responses for control of M. tuberculosis [67–69]. Identification of immune correlates of vaccine-mediated protection (CoP) that are necessary and sufficient for protective immunity would enable rational design of new candidate TB vaccines tailored to induce such protective responses. Features of immune responses that correlate with protection may not necessarily be mechanistically causal. However, if they are easy to quantify and good predictors of vaccine efficacy, such CoP responses could be measured soon after vaccination, circumventing the need to accrue clinical TB disease end-points during long periods of follow-up. This advance could significantly accelerate clinical development of candidate vaccines. Once validated, CoPs may even contribute evidence towards licensure of new products, or extension to new populations for licensed vaccines, through “immunobridging”: measurement of immune responses as efficacy end-points, rather than clinical outcomes such as IGRA conversion or TB disease [70]. Several study designs enable identification of CoPs, but the gold standard relies on samples collected from placebo-controlled, randomised clinical trials with partial vaccine efficacy to allow analysis of vaccine responses in protected and unprotected individuals [71]. Two recently completed phase 2b clinical trials offer the first opportunity to discover human CoPs. As discussed earlier, adolescent BCG revaccination afforded partial protection against sustained IGRA conversion [39], while M72/AS01E vaccination induced partial protection against PTB in IGRA-positive adults [22]. Samples collected from participants in these trials are being studied by two international collaborative research programmes to discover CoPs against sustained IGRA conversion or TB disease. State-of-the-art technologies and an integrated statistical approach are being applied to test prespecified hypotheses and identify features of protective immune responses against M. tuberculosis [72]. To reach their full potential and transform TB vaccine research, candidate CoPs will require independent validation, which may be possible by leveraging the ongoing larger BCG revaccination trial (ClinicalTrials.gov identifier NCT04152161) and the planned phase 3 trial of M72/AS01E, should these trials confirm vaccine efficacy. To be acceptable for immunobridging and licensure studies, CoPs also need to be measurable by validated and relatively simple laboratory assays [71]. Importantly, CoPs may well be specific to different vaccines and clinical outcomes. The studies outlined above will provide a first glimpse into whether common CoPs are induced by a live-attenuated mycobacterial and a protein-subunit vaccine, and whether immune responses associated with protection against TBI and TB disease have any common features. Determining whether such CoPs extend to other vaccine candidates and other clinical outcomes, such as recurrent TB, will require detection of efficacy signals in ongoing phase 2b–3 trials and biobanking of appropriate samples from protected and unprotected participants. Discussion We have shown that the pipeline of new TB vaccine candidates, although including diverse viral-vectored, protein-subunit, live and inactivated mycobacterial and now mRNA platforms, is shallow [40]. The presence of several candidates in, or about to enter, phase 2b–3 trials raises the possibility of new efficacy signals, but the paucity of new candidates moving from preclinical studies into phase 1–2a trials raises concern about sustainability of the pipeline if current efficacy trials do not demonstrate sufficient protection. It is also evident that the TB vaccine field has not swiftly capitalised on recent successes, such as the positive efficacy signal for M72/AS01E against progression from TBI to TB disease in IGRA-positive adults [21, 22], whether due to lack of funder risk appetite, or failure to understand the drivers of global and country-level demand for new TB vaccines. These deficiencies are being addressed actively, through development of a consensus research and development roadmap [7], evaluation of full value and the investment case for new TB vaccines [73], development of evidence considerations for policy [74], and development of a global framework for countries to achieve 172 https://doi.org/10.1183/2312508X.10024922 ERS MONOGRAPH |THE CHALLENGE OF TB IN THE 21ST CENTURY