The Global Plan to End TB 2023-2030 lays out a strategic framework for developing and deploying new TB vaccines through the end of the decade.
This framework is guided by the following priority actions for TB vaccine R&D:
- Diversify and broaden the pipeline of next generation TB vaccine candidates by expanding research on Mtb immunology and basic mycobacteriology, and develop animal models that better reflect human infection and disease.
- Provide resources and support to efficiently move a diverse range of vaccine concepts from the lab to the clinic.
- Significantly accelerate clinical development of vaccine candidates and ensure sufficient financing, resources, and capacity to advance multiple promising candidates through efficacy trials and licensure without delay.
- Conduct research on correlates of vaccine-induced protection during vaccine efficacy trials to inform vaccine design and expedite clinical trials of future vaccine candidates.
- Work with countries and communities to prepare for successful licensure and roll-out of new TB vaccines once licensed.
Priority actions in the following areas will also be necessary to advance TB research and the development of new tools, including vaccines:
- Invest in basic science research
- Create an enabling environment for TB R&D
- Apply best practices in community engagement throughout the R&D process
- Apply access principles in rolling out and optimizing the use of new tools
- Strengthen advocacy for TB R&D
New Vaccines Strategic Framework 2023 - 2030
Vision:
To develop new, more effective vaccines that will directly and safely prevent TB in all age groups and populations and are affordable and accessible to those who most need them.
Goals:
- Develop new TB vaccines that prevent TB infection, TB disease, and/or recurrence of TB disease following successful treatment of TB, thereby interrupting TB transmission
- Incorporate the goal of equitable accessibility throughout the TB vaccine R&D process
- Strengthen community engagement in TB vaccine R&D
In April 2021 the European & Developing Countries Clinical Trials Partnership (EDCTP) and the Amsterdam Institute for Global Health and Development (AIGHD) launched a Global roadmap for research and development of tuberculosis vaccines (Global Roadmap). The Global Roadmap identifies key barriers to TB vaccine R&D and implementation, ways to overcome them, and a shared set of priorities to guide TB vaccine R&D activities. The Global Plan’s strategic framework for TB vaccine R&D has been adapted to align with this Global Roadmap, and funding requirements were applied to these research priorities and activities. More details and information about these activities and priorities can be found in the Global Roadmap.
Priorities to advance TB VACCINE R&D
| Priority | Key Actions | Comments | Funding Required 2023–2030 (US$ millions) |
|---|---|---|---|
| Objective 1 – Diversify the TB vaccine pipeline to increase probability of success in developing effective, new TB vaccines | |||
| Mechanisms of biomarkers and protection | Conduct observational clinical studies combining pathogenesis and immunology, making use of systems biology, epidemiology and modeling | Identify components of the host-pathogen interaction associated with clearance, progression to disease and subclinical disease; identify biomarkers and biosignatures of natural protection | 1000 |
| Study the role of non-conventional, cellular immunity, antibody responses and trained innate immunity in natural and vaccine-induced protective responses | Explore cellular responses through class-I restricted CD8+ T cells, TH17 cells and MAIT cells; B-cell antibody responses including Fc-mediated antibody effector functions; adn innate immune responses through unconventionally restricted T cells and epigenetic reprogramming of monocytes and natural killer cells. investigate their role in human immune responses to M. tuberculosis. | ||
| Identify biomarkers and biosignatures that correlate with vaccine-induced protection | Based on data and biological samples from trials that have shown protection signals; through targeted approaches to detect cellular and/or humoral immune responses and unbiased approaches including transcriptional profiling of blood cells and mycobacterial growth inhibition assays | ||
| Undertake novel approaches to vaccine discovery | Develop new vaccine concepts that induce a broader diversity of potentially protective immune responses | Explore candidates that generate non-conventional cellular immunity, protective antibody responses and trained innate immunity. | |
| Study mucosal immune responses | Explore candidates that generate non-conventional cellular immunity, protective antibody responses and trained innate immunity. | ||
| Discover antigens that are protective in humans | Identify Mtb expressed proteins, peptides and non-protein antigens that can be recognized by the human host immune system, applying IFN-y based screening approaches, including by genome-wide strategies. | ||
| Develop and apply improved vaccine formulations and delivery platforms | Study the effects on vaccination outcomes of adjuvants, vaccine platforms and lineage of the Mtb challenge strain | Amongst others through experimental medicine studies | 200 |
| Explore new routes of administration | Including aerosol and intravenous approaches, amongst others through experimental medicine studies. | ||
| Explore new routes of administration | Including aerosol and intravenous approaches, amongst others through experimental medicine studies. | ||
| Study how vaccines can direct immune responses to the lungs | Evaluate the capacity of different formulations and delivery platforms to induce mucosal immune responses. | ||
| Establish a Controlled Human Infection Model | Develop a controlled human infection model for immunobiology studies | To inform basic knowledge gaps, as well as for proof-of-principle studies to inform down-selection of candidates, platforms and routes of administration. Participant safety; sensitivity and ethical issues will be critical to address. | 50 |
| Advance promising vaccine candidates from early preclinical to clinical development | Conduct the necessary studies for IND or equivalent regulatory submission | To provide development partners, funders and regulators with sufficient evidence of safety (including necessary toxicology studies) and intended biological activity (e.g., immunogenicity; protection in pre-clinical challenge models) to support and enable advancement into phase 1 clinical studies. | 550 |
| Total Objective 1 – Diversify the TB vaccine pipeline | 1800 | ||
| Objective 2 – Optimized animal models | |||
| Optimized animal models | Develop fit for purpose animal models | Back-translate into immunogenicity, infection and disease animal models the results/findings from adolescent/adult and paediatric trials, ideally using the exact same product as in humans, and from clinical studies of disease progression and subclinical disease. | 735 |
| Develop animal models to provide insight into the relation between PoI for PoD | Back-translate results from trials with PoI and, ideally, both PoI and PoD endpoints, as well as from clinical studies of clearance and disease progression. | ||
| Develop immune compromised animal models that can predict/replicate findings in specific human target populations | Back-translate into disease animal models the results that will emerge from trials and clinical studies including/among infants, the elderly and immune compromised humans. | ||
| Comparison of vaccine candidates within and across animal models | Standardize and harmonize animal models | Including harmonization and standardization of challenge strain selection; definition of protection outcomes, including the use of imaging and scoring gross pathology specimens. Identify priorities for future experimental directions, e.g., assessing aerosolized delivery of vaccines. | |
| Perform head-to-head testing of candidate vaccines | In independent laboratories using the standardized models that best predict protection in humans. | ||
| Total Objective 2 – Animal models | 735 | ||
| Priority 3 - Advance candidates through clinical trials | |||
| Conduct clinical trials utilizing portfolio management and common stage-gating criteria | Implement Phase 3 trials of vaccine candidates that meet criteria to advance to licensure and policy recommendations | 6500 | |
| Continue to support vaccine candidates through the clinical pipeline and initiate new Phase I/IIa/IIb trials using PoI, PoR, and POD endpoints | Bias toward selection of PoD endpoint in adolescent/adult population considering likely disproportionate effect on reducing spread of Mtb (as compared to PoI or PoR approaches or studies in infants and young children) | ||
| Include safety trials or safety assessments for people living with HIV in clinical trial planning and implementation | |||
| Include safety trials or safety assessments for people living with HIV in clinical trial planning and implementation | |||
| Ensure adequate trial clinical trial site capacity in high TB burden regions to conduct global regulatory standard human trials of novel vaccines | Make inventory of clinical trial site capacity | Identify potential sites beyond the existing ones; assess quality and suitability in terms of existing technical and laboratory infrastructure. | |
| Collect epidemiological data in sites considered for phase II/III trials | In various parts of the world, as a continuous process: age-stratified data on TB incidence; age- stratified incidence/prevalence of latent TB infection; Mtb lineage distribution; data on special populations such as people living with HIV and other populations considered for vaccine trials. | ||
| Develop vaccine trial sites | Develop infrastructure and human capacity, including mentorship and support of junior investigators, in diverse geographic locations to take account of potential variation in efficacy and safety due to heterogeneity in host and bacteriological genetic background. | ||
| Study potential barriers to trial acceptance | Social science research of barriers to participating in TB vaccine trials and completing follow-up, including TB-associated stigma, other stigma, and social barriers; compile best practices from successful vaccine trial sites. | ||
| Promote community engagement in TB vaccine trials | Community engagement should be part of any phase II or phase III study, and sponsors and developers should start developing plans for community engagement before phase I studies start. | ||
| Trial endpoints | Define standardized PoD trial endpoints that better capture the various TB disease states in diverse target populations | Standardize definition of laboratory-confirmed pulmonary TB; develop clinical endpoints representative of subclinical TB; improve bacteriological confirmation of TB disease in neonates and infants and people living with HIV; improve bacteriological confirmation of extrapulmonary disease. | 8 |
| Define and develop better PoI trial endpoints | Define an endpoint for Mtb infection for establishing PoI; this endpoint should differentiate Mtb infection from vaccine-induced immune response. | ||
| Quantify the clinical translation of PoI into PoD | Analyse existing and new observational data; include secondary PoI endpoints in phase III PoD trials, considering that this quantification may be different for different types of vaccines. | ||
| Correlates of protection | Collect biospecimens for identifying CoPs | In planned and ongoing phase IIb and phase III trials. | 800 |
| Identify CoPs for TB disease | From phase IIa and phase III trials that have shown protection: analyse data and putative CoP values from individual trials and, if possible, from meta-analyses of several trials. | ||
| Validate CoPs for TB disease | Validate putative CoP identified by backtranslation of trial results in terms of vaccine-induced response and clinical protection in immunogenicity studies, new trials with a clinical PoD endpoint and potentially controlled human infection models. Validate identified COP in PWHIV to enable immuno-bridging studies. | ||
| Trial harmonization and design | Harmonize clinical trial protocols | Define an agnostic trial “shell” of standardized outcomes, inclusion criteria and measurements for clinical trials for different vaccine types. This would also address secondary endpoints; inclusion criteria for people living with HIV infection or diabetes; and standardized measurements over time. | 7 |
| Develop new models for TB vaccine trials with increased efficiency | Phase I: explore innovative trial designs that provide information on the local human immune response. Phase IIb/III: efficacy trials within contact investigations, active case finding programs and high-risk populations; adaptive trial designs for evaluating the safety, immunogenicity and efficacy of different vaccine types. | ||
| Improve preclinical and clinical readouts | Standardize reagents, harmonize assays and benchmark relevant signals by forward as well as back-translation/ verification between preclinic and clinic | Gather stakeholder input and come to consensus on path forward; continue to expand on programs to provide reagents to laboratories and research facilities; develop necessary assays based on stakeholder consensus | 150 |
| Total Objective 3 - Clinical trials | 7465 | ||
| TOTAL FUNDING REQUIRED | 10000 | ||
Priorities and actions to ensure public health impact
| Priority | Key Actions | Comments |
|---|---|---|
| Ensure public health impact: Epidemiology and modeling vaccines | ||
| Country-specific data and projections | Conduct in-depth country-specific value proposition analyses | Assess value drivers for new TB vaccines across different countries and stakeholders considering preferred delivery strategies; efficacy relative to safety; manufacturing, strain standardization and price; willingness to pay; and cost of delivery. |
| Study the role of non-conventional, Collect epidemiological data at country and subnational level | To inform economic and impact modelling related to country decisions on introduction of new TB vaccines and market volumes: (sub)national TB disease and infection prevalence including in specific risk groups (people living with HIV, elderly); identify potential target groups for vaccination based on contribution to transmission; map M. tuberculosis genotypic variation. | |
| Modelling to define vaccine development investment cases and country-specific vaccine use cases | Modelling of implementation scenarios, the epidemiological impact, cost-effectiveness and budget impact in consultation with countries for vaccines that are close to market introduction, using transmission and economic modelling as well as other quantitative approaches. | |
| Post-licensure studies | Develop valid approaches for real-life vaccine scale-up studies | Develop designs and validated tools for establishing real-world effectiveness, safety and public health impact following introduction; establish and/or support post-licensure registries making use of existing expertise from introduction of other vaccines; strengthen surveillance systems for collection of baseline epidemiologic data. |
| Priorities and actions to ensure public health impact: research to ensure optimal implementation | ||
| Health system conditions for vaccine introduction | Define the generic public health system requirements to deliver a new TB vaccine | For a vaccine for adolescents and adults: determine in different countries the feasibility of various strategies including vaccination campaigns; conditions for immunization programs to implement these strategies; requirements for optimizing access for different population groups; integration of TB vaccination within and beyond national TB programmes; and approaches to measuring vaccine uptake in adolescents/adults. For a vaccine for neonates and infants: determine the fit in the Expanded Programme on Immunization and required timing with regard to other vaccinations. |
| Conduct pre- and post-introduction assessments of country immunization programmes | Assess the pre-introduction country-specific readiness of immunization programmes and health systems to handle, store and administer the new TB vaccine (considering its characteristics, particularly for delivery to adolescents and adults), to monitor vaccine coverage and adverse events, and to communicate adverse events. | |
| Barriers and enablers of vaccine uptake | Assess drivers of acceptability and uptake of new TB vaccines in various settings | Social and behavioural research to determine across countries and settings decision makers’ and public and health workers’ perceptions around new vaccines, related to dosing, safety concerns, religious concerns, gender, use with other vaccines versus specialized programmes, and for immunotherapeutic vaccines, integration with TB treatment. |
Priorities and actions with regard to enabling conditions for tuberculosis vaccine development
| Priority | Actions |
|---|---|
| Funding | |
| Attract new investments in TB vaccine R&D | Develop a comprehensive global value proposition for TB vaccines that encompasses vaccine characteristics, use case, societal value, business case, investment case, and health and micro/macro-economic impact assessment. |
| Study the role of non-conventional, Broaden the funding base with governments, charitable funders and donors. Mobilize domestic R&D funding from large countries’ governments; get specific donors involved that could contribute to funding downstream aspects of TB vaccine R&D; engage with the HIV and antimicrobial resistance communities. | |
| Attract new entrants in TB vaccine R&D. Involve actors, technologies, models and knowledge from outside the TB vaccine research field; funders should promote such involvement in their funding programmes, e.g., in the specification of calls and eligibility criteria. | |
| Innovate financing for TB vaccine R&D | Create collaborations or partnerships for joint funding of trials with mechanisms for pooling resources between R&D funders, governments and industry with selection procedures that are product and country agnostic, and strict norms for what the funding will be used for and under which conditions. |
| Customize calls to the clinical development pathway through options for their flexibility long term funding (e.g., ten years, with intermediate go/no-go decisions) allowing consortia to adopt a long-term R&D perspective for a specific candidate or approach. | |
| Create mechanisms that attract investment in early stages of development | Reduce commercial uncertainty by providing incentives for stronger engagement from industry and other vaccine developers through grant funding and advance market commitments with a clearly defined path to commercialization, including production of a successful candidate. |
| Ensure that intellectual property can be used efficiently, openly, and equitably to facilitate TB vaccine R&D in ways that promote collaboration among universities, biotech and pharmaceutical companies, and government funders. | |
| Open science | |
| Promote timely and open access of data, specimens and results | Funders and product development partnerships should require registration of all animal and human studies, open access publication of both positive and negative results, data-sharing and posting in open access databases as condition for funding and/or consortium membership. |
| Biospecimens collected in clinical studies should be made available based on peer review, overseen by an access committee. Access to biospecimens should not be granted on first-come first-serve basis but to researchers with the most innovative ideas and approaches. | |
| Establish publicly searchable patent databases for TB vaccine research (as exist for drug development) to promote the diffusion of knowledge by facilitating access to the information disclosed in a patent, including antigens, adjuvants, platforms, and processes. | |
| Create a mechanism for coordinating open science in TB | Establish a platform for data sharing, starting with data from clinical studies, including generic protocols for contextual data (e.g., for what purpose was the data collected); proper use (e.g., ethical rules, privacy regulations) and acknowledgement of original collectors/contributors of the data in secondary use and publications. |
| Develop and coordinate systems and procedures needed for efficient data and specimen sharing across the field of TB research and across TB research funders. | |
| Stakeholder engagement | |
| Create a supportive environment for TB vaccines | Raise political commitment for new TB vaccines to ensure new political commitment at country level and continue high level commitments making sure that existing commitments and defined targets are met, based on clear communication about the need, efficacy and safety for new TB vaccines towards policy makers, including the risk-benefit and cost-benefit analysis of a new TB vaccine. |
| Advocate for development and uptake of new TB vaccines with vaccine developers and the public through positive messaging about opportunities and actions in vaccine development. | |
| Harmonize and fast-track regulatory review and local approval of vaccine trial protocols based on the example of AVAREF; establish NITAGs in countries that do not have them and strengthen their capacity; fast-track regulatory approval of TB vaccines. | |
| Create innovative incentives by forecasting demands from countries and engaging multilateral funders, including GAVI, GFATM, Unitaid and CEPI in offering novel financing mechanisms. | |
| Overcome barriers to delivery and uptake | Engage with end-user communities to address stigma, vaccine hesitancy and adherence; provide and communicate a convincing rationale for (high-risk) target groups to be vaccinated; involve end-user communities in the research process; build resilient information systems to counter vaccine related misinformation and disinformation. |
| Develop approaches to community-level delivery (e.g., through community health workers) to address gaps in access to vaccination; educate healthcare networks, the medical community and the general public about TB vaccine introduction through targeted, country-specific approaches. | |
| Promote TB vaccine and research literacy | Create a global program for community engagement and training for new TB vaccines; develop mechanisms for engaging community representatives in TB vaccine development; engage and educate community representatives who can speak to policy makers to invest in the development and introduction of new vaccines; support community engagement in TB vaccine clinical trials. |
| Foster strategic and reciprocal partnerships between vaccine scientists/sponsors and representatives of civil society and TB affected communities to support the involvement of all parties in advocacy for new TB vaccines. | |