG vaccinated individuals. In addition, this regimen can also be expected to reduce the risk of developing active TB due to reactivation of latent infection.

The HyVac4 Subunit Vaccine Efficiently Boosts BCG-Primed Anti-Mycobacterial Protective Immunity

“…2 and 4). In agreement with our results, Dey et al also observed induction of IL-2 + TNFα + IFNγ + and IL-2 + TNFα + CD4 T cells after boosting BCG with a DNA-vaccine encoding α-crystallin (Rv2031c) [32], and boosting BCG with the MVA-vector expressing Ag85A also resulted in increased numbers of polyfunctional CD4 T cells with similar phenotypes as observed in the present study [33]. However, regarding the protective role of IL-2 + TNFα + IFNγ + T cells against M.tb infection there have been conflicting results [25], [33], [34], [35], [36].…”

The &lt;italic&gt;Mycobacterium bovis&lt;/italic&gt; BCG prime-Rv0577 DNA boost vaccination induces a durable Th1 immune response in mice

“…These results suggested that BCG/ DNA vaccination might be a potential candidate since it was able to generate a much prolonged Th1 immune response when compared with BCG and BCG+ P groups. As many previous studies demonstrated a positive correlation between Th1 immune response and protection [15,50,51], we infer that the improved Th1 immune response elicited by the BCG prime/DNA boost strategy may result in a stronger protection than other groups in this study; however, it still needs to be confirmed by further studies. For future studies, we are planning to develop a viral-based vaccine and rBCG expressing Rv0577 protein, then use subunit vaccines to boost rBCG and to evaluate the protective efficacy and safety of this promising vaccines.…”

Boosting BCG-primed mice with chimeric DNA vaccine HG856A induces potent multifunctional T cell responses and enhanced protection against Mycobacterium tuberculosis

“…Although DNA vaccines are traditionally considered as the priming vector in the design of vaccine strategies, DNA-based anti-TB vaccines are often used to boost BCG since the majority of the human population is already BCG-vaccinated. Numerous reports show that BCG prime-DNA vaccination boost regimens in mice enhance protective efficacy against M. tuberculosis infection compared to BCG vaccination alone [6][7][8][9][10][11].…”

“…This characteristic of DNA vaccination offers great advantage in the design of vaccines against intracellular pathogens such as Mycobacterium tuberculosis (M. tuberculosis), since it is believed that efficient induction of Th1 CD4 T cell immunity is crucial to the deference against M. tuberculosis [5]. Accordingly, although DNA vaccines have traditionally been regarded as priming vectors, it is reported that DNA vaccines also act as effective boosters of anti-TB cellular immunity that has been primed by BCG [6][7][8][9][10][11].…”