Introduction
The integrated clinical development plan (CDP) of a novel TB vaccine candidate should describe the entire clinical programme which includes the successive clinical trials (Phase1, 2a, 2b, 3) needed to generate safety and efficacy data supporting the TPP of the investigational TB vaccine. Each clinical programme should be developed in line with the sponsor’s TPPs for the candidate vaccine, which may include one or more target age groups and indications, and the WHO Evidence Considerations for Vaccine Policy. The aim of clinical operations is to conduct clinical trials in accordance with the clinical development plan and to the relevant ethical and regulatory requirements, including but not limited to ICH-GCP.
Considering best financial practices, and also for ethical and regulatory considerations, funding of each clinical study should be fully secured before the start of the study (with exceptions possible, for example for exploratory analyses).
TB vaccine targetpopulation considerations – dropdown
Two principal target populations are being considered for preventive TB vaccine development. (1) Adolescents and adults, in whom the majority of the TB disease burden occurs and who play a critical role in the transmission of Mtb, and (2) neonates and infants who are in need of a vaccine that will provide better and longer protection and with an improved safety profile compared to BCG. For both populations, the indication is active immunization for prevention of TB disease. Whilst neonates will generally not have been exposed to Mtb before vaccination, a new TB vaccine for adults and adolescents should ideally provide protection and be safe in both Mtb unexposed and Mtb exposed individuals as determined by IGRA test or Mtb antigen-based skin test (TBST) responses.
Other priority populations:
Within these target populations, specific priority groups can be considered in different stages of clinical development for three reasons: because of group-specific safety concerns, because of a need to have a sufficiently large dataset on group-specific efficacy or immunogenicity, and/or. In addition, there may be human rights considerations to not specifically exclude priority groups from late-stage trials.
For the priority population of People living with HIV (PLWH):
PLWH are at higher risk of developing TB disease than HIV-uninfected individuals. New TB vaccine candidates should be studied in PLWH to generate safety and immunogenicity data pre-licensure to enable rapid recommendation for use in this priority population. HIV screening prior to TB vaccination would be a significant barrier to rapid vaccine rollout and TB vaccines are therefore ideally demonstrated to be safe in PLWH for initial policy recommendation (Miner et al., 2022).
Other priority populations include pregnant and breastfeeding individuals, and individuals that are immunocompromised, immunosuppressed, malnourished, or who previously had TB disease. Migrants, refugees, miners, and people that use alcohol or substances, or are deprived of liberty or older than 65 years are also priority populations (from: WHO ECVP).
Vaccine technology specific considerations - dropdown
The objectives and the related clinical operations described in this guidance remain the same regardless of the vaccine type althoughfor live attenuated and vector-virus vaccines Phase 1 studies may evaluate the potential for shedding.
The Integrated Clinical Development Plan (CDP) - dropdown
The CDP will start with safety and immunogenicity Phase 1 trials which comprise typical first administration to humans (First-in-Human, FIH) Phase 1a trial and subsequently first administration to the target population (Phase 1b trials) in TB-endemic regions. More recently first-in-human TB vaccine trials have been done in high TB burden countries. Typically, larger Phase 2a studies will then establish the conditions of optimal safety and immunogenicity in the target population(s) related to the dose, formulation, immunisation schedule and route of administration that are to be selected for subsequent studies aimed at demonstrating the protective efficacy of the vaccine. Sponsors however have the flexibility to conduct initial dose ranging studies in phase 1b studies and seamless phase 1-2 studies using an adaptive design may be considered to accelerate early phase development. As the evaluation of vaccine-induced protection against TB disease requires a large study population and long follow up, novel designs using alternative endpoints related to more frequent events may be utilised to provide evidence that the vaccine-induced immune response is biologically functional. As discussed in the introduction to the TB Vaccine Development Pathway (insert link to intro here) POR and POI trials are no longer recommended to provide pre POC evidence to support a POD licensure trial.
The CDP will describe the evaluation of efficacy of the investigational vaccine in larger efficacy trials, i.e. Phase2b POC study(ies) and/or Phase 3 pivotal trials, typically designed to assess the protective efficacy against bacteriologically confirmed symptomatic TB disease.
These latter studies will also further evaluate the safety profile of the investigational vaccine. Given the compelling need for a validated correlate of protection, the CDP should include a plan for the collection of samples to evaluate correlates of risk and/orvaccine induced protection. See also Clinical immunology.
Available epidemiological data on the incidence of the relevant endpoint (preferably TB disease) in the targeted population should be reviewed, particularly in the specific populations where the trials are to be conducted, if available. These data are used to set assumptions for determination of potential sample sizer equired for appropriate power to demonstrate the clinical benefit of the investigational vaccine and ensure that these are within the limits of study feasibility. If adequate epidemiological data are not available, an epidemiological study(ies) should be conducted in advance of the Phase 2 and 2b clinical trials to inform protocol design and sample size calculations. See also Clinical Efficacy function.
Two principal target populations are being considered for preventive TB vaccine development. (1) Adolescents and adults who largely contribute to the overall TB disease burden and who play a critical role in the transmission of Mtb, and (2) Neonates for whom a new TB vaccine is to be used either as a BCG replacing vaccine or as a BCG boosting vaccine. In the neonatal target population, the vaccine is aimed at providing improved efficacy and/ or an improved safety profile compared to BCG. For both populations, the indication is active immunization for prevention of TB disease. A third target population is represented by patients undergoing or completing treatment for active TB for whom a vaccine, given as an adjunct to antibiotic treatment either increases the cure rate of treatment regimens and/or reduces the recurrence rate. The indication is decrease of the recurrent TB disease rate and/ or increase of the cure rate of antibiotic treatment regimens. Consideration may also be given to investigating the efficacy of candidate TB vaccines to shorten treatment duration and/or reduce the number of antibiotics. These indications apply to both drug sensitive and drug resistant TB disease.
The objectives and the related clinical operations described in this guidance remain the same regardless of the vaccine type although for live attenuated and vector-virus vaccines Phase 1 studies may evaluate the potential for shedding.
The CDP will start with safety and immunogenicity Phase 1 trials which comprise typical first administration to humans (First-in-Human, FIH) Phase 1 trial and subsequently first administration to the target population (Phase 1b trials) in TB-endemic regions. Larger Phase 2a studies will then establish the conditions of optimal safety and immunogenicity in the target population(s) related to the dose, formulation, immunisation schedule and route of administration that are to be selected for subsequent studies aimed at demonstrating the protective efficacy of the vaccine.
As the evaluation of vaccine-induced protection against TB disease requires a large study population and long follow up, alternative endpoints related to more frequent events may be utilised to provide evidence that the vaccine-induced immune response is biologically functional. Hence, Phase 2 studies may also include pre-proof of concept (pre-POC) studies such as prevention of infection (POI) or prevention of recurrence (POR) studies to help build a more robust clinical package before proceeding to large and resource-consuming efficacy trials (ref Ellis et al.).
The CDP will describe the evaluation of efficacy of the investigational vaccine in larger efficacy trials, i.e. Phase2b proof-of-concept (POC) study(ies) and/ or Phase 3 pivotal trials, typically designed to assess the protective efficacy against TB disease. These latter studies will also confirm the safety profile of the investigational vaccine. Given the compelling need for a validated correlate of protection, the CDP should preferably include a plan for the collection of samples to evaluate correlates of risk and vaccine induced protection. See also Clinical immunology.
Available epidemiological data on the incidence of the relevant endpoint (eg, Mtb infection and/or TB disease) in the targeted population should be reviewed, particularly in the specific populations where the trials are to be conducted, if available. These data are used to set assumptions for determination of potential sample size requirements for appropriate power to demonstrate the clinical benefit of the investigational vaccine and ensure that these are within the limits of study feasibility. If adequate epidemiological data are not available, an epidemiologic study(ies) should be conducted in advance of the Phase 2 pre-proof of concept (pre-POC) and Phase 2b clinical trials to inform protocol design and sample size calculations. See also Clinical Efficacy function.
- Draft an initial Clinical Development Plan (CDP)
- Look for existing epidemiology data in target population
- CDP drafted and clinical evaluation feasible
- Existing epidemiology data identified and reviewed
At this stage, a first draft of the CDP to generate safety and efficacy data supporting the TPP of the investigational TB vaccine should be prepared. For more information on CDP refer to the introduction of function ‘clinical development and operations’
- Plan the pathway to FIH and anticipate subsequent Phase 2
- Draft Synopsis of Phase 1
- Engage with communities where clinical research will be conducted
- Update the Clinical Development Plan (CDP)
- Pathway to FIH and subsequent Phase 2 established
- Phase 1 synopsis drafted
- Community engagement programme initiated
- CDP updated
Activities in Stage Care based around planning and preparation for the FIH trial and subsequent Phase 1b trials that are designed to include target population individuals, to provide the data needed to support preparation and conduct of Phase 2 studies. FIH and phase 1b studies can be integrated to expedite early-stage development.
Community Engagement planning is a significant strategic process designed to build long-term relationships and working collaborations with the people most affected by TB disease. The purpose of community engagement is to gather input into developing the TPP (medical need and desired product characteristics) and the protocol. Community engagement initiatives should be planned and implemented at all clinical research centres where the studies will be conducted in preparation for the future studies and these initiatives will be ongoing through the entire development programme. They should include consultation over study design and dissemination of results to trial participants and the broader community. The communication of expected and unexpected outcomes is a significant part of this activity as well as general education about TB and vaccines.
First-in-Human (FIH) Phase 1 study design should ideally be double-blind, randomised, controlled and dose-escalating to evaluate safety and immunogenicity of the investigational vaccine in a limited number of healthy, BCG naïve and, potentially, BCG vaccinated adults with no evidence of sensitisation to TB as determined by IGRA or Mtb antigen-based skin test (TBST) responses. There is now precedence for doing FIH TB vaccine trials in adults that were vaccinated with BCG at birth with negative tests of TB infection in high TB burden countries. Subsequent Phase 1b studies will be designed and conducted in the target population in TB-endemic areas. At this stage the design of Ph1 and the CDP could be presented to NRA at a scientific advisory meeting; for more information refer to function ‘Regulatory’.
A study synopsis for Phase 2a studies to select a dose(s) and the immunisation schedule for further development should be drafted.
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.
TB vaccine target population considerations - dropdown
Adolescent/adult vaccine: FIH studies could be planned to evaluate the safety and immunogenicity of the investigational vaccine in BCG naïve and BCG vaccinated individuals, who have no evidence of prior Mtb sensitisation, sequentially in the same study. In addition, Phase 1b studies are designed to evaluate the safety and immunogenicity of the investigational vaccine in subjects from endemic areas who have evidence of prior Mtb sensitisation.
Neonate/infant vaccine: Phase 1b studies are designed to evaluate the safety and immunogenicity of the candidate vaccine in neonates in TB endemic areas. Study design is dependent on the vaccination strategy, BCG replacement or BCG boosting vaccine.
- Prepare operations for FIH/Phase 1 (including completion of protocol, identification of principal investigator (PI), study site, etc.)
- Community engagement: educate on need for TB vaccines and clinical trials, obtain community input into Phase 1 design.
- Draft synopsis for subsequent Phase 2a, aiming at selection of doses, route, etc.
- Operations for FIH/Phase 1 prepared
- Input from the community obtained
- Draft Phase 2a synopsis prepared
Study protocol for subsequent Phase 1b trials are completed. The Principal Investigators (PIs) andClinical Research Centres (CRCs) for these trials are also selected. The Phase1b study could also be integrated into the FIH study to streamline early development.
Study synopsis for Phase 2a study(ies) should be developed.
FIH and Phase 1b protocols are finalized and CRCs selected as per generic criteria.
The community engagement activities will continue at this stage of the development for more information on community engagement, refer to guidance under Stage C.
- Conduct Phase 1 (including FIH)
- Prepare operations for subsequent Phase 2a
- Obtain community input into Phase 2b trial design
- Prepare plan and obtain funding for engaging communities in the Phase 2a studies in line with Good Participatory Practice (GPP) guidelines
- If necessary, prepare a plan to obtain adequate epidemiology data in target population for Phase 2b (or integrated Phase 2b/3)
- Draft synopsis for Phase 2b
- Update CDP
- Phase 1 completed
- Protocol(s) and operations for Phase 2a prepared
- Community input Phase 2b obtained
- Plan for collecting adequate epidemiology study data for Phase 2b developed
- Synopsis for Phase 2b prepared
- CDP updated
- CDP updated
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.
- Complete operations and conduct subsequent Phase 2a study(ies)
- Prepare protocol and operational plans for Phase 2b
- Collect adequate epidemiology data in target population and in the countries of clinical studies
- Prepare plan and obtain funding for engaging communities in the Phase 2b studies in line with Good Participatory Practice guidelines
- Update CDP including synopsis for Phase 2b-Phase 3
- Provide and discuss results of earlier trials and obtain community input into Phase 2b-3 trial design.
- Phase 2a completed; data available and analysed
- Draft protocol and operation plan for Phase 2b available
- Adequate epidemiology data at sites of Phase 2b available
- Plan for engaging communities in the Phase 2b study and funding in place
- Community engaged on trial design
- CDP updated
Phase 2a studies are completed during this stage. Safety and immunogenicity data are available for analysis and should provide data supporting the vaccine formulation, dose and regimen selected for subsequent efficacy trials.
The study protocol fo rPhase 2b is prepared, and study sites included in the Phase 2b are operational. Epidemiological data that have been collected at study CRCs confirm the expected TB disease incidence related to the primary efficacy endpoint or alternate CRCs are selected.
The community engagement activities will continue at this stage of the development; for more information on community engagement refer to guidance under Stage C.
- Complete operations and conduct Phase 2b
- Draft protocol for Phase 3
- Draft protocol for evaluation of clinical consistency (safety and immunogenicity) as a nested study within Phase 3 or a separate study
- Prepare operational plans for Phase 3, including selection of countries, study site, etc.
- Ensure epidemiology data are available at all study sites.
- Prepare plan and obtain funding for engaging communities in the Phase 3 efficacy trial in line with Good Participatory Practice guidelines
- Provide and discuss results of earlier trials and obtain community input into Phase 3 trial design.
- Update Clinical Development Plan (CDP)
- Phase 2b completed and data available.
- Protocol for Phase 3 drafted
- Protocol for clinical consistency study drafted
- Operational plans for Phase 3 prepared
- Epidemiology data available at all study sites
- Plan and funding in place for engaging communities in the Phase 3 efficacy trial
- Community engaged on trial design
- CDP updated
The Phase 2b study is completed during this stage and data are available for statistical analysis. If data indicate protective efficacy equal to or greater than pre-set Go/ No-go criteria, a study protocol for Phase 3 study is finalised and the identified CRCs are prepared for conducting the Phase 3 study. Epidemiological data at the potential study sites are available to confirm the site selection and to determine Phase 3 sample size. The Phase 3 study should be conducted with at least one vaccine lot produced at the intended scale for marketing and its design should consider a clinical assessment of vaccine consistency.
The CDP will be updated to reflect the Phase 2b data and possible consequences on the Phase 3 study.
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
Adolescent/ adult vaccine: The study population age should be consistent with the predominant age range in TB disease burden in the region. Screening for Mtb exposure status by IGRA or TBST may be considered to limit the trial’s required sample size, although the efficiency gain may be dependent on the TB incidence in the population(s) where the trial is conducted. As pre-vaccination screening for infection status cannot be routinely considered for programmatic reasons, it is critical that Phase 3 study populations include Mtb unexposed in addition to Mtb exposed individuals.
Neonate/infant vaccine: Safety and immunogenicity data from study(ies) of concomitant administration with EPI vaccines should be available before conduct of Phase 3, or a rationale developed and agreed with National Regulatory Authorities justifying why this is not required.
For the priority population of PLWH: The timing of when to include PLWH in TB vaccine trials should be based on considerations of risks (safety) and they should be included as soon as safely possible to minimize the time to them accessing effective TB vaccines that reach market approval (Miner et al., 2022).
For the priority population of breastfeeding and pregnant individuals: the timing should be aligned to the consensus statement on “Optimal and early inclusion of pregnant and women intuberculosis research: consensus statement.” Geneva: World Health Organization; 2025 (see Fig 1b).
- Finalise plan for community engagement for Phase 3, in line with Good Participatory Practice guidelines
- Complete operations and conduct Phase 3
- Perform safety, immunogenicity and efficacy data analysis
- Document consistency of the various lots
- Prepare clinical study report (CSR)
- Initiate planning for Phase 4 studies
- Community engagement plan in place for Phase 3
- Phase 3 completed
- Safety, immunogenicity and efficacy data analysed
- Product consistency established
- CSR is available
- Draft Phase 4 plan established
The Phase 3 study has been completed; safety and efficacy data are analysed. The complete study report is prepared. Ideally, vaccine consistency would have been established in parallel with or nested in the phase 3 trial. If vaccine consistency has not been established at this stage, a study of safety and immunogenicity consistency of lots should be carried out.
Draft a plan for Phase4 studies to assess vaccine safety and effectiveness in field conditions and in populations that have not yet been studied during Phase 3 studies e.g., pregnant and breastfeeding individuals.
- Finalise clinical section of the MAA dossier
- Update protocol and update operational plans for Phase 4
- Provide and discuss results of previous trials, and obtain community input into Phase 4 trial design
- Clinical section of the MAA dossier finalised
- Protocol and operational plan for Phase 4 updated
- Community engaged on trial design
The different sections related to the clinical documentation of the dossier are prepared for inclusion in the MAA dossier.
Relevant Phase 4 study protocols are drafted to assess vaccine safety and effectiveness in terms of magnitude and duration of vaccine-induced protection under field conditions.
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.
Adolescent/adult vaccine: Safety and effectiveness Phase 4 studies should also be considered in relevant populations that have not yet been fully studied, e.g. IGRA or TBST negative populations to confirm Phase 3 efficacy trend or that would not have been studied in Phase 3 e.g. elderly, HIV-infected adults, if not already studied, pregnant and breastfeeding individuals, people deprived of liberty. [TB vaccine target population considerations]
Neonate/infant vaccine. Safety and protective efficacy should also be considered in sub populations such as pre-term neonates and neonates born to HIV-infected mothers that may not have been assessed in Phase 3 trials.
- Complete operations and conduct Phase 4 studies
- Phase 4 studies conducted