Article

A multistage tuberculosis vaccine that confers efficient protection before and after exposure.

Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark.
Nature medicine (Impact Factor: 28.05). 02/2011; 17(2):189-94. DOI: 10.1038/nm.2285
Source: PubMed

ABSTRACT 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.

1 Follower
 · 
215 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: One-third of the world's human population is latently infected with Mycobacterium tuberculosis (M. tb), and adult tuberculosis (TB) is largely caused by the resuscitation of latent M. tb. Rv2660c, an M. tb dormancy-related antigen, is preferentially expressed during latent infection. Identification and characterization of Rv2660c are crucial to understanding host-pathogen interactions and to develop drug target and vaccine candidates. In this study, T-cell and antibody immune responses against recombinant Rv2660c protein were respectively investigated in latent M. tb infection (LTBI) cases, pulmonary tuberculosis (PTB) patients, and healthy individuals (HI). After stimulation with recombinant Rv2660c protein, stronger cellular responses were induced in LTBI cases compared with those in PTB patients or in HI. Meanwhile, Rv2660c stimulated higher levels of IgG, IgG1, and IgG2a antibody titers in LTBI cases compared with those in PTB patients. The results showed that Rv2660c is able to elicit prominent cellular immune responses and strong humoral immunity in a Chinese LTBI population, suggesting that Rv2660c is a potential target to develop new vaccines and drugs to control LTBI.
    European Journal of Clinical Microbiology 02/2015; DOI:10.1007/s10096-015-2335-8 · 2.54 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Novel tuberculosis vaccines should be safe, immunogenic, and effective in various population groups, including HIV-infected individuals. In this phase II multi-centre, double-blind, placebo-controlled trial, the safety and immunogenicity of the novel H1/IC31 vaccine, a fusion protein of Ag85B-ESAT-6 (H1) formulated with the adjuvant IC31, was evaluated in HIV-infected adults. HIV-infected adults with CD4+ T cell counts >350/mm3 and without evidence of active tuberculosis were enrolled and followed until day 182. H1/IC31 vaccine or placebo was randomly allocated in a 5∶1 ratio. The vaccine was administered intramuscularly at day 0 and 56. Safety assessment was based on medical history, clinical examinations, and blood and urine testing. Immunogenicity was determined by a short-term whole blood intracellular cytokine staining assay. 47 of the 48 randomised participants completed both vaccinations. In total, 459 mild or moderate and 2 severe adverse events were reported. There were three serious adverse events in two vaccinees classified as not related to the investigational product. Local injection site reactions were more common in H1/IC31 versus placebo recipients (65.0% vs. 12.5%, p = 0.015). Solicited systemic and unsolicited adverse events were similar by study arm. The baseline CD4+ T cell count and HIV viral load were similar by study arm and remained constant over time. The H1/IC31 vaccine induced a persistent Th1-immune response with predominately TNF-α and IL-2 co-expressing CD4+ T cells, as well as polyfunctional IFN-γ, TNF-α and IL-2 expressing CD4+ T cells. H1/IC31 was well tolerated and safe in HIV-infected adults with a CD4+ Lymphocyte count greater than 350 cells/mm3. The vaccine did not have an effect on CD4+ T cell count or HIV-1 viral load. H1/IC31 induced a specific and durable Th1 immune response. Pan African Clinical Trials Registry (PACTR) PACTR201105000289276.
    PLoS ONE 12/2014; 9(12):e114602. DOI:10.1371/journal.pone.0114602 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tuberculosis (TB) is a leading cause of death worldwide despite the availability of effective chemotherapy for over 60 years. Although Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination protects against active TB disease in some populations, its efficacy is suboptimal. Development of an effective TB vaccine is a top global priority that has been hampered by an incomplete understanding of protective immunity to TB. Thus far, preventing TB disease, rather than infection, has been the primary target for vaccine development. Several areas of research highlight the importance of including preinfection vaccines in the development pipeline. First, epidemiology and mathematical modeling studies indicate that a preinfection vaccine would have a high population-level impact for control of TB disease. Second, immunology studies support the rationale for targeting prevention of infection, with evidence that host responses may be more effective during acute infection than during chronic infection. Third, natural history studies indicate that resistance to TB infection occurs in a small percentage of the population. Fourth, case-control studies of BCG indicate that it may provide protection from infection. Fifth, prevention-of-infection trials would have smaller sample sizes and a shorter duration than disease prevention trials and would enable opportunities to search for correlates of immunity as well as serve as a criterion for selecting a vaccine product for testing in a larger TB disease prevention trial. Together, these points support expanding the focus of TB vaccine development efforts to include prevention of infection as a primary goal along with vaccines or other interventions that reduce the rate of transmission and reactivation. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    Microbiology and molecular biology reviews: MMBR 12/2014; 78(4):650-671. DOI:10.1128/MMBR.00021-14 · 15.26 Impact Factor

Full-text (2 Sources)

Download
104 Downloads
Available from
Jun 2, 2014