ESAT-6 Subunit Vaccination againstMycobacterium tuberculosis

Abstract

The ESAT-6 antigen from Mycobacterium tuberculosis is a dominant target for cell-mediated immunity in the early phase of tuberculosis (TB) in TB patients as well as in various animal models. The purpose of our study was to evaluate the potential of ESAT-6 in an experimental TB vaccine. We started out using dimethyl dioctadecylammonium bromide (DDA), an adjuvant which has been demonstrated to be efficient for the induction of cellular immune responses and has been used successfully before as a delivery system for TB vaccines. Here we demonstrate that, whereas immune responses to both short-term-culture filtrate and Ag85B are efficiently induced with DDA, this adjuvant was inefficient for the induction of immune responses to ESAT-6. Therefore, we investigated the modulatory effect of monophosphoryl lipid A (MPL), an immunomodulator which in different combinations has demonstrated strong adjuvant activity for both cellular and humoral immune responses. We show in the present study that vaccination with ESAT-6 delivered in a combination of MPL and DDA elicited a strong ESAT-6-specific T-cell response and protective immunity comparable to that achieved with Mycobacterium bovis BCG.

Mycobacterium tuberculosisAntigens Induce the Differentiation of Dendritic Cells from Bone Marrow

“…tb Ags have been in focus for more than a decade ever since their identification in axenic cultures. Since then, a number of studies document the potential of these Ags in regulating immune responses in animal models and in humans, which among others includes the use of these Ags as potential vaccine candidates in the form of either adjuvants or even DNA (32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Despite these studies, lacunae still exist regarding their physiological roles at sites of infection.…”

“…They have been shown to elicit delayed-type hypersensitivity responses in guinea pig models of tuberculosis. Furthermore, ESAT-6 has been considered as a potential candidate for subunit-based vaccines (39). Ag85b is a member of the Ag 85 complex, a family of fibronectin-binding proteins involved in the mycobacterial cell wall biosynthesis (40).…”

Multivalent TB vaccines targeting the esx gene family generate potent and broad cell-mediated immune responses superior to BCG

“…In addition, they have been demonstrated to serve as targets for not just CD4 but also CD8 T cells, 12 suggesting their potential to drive both a CD4 and CD8 T cell epitopic repertoire. Although immunizations with a single esx antigen preparation have been inadequate for controlling TB, 14,[16][17][18] many studies have described that levels of protection and pathogenspecific cellular immunity can be enhanced by combining esx antigens with other TB-associated antigens. 8,9,14,[17][18][19][20][21][22] For example, the animal challenge studies of the vaccine candidate Ag85B-ESAT6 have described that 2 Mtb antigens combined can be more effective than either antigen alone in protecting against TB infection.…”

Perspectivas para nuevas vacunas antituberculosas en la era posgenómica.

“…Los mejores antígenos para este fin son las moléculas secretadas presentes en el filtrado de cultivos que inducen una fuerte respuesta de linfocitos T CD4+ productores de IFNγ. Estas moléculas pueden obtenerse a par tir de electroeluidos de electroforesis en dos dimensiones de los filtrados que, luego, se identifican por microsecuenciación (38,39) y se ensayan con células de animales infectados o clonas de linfocitos T obtenidas de individuos sanos tuberculino positivos (40)(41)(42)(43)(44). Sin embargo, la disponibilidad del genoma micobacteriano ha permitido identificar genes propios de M. tuberculosis (45) y mediante clonaje en vectores de expresión realizar un tamizaje de aquéllos con mayor capacidad de inducir respuestas Th1 y, luego, evaluarlos como candidatos.…”