Aagaard, C. et al. A multistage tuberculosis vaccine that confers efficient protection before and after exposure. Nat Med 17, 189-194

Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark.
Nature medicine (Impact Factor: 27.36). 02/2011; 17(2):189-94. DOI: 10.1038/nm.2285
Source: PubMed


All tuberculosis vaccines currently in clinical trials are designed as prophylactic vaccines based on early expressed antigens. We have developed a multistage vaccination strategy in which the early antigens Ag85B and 6-kDa early secretory antigenic target (ESAT-6) are combined with the latency-associated protein Rv2660c (H56 vaccine). In CB6F1 mice we show that Rv2660c is stably expressed in late stages of infection despite an overall reduced transcription. The H56 vaccine promotes a T cell response against all protein components that is characterized by a high proportion of polyfunctional CD4(+) T cells. In three different pre-exposure mouse models, H56 confers protective immunity characterized by a more efficient containment of late-stage infection than the Ag85B-ESAT6 vaccine (H1) and BCG. In two mouse models of latent tuberculosis, we show that H56 vaccination after exposure is able to control reactivation and significantly lower the bacterial load compared to adjuvant control mice.

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Available from: Claus Aagaard
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    • "H56 is a promising vaccine candidate consisting of 6-kDa early secretory antigenic target (ESAT-6), Ag85B, and the protein Rv2660, that is a component of vaccines currently in clinical trials ( Identifier numbers: NCT01967134, NCT01865487) [27]. The soluble antigen was here combined with the adjuvant CAF01, a liposome system that has been shown to induce combined Th1 and Th17 responses and promote robust long-lived memory immunity [28] [29] [30]; CAF01 has recently been also tested in human studies [31]. "
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    ABSTRACT: CD4(+) T-cell priming is an essential step in vaccination due to the key role of T helper cells in driving both effector and memory immune responses. Here we have characterized in C57BL/6 mice the T helper subtype differentiation among tetramer-specific CD4(+) T cells primed by subcutaneous immunization with the tuberculosis vaccine antigen H56 plus the adjuvant CAF01. Peptide-specific population identified by the MHC class II tetramers differentiated into several T helper subtypes upon antigen encounter, and the frequency of subpopulations differed according to their localization. Th1 (CXCR3(+)T-bet(+)), Tfh (CXCR5(+)PD-1(+)Bcl-6(+)) and RORγt(+) cells were induced in the lymph nodes draining the immunization site (dLN), while Th1 cells were the predominant subtype in the spleen. In addition, CD4(+) T cells co-expressing multiple T-cell lineage-specifying transcription factors were also detected. In the lungs, most of the tetramer-binding T cells were RORγt(+), while Tfh and Th1 cells were absent. After boosting, a higher frequency of tetramer-binding cells co-expressing the markers CD44 and CD127 was detected compared to primed cells, and Tet(+) T cells showed a prevalent Th1 phenotype in both dLN and spleens, while Tfh cells were significantly reduced. In conclusion, these data demonstrate that parenteral immunization with H56 and CAF01 elicits a distribution of antigen-specific CD4(+) T cells in both lymphoid tissues and lungs, and gives rise to multiple T helper subtypes, that differ depending on localization and following reactivation.
    Full-text · Article · Oct 2015 · Vaccine
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    • "Subunit vaccines are administered after BCG and focus immunity to a single or a few immunodominant antigens. Subunit vaccine antigens are delivered as either adjuvanted protein [6] [7] [8] [9] or in viral vectors. There are currently seven subunit candidates being evaluated in clinical trials [10]. "
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    ABSTRACT: A replication-deficient chimpanzee adenovirus expressing Ag85A (ChAdOx1.85A) was assessed, both alone and in combination with modified vaccinia Ankara also expressing Ag85A (MVA85A), for its immunogenicity and protective efficacy against a Mycobacterium tuberculosis (M.tb) challenge in mice. Naïve and BCG-primed mice were vaccinated or boosted with ChAdOx1.85A and MVA85A in different combinations. Although intranasally administered ChAdOx1.85A induced strong immune responses in the lungs, it failed to consistently protect against aerosol M.tb challenge. In contrast, ChAdOx1.85A followed by MVA85A administered either mucosally or systemically, induced strong immune responses and was able to improve the protective efficacy of BCG. This vaccination regime has consistently shown superior protection over BCG alone and should be evaluated further.
    Full-text · Article · Oct 2015 · Vaccine
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    • "Vaccine development from bench to field is a long lasting process and the last decade witnessed considerable research efforts to develop more protective TB vaccines. Candidates include recombinant BCG [6], attenuated strains of M. tuberculosis [7], recombinant Mycobacterium smegmatis [8], subunit vaccines [9] and recombinant viruses [10]. Many more candidate vaccines have been explored, however, the attrition rate proved to be high [11] [12]. "
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    ABSTRACT: Having demonstrated previously that deletion of zinc metalloprotease zmp1 in Mycobacterium bovis BCG increased immunogenicity of BCG vaccines, we here investigated the protective efficacy of BCG zmp1 deletion mutants in a guinea pig model of tuberculosis infection. zmp1 deletion mutants of BCG provided enhanced protection by reducing the bacterial load of tubercle bacilli in the lungs of infected guinea pigs. The increased efficacy of BCG due to zmp1 deletion was demonstrated in both BCG Pasteur and BCG Denmark indicating that the improved protection by zmp1 deletion is independent from the BCG sub-strain. In addition, unmarked BCG Δzmp1 mutant strains showed a better safety profile in a CB-17 SCID mouse survival model than the parental BCG strains. Together, these results support the further development of BCG Δzmp1 for use in clinical trials. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Feb 2015 · Vaccine
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