Introduction
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.
Guidance is provided and accessed via a “Guidance” button beneath each table. The guidance 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 information on TB-relevant vaccine technologies and target populations is provided, drawing upon existing expertise in TB vaccine development and, where relevant, using generic guidelines, for example for technology platforms or for regulatory compliance.
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.
Commonly, measurement of antibody responses provides the tool to monitor the quality and quantity of the adaptive immune response to vaccines, but BCG is a rare example of a marketed vaccine against infectious diseases for which antibodies do not provide the main mechanism of action. The measurement of the quantity and quality of the innate immune response and a T-cell mediated response provides a greater challenge, and this is a key consideration for novel TB vaccine development.
The TB Vaccine Development Pathway tool addresses and provides guidance for such TB vaccine-specific challenges.
Vaccine technology specific considerations
In the field of vaccinology, new technological platforms have emerged, each with specific challenges for development. Two classical vaccine products stay close to the original pathogen, either as an inactivated or a modified live version that causes no disease. There are several examples of attenuated and inactivated vaccines against viral diseases (e.g. MMR and IPV), whereas there are fewer examples for bacterial pathogens. BCG is a rare example of marketed live attenuated vaccine and whole-cell pertussis is one of the few inactivated vaccines. For TB, recombinant BCG and live attenuated M. tuberculosis candidates are in advanced stages of clinical development.
Subunit vaccines combine pathogen-specific antigens with an adjuvant as a supportive immunostimulant. Examples are the Hepatitis B subunit vaccine, bacterial toxoid vaccines e.g. Tetanus and Diphtheria, and conjugate vaccines e.g. pneumococcal vaccines. For TB, single recombinant polypeptide antigens and multiple, fused proteins combined with liposomes and Toll-like Receptor specific adjuvants, are in advanced stages of clinical development.
The recombinant viral vector vaccines use a replicating or non-replicating (abortive) viral vector as a carrier for antigens of a pathogen and production of the antigens is induced in cells infected with the viral vector. They aim to induce a specific adaptive response against the pathogen specific antigen structures, while also providing some innate immune stimulation. An example are the recently licensed adenovirus vector-based COVID-19 vaccines. For TB, several candidate vaccines based on viral vectors, including Modified Vaccinia Ankara (MVA) and adenoviruses, are in early stages of clinical development.
The DNA/RNA vaccines contain the genetic information of a pathogen specific antigen which is then produced by target cells inoculated with the DNA or mRNA. Progress has been made in the delivery of DNA (electroporation) and of mRNA formulated into lipid nanoparticles (LNP). Examples are the licensed mRNA vaccines for COVID-19. For TB, nucleic acid-based candidate vaccines have yet to enter clinical development stages.
Vaccine target populations considerations
Information is given for 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 3 and 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 vaccines.
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 is available in the WHO PPC for therapeutic vaccines.