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.

Download full-text


Available from: Claus Aagaard,
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Vaccine 02/2015; 33(11). DOI:10.1016/j.vaccine.2015.01.058 · 3.62 Impact Factor
  • Source
    • "done in accordance with the EU directive 2010/63EU for animal experiments. The vaccines were prepared by mixing the liposomal dispersions with 5 lg Mycobacterium tuberculosis antigen H56 (Ag85B-ESAT-6-Rv2660c fusion protein) [28] in 10 mM sterile Tris buffer (pH = 7.4). The vaccines were left at room temperature with intermittent mixing to allow for full adsorption of antigen to the liposomes [12]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Linking physicochemical characterization to functional properties is crucial for defining critical quality attributes during development of subunit vaccines toward optimal safety and efficacy profiles. We investigated how the trehalose 6,6′-diester (TDX) chain length influenced the physicochemical and immunopotentiating properties of the clinically tested liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and analogues of trehalose-6,6′-dibehenate (TDB). TDB analogues with symmetrically shortened acyl chains [denoted X: arachidate (A), stearate (S), palmitate (P), myristate (Myr) and laurate (L)] were incorporated into DDA liposomes and characterized with respect to size, polydispersity index, charge, thermotropic phase behavior and lipid-lipid interactions. Incorporation of 11 mol% TDX into DDA liposomes significantly decreased the polydispersity index when TDA, TDS, TDP and TDMyr were incorporated, whereas both the initial size and the charge of the liposomes were unaffected. The long-term colloidal stability was only decreased when including TDL in DDA liposomes. The fatty acid length of TDX affected the phase transition of the liposomes, and for the DDA/TDP and DDA/TDS liposomes a homogeneous distribution of the lipids in the bilayer was indicated. The membrane packing was studied further by using the Langmuir monolayer technique. Incorporation of TDS improved the packing of the lipid monolayer, as compared to the other analogues, suggesting the most favorable stability. Finally, immunization of mice with the recombinant tuberculosis fusion antigen Ag85B-ESAT-6-Rv2660c (H56) and the physicochemically most optimal formulations (DDA/TDB, DDA/TDS and DDA/TDP) induced comparable T-cell responses. In conclusion, of the investigated TDB analogues, incorporation of 11 mol% TDS or TDP into DDA liposomes resulted in an adjuvant system with the most favorable physicochemical properties and an immunological profile comparable to that of DDA/TDB.
    European Journal of Pharmaceutics and Biopharmaceutics 11/2014; DOI:10.1016/j.ejpb.2014.10.015 · 3.38 Impact Factor
  • Source
    • "Based on immunological data as well as physicochemical stability data the optimal weight ratio of DDA to TDB was found to be 5:1 [8]. In animal models, CAF01 promotes a broad and complex immune response characterized by multifunctional T-cells with a Th1 profile and possesses the same ability to induce long-lived immune responses as IC31 ® presumably through the establishment of a vaccine depot [8] [9] [10] [11] [12] [13]. In preclinical studies, CAF01 also induced a Th17 response due to TDB signaling through the C-type lectin receptor Mincle [14]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Here, we report on a first-in-man trial where the tuberculosis (TB) vaccine Ag85B-ESAT-6 (H1) was adjuvanted with escalating doses of a novel liposome adjuvant CAF01. On their own, protein antigens cannot sufficiently induce immune responses in humans, and require the addition of an adjuvant system to ensure appropriate delivery and concomitant immune activation. To date no approved adjuvants are available for induction of cellular immunity, which seems essential for a number of vaccines, including vaccines against TB. We vaccinated four groups of human volunteers: a non-adjuvanted H1 group, followed by three groups with escalating doses of CAF01-adjuvanted H1 vaccine. All subjects were vaccinated at 0 and 8 weeks and followed up for 150 weeks. Vaccination did not cause local or systemic adverse effects besides transient soreness at the injection site. Two vaccinations elicited strong antigen-specific T-cell responses which persisted after 150 weeks follow-up, indicating the induction of a long-lasting memory response in the vaccine recipients. These results show that CAF01 is a safe and tolerable, Th1-inducing adjuvant for human TB vaccination trials and for vaccination studies in general where cellular immunity is required.
    Vaccine 10/2014; 32(52). DOI:10.1016/j.vaccine.2014.10.036 · 3.62 Impact Factor
Show more