μÀÑ Vaccine development for Tuberculosis: Past, Present and Future Challenges

About one third of the world's population is infected with Mycobacterium tuberculosis (M. tb), and new infections occur at a rate of about one per second. Additionally, more people in the developed world contact tuberculosis (TB) because their immune systems are more likely to be compromised due to higher exposure to immunosuppressive drugs, substance abuse, or AIDS. The distribution of tuberculosis is not uniform across the globe, still the treatment is difficult and requires long courses of multiple antibiotics. However, antibiotic resistance is a growing problem in multidrugresistant (MDR) tuberculosis. But mostly the prevention relies on screening programs and vaccination, usually with Bacillus CalmetteGuérin (BCG) vaccine. BCG is the most commonly used vaccine worldwide, but not as a powerful vaccine. BCG also provides some protection against severe forms of pediatric TB, but has been shown to be unreliable against adult pulmonary TB which accounts for most of the disease burden worldwide. Currently, there is an urgent need for novel, more effective vaccine that can prevent all forms of TB including drug resistant strains for all age groups and among people with HIV. The first recombinant tuberculosis vaccine rBCG30, entered clinical trials in year 2004, but, still no effective vaccine is available in a market. Study showed that DNA TB vaccine given with conventional chemotherapy can accelerate the disappearance of bacteria as well as protect against re-infection in mice and it is quite effective against TB. A very promising TB vaccine, MVA85A, is currently in phase II trials and is based on a genetically modified vaccinia virus. Many other strategies are also being used to develop novel vaccines, including both subunit vaccines such as Hybrid-1, HyVac4 or M72, and recombinant adenoviruses such as Ad35. Some of these vaccines can be effectively administered without needles making them preferable for areas where HIV is very common and few of these vaccines have been successfully tested in humans and are now in extended testing in TB-endemic regions. To encourage further discovery, researchers and policymakers across the globe are promoting new economic models of vaccine development including prices, tax incentives and advance market commitments. This review gives the basic idea of various vaccine development approaches and its effective application in TB control. *Corresponding author, Mailing address: Dr. Dileep Tiwari, Gennova Biopharmaceuticals Ltd., P-1, I.T.-B.T. Park Phase -II, MIDC Hinjwadi, Pune-411057, India E-mail: [email protected], [email protected] R e v i e w & R e s e a r c h P a p e r C o v e r e d i n O f f i c i a l P r o d u c t o f E l s e v i e r , T h e N e t h e r l a n d s Article History:-----------------------Date of Submission: 16-05-2011 Date of Acceptance: 15-6-2011 Conflict of Interest: NIL Source of Support: NONE Int. J. Drug Dev. & Res., April-June 2011, 3 (2): 75-84 Covered in Scopus & Embase, Elsevier 75 deaths annually and latently infects one-third of the world population (estimated ~2 billion). Successful global TB control faces many obstacles including the difficulty of timely diagnosis, lack of effective vaccines, and the fact that TB treatment requires many months of chemotherapy. The situation has been further compounded with the advent of M. tb/HIV co-infection and the emergence of multidrugresistant (MDR) and extensively drug-resistant (XDR) TB. In 2006, the global burden of MDR-TB, defined as resistance to isoniazid and rifampin, was estimated at 500,000 cases. Additionally, the incident of XDR-TB, caused by MDR strains that are also resistant to fluoroquinolone and at least one second-line injectable agent (amikacin, kanamycin, or capreomycin), is increasing in many countries. A deadly association between HIV and TB has been known since the start of the HIV epidemic. Of the 1.7 million people who died from TB in the year 2010, approximately 200,000 were co-infected with HIV. In light of these developments, a new and effective vaccine is urgently needed, which is essential for reducing the estimated 8-10 million new TB infections that occur annually. According to the Global plan to Stop TB (2006-2015), the introduction of effective TB vaccines will be an essential component of any strategy to control TB by 2050 History of BCG Vaccine In 1908, Camille Guerin and Albert Calmette initiated their attempts to produce an anti-TB vaccine from a virulent bovine strain. In 1921, vaccination with BCG, an attenuated vaccine, was introduced (Sakula, 1983). The efficiency of the BCG vaccine has been questioned since its early use and therefore, a large number of trials have been carried out to determine its efficacy. In these studies it was found that, the BCG vaccine protected efficiently against leprosy (Fine and Rodrigues, 1990) as well as childhood manifestations of TB (disseminated TB) (Rodrigues et al., 1993). However, the protective efficacy against pulmonary TB was limited (Tuberculosis Research Centre [ICMR], Chennai, India, 1999). Fig.:1 Various hypotheses have been suggested to explain the low protective efficacy of BCG against pulmonary TB. These hypotheses include inappropriate treatment and storage of the vaccine, the use of different strains of BCG (Fine, 1995), and lack of an effective stimulation of the optimal blend of T-cell populations and in particular that of the CD8+ T-cells (Hess and Kaufmann, 1999). In addition to these hypotheses, the currently used intradermal route of immunization has been suggested as another factor influencing the capacity of BCG to induce optimal immunity in the lungs. In this regard, intranasal (i. n.) route of immunization has recently been evaluated as a possible route for BCG delivery, in mouse experimental models. Results from this study showed a high degree of protection against challenge with M. tb in BALB/c mice, following BCG vaccination (Falero-Diaz et al., 2000). In a similar model, vaccination with BCG conferred as good, if not better protection than subcutaneous (s. c.) route, against challenge with virulent M. bovis (Lyadova et al., 2001). Prospects for new vaccines Given the limitations of BCG in protection against adult pulmonary TB, there is a considerable scope for improved vaccination strategies. Immunological research has a key position in understanding the pathogenesis of TB, and thereby in developing novel designs for effective prophylactic vaccination, immunodiagnostic tools and immunotherapeutic agents. Two approaches have been considered for vaccine development. One involves the replacement of BCG by a more potent vaccination inducing immune responses capable of either complete elimination of the bacilli, or of reliable containment of persistent infection. The second approach involves the post-exposure vaccination to boost immunity in Int. J. Drug Dev. & Res., April-June 2011, 3 (2): 75-84 Covered in Scopus & Embase, Elsevier 76 Dileep Tiwari et al: Vaccine development for Tuberculosis: Past, Present and Future Challenges