Abstract
BackgroundHigh levels of death and morbidity worldwide caused by tuberculosis has stimulated efforts to develop a new vaccine to replace BCG. A number of Mycobacterium tuberculosis (Mtb)-specific antigens have been synthesised as recombinant subunit vaccines for clinical evaluation. Recently a fusion protein of TB antigen Ag85B combined with a second immunodominant TB antigen TB10.4 was emulsified with a novel non-phospholipid-based liposomal adjuvant to produce a new subunit vaccine, investigated here. Currently, there is no consensus as to whether or not long-term T cell memory depends on a source of persisting antigen. To explore this and questions regarding lifespan, phenotype and cytokine patterns of CD4 memory T cells, we developed an animal model in which vaccine-induced CD4 memory T cells could transfer immunity to irradiated recipients.Methodology/Principal FindingsThe transfer of protective immunity using Ag85B-TB10.4-specific, CD45RBlow CD62Llow CD4 T cells was assessed in sub-lethally irradiated recipients following challenge with live BCG, used here as a surrogate for virulent Mtb. Donor T cells also carried an allotype marker allowing us to monitor numbers of antigen-specific, cytokine-producing CD4 T cells in recipients. The results showed that both Ag85B-TB10.4 and BCG vaccination induced immunity that could be transferred with a single injection of 3×106 CD4 T cells. Ten times fewer numbers of CD4 T cells (0.3×106) from donors immunised with Ag85B-TB10.4 vaccine alone, transferred equivalent protection. CD4 T cells from donors primed by BCG and boosted with the vaccine similarly transferred protective immunity. When BCG challenge was delayed for 1 or 2 months after transfer (a test of memory T cell survival) recipients remained protected. Importantly, recipients that contained persisting antigen, either live BCG or inert vaccine, showed significantly higher levels of protection (p<0.01). Overall the numbers of IFN-γ-producing CD4 T cells were poorly correlated with levels of protection.Conclusions/SignificanceThe Ag85B-TB10.4 vaccine, with or without BCG-priming, generated TB-specific CD4 T cells that transferred protective immunity in mice challenged with BCG. The level of protection was enhanced in recipients containing a residual source of specific antigen that could be either viable or inert.
Highlights
Tuberculosis remains one of the world’s leading causes of mortality and morbidity [1] despite the widespread use of the BCG vaccine (Mycobacterium bovis, bacille Calmette-Guerin)
Since immunity to Mycobacterium tuberculosis (Mtb) has been correlated with a Th1 IFN-c response, spleen cell were stimulated in vitro with Ag85B-TB10.4 antigen and stained for intracellular cytokine (ICC) IFN-c
In the more advanced stages of infection, Mtb appears to induce a subset of CD8 T cells not seen after BCG vaccination [21], but the role of these CD8 T cells in protection has never been formally demonstrated
Summary
Tuberculosis remains one of the world’s leading causes of mortality and morbidity [1] despite the widespread use of the BCG vaccine (Mycobacterium bovis, bacille Calmette-Guerin). One strategy for developing new live vaccines is to introduce highly immunogenic, but non-pathogenic, epitopes from Mycobacterium tuberculosis (Mtb) into the BCG genome or alternatively to use a mutated Mtb in which at least two virulence genes have been altered so as to render the microorganism harmless [5]. Another option is to express Mtb antigens in the modified vaccinia virus Ankara (MVA) as a vaccine to boost subjects previously immunised with BCG [6]. To explore this and questions regarding lifespan, phenotype and cytokine patterns of CD4 memory T cells, we developed an animal model in which vaccine-induced CD4 memory T cells could transfer immunity to irradiated recipients
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