Alteration of epitope recognition pattern in Ag85B and ESAT‐6 has a profound influence on vaccine‐induced protection against Mycobacterium tuberculosis

Abstract

To analyze the effect of vaccine delivery systems on antigen recognition and vaccine efficacy, we compared immune responses in mice immunized either with an adenovirus vector expressing a fusion of Ag85B and ESAT-6 or with the recombinant fusion protein in a liposomal adjuvant. Both vaccines induced high levels of antigen-specific IFN-c production. The adjuvanted protein vaccine induced primarily a CD4 T cell response directed to the epitope Ag85B 241-255 and gave efficient protection against subsequent Mycobacterium tuberculosis infection. In contrast, the adenoviral construct induced a strong CD8 response predominantly targeted to the epitope ESAT-6 15-29 and no significant protection against infection. Vaccination with the protein vaccine resulted in highly accelerated recall of Ag85B 241-255 -specific T cells immediately post M. tuberculosis challenge whereas the ESAT-6 15-29 epitope was barely recognized during infection. Delivery of the viral construct in cationic liposomes switched the immune response to a protective one dominated by CD4 T cells targeted to the Ag85B [241][242][243][244][245][246][247][248][249][250][251][252][253][254][255] epitope. These data demonstrate that the nature of the T cell response to a vaccine antigen is more important than its magnitude with respect to protective efficacy and that vaccine-mediated changes in immunodominance can result in T cell responses of limited relevance during the natural infection.

CD4 and CD8 T-Cell Responses to Mycobacterial Antigens in African Children

“…Transfer of early secretory antigenic target (ESAT)-6-specific memory Th1 cells to recipient mice before M. tuberculosis challenge showed that higher numbers of specific T cells confer better protection than lower numbers (35). However, numerous other animal and human studies have shown that the CD4 T-cell IFN-g response does not necessarily correlate with protection but may rather reflect bacterial load or degree of inflammation (25,(36)(37)(38)(39)(40). This is also consistent with our finding of the highest T-cell responses in TB-affected children.…”

Vaccine-Elicited 10-Kilodalton Culture Filtrate Protein-Specific CD8 + T Cells Are Sufficient To Mediate Protection against Mycobacterium tuberculosis Infection

“…Vaccine strategies affect the selection of epitopes that prime CD4 ϩ and CD8 ϩ T cells in ways that are not yet understood. We now recognize that the epitopes that stimulate T cells after vaccination can differ from the epitopes that stimulate T cells after M. tuberculosis infection (1,6). This scenario can result in antigen-specific T cells induced by vaccination that are unable to recognize infected cells.…”

Next generation: tuberculosis vaccines that elicit protective CD8+T cells

“…The most effective and practical way to elicit a CD8 + T cell response, whether experimentally or clinically, is to vaccinate with a viral vector or with plasmid DNA (for example see [107]). However, Skeiky et al have evaluated the vaccine 72F.…”

“…In another dramatic example of how the way a vaccine is delivered can alter which epitopes elicit immune T cells, Peter Andersen developed a fusion protein consisting of ESAT6 covalently linked to Ag85B as a subunit vaccine [107]. This vaccine elicits a CD4 + T cell dominated response to ESAT6 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] and Ag85B 241-255 , and induces protective immunity in C57BL/6 mice.…”