BCG revaccination Randomised controlled trials of primary BCG vaccination have shown wide variability in efficacy results in both younger and older age groups, but overall, despite limited efficacy against all forms of TB in older children, adults and previously M. tuberculosis-sensitised individuals, BCG appears to offer protection against severe and disseminated TB in infants and young children, especially M. tuberculosis-unsensitised individuals [55]. Two large randomised controlled trials of BCG revaccination showed no efficacy against TB disease in adolescents and adults of unknown IGRA or TST status [56, 57]. However, case–control studies suggest that primary BCG vaccination may protect against childhood IGRA conversion [58], and subanalyses of randomised controlled trials are consistent with low-to-moderate efficacy against TB disease in younger children with no or lower rates of M. tuberculosis sensitisation [59, 60]. A recent trial of BCG revaccination and H4:IC31 vaccination versus placebo in 989 IGRA-negative South African adolescents showed no significant efficacy against conversion to IGRA positivity. However, BCG revaccination was associated with 45.4% efficacy (95% CI 6.4–68.1%) based on a secondary end-point of sustained IGRA conversion over 6 months, compared with placebo [39]. Sustained IGRA conversion may reflect established TBI. A follow-on trial of BCG revaccination is being conducted to confirm these findings in a larger study population of 1800 IGRA-negative adolescents, with sustained IGRA conversion as the primary end-point, in a population of a wider age range (10–18 years), at multiple sites in South Africa, and with longer follow-up of up to 48 months (ClinicalTrials.gov identifier NCT04152161). The results of the primary event-driven analysis, expected at the end of 2023, will inform modelling projections of the potential impact of BCG revaccination on rates of TBI and TB disease. A very large, and possibly unaffordable, prevention of disease efficacy trial would be necessary to quantify the contribution of prevention of TBI to a reduction in TB disease incidence in an IGRA-negative population. These considerations will be critical for national health departments to estimate the cost-effectiveness of a BCG revaccination programme for TB control in adolescents and young adults. mRNA candidate vaccines BNT164a1/b1 The most recent entrants to the TB vaccine development pipeline, two variants of an mRNA TB vaccine candidate based on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine backbone from BioNTech (BNT164a1 and BNT164b1), recently started a first-in-human trial in Germany (ClinicalTrials.gov identifier NCT05537038), with a second trial (ClinicalTrials.gov identifier NCT05547464) to follow in South Africa. Immune correlates of protection against TB Interactions between M. tuberculosis and its human host are complex, and host defence includes several immune cell subsets and effector mechanisms [61]. Likewise, TB vaccines stimulate a variety of immune responses by multiple subsets of myeloid and lymphoid cells (T- and/or B-cells) [61]. However, it is unclear which immune subsets or responses correlate with protection against TB. Animal models and human studies suggest that CD4+ T-cells, in particular IFN-γ-expressing Th1 cells, are the cornerstone of immunity against M. tuberculosis [62]. Accordingly, most viral-vectored and subunit vaccine candidates were designed to specifically induce Th1 immune responses. However, a phase 2b trial of the candidate vaccine MVA85A [63], and studies that aimed to identify correlates of TB risk [64–66], have shown that frequencies of Th1 responses were not associated with TB outcome. Recent preclinical (in animal models) and observational studies point to possible contributing roles of antigen- specific Th1 and Th17 cells, antigen-specific CD8+ T-cells, humoral and “trained” innate cell https://doi.org/10.1183/2312508X.10024922 171 RECENT ADVANCES IN VACCINES |A.K.K. LUABEYA ET AL.