A Live Experimental Vaccine againstBurkholderia pseudomalleiElicits CD4⁺T Cell–Mediated Immunity, Priming T Cells Specific for 2 Type III Secretion System Proteins

Abstract

Burkholderia pseudomallei is the etiological agent of melioidosis, a serious human disease for which no vaccine is available. Immunization of susceptible BALB/c mice with the live attenuated mutant B. pseudomallei ilvI (referred to as "2D2") generated significant, although incomplete, immunity. Splenic B. pseudomallei-specific T cells, detected in immunized mice, proliferated and produced interferon-gamma in vitro in response to dead bacteria. Assessment of T cell antigen specificity indicated that subpopulations of B. pseudomallei-reactive T cells were responsive to BopE, a type III secretion system (TTSS) effector protein, and to a lesser extent to BipD, a TTSS translocator protein. Increased survival of severe combined immunodeficient mice adoptively transferred with T cells from immunized mice, compared with that of naive T cell recipients, demonstrated that immunization with 2D2 generated T cell-mediated immunity. CD4+ and CD8+ cell depletion studies demonstrated that CD4+ cells, but not CD8+ cells, mediated this protection in vivo. Thus, CD4+ T cells can mediate vaccine-induced immunity to experimental melioidosis.

Role for theBurkholderia pseudomalleiCapsular Polysaccharide Encoded by thewcbOperon in Acute Disseminated Melioidosis

“…It has also been demonstrated that IFN-␥ production is critical for host survival after a B. pseudomallei challenge in murine infection models, both in antibody depletion studies and in studies with IFN-␥ knockout mice (13,30). These findings correlate well with clinical findings, which indicate that IFN-␥ levels are elevated in melioidosis patients, particularly during septicemic melioidosis, suggesting that an increase in the IFN-␥ level is a key host response for clearance of B. pseudomallei (17).…”

“…Several host cell types have been implicated in the production of IFN-␥ during the course of a B. pseudomallei infection, including NK cells, T cells, and macrophages in murine models (13,16,20). Similarly, NK and T cells have been demonstrated to be the sources of IFN-␥ in seropositive human blood (40).…”

Programmed Death Ligand 1 on Burkholderia pseudomallei–Infected Human Polymorphonuclear Neutrophils Impairs T Cell Functions

“…Protective immunity against B. pseudomallei requires effective innate and adaptive immune responses. Experimental models of melioidosis in mice clearly demonstrated PMNs (13) and IFN-g produced by NK cells and Ag-specific CD4 + T cells are important for protection against B. pseudomallei infection (14)(15)(16). However, genome array studies in the peripheral blood of patients with melioidosis suggest that T cell functions may be impaired, with underexpression of transcripts related to T cells and cytotoxic cells.…”

Protection against Experimental Melioidosis following Immunization with Live Burkholderia thailandensis Expressing amanno-Heptose Capsule

“…Clearly it is highly desirable for a vaccine to prompt clearance of infection from all individuals, and in this study that was not achieved. However, there is considerable scope to optimize this vaccine, through prime-boost strategies for example (6,9), and to use the vaccine in combination with conventional antibiotic therapy to promote bacterial clearance, approaches which are currently being examined. The combination of antibiotics and vaccines may be a particularly promising approach.…”

“…The most efficacious candidates to date have been live vaccines based on attenuated strains of B. pseudomallei, of which a number have been described in the literature (6)(7)(8)(9)(10)(11)(12)(13). However, these vaccines have not induced sterilizing immunity in animal models and, more importantly, there are safety concerns with the use of live attenuated vaccines due to the potential for reversion to a fully virulent phenotype.…”