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TBVAC2020: Advancing Tuberculosis Vaccines from Discovery to Clinical Development

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TBVAC2020: Advancing Tuberculosis Vaccines from Discovery to Clinical Development REVIEW published: 04 October 2017 doi: 10.3389/fimmu.2017.01203 TBVAC2020: Advancing Tuberculosis Vaccines from Discovery to Clinical Development Stefan H. E. Kaufmann1*, Hazel M. Dockrell 2, Nick Drager 3, Mei Mei Ho4, Helen McShane5, Olivier Neyrolles 6, Tom H. M. Ottenhoff 7, Brij Patel 8, Danielle Roordink3, François Spertini 9, Steffen Stenger10, Jelle Thole3, Frank A. W. Verreck11, Ann Williams12 and TBVAC2020 Consortium 1 Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany, 2 Immunology and Infection Department, London School of Hygiene and Tropical Medicine, London, United Kingdom, 3 Tuberculosis Vaccine Initiative (TBVI), Lelystad, Netherlands, 4 Bacteriology Division, MHRA-NIBSC, Potters Bar, United Kingdom, 5 University of Oxford, Oxford, United Kingdom, 6 Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France, 7 Leiden University Medical Center, Leiden, Netherlands, 8 RegExcel Consulting Ltd, Surrey, United Kingdom, 9 Centre Hospital Universitaire Vaudois, Lausanne, Switzerland, 10 University Hospital of Ulm, Ulm, Germany, Edited by: 11 Biomedical Primate Research Centre, Rijswijk, Netherlands, 12 Public Health England, London, United Kingdom Kuldeep Dhama, Indian Veterinary Research Institute (IVRI), India TBVAC2020 is a research project supported by the Horizon 2020 program of the Reviewed by: European Commission (EC). It aims at the discovery and development of novel tuber- Adel M. Talaat, University of Wisconsin-Madison, culosis (TB) vaccines from preclinical research projects to early clinical assessment. The United States project builds on previous collaborations from 1998 onwards funded through the EC Shoor Vir Singh, framework programs FP5, FP6, and FP7. It has succeeded in attracting new partners Central Institute for Research on Goats (ICAR), India from outstanding laboratories from all over the world, now totaling 40 institutions. Next Ed C. Lavelle, to the development of novel vaccines, TB biomarker development is also considered Trinity College, Dublin, Ireland an important asset to facilitate rational vaccine selection and development. In addition, *Correspondence: TBVAC2020 offers portfolio management that provides selection criteria for entry, gating, Stefan H. E. Kaufmann [email protected] and priority settings of novel vaccines at an early developmental stage. The TBVAC2020 consortium coordinated by TBVI facilitates collaboration and early data sharing between Specialty section: partners with the common aim of working toward the development of an effective TB This article was submitted to Microbial Immunology, vaccine. Close links with funders and other consortia with shared interests further con- a section of the journal tribute to this goal. Frontiers in Immunology Received: 07 July 2017 Keywords: tuberculosis, bacille Calmette–Guérin, vaccination, biomarker, clinical trial, portfolio management, discovery Accepted: 11 September 2017 Published: 04 October 2017 Citation: Kaufmann SHE, Dockrell HM, INTRODUCTION Drager N, Ho MM, McShane H, Neyrolles O, Ottenhoff THM, Patel B, One hundred years ago, Albert Calmette (1863–1933) and Camille Guérin (1872–1961) had almost Roordink D, Spertini F, Stenger S, reached their goal (1). They had passaged Mycobacterium bovis 200 times at 14 d intervals on potato Thole J, Verreck FAW, Williams A slices soaked with ox gall in their attempt to generate an attenuated vaccine against tuberculosis and TBVAC2020 Consortium (2017) (TB). They had started their program in 1906 and had already obtained preliminary evidence for TBVAC2020: Advancing Tuberculosis Vaccines from Discovery to safety and protection of their candidate in 1913. Yet, they continued until they had completed the Clinical Development. 230th passage before verifying its efficacy and safety in experimental animals including guinea pigs, Front. Immunol. 8:1203. rabbits and non-human primates (NHPs) as well as in the natural host, cattle. The data obtained doi: 10.3389/fimmu.2017.01203 were highly promising so Calmette and Guérin started the first vaccination of a human neonate born Frontiers in Immunology | www.frontiersin.org 1 October 2017 | Volume 8 | Article 1203 Kaufmann et al. TBVAC2020 into a household with a TB patient. Risk of TB in a household- research and development and ensured a well-coordinated and contact infant at those times was extremely high. Yet, the baby efficient TB vaccine research consortium. did not develop TB and after additional encouraging results, At the same time, the pipeline needs to be fed constantly with vaccinations of more than 20,000 neonates in households with new innovative candidates since it is unlikely that one single at least one TB patient were performed between 1921 and 1924. vaccine could protect against all different forms of TB disease in The results of this trial revealed that of the vaccinees 5% had died all age groups and for all indications. Thus, the concept of diver- and 1% of these of TB, whereas knowledge of the time held that a sification gained increasing importance. Different vaccine types quarter of non-vaccinated newborns would die in the first years (subunit vaccines vs. whole cell vaccines), different administra- of life, many of them of TB (1). This is the start of Bacille Bilié tion schedules (pre-exposure vs. post-exposure), different age Calmette-Guérin, later shortened to Bacille Calmette–Guérin groups (neonates vs. adults) and different purposes (prevention (BCG), which remains the only licensed vaccine against TB until of infection vs. disease vs. recurrence of disease), and perhaps today. Although not perfect, this vaccine partially fulfills the even therapeutic TB vaccines have all to be considered. goal set by Calmette and Guérin, since it protects against extra- Already before the beginning of TBVAC2020, it was realized pulmonary forms of disease in infants, including life threatening that an isolated vaccine development approach was inadequate TB meningitis. Unfortunately, in most settings, BCG does not and needed to be complemented by deeper knowledge of patho- reliably prevent pulmonary TB, the most prevalent and the most mechanisms, immunology, and microbiology; by established as contagious form in all age groups from the neonatal to the elderly well as novel animal models; by identifying biosignatures of TB population. The lack of an efficient vaccine against pulmonary disease, risk of disease, vaccine efficacy, and safety (3–6). Finally, TB is a major obstacle to control TB satisfactorily until today. with increasing numbers of vaccines being ready for clinical In 1993, the World Health Organization (WHO) declared TB testing, early clinical trials needed to be integrated. Although a global emergency at a time when some 4–6 million new TB TBVAC2020 and its predecessors respect individual researchers’ cases per year were notified. With the introduction of a new treat- autonomy, it was deemed of increasing importance to also pro- ment regimen, called directly observed treatment, short-course vide a portfolio management process, including consensus gating (DOTS) program, WHO claimed to bring TB under control and criteria, to objectively and transparently guide further product predicted a decline from 6–8 million new cases in 1997 to 2–3 and clinical development of TB vaccine candidates (7). This arti- million new cases by 2017 by implementing highly intensive cle describes the different activities of the Horizon 2020 funded DOTS (2). Unfortunately, this hope failed miserably. The most TBVAC2020 project which is coordinated by TBVI summarizing recent notifications reveal a stunning 10.4 million new cases and recent achievements and future goals as part of the European 1.8 million deaths in 2015. Building on better drug regimens effort to successfully combat TB.Figure 1 provides an overview alone not only proved to be insufficient in controlling TB, it also of the close interactions between different WorkPackage (WP) led to increasing incidences of multi-drug-resistant forms of TB. activities and progression of promising vaccine candidates from At this time, researchers interested in the mechanisms under- discovery via preclinical testing to clinical trial. Although TBVI lying immunopathology and immune protection of TB were has coordinated much of the European research efforts on TB concerned that the efficacy of DOTs might be overestimated vaccine development to date, there are other ongoing activities, and considered a better TB vaccine a necessity for efficient TB for example, through the Aeras Foundation1 and the EMI-TB control. Thus, a proposal on TB vaccines was submitted to the Consortium.2 European Commission (EC) funded framework program (FP) 5 and this was funded from 1998 to 2002. The subsequent FP 6 and WP1 DISCOVERY OF NOVEL TB FP 7 programs continued to support TB vaccine-related research VACCINE STRATEGIES until 2013. During this period, enormous progress was achieved, not only resulting in the development of a number of promising A major objective of TBVAC2020 is the identification of novel vaccine candidates but also providing deeper understanding of vaccine candidates for subsequent preclinical and early clinical immune mechanisms underlying protection and pathology in development. To this end, the objective of WP1 is to develop TB as well as identifying new TB biomarkers (BMs). These FP5 innovative approaches and platforms for TB vaccination in to FP7 activities were succeeded by the Horizon 2020 program
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