Abstract
BackgroundEfficient control of tuberculosis (TB) requires development of strategies that can enhance efficacy of the existing vaccine Mycobacterium bovis Bacille Calmette Guerin (BCG). To date only a few studies have explored the potential of latency-associated antigens to augment the immunogenicity of BCG.Methods/Principal FindingsWe evaluated the protective efficacy of a heterologous prime boost approach based on recombinant BCG and DNA vaccines targeting α-crystallin, a prominent latency antigen. We show that “rBCG prime - DNA boost” strategy (R/D) confers a markedly superior protection along with reduced pathology in comparison to BCG vaccination in guinea pigs (565 fold and 45 fold reduced CFU in lungs and spleen, respectively, in comparison to BCG vaccination). In addition, R/D regimen also confers enhanced protection in mice. Our results in guinea pig model show a distinct association of enhanced protection with an increased level of interleukin (IL)12 and a simultaneous increase in immuno-regulatory cytokines such as transforming growth factor (TGF)β and IL10 in lungs. The T cell effector functions, which could not be measured in guinea pigs due to technical limitations, were characterized in mice by multi-parameter flow cytometry. We show that R/D regimen elicits a heightened multi-functional CD4 Th1 cell response leading to enhanced protection.Conclusions/SignificanceThese results clearly indicate the superiority of α-crystallin based R/D regimen over BCG. Our observations from guinea pig studies indicate a crucial role of IL12, IL10 and TGFβ in vaccine-induced protection. Further, characterization of T cell responses in mice demonstrates that protection against TB is predictable by the frequency of CD4 T cells simultaneously producing interferon (IFN)γ, tumor necrosis factor (TNF)α and IL2. We anticipate that this study will not only contribute toward the development of a superior alternative to BCG, but will also stimulate designing of TB vaccines based on latency antigens.
Highlights
The ability of Mycobacterium tuberculosis to survive the hostile immune responses and persist in a non-replicating dormant state is fundamental to its success as a human pathogen
We have previously reported a DNA vaccine expressing acrystallin (DNAacr) that protected guinea pigs against M. tuberculosis infection, it could not surpass the protective efficacy of Bacille Calmette Guerin (BCG) [6]
Analysis of expression and in vitro growth of rBCG strain over-expressing a-crystallin rBCG strain over-expressing a-crystallin of M. tuberculosis was prepared by transformation of BCG with a recombinant plasmid engineered to over-express a-crystallin under the transcriptional control of promoter of the hsp65 gene of M. leprae (Fig. 1A)
Summary
The ability of Mycobacterium tuberculosis to survive the hostile immune responses and persist in a non-replicating dormant state is fundamental to its success as a human pathogen. Latently infected individuals (healthy PPD+ and household contacts) exhibit increased lympho-proliferative and IFNc response to a-crystallin as compared to patients with active TB [5]. These observations signify a crucial role of a-crystallin in the elicitation of protective immune responses and maintenance of a disease free state in PLoS ONE | www.plosone.org a-Crystallin Based Prime-Boost Vaccine for TB these subjects, making this antigen an attractive target for the development of new TB vaccines. Efficient control of tuberculosis (TB) requires development of strategies that can enhance efficacy of the existing vaccine Mycobacterium bovis Bacille Calmette Guerin (BCG).
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