Function

The aim of this function is to conduct detailed immunogenicity studies, even in the early stages of development, in order to guide decisions for example on the optimal doses or routes of vaccination. While it is possible, and strongly encouraged, to evaluate a range of doses in early challenge studies, resource constraints will likely preclude pursuing this strategy through the entire development process, and particularly in nonhuman primates (NHPs). An understanding of the immunology and protection associated with a range of doses and routes should help guide dose selection in later preclinical and early clinical development. In addition, in-depth mechanistic studies should be conducted which aim to identify specific and quantifiable immune responses that correlate with protection. In the later pre-clinical stages, consideration should be given to the immunogenicity assays, which are transferable to human trials. However, it is important to understand the limitations of the animal data caused by the absence of validated immune correlates of protection and insufficient clinical efficacy data to identify which animal model best predicts vaccine efficacy in humans.

Stage 
A
Perform discovery, safety, immunogenicity and efficacy evaluation in initial animal model
Gate 
A
Progress to proof of concept (POC) studies in animals
Main Activities
  • Evaluate immunogenicity
  • Compare to benchmark, if applicable
CRITERIA REQUIRED
  • Evidence of relevant immunogenicity to antigens in at least one animal species
  • Above baseline and/or benchmark (if applicable) responses to antigens preferred
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Guidance

In Stage A, immunogenicity studies should demonstrate that a clear immune response to the target antigens can be induced in the same animal model used to demonstrate protection. Mice are often used in early studies, but may not be appropriate for all candidates (for example, it would not be appropriate to evaluate vaccines based on CD1-associated lipids, as mice lack most CD1 molecules). Balb/C or C57Bl/6 strains of mice are frequently used but, as there may be differences in the immune response caused by MHC-restriction, an alternative is to use CB6F1 mice (see Stylianou et al 2018 and Aagaard et al., 2011. In the absence of a correlate of protection, the immune parameters measured should be relevant to immunity to Mtb and to the proposed mechanism of action of the vaccine. Due to the costs of Mtb protection studies, early-stage decisions e.g. on doses, formulations etc, would be most likely based upon immunogenicity, such as the magnitude of antigen-specific T-cells. A response above baseline is considered a minimum requirement but, if similar to others in development, the candidate should show an obvious differentiating characteristic – qualitative or quantitative. In addition to optimisation of doses and routes of administration of individual candidates, immunogenicity studies in stage A may play an important role in prioritisation or selection between different candidates. For example to select between different antigens or vectors, or even in a portfolio management context to discriminate between different vaccine types, although such decisions are most likely to be multifactorial, with immunogenicity being only one factor.

Stage 
B
Perform POC studies in animals
Gate 
B
Progress to Pre-Clinical
Main Activities
  • Confirm and characterise immunogenicity
  • Develop hypothesis for immunological mechanism of action; design the Non-Human Primate (NHP) (or other model) study with appropriate outcomes, sample size, read-outs, data analysis plan, etc.
CRITERIA REQUIRED
  • Confirmed consistent immune response to antigens in at least one animal species
  • Hypothesis for immunological mechanism of action defined; synopsis of NHP study (or another advanced model) available
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Guidance

Immunogenicity studies in Stage B should demonstrate that the candidate is immunogenic in the animal model chosen to confirm protection with the aim to link or correlate specific immune responses to protection. A more detailed characterisation of the immune response should be therefore be performed, for example identifying specific T-cell subsets or cytokine secretion profiles and, as with stage A the types of immune response should support the proposed mechanism of action of the candidate. The immune response profile identified in stages A and B should also be used to assist the design of studies in the NHP (or other advanced) model in Stage C. This would include informing the optimal immunisation protocol (e.g. the timing of prime and boost vaccinations) and to identify the most appropriate assays and samples to be taken. Immunogenicity studies in stage B might also include dose-finding in the context of live-attenuated mycobacteria in order to demonstrate that a relevant immune response is achieved with doses of vaccine that are safe and feasible (for example, for manufacture). The immunogenicity data generated in stage B would be used as part of the data package to select between the candidates chosen to advance to stage C.

Stage 
C
Perform Pre-Clinical evaluations
Gate 
C
Progress to preparation for Phase 1, First-In-Human
Main Activities
  • Confirm immunogenicity against relevant benchmark
  • Expand immunogenicity (Th1, ,Th17, γδ T cells etc.) to explore mechanism in same species used to demonstrate efficacy
CRITERIA REQUIRED
  • Immune response against relevant benchmark established
  • Immune mechanisms and breadth of immune response explored
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Guidance

Pre-clinical studies in Stage C are typically conducted in NHP or another highly relevant (and often resource-intensive) model. As the results of these studies are used as key gating criteria for advancement into clinical trials, they should be conducted as carefully and thoroughly as possible. Importantly, before proceeding to a challenge study, the vaccine dose and regimen should be optimised for the model selected and based upon the proposed mechanism of action (for example, dose or route selection for an adenovirus-based candidate may be based upon CD8+ T-cell responses characterised by intracellular cytokine staining, see Hokey et al., 2014). Immunogenicity evaluations should then be expanded in the challenge study. In addition to the inclusion of assays to confirm vaccine “take,” additional exploratory assays should be included to explore the mechanism of action and identify potential correlates of protection. These may include the use of multiple or more extensive intracellular cytokine staining panels (to characterise Th1, Th17, gamma delta T-cells, etc.), antibody assays, and systems biology approaches. In order to conserve resources, samples for such exploratory assays can be collected and stored for analysis pending the challenge outcome. A recommendation is to consider the use of technologies provided by providers of platforms such as transcript- or other omics, e.g., GH-VAP (ghvap.org), and TRANSVAC (transvac.org), which offer unbiased and specialised expert assessments. Finally, consideration should be given to how key assays might bridge to the clinic.

Stage 
D
Perform GMP and toxicity studies and prepare Clinical Trial Application
Gate 
D
Progress to First-In-Human/Phase1
Main Activities
  • Not applicable, meaning that no additional data are required, on top of what was provided in the previous stage(s)
CRITERIA REQUIRED
  • Not applicable