Lipidated promiscuous peptides vaccine for tuberculosis-endemic regions Uthaman Gowthaman 1*, y , Pradeep K. Rai 1* , Nargis Khan 1* , David C. Jackson 2 and Javed N. Agrewala 1 1 Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh-160036, India 2 Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia Despite nine decades of Bacillus Calmette–Gue ´ rin (BCG) vaccination, tuberculosis continues to be a major global health challenge. Clinical trials worldwide have proved the inadequacy of the BCG vaccine in preventing the manifestation of pulmonary tuberculosis in adults. Ironi- cally, the efficacy of BCG is poorest in tuberculosis endemic areas. Factors such as nontuberculous or envi- ronmental mycobacteria and helminth infestation have been suggested to limit the efficacy of BCG. Hence, in high TB-burden countries, radically novel strategies of vacci- nation are urgently required. Here we showcase the prop- erties of lipidated promiscuous peptide vaccines that target and activate cells of the innate and adaptive im- mune systems by employing a Toll-like receptor-2 ago- nist, S-[2,3-bis(palmitoyloxy)propyl]cysteine (Pam2Cys). Such a strategy elicits robust protection and enduring memory responses by type 1 T helper cells (Th1). Conse- quently, lipidated peptides may yield a better vaccine than BCG. Tuberculosis: a worldwide scourge Tuberculosis (TB) is one of the three major infectious diseases, along with HIV/AIDS and malaria that account for large numbers of worldwide deaths annually. Accord- ing to the World Health Organization (WHO), each year Mycobacterium tuberculosis (Mtb) infects 9 million people and causes approximately 2 million deaths. It is estimated that one-third of the world population is infected with Mtb [1–3]. The WHO has announced TB as a global emergency in the wake of emerging multidrug resistant – and more recently total drug resistant – strains of Mtb, the alarming number of TB cases around the world, and its co-occur- rence with HIV [4]. Although the immune system efficient- ly controls the active infection, in most cases it is incapable of sterile eradication of Mtb [5]. Therefore, the infection becomes latent and is associated with a risk of reactivation and further spreading of the disease [1,3]. Some drug regimens can cure TB, but they may also facilitate the emergence of drug resistance, particularly when the regimens are lengthy, complex, and have low rates of compliance [6]. Effective vaccines (see Glossary) against TB are a rational approach for its eradication. The only available vaccine for TB is Bacillus Calmette– Gue ´rin (BCG), a live, attenuated strain of the related bacterium Mycobacterium bovis that is estimated to have been administered to more than 4 billion people [7]. None- theless, the ever increasing number of TB cases indicates that BCG immunization will fall short of achieving the target of the WHO STOP TB program, which aims to reduce the number of new cases to 1 per million [1,8]. Despite its wide usage, BCG has not adequately reduced the global TB burden and its efficacy is very poor in high TB-endemic countries [7–9]. This warrants serious attempts to radically improve BCG or to develop altogether novel vaccination strategies [3,7]. The ‘immune landscape’ of TB-endemic regions is different from non-endemic Review Glossary Adjuvant: a substance that is added to an antigen and/or vaccine to stimulate the immune system against the target immunogen. Adjuvants by themselves do not confer immunity. They function as a depot for slow release of the antigen, therefore maximizing the immune response. CD4 + T cells: these lymphocytes are subdivided mainly into Th1, Th2, Th17, and regulatory T cells (Tregs). Th1 cells secrete chiefly IFN-g, provide cell- mediated immunity, and confer protection against intracellular pathogens. These cells are regulated by transcription factor T-bet. Th2 cells produce mainly IL-4 and promote humoral immunity and protection against extra- cellular parasites. These cells are regulated by transcription factor GATA-3. Tregs mediate immune suppression or homeostasis by releasing IL-10 and transforming growth factor (TGF)-b. These cells are regulated by transcription factor FOXP3. Memory T cells: are antigen-experienced and long-lived T lymphocytes. Memory cells rapidly acquire effector functions upon encounter with an antigen. Nontuberculous mycobacteria (NTM): are strains of mycobacteria that do not cause tuberculosis or leprosy. They are also known as atypical mycobacteria or environmental mycobacteria. NTM share significant structural and biochemical similarities with pathogenic mycobacteria. T cells: these lymphocytes are categorized into CD4 + T helper and CD8 + cytotoxic T cells, based on their molecular phenotypes and different effector functions. Toll-like receptors (TLRs): TLRs are well-characterized pathogen recognition receptors (PRRs). These molecules are expressed as extracellular and intracellular receptors on the cells of the body and play an essential role in recognizing microbial components to alarm the immune system. In humans, more than ten TLRs have been identified. Vaccine: consists of either attenuated or killed form of microbe or its proteins/ peptides/toxins that stimulate the immune system to generate enduring immunological memory and confer subsequent protection. Corresponding author: Agrewala, J.N. (javed@imtech.res.in) Keywords: tuberculosis; vaccine; BCG; TLR-2; promiscuous peptides; T cell epitopes; dendritic cells; Pam2Cys; TB-endemic area. * These authors contributed equally. y Current address: Department of Orthopedics and Rehabilitation, Yale School of Medicine, New Haven, CT, USA. 1471-4914/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2012.07.008 Trends in Molecular Medicine, October 2012, Vol. 18, No. 10 607