rapid introduction of new TB vaccines for adults and adolescents. Nevertheless, a phase 3 licensure trial of M72/AS01E will probably start almost 5 years after completion of the successful phase 2b trial, with results not expected until 2028. Positive new developments of the last decade include the entry of eight new candidates into clinical trials, including, most recently, two mRNA vaccine candidates (ClinicalTrials.gov identifier NCT05547464). Another protein-subunit vaccine, H107e/CAF10b, is also poised to enter clinical development in 2023 [47]. It is notable that two live mycobacterial vaccines, MTBVAC and VPM1002, have progressed steadily through safety and immunogenicity studies in infants and adults and have entered efficacy trials. Demonstration of vaccine safety in PLHIV who are established on ART and are virally suppressed are important given the increased risk of TB among PLHIV, who should ideally be included in future licensure trials of these live vaccines [5]. It is also highlighted that MTBVAC and the several new candidates that include either CFP-10 or ESAT-6 antigen are expected to result in vaccine-induced IGRA positivity and complicate testing for M. tuberculosis sensitisation. Clearly, if such a vaccine proves to be effective, development of an IGRA or other diagnostic platform based on alternative antigens would be beneficial for diagnosis of post-vaccination TB exposure. Critical knowledge gaps remain. Approximately three-quarters of the global population are not M. tuberculosis sensitised [75], and we know that risk of progression to TB disease is greatest in the 2 years immediately after TBI [76]. In the absence of known exposure–infection events, vaccinating young, IGRA-negative adolescents before they become infected with M. tuberculosis would seem logical. It is unclear whether current candidate vaccines are immunogenic or protective in this population. The large size and long duration of TB disease efficacy trials necessary to test this hypothesis in IGRA-negative populations would be a considerable disincentive. However, modelling projections suggest that effective vaccination of IGRA-positive populations alone would still have a major impact on the reduction in TB incidence and mortality [77]. Another challenge for design of future efficacy trials, which currently focus on protection against symptomatic disease, is demonstration of protection against subclinical TB, which formed more than half of all bacteriologically confirmed PTB in a recent South African prevalence survey [78]. It remains to be seen whether an asymptomatic, subclinical TB end-point, presumably reflecting early disease, would represent a higher bar to demonstration of vaccine efficacy than symptomatic, clinical TB. In summary, ongoing and imminent prevention of disease efficacy trials in infant and adolescent/ adult populations will soon report results of proof-of-concept prevention of infection, prevention of recurrence and therapeutic efficacy studies that may accelerate entry of vaccine candidates into new licensure trials. However, the best-case scenario for even the most promising candidates is that they deliver licensure efficacy trial results by 2028. It is critical that this time is not wasted. Initiatives such as the investment case for new TB vaccines, development of evidence considerations for policy, and development of a global framework for country-level introduction will be critical in driving demand and securing the funding necessary for implementation. The final key component is the need for renewed focus on TB vaccine advocacy and community sensitisation to address vaccine hesitancy, so that when the world finally gets a new, effective TB vaccine, those most in need of protection are well informed and willing to receive it. References 1 Colditz GA, Berkey CS, Mosteller F, et al. The efficacy of bacillus Calmette–Guerin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature. Pediatrics 1995 96: 29–35. 2 Lancione S, Alvarez JV, Alsdurf H, et al. Tracking changes in national BCG vaccination policies and practices using the BCG World Atlas. BMJ Glob Health 2022 7: e007462. https://doi.org/10.1183/2312508X.10024922 173 RECENT ADVANCES IN VACCINES |A.K.K. LUABEYA ET AL.