We urgently need a new TB vaccine that is effective in adolescents and adults, including PLHIV [5]. WHO preferred product characteristics recommend such a vaccine should: 1) be protective in people with and without evidence of prior TBI at the time of vaccination 2) prevent progression to TB disease following primary infection, re-infection and re-activation of latent infection 3) and demonstrate protection for ⩾2 years after vaccination [6]. How can such a TB vaccine be achieved? A Global Roadmap for Research and Development of TB Vaccines, developed recently in consultation with global stakeholders, describes the short-, medium- and long-term priorities to accelerate TB vaccine development [7]. These priorities include greater diversity of immunological approaches to vaccine design and delivery, validated preclinical models, more efficient clinical trial designs, and greater understanding of demand for new cost-effective vaccines and integration into existing TB control programmes to stimulate vaccine production. Integral to acceleration of novel TB vaccine development will be the discovery of vaccine-induced immune correlates of protection using samples from recently completed efficacy trials. A reliable immune correlate of protection, ideally one that is generalisable across vaccine types, would allow estimation of the potential for protection against TB soon after vaccination, without waiting for completion of lengthy efficacy trials and clinical end-point accrual. Fundamentally, greater investment in TB vaccine research and development is needed. How close are we to implementing a new TB vaccine strategy? This chapter discusses candidate TB vaccines designed for use in infant, adolescent and adult populations for pre-exposure (IGRA-negative) and post-exposure (IGRA-positive) vaccination strategies and for prevention of TBI, progression from infection to disease, or unfavourable treatment outcome. Candidate TB vaccines in the clinical development pipeline The WHO Global Tuberculosis Report 2022 lists 14 candidate TB vaccines in the clinical development pipeline (table 1) [40]. The 2022 pipeline is dominated by candidates in phase 2b–3 trials, which raises the possibility of positive efficacy signals in the short term. However, it also flags the long-term risks of an empty upstream pipeline with few candidates advancing from preclinical testing, in the event that candidates in planned efficacy trials are not successful. It should also be noted that several of these efficacy trials are not traditional prevention of TB disease trials, but are being conducted for nontraditional prevention of TBI, prevention of recurrent disease or therapeutic indications, or in special populations. Such trials might not lead directly to licensure, or might support licensure only for very limited indications and/or populations. Viral-vectored candidate vaccines Three viral-vectored vaccines are in phase 1–2a trials. Ad5Ag85A vaccine Ad5Ag85A is a replication-deficient, adenovirus type 5 (Ad5) viral vector that expresses the mycobacterial antigen 85A (Ag85A). Animal studies have shown that Ad5Ag85A elicited a robust systemic antigen-specific T-cell response after intradermal injection but did not protect against TB in the lungs [41, 42]. However, when administered via the mucosa, a robust protective effect against M. tuberculosis lung challenge was observed [42]. Phase 1 trials have shown that Ad5Ag85A is well tolerated in both BCG-vaccinated and BCG-naïve adults, and Ad5Ag85A-induced T-cell responses were higher in BCG-vaccinated than in BCG-naïve individuals. As observed for HIV vaccine candidates based on Ad5 vectors [43], there is concern that vector-specific neutralising antibody responses in those with prior Ad5 infection may dampen the vaccine-induced immune response [8, 9]. https://doi.org/10.1183/2312508X.10024922 165 RECENT ADVANCES IN VACCINES |A.K.K. LUABEYA ET AL.