## 6 Target Population for a New TB Vaccine  
In its Preferred Product Characteristics (PPC) document for TB vaccines, WHO defines two target populations for which a new TB vaccine could play a very important role in the fight against TB including resistant forms of the disease [3; 4]. The WHO prioritizes two types of strategies one, safe, effective and affordable TB vaccines for adolescents and adults and the other, a TB vaccine for neonates and infants with improved safety and efficacy as compared to BCG. Following the negative results of the first efficacy study which was conducted with MVA5A in infants, the priority population was changed to mainly adults. Modelling studies suggest that new effective vaccines for adolescents and adults, who are responsible for disease transmission, would have the greatest impact in halting TB incidence [71; 72]. These studies suggest that although disease incidence in children under five years of age is considerable, TB transmission among this age-group is not common [73]. Prophylactic prime vaccines should be compared to BCG, since whole-cell vaccines seek to protect better than BCG. The immune responses elicited by live mycobacterial vaccines are considered to be specific and long-lasting, and these responses are not obtained with subunit vaccines. Vaccine persistence or restricted replication in vivo could account for the differences of immune responses, as observed for other live human vaccines, such as polio, measles, and yellow fever [48]. Considering the variability in BCG formulations, new TB vaccine trials which use BCG as reference comparator, should be interpreted cautiously with reference to a specific BCG formulation avoiding generalization of data to all BCGs [13]. Since the majority of the adolescent and adult population in countries endemic of TB has been previously vaccinated with BCG at birth, what is sought with subunit candidates comprising specific \(Mtb\) antigens is to potentiate the pre-existing immunity induced by BCG [2; 46; 62]. Recent studies indicate that new TB vaccines that are compared to BCG should be interpreted cautiously with reference to a specific BCG formulation and not presumed to generalize to all BCGs [13]. In addition, testing the new concepts of vaccines in relevant animal models such as NHP, should be key before advancing into expensive clinical trials of efficacy [74; 75]. Something that has been questioned in the MVA85A efficacy study [38] was that the efficacy experiments in NHP, which showed lack of efficacy by the tested clinical route and dose of administration [76; 77]. We should be very careful not to repeat mistakes with new candidates. Recently, it was published in NHP, that boosting BCG with M72/ASO1E or H56/CAF01 or ArAd5 failed to enhance BCG-induced protection against TB [78]. Thus, care should be taken with the advanced clinical development of such candidates. Healthy newborns represent the most sensitive population without pre-existing immunity to BCG or environmental mycobacteria, which in older groups can lead to possible effects of masking and blocking vaccination [79; 80]. We, therefore, think that the efficacy should be studied in newborns as first step, and once the efficacy of a new vaccine has been established, then such new candidates should be tested for efficacy in adolescents and adults where the impact on TB will be greater given that the pulmonary forms are responsible for this transmission [80]. Writing--review and editing, [PERSON], [PERSON], [PERSON] and [PERSON]-[PERSON]. All authors have read and agreed to the published version of the manuscript. This work has been funded by the Ministry of Science (RTI2018-097625-B-I00) and the European and Developing Countries Clinical Trials Partnership (EDCTP) RIA2016V-1637. In this section, you can acknowledge any support given which is not covered by the author contribution or funding sections. This may include administrative and technical support, or donations in kind (e.g., materials used for experiments).