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      Evaluation of the immunogenicity and efficacy of BCG and MTBVAC vaccines using a natural transmission model of tuberculosis

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          Abstract

          Effective vaccines against tuberculosis (TB) are needed in order to prevent TB transmission in human and animal populations. Evaluation of TB vaccines may be facilitated by using reliable animal models that mimic host pathophysiology and natural transmission of the disease as closely as possible. In this study, we evaluated the immunogenicity and efficacy of two attenuated vaccines, BCG and MTBVAC, after each was given to 17 goats (2 months old) and then exposed for 9 months to goats infected with M. caprae. In general, MTBVAC-vaccinated goats showed higher interferon-gamma release than BCG vaccinated goats in response to bovine protein purified derivative and ESAT-6/CFP-10 antigens and the response was significantly higher than that observed in the control group until challenge. All animals showed lesions consistent with TB at the end of the study. Goats that received either vaccine showed significantly lower scores for pulmonary lymph nodes and total lesions than unvaccinated controls. Both MTBVAC and BCG vaccines proved to be immunogenic and effective in reducing severity of TB pathology caused by M. caprae. Our model system of natural TB transmission may be useful for evaluating and optimizing vaccines.

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          Correlation of ESAT-6-specific gamma interferon production with pathology in cattle following Mycobacterium bovis BCG vaccination against experimental bovine tuberculosis.

          Vaccine development and the understanding of the pathology of bovine tuberculosis in cattle would be greatly facilitated by the definition of immunological correlates of protection and/or pathology. To address these questions, cattle were vaccinated with Mycobacterium bovis bacillus Calmette-Guérin (BCG) and were then challenged with virulent M. bovis. Applying a semiquantitative pathology-scoring system, we were able to demonstrate that BCG vaccination imparted significant protection by reducing the disease severity on average by 75%. Analysis of cellular immune responses following M. bovis challenge demonstrated that proliferative T-cell and gamma interferon (IFN-gamma) responses towards the M. bovis-specific antigen ESAT-6, whose gene is absent from BCG, were generally low in vaccinated animals but were high in all nonvaccinated calves. Importantly, the amount of ESAT-6-specific IFN-gamma measured by enzyme-linked immunosorbent assay after M. bovis challenge, but not the frequency of responding cells, correlated positively with the degree of pathology found 18 weeks after infection. Diagnostic reagents based on antigens not present in BCG, like ESAT-6 and CFP-10, were still able to distinguish BCG-vaccinated, diseased animals from BCG-vaccinated animals without signs of disease. In summary, our results suggest that the determination of ESAT-6-specific IFN-gamma, while not a direct correlate of protection, constitutes nevertheless a useful prognostic immunological marker predicting both vaccine efficacy and disease severity.
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            New vaccines for tuberculosis.

            New vaccines are urgently needed if we want to reach the goal of substantially reducing the incidence of tuberculosis by 2050. Despite a steady increase in funding over the past decade, there is still a striking financial shortfall for vaccine research and development for tuberculosis. Yet, around ten vaccine candidates have left the laboratory stage and entered clinical trials. These vaccines are either aimed at replacing the present vaccine, BCG, or at enhancing immunity induced by BCG. However, these pre-exposure candidates are designed for prevention of disease and will therefore neither eradicate the pathogen, nor prevent stable infection. Long-term vaccination strategies need to target these more ambitious goals. Even though vaccine development will have a price, the return of investment will greatly exceed original costs. Copyright 2010 Elsevier Ltd. All rights reserved.
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              Bovine Tuberculosis in Britain and Ireland – A Perfect Storm? the Confluence of Potential Ecological and Epidemiological Impediments to Controlling a Chronic Infectious Disease

              Successful eradication schemes for bovine tuberculosis (bTB) have been implemented in a number of European and other countries over the last 50 years. However, the islands of Britain and Ireland remain a significant aberration to this trend, with the recent exception of Scotland. Why have eradication schemes failed within these countries, while apparently similar programs have been successful elsewhere? While significant socio-economic and political factors have been discussed elsewhere as key determinants of disease eradication, here we review some of the potential ecological and epidemiological constraints that are present in these islands relative to other parts of Europe. We argue that the convergence of these potential factors may interact additively to diminish the potential of the present control programs to achieve eradication. Issues identified include heterogeneity of diagnostic testing approaches, the presence of an abundant wildlife reservoir of infection and the challenge of sustainably managing this risk effectively; the nature, size, density and network structure of cattle farming; potential effects of Mycobacterium bovis strain heterogeneity on disease transmission dynamics; possible impacts of concurrent endemic infections on the disclosure of truly infected animals; climatological differences and change coupled with environmental contamination. We further argue that control and eradication of this complex disease may benefit from an ecosystem level approach to management. We hope that this perspective can stimulate a new conversation about the many factors potentially impacting bTB eradication schemes in Britain and Ireland and possibly stimulate new research in the areas identified.
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                Author and article information

                Contributors
                alvaro.roy@ucm.es
                aitome@ucm.es
                bromerom@ucm.es
                vicloren@ucm.es
                ja.infantes@ucm.es
                mdominguez@isciii.es
                carlos@unizar.es
                naguilo@unizar.es
                e.puentes@biofabri.es
                e.rodriguez@czvaccines.com
                dejuan@ucm.es
                MariaA.Risalde@uclm.es
                Christian.Gortazar@uclm.es
                lucasdo@visavet.ucm.es
                jbezosga@visavet.ucm.es
                Journal
                Vet Res
                Vet. Res
                Veterinary Research
                BioMed Central (London )
                0928-4249
                1297-9716
                15 October 2019
                15 October 2019
                2019
                : 50
                : 82
                Affiliations
                [1 ]BIOFABRI S.L., Porriño, Pontevedra Spain
                [2 ]ISNI 0000 0001 2157 7667, GRID grid.4795.f, VISAVET Health Surveillance Centre, , Universidad Complutense de Madrid, ; Madrid, Spain
                [3 ]Servicio de Inmunología Microbiana, Centro Nacional de Microbiología, Instituto de Investigación Carlos III, Majadahonda, Madrid, Spain
                [4 ]ISNI 0000 0001 2152 8769, GRID grid.11205.37, Grupo de Genética de Micobacterias, Departamento de Microbiología y Medicina Preventiva, Facultad de Medicina, , Universidad de Zaragoza, ; Zaragoza, Spain
                [5 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, CIBER Enfermedades Respiratorias, , Instituto de Salud Carlos III, ; Madrid, Spain
                [6 ]ISNI 0000 0000 9854 2756, GRID grid.411106.3, Servicio de Microbiología, , Hospital Universitario Miguel Servet, IIS Aragón, ; Zaragoza, Spain
                [7 ]ISNI 0000 0001 2157 7667, GRID grid.4795.f, Dpto. de Sanidad Animal, Facultad de Veterinaria, , Universidad Complutense de Madrid, ; Madrid, Spain
                [8 ]ISNI 0000 0001 2183 9102, GRID grid.411901.c, Dpto. de Anatomía y Anatomía Patológica Comparadas, , Universidad de Córdoba, ; Córdoba, Spain
                [9 ]ISNI 0000 0001 2183 9102, GRID grid.411901.c, Infectious Diseases Unit, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, , Universidad de Córdoba, ; Córdoba, Spain
                [10 ]GRID grid.452528.c, SaBio (Health and Biotechnology), , Instituto de Investigación en Recursos Cinegéticos IREC (CSIC-UCLM), ; Ciudad Real, Spain
                Author information
                http://orcid.org/0000-0003-1913-0545
                Article
                702
                10.1186/s13567-019-0702-7
                6792192
                31615555
                07f5090f-35a9-4acf-a161-3c4e7f785738
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 22 April 2019
                : 25 September 2019
                Funding
                Funded by: MINECO
                Award ID: IPT-2012-0327-090000
                Award ID: DI15-08110
                Award ID: IJCI-2015-24805
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Veterinary medicine
                Veterinary medicine

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