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.
Highlights
The success of Mycobacterium tuberculosis as a human pathogen relies immensely on its ability to subvert the host immune responses and persist in a dormant state
We have reported the development of DNA vaccine (DNAacr) expressing a-crystallin [14] – a key component of the dormancy regulon and one of the most abundantly produced proteins during exposure of M. tuberculosis to hypoxia, nutrient starvation as well as in the late stages of infection [4,5,6]. We showed that this DNA vaccine induces Th1 response and protects guinea pigs against M. tuberculosis infection, even though, it could not surpass the protective efficacy of Bacille CalmetteGuerin (BCG), when employed alone in a prophylactic mode [14]
To evaluate the protective efficacy of ‘BCG prime-DNAacr boost’ regimen (B/D), at 12 weeks after the primary immunization, guinea pigs were infected with M. tuberculosis by aerosol route and lung and spleen bacillary load were determined at 10 (Exp-I) and 16 weeks (Exp-II) post-infection
Summary
The success of Mycobacterium tuberculosis as a human pathogen relies immensely on its ability to subvert the host immune responses and persist in a dormant state. The inability of BCG to provide sterilizing immunity at the time of primary infection leads to an enormous reservoir of asymptomatically infected individuals worldwide (,2 billion) These latently infected individuals have a persistent risk of developing clinical disease due to endogenous reactivation if the immune system is compromised due to several reasons such as HIV infection, malnourishment etc. In spite of a consistent protection against tuberculosis (TB) in children, Mycobacterium bovis Bacille CalmetteGuerin (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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
