Medical and Life Sciences Translational Fund (MLSTF) Exemplar Case for Support Application Form
Project Title
Evaluation of the efficacy of an mRNA-based multi-antigen vaccine against tuberculosis (TB) disease in guinea pigs.
Non-confidential lay summary
Guidance
This information could be shared with external agencies such as funders and potential industry partners if deemed within the best interest of the PI. Please Include a description of your innovation and its impact, who the potential partners and/or end user could be, the competitive advantage, how the funding will be used to reach a critical milestone. Max. 250 words
Exemplar
TB remains a significant global health issue, with 1. 7 million deaths and 10.6 million new infections in 2022. Bacille Calmette-Guerin (BCG) vaccine, administered at birth, offers limited efficacy in adults responsible for more than 90% of TB cases. To address this gap, our work has been focused on developing a BCG-booster vaccine. Our approach involves utilising the promising mRNA platform for TB prevention. Recognising the complexity of Mycobacterium tuberculosis (M.tb), the causative agent of TB, and the need to boost BCG, we have identified key protective antigens. Collaborating with Moderna, a leading mRNA manufacturer, we have successfully produced and tested mRNA encoding our most promising antigens. Experiments in mice have demonstrated the protective efficacy of our vaccine, prompting us to progress to the next phase. We now need to validate this protective effect in guinea pigs, a necessary step before advancing to non-human primate studies and subsequent human clinical trials. This will be the first study to test mRNA protection against TB in guinea pigs, offering valuable insights into its potential efficacy in humans. The funding sought will be instrumental in reaching a critical milestone and protection observed in guinea pigs will allow progression to non-human primate studies and human phase trials with Moderna, ensuring a translational pathway. The end users of this mRNA vaccine are the global population vulnerable to TB, particularly in regions with high TB prevalence.
Scientific justification and Project Developmental Plan
What are the panel looking for?
Please use this section to include additional information that is not already in the non-confidential summary. Please use this section to include scientific background information and justification such as:
- The unmet clinical need of your proposed project,
- Background data and progress to date,
- MLSTF project objectives, milestones, go/no-go success criteria and proposed end-point outcomes.
- Next steps in the development plans post MLSTF
You will need to append the following as separate PDFs:
- Supporting data and information (figures / tables) (1 page maximum)
- A comprehensive Gantt chart on the milestones and timeline of your project (1 page maximum, see link to an example at the end of this form)
Max 500 words.
Exemplar
Tuberculosis (TB) caused 1.7 million deaths and 10.6 million new cases in 2022, making it the leading cause of death from a single infectious agent1. Existing control measures are unable to control the epidemic, exacerbated by the rise of drug-resistant strains. The century-old Bacillus Calmette-Guerin (BCG) vaccine, the sole licensed vaccine against TB, is administered within 7 days of birth, providing protection against disseminated forms but loses efficacy in adults, responsible for most cases.
To improve BCG, strategies involve replacing or boosting its immunity with subunit vaccines. Subunit vaccines consist of selected mycobacterial antigens delivered through a platform. However, the lack of immune correlates of protection complicates the selection of an optimal delivery platform, as immunogenicity alone is not sufficient. Consequently, animal efficacy studies are crucial to identify promising candidates. While mice are initially used for testing, their limitations include granulomas that rarely progress to necrosis, caseation, and liquefaction, characteristic of human TB disease2. Guinea pigs, exhibit disease progression similar to humans, making them a more relevant model. Vaccine candidates demonstrating efficacy in mice typically advance to guinea pig testing.
mRNA vaccines were effective against COVID-19. Considering the shared respiratory nature of SARS-CoV-2 and M.tb, we hypothesised that mRNA vaccination would be also effective against TB. Collaborating with Moderna, we obtained mRNA for five of our most promising M.tb antigens. Our approach involved the development of a multi-antigen subunit vaccine, with each antigen eliciting a distinct immune response e.g. XXX was selected for its strong recognition by CD8+ T -cells from infected individuals, and YYY induces a robust antibody response. Mice received mRNA for each individual antigen and a group received a combination.
All groups displayed strong antigen-specific responses, with each antigen retaining its ability to engage with the immune system as originally intended (Figure 2). For efficacy testing, mice were challenged with aerosolised M.tb, and lung and spleens were collected four weeks post-challenge for bacterial (CFU) enumeration. The REDACTED group significantly improved both lung and spleen CFU compared to unvaccinated animals. We are currently conducting a BCG prime-mRNA boost challenge study in mice (Figure 3).
This MLSTF funding will enable us to assess the efficacy of the REDACTED vaccination regimen in the more stringent guinea pig model. The study will be performed at UKSHA, and will involve four groups: 1) REDACTED, 2) REDACTED, 3) REDACTED, and 4) REDACTED. The objective is to evaluate both the standalone protective capacity of mRNA and its potential as a booster to BCG, aligning with the intended clinical application of this regimen. Vaccination intervals will mirror those employed in the mouse study, except for an 8-week interval between last vaccination and challenge. This guinea pig study will be the first to test the efficacy of mRNA vaccines against TB and will provide a valuable insight into the platforms potential to confirm protection. If mRNA vaccination is effective, we will apply for funding for further testing in non-human primates and subsequent progression to clinical trials.
If you require an accessible version of the Gantt Chart below, please contact the Translational Research Office.
Key risks to delivering the project
What are the panel looking for?
Please list the risks from:
- Based on the likelihood of occurring during the course of the project (Unlikely-highly likely)
- What their impact would be on the successful completion of the project. (Low, moderate, High)
- How will these risks be managed? What mitigation plans will be in place?
Max 500 words.
Exemplar
There are minimal to no risks associated to this project.
Moderna has constructed mRNA expressing each of the five antigens and we have demonstrated their successful antigen expression in vitro (cell lines) and in vivo following delivery of formulated mRNA in lipid nano-particles in mouse immunogenicity studies.
Moderna will be scaling up mRNA for these studies, and we have allowed for 2 months within the time frame of the project.
Dr REDACTED and his team at the UK Health Security Agency have extensive experience in performing M.tb aerosol challenge studies in guinea pigs.
Competitiveness of the approach
Guidance
Discuss the competitive landscape in both academic and industry sectors and what the significant advantages the proposed research will offer over the methodologies already on the market or in development by your competitors. Max 400 words.
What are the panel looking for?
Please use this section to elaborate if you already have an industrial collaborator on board?
If so, please give details here including their contribution in your project. Please also elaborate if there is a research collaboration in place.
If there are discussions taking place already with industry, please elaborate the details here including what sort of interest have they shown if any?
Exemplar
Currently, there are eight subunit vaccine candidates in clinical trials for TB: three utilising viral vectors, four employing protein-adjuvant formulations and one mRNA-based vaccine that recently entered a phase I clinical trial. While mRNA vaccines have shown efficacy against other infectious diseases, including SARS-CoV-2 and Lassa virus, there is a lack of published data regarding their effectiveness against TB.
Recently, our work has focused on the identification of promising antigens from the 4000 Mycobacterium tuberculosis (M. tb) genes, with the aim of developing a multi-antigen vaccine which includes antigens expressed during the course of human infection, and with the capability to induce cellular and antibody responses, both important for M.tb control. Our work led to the selection of five antigens.
AAA and BBB, recognised by samples from CD4+ and CD8+ T-cells from TB-infected individuals chosen to ensure their recognition throughout the course of human TB disease. CCC was selected via reverse vaccinology over 74 other mycobacterial antigens with the potential of inducing a protective response. This antigen is expressed on the cell surface and we have confirmed its ability to induce an antibody response. DDD is crucial for M.tb virulence and abundantly expressed during disease. EEE was identified using mass-spectrometry-based immunopeptidomics of M.tb infected human cells with the potential of inducing CD4+ T cells.
Vaccination with mRNA-expressing antigens demonstrated the platform's compatibility with each selected antigen, successfully inducing the intended immune responses. Importantly the combination of the five antigens into a single regime resulted in the induction of CD4+, CD8+ and antibody responses, and demonstrated efficacy in a mouse challenge study. Since three of the five antigens are expressed by BCG, our regimen provides both a booster for BCG and complements it through the utilization of XXX
The proposed work will be the first study to test the efficacy of mRNA in guinea pigs (although the mRNA platform from Moderna was previously tested in guinea pigs using other non-TB vaccines). The guinea-pig model mirrors human TB disease progression, thereby providing a valuable insight into the platform's translational relevance. Promising data from this work will allow progression of this regime in non-human primates and phase I clinical trials with our partner Moderna, ensuring a translational pathway.
Industry Engagement
Guidance
Provide the details of an industrial collaborator, if you have one, and what their contribution will be. If there is no collaboration currently in place, please describe any conversations that you may have had with industry or what your plans are for engaging with the commercial sector. Max 200 words.
What are the panel looking for?
Please use this section to elaborate if you already have an industrial collaborator on board?
If so, please give details here including their contribution in your project. Please also elaborate if there is a research collaboration in place.
If there are discussions taking place already with industry, please elaborate the details here including what sort of interest have they shown if any?
Exemplar
Moderna is our industry partner in this project. University of Oxford has an REDACTED Collaboration Agreement with Moderna, and as such they have been providing us with formulated mRNA of our five antigens, Mouse experimental details were previously approved by Moderna prior to the provision of mRNA. Moderna has reviewed the current proposal for the evaluation of the mRNA regime in the guinea pig model and can provide a letter of support if required
Regulatory management
Guidance
Provide evidence and details of consultation with the appropriate regulatory body or regulatory experts and summarise the outcomes of these discussions. Alternatively, summarise why regulatory discussions are not necessary at this stage. Max 300 words.
What are the panel looking for?
Have you consulted with the appropriate regulatory body/ies (e.g. MHRA) or another relevant regulatory expert? If so, please summarise the outcome of the discussions; if not, please summarise why this is not necessary at this stage.
Exemplar
We have not consulted with a regulatory body at this stage.
Although protection was observed in the mouse model, confirmation in at least a second animal model, in this instance guinea pigs, is necessary for progression of vaccines to phase I clinical trials.
The mRNA platform from Moderna has demonstrated safety, immunogenicity and efficacy in humans during the COVID-19 pandemic. The McShane group has extensive experience in clinical TB vaccine development - having taken the first new TB vaccine into clinical trials in 2002 and completing the first efficacy trial since BCG in 2013. A network of collaborators across Africa together with extensive experience in first-time-in-man and early phase studies within Oxford provide a straightforward translational pathway should the data in guinea pigs be promising.
Justification for support
Guidance
Provide a description of what resources (models, equipment, infrastructure, expertise) are needed to undertake the proposed project. Also provide justification for the funds being requested and state why the MLSTF scheme is an appropriate scheme for your proposal. Max 200 words.
What are the panel looking for?
What resources (models, equipment, infrastructure, expertise) are needed to undertake the proposed project?
Why the MLSTF scheme is an appropriate scheme for your proposal?
Exemplar
We are seeking REDACTED of which will contribute to the costs of mRNA scaling up and shipping costs from Moderna to UOXF and from UOXF to UKHSA.
The remaining REDACTED will cover the costs of the guinea pig study at UKHSA as per attached quote. The costs will include animal purchasing, housing, challenge, organ collection and processing, analysis of data and compilation of report.
Sources of matched funding
Guidance
Provide details of other sources of funding to match the MLSTF award. These could include: industry cash or in-kind, internal/external awarded grants, Departmental support. Max 100 words.
What are the panel looking for?
Please provide examples of sources that could include: industry cash or in-kind, internal/external awarded grants, Departmental support.
Exemplar
ES and HMcS time will be provided in kind
Note from TRO: Panel considers this a great value for money as ES and HMcS are supported through other funding sources, and the resources requested were predominantly for the work proposed.