The TPP and PDP are updated and include data on safety and immunogenicity from Phase 1.  While most Phase 1 studies are performed in a single clinical site, Phase 2a studies may be multi-site, and can involve several countries.  As clinical development progresses, the need for additional resources in clinical and regulatory aspects increases, and coordination is more complex.  The PDP further details the strategy related to the Phase 2 programme, and, if needed, a new GMP production for clinical trial material.  The PDP anticipates the need for a proof-of-concept efficacy study (Phase 2b) and describes its design, overall operations and resources needed, and regulatory strategy. The Gantt chart and budget are updated.

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As the project enters clinical development, the business plan will be refined according to emerging data and project needs.  Potential partnerships, in particular for clinical development and commercial aspects should be further evaluated.

The IP position and strategy should be further refined, owned IP filings should be pursued and potentially supplemented.  The patent landscape should be monitored on an ongoing basis.

Funding for activities covering the whole stage should be secured.  In particular, funding should be available to cover Phase 2 before the start of the trial.

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During Phase 1, the assays for Critical Quality Attributes (CQA) continue their qualification, progressing to validation.  The assays used for product characterisation could be slightly modified, to improve the sensitivity or accuracy of the test.  This should not change the qualification or later validation status of the assays.  Up to this point, the product reference would be from well described R&D production runs and be used to standardise assays.  It could now be replaced by a GMP compliant reference.  

The assays are used to release any new GMP material produced, or to document changes in the drug product (within certain limits), and in the continuing stability studies.

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Further process development involving scale-up towards targeted market scale and process validation are the aims of Stage E.

A live attenuated TB vaccine is used as an example.  The anticipated clinical dose is relatively low and, therefore, the scale could be 10 to 100L bioreactors, even for vaccines requiring multi-million doses because one mL of reactor volume could contain 10⁶doses.  Minimal purification is required with low impact on yield, although loss can be caused by lyophilisation.  A contrasting example is that of a non-live vaccine where the equivalent reactor volume (1 mL) is unlikely to produce a similar number of purified antigen doses as a live vaccine.

Assuming a down-stream process yield of 50%, and target dose of 10 µg, it means that for a multi-million dose requirement multiple 1000L reactor runs would be needed. In any event, the scale-up process for commercial batches should be defined at this stage.

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The regulatory strategy depends on the indication sought and goes hand-in-hand with the development of a market access strategy.

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The FIH trial is completed during this stage, as well as Phase1b in primary target populations.

Study protocols for Phase 2a studies to establish the optimal dose, formulation, route of administration and schedule of immunisation are developed and the PIs and study CRCs are selected.

Planning for a Phase 2b POC or integrated Phase2b/3 trial should be initiated.  A plan should also be drafted to generater eliable epidemiological data on TB disease endpoints in the target population in different regions and at the different study sites to be considered for Phase 2b and/or 3 trials.

The CDP will be updated to reflect any new relevant information that has become available from the pre-clinical programme and/or general advances in the field of TB vaccine research.

The community engagement activities will continue at this stage of the development for more information on community engagement refer to guidance under Stage C.

TB vaccine target population considerations - dropdown

Adolescent/adult vaccine: A plan for a Phase 2b trial to assess the protection against pulmonary TB Disease (POD) should be developed at this stage.  POD Phase 2b could be conducted among individuals considered at higher risk of disease to reduce sample size and study duration, e.g. previously Mtb exposed individuals, health care workers, or household contacts.  However, if for most trial participants Mtb exposure has been recent, such as household contacts, a relatively large proportion (higher than in the general population) may be in a state of advanced disease progression that the vaccine candidate may not be able to halt, resulting in underestimation of the vaccine efficacy and thereby a false negative trial result.  Vaccine developers should be aware of the fact that a positive IGRA test is not a perfect predictor of future disease risk in endemic areas with mass BCG vaccination (Hamada et al., 2023).   Reversions of IGRA status have also been shown to occur frequently during follow up in endemic areas without a clear correlation with development of disease (Chen et al., 2025).  Participants at the highest risk of developing TB are probably those who converted within the previous two years to IGRA positive from an initial IGRA negative status (Cobelens et al., 2025).  As a result, the risk of TB disease among adolescents and adults witha positive IGRA will on average decrease with age, and this decrease will be steeper with increasing TB incidence in the trial population.  Thereby the sample size efficiency gain of doing a trial in previously exposed (IGRA or TBST positive) adults and adolescents may be limited in high-incidence populations (Cobelens et al., 2025).  The sample size advantage of other trial populations at higher risk of disease for phase 2b trials should also be carefully weighed against their requirements and risk.  Household contacts of infectious TB patients have 5 to 10-fold higher incidence of TB over a 1–2-year period compared to the general population in high TB burden settings.  However, there may be a requirement to provide Mtb exposed household contacts TB preventive therapy, which will reduce their risk of developing TB disease.  In addition, Mtb exposed household contacts may develop disease shortly after randomization, and despite screening negative for TB disease at enrolment, already have a level of pathology and mycobacterial multiplication that cannot be reversed by immunization. This would reduce the observed vaccine efficacy.

The CDP should be updated to reflect how a broader label, i.e. beyond the POC population, will be achieved in Phase 3.

Neonate/infantvaccine:  FIH and Phase 1b studies in neonates from endemic countries are completed during this stage.  As per generic plan, the dose and regimen of a BCG replacement or a BCG boosting vaccine will be evaluated during safety and immunogenicity Phase 2a studies.  Definition of the control arm differs by vaccination strategy; for BCG replacement, BCG or the investigational vaccine only are administered at birth in the control and test group, respectively and for BCG boosting, the control group receives a placebo and the test group the investigational vaccine, both administered at a pre-defined time after birth BCG vaccination

Safety and immunogenicity studies of concomitant administration with Expanded Programme onImmunisation (EPI) recommended vaccine(s) should be planned to be conducted before or during Phase 2b studies.

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The safety data of the Phase 1a study and Phase 1b in the target population (e.g. healthy neonates, or Mtb non-exposed and/or exposed adults from endemic regions) should indicate an acceptable reactogenicity profile of the different vaccine doses which are being considered for Phase 2a studies.  No safety concerns precluding further clinical development should have been identified.

TB vaccinetarget population considerations

Adolescent/adultvaccine:  Safety data in both IGRA-negative and IGRA-positive adults are required.

Neonate/infant vaccine:  Develop a plan to assess safety in HIV exposed, as well as unexposed neonates and infants.   For a neonatal BCG-replacement vaccine candidate, plan to evaluate safety in comparison to BCG in HIV exposed neonates.  Similarly, an infant booster vaccine should be tested in comparison to a BCG prime alone.

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Immunogenicity data of the Phase 1a and Phase 1b studies will be analysed to characterise immunogenicity using primary, co-primary, secondary and exploratory endpoints.  The elicited immune responses must provide evidence that the candidate induces vaccine antigen-specific immune responses and an evaluation must be made of whether these responses are sufficient to progress development of the candidate vaccine.  In addition to safety, immunogenicity will guide the selection of the dose(s) to be further evaluated in Phase 2a studies.

Wherever possible a biomarker plan must be prepared prior to embarking on clinical efficacy studies: plans should be made for samples to be collected from Phase 1 studies and bio-banked for future correlates analyses – these samples will be vital for the potential discovery and characterization of correlates of protection or risk.

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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).

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The market assessment is refined according to new data.

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