Introduction
The aim is to define the immunogenicity of the candidate vaccine in humans. Its evaluation should be consistent with the hypothetical immunological mechanisms by which the vaccine is assumed to confer protection against TB infection and/ or disease. Relevant immunological parameters should be defined accordingly and suitable assays developed and validated as the clinical plan progresses. In addition, the thorough analysis of the immunogenicity of a vaccine candidate is an important opportunity for the identification of correlates of protection in TB.
Vaccine technology specific considerations
The clinical evaluation of vaccine induced specific immune responses and related procedures is generally the same regardless of the vaccine type. For viral vectored TB vaccines the impact of pre-existing immunity and/or vaccine induced responses against the viral vector must be shown to be minimal. For adjuvanted TB vaccines the quantitative and qualitative effects of the adjuvant on the immune response (antibodies, cell mediated immunity) to vaccine antigens must be assessed to confirm the justification of the adjuvanted formulation.
- Define the primary and exploratory immunogenicity endpoints based on putative mechanism of immune protection (“potential immune correlates”) for Phase 1
- Plan drafted to develop assays to measure primary and exploratory immunological endpoints
- Develop primary and exploratory clinical immunological assays and qualify performance of primary assays
- Clinical immunological assays optimised and qualified
Immunological assays to characterise the immunogenicity profile of the candidate vaccine should be developed, optimised for clinical use, and qualified prior to FIH studies.
- Analyse FIH/Phase 1 immunogenicity data
- Characterise immune responses using primary and exploratory endpoints
- Prepare a collection and storage plan for relevant bio-specimens from Phase 2a based on primary and exploratory immunogenicity
- From FIH/Phase 1, evidence of sufficient immune response based on primary endpoints at vaccine dose level(s) that is/are safe
- Potential biomarkers for Phase 2a identified; plan for their evaluation prepared
- Biobanking plan established
Immunogenicity data of the Phase 1 and other 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 as of Phase 1 studies and bio-banked for future correlates analyses – these samples will be vital for the potential discovery of correlates of risk and/or protection.
- Analyse all immunogenicity data from Phase 2a
- Select dose for Phase 2b
- Confirm validation of primary immunological assays
- Review potential biomarkers from previous studies and identify assays for Phase 2b (including immunogenicity and correlate analyses)
- Prepare operations for immunological assays and sample collection/storage
- If relevant, prepare plans for non-interference study (ies) with co-administered vaccine(s)
- Data from Phase 2a indicate significant immune responses and dose-response pattern allows selection of a dose
- Immunogenicity at the dose selected for Phase 2b acceptable
- Validation of assays confirmed
- Potential biomarkers reviewed, plan for analyses established and primary endpoint immunological assays identified
- Operations for immunoassays prepared
- Plans for non-interference study prepared, if relevant
Safe and well-tolerated dose(s) providing the most robust immune response, after evaluation of the dose response pattern, should be selected from the doses evaluated in Phase 2a and in pre-proof of concept study eg POI for further study in Phase 2b. Immunogenicity data from earlier studies should be evaluated to determine if additional assays should be considered for evaluation of immune response in Phase 2a.
Immunological assays should be validated prior to the Phase 2b study.
Biomarker studies should be designed prior to the onset of Phase 2b clinical efficacy studies.
If the candidate vaccine is likely to be administered at or around the time of other vaccines, non-interference studies should be planned.
TB vaccine target population considerations
Neonate/infant vaccine: Biomarker studies should be designed prior to the onset of Phase 2b clinical efficacy studies taking into consideration the limited volume of blood sample that can be drawn from infants. If the candidate vaccine is likely to be administered concomitantly with other vaccines recommended at birth (eg hepatitis B vaccine) or at later infant immunisation visits (e.g. EPI infant vaccines), non-interference studies should be planned.
- Analyse all immunogenicity data from earlier trials, including Phase 2b for their consistency
- Analyse Phase 2b data for correlates of protection (CoP)
- Develop a plan to incorporate biomarkers / CoP into Phase 3
- Conduct and complete non-interference studies with other vaccines used concomitantly
- Immune responses in target populations in Phase 2b consistent with earlier trials
- Phase 2b data analysed
- Biomarker plan for Phase 3 established
- Non-interference documented
Immunogenicity data from Phase 2b should be evaluated and be consistent with that observed in earlier studies and support continued development of the candidate vaccine. Biomarker samples collected during the Phase 2b study should be analysed for potential correlates of protection and/ or risk. These data, if available in time, should inform the development of the Phase 3 programme. A plan should be made for collection of further biospecimens for evaluation or discovery of biomarkers in Phase 3. Non-interference studies with concomitantly administered vaccines, if needed, should have been conducted during Phase 2b and no clinical or immunological interference demonstrated.
- Perform secondary endpoints for analysis
- Develop an investigational plan to identify correlates of protection (CoP) based on Phase 3 immunogenicity and efficacy data
- Collect samples as per banking
- Secondary immunological endpoints analysed
- CoP plan developed and evaluated
- Samples collected
During the Phase 3 trial an appropriate range of biological specimens have been collected. The investigational plan to identify a Correlate of Protection should be developed based on the analysis of Phase 3 immunogenicity and efficacy data.
- Conduct analyses for CoP establishment
- Perform assays
- Analyses of CoP completed
- Immunological assays performed
Biomarkers assays are performed on samples collected during the Phase 3 study. Biomarkers are measured and analysed to detect potential correlates of risk and/ or protection.