Introduction
The aim is to evaluate the efficacy of the candidate vaccine to conclusively demonstrate that vaccination induces protection against TB disease. Prevention of active TB disease in a general, healthy population remains the primary focus of vaccine development. This assessment will need a large sample size and long duration of follow-up.
Another consideration is the definition of the POD endpoint in a phase 2b or phase 3 trial. Such trials have thus far defined the primary endpoint as positive Mtb sputum culture in trial participants who have symptoms suggestive of TB disease (symptomatic TB). This primary endpoint is ascertained by screening trial participants for specified symptoms, followed by bacteriological testing if symptom screen-positive. National TB prevalence surveys have however shown that at least half of adults in high TB burden settings who are found to have positive Mtb sputum cultures do not report TB suggestive symptoms (asymptomatic TB) (Frascella et al., 2021 and Stuck et al., 2024). Modelling studies suggest that including a symptomatic TB in a primary composite endpoint with symptomatic TB would allow POD trials to have considerably smaller sample sizes and shorter durations (White et al., 2025). Asymptomatic TB could then be ascertained by symptom-agnostic TB screening, using chest X-ray or other screening tools, followed by bacteriological testing if screen-positive.
The potential limitation of including asymptomatic TB is that once diagnosed, asymptomatic TB in a trial participant will require antituberculosis treatment, whereby symptomatic TB in that participant will no longer develop and the number of symptomatic TB endpoints that is expected to accrue in the trial will be less. If a candidate vaccine has similar efficacy in preventing both asymptomatic and symptomatic TB, detecting and treating asymptomatic TB will not compromise the efficacy evaluation. If however the vaccine is more efficacious in preventing symptomatic TB than asymptomatic TB, including asymptomatic TB in a composite endpoint may result in a false negative trial result. If however the vaccine is more effective in preventing asymptomatic TB than symptomatic TB, including asymptomatic TB in a composite endpoint may lead to a false positive result (Churchyard et al., 2024). Whether a combined symptomatic-asymptomatic endpoint can be used in phase 3 trials therefore depends on whether there is sufficient evidence to convince regulators and policy makers that asymptomatic TB is clinically relevant and that phase2b results demonstrate no or minimal difference in efficacy for symptomatic and asymptomatic TB endpoints. As part of the TBvaccine accelerator, the WHO is gathering the evidence to support using asymptomatic TB as an efficacy endpoint, including as a co-primary endpoint, and is engaging with regulators, policy makers and other stakeholders and will in time make a recommendation regarding the use of asymptomatic TB as an efficacy endpoint.
- Define endpoints for efficacy in a Phase 2b/3
- Endpoints and necessary assays for first efficacy trial defined
Phase 1 FIH studies generally focus on safety and immunogenicity of a vaccine candidate entering clinical development. Evaluation of vaccine efficacy will occur at later stages of clinical development. Of note, the immunological read-outs used to currently define infection may not be applicable to vaccines that include the antigens used to define Mtb infection.
The study design for Phase 2b should reflect the statistical hypothesis: usually superior efficacy over either placebo or benchmark vaccine (e.g. BCG in an infant population). The magnitude of superiority should reflect the expected improvement in public health outcomes. The preferred primary endpoint for Phase 2b should be bacteriologically confirmed i.e., culture and/or GeneXpert positive TB disease using standardised case definitions.
TB vaccine target population considerations
Adolescent/adult vaccine: The study design for Phase 2b should reflect the statistical hypothesis of superior efficacy over placebo as there is no current recommendation for BCG booster immunisation. The magnitude of efficacy should be consistent with an expected substantial impact on the epidemic, that is ≥50% efficacy in IGRA+ (Knight et al., 2014, WHO ECVP).
Neonate/infant vaccine: In infants, testing for superiority of efficacy over BCG will be conducted and the magnitude of superiority should reflect the expected improvement in reduced risk of TB disease. Non-inferiority efficacy testing could be considered for an investigational vaccine offering a substantial benefit compared to BCG (e.g. safety in HIV exposed infants) (see also: WHO PPC for New TB Vaccines).
- Confirm efficacy endpoints of Phase 2b
- Efficacy endpoints for Phase 2b confirmed
A convincing robust data package demonstrating pre-clinical and clinical safety and immunogenicity needs to be assembled to proceed to Phase 2b.
The current approach to obtaining proof of concept is to conduct a Phase 2b POD trial in a population with high risk of disease (to keep size and cost of the trial as low as possible), but may increase the risk of obtaining a false negative trial result. [refer to ‘target population considerations’ at function 9] This could be a IGRA positive or TBST-positive adult population, as one example, if the vaccine candidate is hypothesised to prevent disease post-infection.
Primary and secondary endpoints of protective efficacy against TB disease in line with WHO definitions are agreed/confirmed for the Phase 2b trial.
See Stage F function ‘Clinical Development and Operations’.
- Demonstrate protective efficacy against the primary case definition endpoint
- Evidence of efficacy from Phase 2b or interim analysis consistent with minimal (predefined) TPP criteria
Analysis of the data from the Phase 2b trial should demonstrate protective efficacy against the primary case definition endpoint that is greater than or equal to the minimum predefined efficacy criterion as set in the TPP, allowing for extending efficacy evaluation in a Phase 3 trial.
If PLWH are included in phase 2b trials, consideration should be given to providing TB preventive treatment (TPT) according to local policy. Various trial designs have been proposed to accommodate the need to provide TPT to PLWH in TB vaccine efficacy trials(Rangaka et al., 2023).
- Evaluate clinical efficacy against TPP
- Establish plan for phase 3 extension, if needed
- Protective efficacy meets TPP
- Plan for phase 3 extension established, if needed
Analysis of the data from the Phase 3 trial should confirm protective efficacy against the primary case definition endpoint greater or equal to the minimum predefined efficacy asset in the TPP in the target population for licensure.
TB vaccine priority population considerations
PLWH: PLWH would benefit from participating in TB vaccine trials as soon as safely possible (endorsed by the European AIDS Treatment Group (EATG)). Clinical characteristics, such as CD4+ T-cell counts and viral load, should be included as eligibility criteria and only PLWH receiving ART that meet pre-specified thresholds should be considered for inclusion in TB vaccine trials. Efficacy endpoints for PLWH overall should be the same as for people without HIV in POD vaccine trials (Miner et al., 2022).
- Finalise post-licensure evaluation plan for Phase 4 effectiveness under field conditions, including concomitant vaccines, if relevant
- Evaluationplan for post-licensure effectiveness, including administration of concomitant vaccines finalized and approved
Study protocols should be prepared for Phase 4 studies designed to confirm vaccine effectiveness in the target population under field conditions, to evaluate the duration of protection and possible need for booster immunisations.
A study protocol should also be established for Phase 4 effectiveness studies in specific sub-populations e.g. HIV infected populations and other subpopulations such as pregnant and breastfeeding individuals, if not already done. Of note, new draft guidelines on inclusion of pregnant and breastfeeding individuals in clinical trials were released by WHO and for public consulting by EMA and FDA.
See also Function ‘Regulatory’
- Evaluate vaccine effectiveness in Phase 4 studies
- Conduct additional co-administration studies, as required
- Vaccine effectiveness Phase 4 studies evaluated
- Additional co-administration studies conducted
Phase 4 studies to determine vaccine effectiveness are initiated and carried out as planned.