Induction of Unconventional T Cells by a Mutant Mycobacterium bovis BCG Strain Formulated in Cationic Liposomes Correlates with Protection against Mycobacterium tuberculosis Infections of Immunocompromised Mice

Abstract

Despite the widespread use of Mycobacterium bovis BCG vaccine and the availability of effective chemotherapy, tuberculosis (TB) remains an immense global public health challenge, with approximately 9 million new cases and 1.4 million deaths per year. Overall, an estimated 2 billion people are infected with M. tuberculosis worldwide (1, 2). These alarming statistics have made it obvious that current interventions are not controlling the epidemic. The reasons for the current TB problem are multifaceted and include the lack of an efficacious vaccine and the emergence of multidrug-resistant and extremely drug-resistant M. tuberculosis strains (1, 3). Importantly, the convergence of the HIV and TB epidemics has, without question, intensified the TB problem. Since HIV-infected individuals are considerably more susceptible to pathogens due to their immunocompromised state, coinfected individuals are 30 times more likely to develop active TB than those infected with M. tuberculosis only. In fact, TB causes 25% of all HIV-related deaths worldwide (2).While BCG is one of the most widely used global vaccines, its impact on the current TB epidemic has clearly been inadequate. Randomized controlled clinical trials and retrospective case-control studies have shown that BCG immunization is effective in reducing cases of severe disseminated TB in children; however, the effectiveness of BCG in preventing pulmonary TB has been highly variable, ranging from 0% to 80% (4). Furthermore, protection is often not highly persistent, with substantial waning of BCG-induced protective responses generally seen during the first decade after immunization (5). Given the suboptimal efficacy in the context of the devastating TB epidemic, there is an urgent global health need to develop a new TB immunization strategy. Consequently, many TB researchers are developing strategies to amplify BCG-induced antituberculosis protective responses. A popular approach involves boosting with protein-or virus-vectored vaccines after a priming BCG immunization. Alternatively, a potentially simpler and less expensive strategy involves formulating BCG in a liposome-forming adjuvant. Lipid encapsulation of BCG has been shown to improve the immunogenicity and protective efficacy of BCG immunization in mice, guinea pigs, badgers, and cattle (6-10).Our group recently demonstrated that formulation of a BCG⌬mmaA4 (BCG-A4) mutant in DDA/TDB adjuvant (A4/ Adj) increased the level and persistence of BCG-induced immune responses relative to those produced by conventional BCG and

IL-17 Production from T Helper 17, Mucosal-Associated Invariant T, and γδ Cells in Tuberculosis Infection and Disease

“…γδ T cells comprise 1–5% of peripheral blood lymphocytes ( 13 , 14 ) and occur in a pre-activated differentiation state at high clonal frequencies, allowing for much faster responses compared to other cell types ( 15 ). The invariant γδ TCR recognizes phospho-antigens originating from both the host and bacteria ( 16 ), and evidence of their contribution to the immune response against TB has grown steadily over the years ( 17 ). γδ T cells are well documented as an early source of IL-17 and IFN-γ following a range of immune challenges ( 18 , 19 ).…”

Liposomal vaccine formulations as prophylactic agents: design considerations for modern vaccines

“…Other studies have focus their attention on cell components, synthetic lipid analogues or mycobacterial lipids as antigens for subunit vaccine development employing DDA as the principal component in the lipid bilayer. Mutant M. bovis BCG ΔmmaA4 strain was formulated in cationic liposomes of DDA:TDB (A4/Adj) and administered subcutaneously [ 129 ]. The mutation deletes the mmaA4 gene that encodes a S -adenosylmethionine-dependent methyltransferase involved in mycolic acid biosynthesis in the tubercle bacillus [ 130 ].…”