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      Vaccines against Tuberculosis: Where Are We and Where Do We Need to Go?

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      1 , * , 2
      PLoS Pathogens
      Public Library of Science

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          Abstract

          In this review we discuss recent progress in the development, testing, and clinical evaluation of new vaccines against tuberculosis (TB). Over the last 20 years, tremendous progress has been made in TB vaccine research and development: from a pipeline virtually empty of new TB candidate vaccines in the early 1990s, to an era in which a dozen novel TB vaccine candidates have been and are being evaluated in human clinical trials. In addition, innovative approaches are being pursued to further improve existing vaccines, as well as discover new ones. Thus, there is good reason for optimism in the field of TB vaccines that it will be possible to develop better vaccines than BCG, which is still the only vaccine available against TB.

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          Most cited references119

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          Development of monocytes, macrophages, and dendritic cells.

          Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate arm of the immune system. Dendritic cells initiate and regulate the highly pathogen-specific adaptive immune responses and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.
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            Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major.

            CD4+ T cells have a crucial role in mediating protection against a variety of pathogens through production of specific cytokines. However, substantial heterogeneity in CD4+ T-cell cytokine responses has limited the ability to define an immune correlate of protection after vaccination. Here, using multiparameter flow cytometry to assess the immune responses after immunization, we show that the degree of protection against Leishmania major infection in mice is predicted by the frequency of CD4+ T cells simultaneously producing interferon-gamma, interleukin-2 and tumor necrosis factor. Notably, multifunctional effector cells generated by all vaccines tested are unique in their capacity to produce high amounts of interferon-gamma. These data show that the quality of a CD4+ T-cell cytokine response can be a crucial determinant in whether a vaccine is protective, and may provide a new and useful prospective immune correlate of protection for vaccines based on T-helper type 1 (TH1) cells.
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              IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge.

              Interferon-gamma is key in limiting Mycobacterium tuberculosis infection. Here we show that vaccination triggered an accelerated interferon-gamma response by CD4(+) T cells in the lung during subsequent M. tuberculosis infection. Interleukin 23 (IL-23) was essential for the accelerated response, for early cessation of bacterial growth and for establishment of an IL-17-producing CD4(+) T cell population in the lung. The recall response of the IL-17-producing CD4(+) T cell population occurred concurrently with expression of the chemokines CXCL9, CXCL10 and CXCL11. Depletion of IL-17 during challenge reduced the chemokine expression and accumulation of CD4(+) T cells producing interferon-gamma in the lung. We propose that vaccination induces IL-17-producing CD4(+) T cells that populate the lung and, after challenge, trigger the production of chemokines that recruit CD4(+) T cells producing interferon-gamma, which ultimately restrict bacterial growth.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                May 2012
                May 2012
                10 May 2012
                : 8
                : 5
                : e1002607
                Affiliations
                [1 ]Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
                [2 ]Deptartment of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany
                International Centre for Genetic Engineering and Biotechnology, India
                Author notes
                Article
                PPATHOGENS-D-11-02662
                10.1371/journal.ppat.1002607
                3349743
                22589713
                bac3f9f3-551d-4c1d-9e00-7bdef7dce64a
                Ottenhoff, Kaufmann. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Page count
                Pages: 12
                Categories
                Review
                Biology
                Immunology
                Immunity
                Adaptive Immunity
                Humoral Immunity
                Immune Activation
                Immune Defense
                Immunity to Infections
                Immunizations
                Innate Immunity
                Immunopathology
                Medicine
                Clinical Immunology
                Immunity
                Vaccination
                Vaccines
                Vaccine Development
                Adaptive Immunity
                Humoral Immunity
                Immune Activation
                Immune Defense
                Immune Suppression
                Immunity to Infections
                Immunizations
                Inflammation
                Innate Immunity
                Infectious Diseases
                Bacterial Diseases
                Mycobacterium
                Tuberculosis
                Infectious Disease Control

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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