Guidance

Vaccine development is a complex and long endeavour that requires multiple expertise, management of activities running in parallel, and decision points. The Stage Gate Criteria (SGC) is a project management methodology that assists in the management of such large, long and complex projects. The SGC approach organises a project along two elements: (1) the stages, which describe packages of activities that occur in parallel and generate material and data, and (2) the gates that follow each stage and consist of a review of data from the preceding stage using defined criteria. These defined stages and gate criteria help to assess progress and decide to advance a project to the next stage, to stop, hold or recycle it. This methodology is applied by the TB Vaccine Development Pathway.  

The pathway is laid out in a series of tables which describe the stages and gate criteria for the development of a vaccine against TB, from discovery and initial stage of the design of the vaccine and its Target Product Profile (TPP) (Stage A), to launch and implementation in vaccination programmes (Stage J). While the development path is organised by stages and gates, its management is structured by ‘functions’ or ‘expertise’needed to execute activities. The management is integrated, meaning that these functions work together or in sequence, based on activities as vaccine candidates progress.

The stage gates that relate to the preclinical and clinical aspects of TB vaccine development are described under three separate functions: ‘safety’, ‘immunogenicity’ and ‘protection/ efficacy’. In addition, there is a separate clinical ‘operations’ function. The SGC per function can be directly accessed through the ‘Function buttons’ in the webtool. Alternatively, all of the SCG for a specific Stage is accessed through the pathway infographic.

TB specific considerations

A key challenge in TB vaccine development is the lack of accepted or validated immune correlates or surrogates of protection. This has an impact on pre-clinical screening of potential candidates and on optimisation of the vaccine formulation, since lengthy and costly protection experiments must be performed using animal models that have not yet been validated to predict clinical efficacy. The lack of an established immune correlate also hampers the development of an appropriate, qualified assay to measure potency which would accelerate and harmonise product characterisation and Quality Control. The TB Vaccine Development Pathway tool addresses and provides guidance for TB vaccine-specific challenges.

Guidance for each of the functions and stages is supported by examples, references and guidelines that are relevant to TB vaccines, in particular those related to the existing BCG vaccine. Whilst particularly useful for the development of new live-attenuated TB vaccines, the guidelines for BCG are of limited relevance for the various novel TB vaccine candidates in development. Thus, additional guidance is proposed, drawing upon existing expertise in TB vaccine development and, where relevant, using generic guidelines, for example for technology platforms or for regulatory compliance.

The guidance also includes information on specific TB vaccine target populations or indications for which there may be different types of vaccines or distinct approaches or requirements for the development pathway. Three main target indications have been considered, listed below. This guidance refers to, and is aligned, with the Preferred Product Characteristics (PPCs) for different TB vaccines prepared by the WHO.

1) Adolescent/ adult populations
Adolescents and adults are the primary sources of Mtb transmission, and modelling predicts that vaccination of these two populations would have greater and more rapid impact on the TB epidemic than neonatal vaccines (Harris et al., 2016). New TB vaccines for adolescents and adults must cover those with and without evidence of latent Mtb infection and be safe for use in HIV-infected populations. Vaccination aims at preventing TB disease whether it results from reactivation or new infection. In general, the specific considerations for these targeted indications are related to the clinical evaluation of the vaccines in the adult/ adolescent populations and to several factors that will influence the budget, pricing and implementation strategies. The relevant WHO PPC is described in section 6 of the document WHO Preferred Product Characteristics for New Tuberculosis Vaccines.

2) Neonates/ infant populations
New TB vaccines for neonates could either be in the form of a replacement for neonatal BCG or a booster vaccination administered to infants with the aim to improve current BCG vaccination, providing greater protection (prevention of disease)and having a better safety profile. Therefore, the benchmark for the development stages and functions is BCG. Benefits of a BCG replacement vaccine should be evaluated in Phase 4 clinical studies. Information and recommendations for the use of BCG can be found in the WHO Report on BCG vaccine use, and section 7 of the document WHO Preferred Product Characteristics for New Tuberculosis Vaccines, which describes the PPC for neonate/ infant TB vaccine.

3) Therapeutic vaccines
Therapeutic vaccines are deployed as an adjunct to chemotherapy in any age group. The aim of therapeutic vaccination is to improve treatment efficacy in individuals who currently suffer from TB disease. The development pathway for therapeutic TB vaccines is substantially different from prophylactic indications, in particular the design of clinical studies. The target outcomes of therapeutic vaccines are to improve success of treatment, particularly for multi-drug resistant TB, or to decrease or prevent relapse. Shortening the duration of drug treatment and/ or reducing the number of drugs necessary to cure TB disease should also be considered. Because of these multiple possible outcomes, there will be a number of aspects of the development pathway which differ compared to prophylactic vaccines. Notably, clinical trial designs will need to evaluate safety, define optimal timings and dosage in relation to drug treatment and ensure that standard chemotherapy is not adversely affected by vaccination. More information will become available in the WHO PPC for therapeutic vaccines.