Function

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.

Stage 
C
Perform Pre-Clinical evaluations
Gate 
C
Progress to preparation for Phase 1, First-In-Human
Main Activities
  • Define the primary and exploratory immunogenicity endpoints based on putative mechanism of immune protection (“potential immune correlates”) for Phase 1
CRITERIA REQUIRED
  • Plan drafted to develop assays to measure primary and exploratory immunological endpoints
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Guidance

Vaccine immunogenicity may be a co-primary or secondary objective of Phase 1 studies.

Stage 
D
Perform GMP and toxicity studies and prepare Clinical Trial Application
Gate 
D
Progress to First-In-Human/Phase1
Main Activities
  • Develop primary and exploratory clinical immunological assays and qualify performance of primary assays
CRITERIA REQUIRED
  • Clinical immunological assays optimised and qualified
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Guidance

Immunological assays to characterise the immunogenicity profile of the candidate vaccine should be developed, optimised for clinical use, and qualified prior to FIH studies.

Stage 
E
Perform, First-in-human/Ph1
Gate 
E
Progress to Ph2
Main Activities
  • ¥ 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
CRITERIA REQUIRED
  • Evidence of sufficient immune response based on primary endpoints at safe vaccine dose level(s) in FIH/Phase 1
  • Potential biomarkers for Phase 2a identified; plan for their evaluation prepared
  • Biobanking plan established
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Guidance

Immunogenicity data of the Phase 1 and other Phase 1b studies will be analysed to characterise immunogenicity. The elicited immune responses must provide evidence that the candidate induces vaccine antigen(s)-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 study(ies).

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

Stage 
F
Perform Ph2 (including Pre-POC) studies
Gate 
F
Progress to Ph2b Efficacy
Main Activities
  • 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)
CRITERIA REQUIRED
  • 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
  • Primary endpoint immunological assays validated
  • Potential biomarkers reviewed and plan for analyses established
  • Operations for immunoassays prepared
  • Plans for non-interference study prepared, if relevant
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Guidance

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.

Stage 
G
Perform Ph2b Efficacy
Gate 
G
Progress to Ph3
Main Activities
  • Analyse all immunogenicity data from earlier trials, including Phase 2b
  • Conduct and complete non-interference studies with other vaccines used concomitantly
  • Analyse Phase 2b data for correlates of protection and incorporate into Phase 3
CRITERIA REQUIRED
  • Immune responses in target populations consistent in Phase 2b and earlier trials
  • Non-interference documented
  • Phase 2b data analysed and biomarker plan for Phase 3 established
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Guidance

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, if needed, should have been conducted during Phase 2b and no clinical or immunological interference demonstrated.

Stage 
H
Perform Ph3
Gate 
H
Progress to licensure
Main Activities
  • Analyse correlates of protection based on Phase 3 immunogenicity and efficacy data
CRITERIA REQUIRED
  • Correlates of protection evaluated
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Guidance

Evaluate the biomarker samples collected during Phase 3 to detect potential correlates of risk and/ or protection. Evaluate samples from earlier studies utilising advances in the field that may have generated assays or correlates that were not available previously.