REASSESSING TWENTY YEARS OF VACCINE DEVELOPMENT AGAINST TUBERCULOSIS EDITED BY : Ulrich E. Schaible and Stefan H. Kaufmann PUBLISHED IN : Frontiers in Immunology Frontiers Copyright Statement About Frontiers © Copyright 2007-2018 Frontiers Media SA. All rights reserved. Frontiers is more than just an open-access publisher of scholarly articles: it is a pioneering All content included on this site, approach to the world of academia, radically improving the way scholarly research such as text, graphics, logos, button icons, images, video/audio clips, is managed. The grand vision of Frontiers is a world where all people have an equal downloads, data compilations and software, is the property of or is opportunity to seek, share and generate knowledge. Frontiers provides immediate and licensed to Frontiers Media SA permanent online open access to all its publications, but this alone is not enough to (“Frontiers”) or its licensees and/or subcontractors. 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With their The above represents a summary unique mix of varied contributions from Original Research to Review Articles, Frontiers only. For the full conditions see the Research Topics unify the most influential researchers, the latest key findings and historical Conditions for Authors and the Conditions for Website Use. advances in a hot research area! Find out more on how to host your own Frontiers ISSN 1664-8714 Research Topic or contribute to one as an author by contacting the Frontiers Editorial ISBN 978-2-88945-446-4 DOI 10.3389/978-2-88945-446-4 Office:[email protected] Frontiers in Immunology 1 March 2018 | Reassessing Twenty Years of Vaccine Development REASSESSING TWENTY YEARS OF VACCINE DEVELOPMENT AGAINST TUBERCULOSIS Topic Editors: Ulrich E. Schaible, Forschungszentrum Borstel - Leibniz Lung Center (LG), Germany Stefan H. Kaufmann, Max Planck Institute for Infection Biology (MPG), Germany Tuberculosis (TB) remains the prime bacterial infection worldwide with 10.4 million infections and a death toll of 1.7 million people in 2016 according to WHO statistics. Tuberculosis is caused by members of the Mycobacterium tuberculosis complex, facultative intracellular bacteria able to thrive within otherwise potent innate defense cells, the macrophages. In a world of increasing numbers of infections with drug resistant M. tuberculosis strains, the daunting race between developing new therapeutics and emerging resistant strains will hardly produce a winner. This cycle can only be broken by enhancing population wide immune control through a better vaccine as the only one currently in use, M. bovis Bacillus Calmette Guerin (BCG). The protective efficacy of BCG against pulmonary tuberculosis in all age groups is dissatisfying and geographically highly diverse with the tropical areas showing the lowest efficacy rates. Despite worldwide vaccination coverage, the impact of BCG on the steep decrease of tuberculosis incidence rates in the developed world seems therefore questionable and can rather be attributed to improved social, housing and nutritional conditions, better health care, surveillance and treatment systems. The last 15 years saw tremendous efforts to improve vaccination strategies against tuberculosis. Different paths of vaccine approaches were followed including genetically improved BCG strains, attenuated M. tuberculosis variants, recombinant viral vectors and subunit vaccine candidates combined with novel more potent adjuvants. With the first novel vaccine candidates being evaluated in clinical phases II and III and initial results chastening the expectations, a critical reassessment of all candidates is inevitable. Here, we assembled experts to review and assess the current status of novel anti- tuberculosis vaccine candidates, their efficacy and prospects for implementation as well as the pitfalls and possible measures for improvement. Frontiers in Immunology 2 March 2018 | Reassessing Twenty Years of Vaccine Development Human neutrophils infected with virulent Mycobacterium tuberculosis quickly succumb to necrotic cell death. However, when they get infected by attenuated M. tuberculosis strains such as those lacking the ESX1 secretion system they die of apoptosis. M. tuberculosis delivered into macrophages through necrotic neutrophils interfere with phagosome maturation and proliferate, whereas those enwrapped in apoptotic neutrophils end up in phagolysosomes and are controlled. Therefore, apoptotic host cell death is beneficial for protective immunity (See: Schaible et al. in this issue). The image depicts a LAMP1-positive (blue) phagolysosome containing an attenuated ESX1-deficient M. tuberculosis mutant (red) enwrapped in an apoptotic neutrophil (green). Image: Tobias Dallenga, Forschungszentrum Borstel. Citation: Schaible, U. E., Kaufmann, S. H., eds. (2018). Reassessing Twenty Years of Vaccine Development Against Tuberculosis. Lausanne: Frontiers Media. doi: 10.3389/978-2-88945-446-4 Frontiers in Immunology 3 March 2018 | Reassessing Twenty Years of Vaccine Development Table of Contents 05 Editorial: Reassessing Twenty Years of Vaccine Development against Tuberculosis Ulrich E. Schaible and Stefan H. E. Kaufmann 1. Lessons from BCG 07 What Have We Learnt about BCG Vaccination in the Last 20 Years? Hazel M. Dockrell and Steven G. Smith 17 What We Have Learned and What We Have Missed in Tuberculosis Pathophysiology for a New Vaccine Design: Searching for the “Pink Swan” Pere-Joan Cardona 2. The New Vaccine Types 28 MTBVAC: Attenuating the Human Pathogen of Tuberculosis (TB) Toward a Promising Vaccine against the TB Epidemic Jesus Gonzalo-Asensio, Dessislava Marinova, Carlos Martin and Nacho Aguilo 36 The Recombinant Bacille Calmette–Guérin Vaccine VPM1002: Ready for Clinical Efficacy Testing Natalie E. Nieuwenhuizen, Prasad S. Kulkarni, Umesh Shaligram, Mark F. Cotton, Cyrill A. Rentsch, Bernd Eisele, Leander Grode and Stefan H. E. Kaufmann 45 TBVAC2020: Advancing Tuberculosis Vaccines from Discovery to Clinical Development Stefan H. E. Kaufmann, Hazel M. Dockrell, Nick Drager, Mei Mei Ho, Helen McShane, Olivier Neyrolles, Tom H. M. Ottenhoff, Brij Patel, Danielle Roordink, François Spertini, Steffen Stenger, Jelle Thole, Frank A. W. Verreck, Ann Williams and TBVAC2020 Consortium 3. Targeting Immune Functions 63 Polyfunctional CD4+ T Cells As Targets for Tuberculosis Vaccination Deborah A. Lewinsohn, David M. Lewinsohn and Thomas J. Scriba 85 Review: Impact of Helminth Infection on Antimycobacterial Immunity— A Focus on the Macrophage Roland Lang and Judith Schick 96 Strategies to Improve Vaccine Efficacy against Tuberculosis by Targeting Innate Immunity Ulrich E. Schaible, Lara Linnemann, Natalja Redinger, Emmanuel C. Patin and Tobias