## 4 New TB Vaccine Candidates from Discovery to Clinical Trials  
The most effective licensed vaccines against different infectious diseases confer protective immunity by /inducing neutralizing antibodies. Whereas, while for other diseases, such as HIV, malaria or TB, a strong response of cellular immunity is necessary, and we don't have correlated protection that could anticipate the efficacy of a new vaccine candidate [31]. The last 20 years have seen important breakthroughs in TB vaccinology, ranging from novel adjuvant systems or viral vectors for intracellular antigen presentation to advanced genetic engineering techniques for rational attenuation of _Mtb_. All these advances in vaccinology have led to the development of new TB vaccine candidates including novel prime and prime-boost regimes that could reach all age groups and TB population spectrums. The biology behind the host immune responses to _Mtb_ are not yet understood [32; 33]. Developing a protective vaccine requires not only finding the right antigens, but also activating the right ratio of protective and suppressive immune cells against these pathogens. In [PERSON]'s words, \"we need efficacious vaccines to understand immunology of TB\" and we need \"immunology studies to design a good TB vaccine\". Given the lack of BCG protection against respiratory forms of TB, in the last 20 years an enormous effort has been made in the research and development of new vaccines against TB. In the discovery phase, thousands of potential candidates were identified, of which hundreds have passed to preclinical evaluation in animal models and only a little more than a dozen have happened to be tested in early clinical studies in humans to date. There are different stages that each vaccine candidate needs to perform, including early first-in-human Phase I, then Phase II, and finally Phase III clinical trials, to reach marketing authorization. In the United States, for nearly two decades former Aeras (now International AIDS Vaccine Initiative, IAVI) [34], supported by the Bill and Melinda Gates Foundation, were dedicated to the discovery of new TB vaccine candidates. At the end of 2018, Aeras transferred its preclinical assets and clinical programs, biorepository, clinical staff, funding and other assets to International AIDS Vaccine Initiative (IAVI) [34]. In Europe, the research promoted by the different European Commission (EC) Framework Programs has made possible for hundreds of candidates to pass to preclinical evaluation of which several are currently in clinical trials [35]. In 2008, thanks to the EC funding programmes, the European TB Vaccine Initiative (TBVI) [36] was founded integrating at least 50 R&D consortium partners from the public (academia) and private (industry) sectors. TBVI is a non-profit product development partnership that facilitates the discovery and development of new, safe and effective TB vaccines and biomarkers that are accessible and affordable for global use. Clinical trials of a small number of selected TB vaccine candidates are supported by IAVI with funding sources from US NIH funding programmes and by the European and Developing Countries Clinical Trials Partnership (EDCTP) [37]. Given that the protection of BCG administered intradermally shows such limited results of efficacy, new studies changing the routes of administration of BCG have demonstrated encouraging results in non-human primates (NHP) applying BCG by the intravenous (IV) route against virulent _M. tuberculosis_ challenge [38]. Although the difficulties of using the IV route for mass vaccination campaigns, the efficacy results demonstrating ability of IV BCG to substantially limit _Mtb_ infection in highly susceptible rhesus macaques could have important implications in the preclinical evaluation of new candidates, as it could provide a prototype for identifying immune biomarkers and mechanisms of vaccine-induced protection against TB. The respiratory administration of BCG has demonstrate to be very promising by conferring very good immunity and protection in NHP [39].