New vaccine adjuvants from metal organic frameworks
Lead Research Organisation:
University College London
Department Name: School of Pharmacy
Abstract
Prophylactic vaccination is arguably the most effective medical intervention ever developed, saving some 3 million lives per year. A vaccine is a preparation that causes an individual to develop effective biological defence mechanisms (immunity) against a pathogen. Most often, vaccination is used to protect against an infectious disease, though cancers are also increasingly being targeted. Typically a vaccine will contain a small amount of a material which resembles a disease-causing agent (the 'antigen' - a viral, microbial or tumour component), but does not carry an infectious risk. The vaccine causes the immune system to recognize the antigen as foreign, eliminate it, and "remember" it, thereby conferring effective immunity against the pathogen. In order to ensure that robust immunity is inculcated, an "adjuvant" is usually added to vaccines to mimic the danger signals that naturally trigger immune responses. At present, inorganic compounds known as 'alums' (usually either AlOOH or amorphous aluminium hydroxyphosphate) are used as adjuvants in the majority of cases. 'Alum' can lead to strong immunity to microbes and larger parasites, but does not provoke the necessary immune response to overcome viral infections or the majority of cancers. There is at present a lack of alternative adjuvants able to drive such responses; in this work, we seek to redress this deficiency.
Recent work has established that a family of inorganic materials known as layered double hydroxides can act as potent adjuvants whose immunogenicity can be systematically varied through control of their physicochemical properties. In this work, we will explore the metal organic framework (MOF) family of materials. MOFs are a class of materials containing metal centres connected in three dimensions by organic linkers. They have enormous structural diversity, and commonly contain empty 'pores' into which antigens may be incorporated. MOFs have successfully been used for drug delivery and other biomedical applications. They have however never been explored for use as adjuvants. We will systematically synthesise three sets of MOFs (known materials, known materials with immunogenic moieties embedded, and MOFs where the organic linker is immunogenic) and investigate the immune response to these in vitro. This work will be complemented with a detailed systems-level study looking to draw correlations between the materials' physicochemical properties and the immune responses they invoke.
Recent work has established that a family of inorganic materials known as layered double hydroxides can act as potent adjuvants whose immunogenicity can be systematically varied through control of their physicochemical properties. In this work, we will explore the metal organic framework (MOF) family of materials. MOFs are a class of materials containing metal centres connected in three dimensions by organic linkers. They have enormous structural diversity, and commonly contain empty 'pores' into which antigens may be incorporated. MOFs have successfully been used for drug delivery and other biomedical applications. They have however never been explored for use as adjuvants. We will systematically synthesise three sets of MOFs (known materials, known materials with immunogenic moieties embedded, and MOFs where the organic linker is immunogenic) and investigate the immune response to these in vitro. This work will be complemented with a detailed systems-level study looking to draw correlations between the materials' physicochemical properties and the immune responses they invoke.
Planned Impact
- Who will benefit from this research?
This project has the potential to provide extensive benefits to research scientists and medical practitioners, members of the general public who are directly or indirectly affected by diseases or conditions where effective vaccines are not available (e.g. malaria, HIV), and companies working on vaccine and adjuvant development (principally the pharmaceutical industry).
- How will they benefit?
These groups will benefit when the outcomes of this project are promulgated into the public domain through conference presentations and journal articles. Beyond this, the project will directly transfer technical and managerial skills to the post-doctoral research assistant (PDRA) employed on the contract, and indirectly to PhD, MPharm and MSc students working in the research group. This will help us to build up an international skills base as these students and the PDRA move on to positions in other academic institutions, in industry or in government.
- What will be done to ensure the beneficiaries have the opportunity to benefit from this research?
The work proposed in this project will identify metal organic frameworks (MOFs) with the potential to increase vaccine efficacy, and hence should ultimately lead to advances in human health and well-being. As a result of the elucidation of relationships between the physicochemical properties of the MOF materials and the immune response stimulated, researchers in materials science, biomaterials and vaccinology will benefit from our findings. In the short term (1 - 3 years), they will receive this benefit via our presentation of the results at large international conferences and in articles in peer-reviewed and internationally recognised journals. The past impact of GRW's work is evidenced by an h-index of 14 and a total number of citations of 710 (Aug 2013). In the medium- to long-term (5 - 10 years) possible benefits include new adjuvants being taken forward into trials, and the streamlining of the adjuvant discovery process as a result of new structure-property relationships permitting systematic adjuvant design and reduced use of animals in the vaccine development pathway. This in turn should result in considerable cost savings for the pharmaceutical industry.
This project has the potential to provide extensive benefits to research scientists and medical practitioners, members of the general public who are directly or indirectly affected by diseases or conditions where effective vaccines are not available (e.g. malaria, HIV), and companies working on vaccine and adjuvant development (principally the pharmaceutical industry).
- How will they benefit?
These groups will benefit when the outcomes of this project are promulgated into the public domain through conference presentations and journal articles. Beyond this, the project will directly transfer technical and managerial skills to the post-doctoral research assistant (PDRA) employed on the contract, and indirectly to PhD, MPharm and MSc students working in the research group. This will help us to build up an international skills base as these students and the PDRA move on to positions in other academic institutions, in industry or in government.
- What will be done to ensure the beneficiaries have the opportunity to benefit from this research?
The work proposed in this project will identify metal organic frameworks (MOFs) with the potential to increase vaccine efficacy, and hence should ultimately lead to advances in human health and well-being. As a result of the elucidation of relationships between the physicochemical properties of the MOF materials and the immune response stimulated, researchers in materials science, biomaterials and vaccinology will benefit from our findings. In the short term (1 - 3 years), they will receive this benefit via our presentation of the results at large international conferences and in articles in peer-reviewed and internationally recognised journals. The past impact of GRW's work is evidenced by an h-index of 14 and a total number of citations of 710 (Aug 2013). In the medium- to long-term (5 - 10 years) possible benefits include new adjuvants being taken forward into trials, and the streamlining of the adjuvant discovery process as a result of new structure-property relationships permitting systematic adjuvant design and reduced use of animals in the vaccine development pathway. This in turn should result in considerable cost savings for the pharmaceutical industry.
Organisations
- University College London (Lead Research Organisation)
- Hanoi University (Collaboration)
- Southern Federal University (Collaboration)
- City, University of London (Collaboration)
- University of St Andrews (Collaboration)
- City, University of London (Project Partner)
- Imperial College London (Project Partner)
People |
ORCID iD |
Gareth Williams (Principal Investigator) |
Publications
Williams GR
(2016)
The potential for a protective vaccine for rhinovirus infections.
in Expert review of vaccines
Description | In this work, we sought to investigate the potential of metal organic frameworks (MOFs; a diverse family of inorganic materials) as "adjuvants", compounds added to vaccines to enhance their potency and ensure immunity to a disease is inculcated. A range of Al-containing MOFs was first prepared and the immune response stimulated in vitro found to be clearly dependent on the organic linker which connects the Al ions in the framework. The MOFs performed better than commercial "alum" adjuvants in many cases. The effect of the metal ion was next probed using a family of MOFs where different metal centres were connected by the same linker molecule. This showed that the metal centre is also important in controlling the immune response stimulated, with the MOFs again often performing better than commercial adjuvants. MOFs contain large empty pores which can be filled with other species. We thus next intercalated a range of immunogenic molecules into selected MOFs, and found that the incorporation of the immunopotentiator succinic acid in particular could increase the immune response seen. Finally, MOFs were prepared in which the linkers themselves were immunogenic, and succinic acid again found to be particularly potent. A systems level statistical analysis has been undertaken to explore the relationship between the MOF physicochemical properties and the immune response. Statistically significant differences have been observed in many cases as a result of linker/metal ions being changed, showing that the properties of the MOFs have a profound influence on the immune response. This work has thus comprehensively developed that MOFs are potent and tuneable adjuvants. This opens up the question of whether they can be loaded with antigens (subunits of a pathogen) in order to prepare vaccines which are both tuneable and able to stabilise the antigen to heat and light. If so, a paradigm shift in vaccination may be possible - at present, many vaccines are exposed to elevated temperatures during transport, as a result of which the formulation degrades. |
Exploitation Route | Our findings have already been shared with the community through conference presentations and invited seminars. Papers reporting these results are under preparation and will be submitted to prestigious journals in the coming months. The results we have obtained can be taken forward by academic investigators working on adjuvants and vaccines, since we have identified potent new adjuvant materials. Non-academic users working on adjuvants will also be able to build on our findings in similar manners. The latter are likely to be in the healthcare or biotechnology sectors, and in addition to publication/presentation efforts are underway to engage these potential end users in accordance with the original workplan. Personal contacts, the fora offered by the UCL-Nottingham CDT Centre for Doctoral Training in Advanced Therapeutics and Nanomedicines, and RSC/APS focus groups are being exploited to make putative end users aware of the work. The findings of this work could ultimately be used to make vaccine formulations stable to elevated temperatures and light, potentially solving a major problem in the provision of vaccines to the developing world. |
Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
Description | AAPS Travel Bursary |
Amount | $1,000 (USD) |
Organisation | American Association of Pharmaceutical Scientists |
Sector | Charity/Non Profit |
Country | United States |
Start | 11/2017 |
End | 11/2017 |
Description | Layered double hydroxide vaccine adjuvants |
Amount | £231,000 (GBP) |
Organisation | SCG Chemicals |
Sector | Private |
Country | Thailand |
Start | 03/2021 |
End | 03/2022 |
Description | UCL Hospitals Charity / NIHR fast Track Scheme |
Amount | £38,687 (GBP) |
Funding ID | F200 |
Organisation | UCL Hospitals Charity |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2016 |
End | 05/2017 |
Description | UK-Indonesia Conference on Porous Materials |
Amount | £1,000 (GBP) |
Organisation | British Council |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2015 |
End | 02/2015 |
Description | Collaboration with Prof Mark Broom, City University |
Organisation | City, University of London |
Department | Department of Mathematics |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Data generated from our experiments in this grant have been used for mathematical model construction. |
Collaborator Contribution | Application of statistical models to develop structure/property relationships between MOF properties and immunological outputs. |
Impact | We have recently applied for a joint grant from the Humane Research Trust to further this research. The collaboration is multidisciplinary, involving mathematics/statistics, materials chemistry, and immunology. |
Start Year | 2015 |
Description | Collaboration with Smart Materials Research Institute, Southern Federal University, Russia |
Organisation | Southern Federal University |
Country | Russian Federation |
Sector | Academic/University |
PI Contribution | This is a nascent collaboration, but the team at Southern Federal University have a great deal of experience in MOF synthesis and a large library of materials, and we are building a collaboration such that UCL can get access to this library to explore for adjuvanticity. This will enable us to significantly expand the range of MOFs we have been able to explore to date, and strengthen our structure-property models. |
Collaborator Contribution | This is a nascent collaboration, but the team at Southern Federal University have a great deal of experience in MOF synthesis and a large library of materials, and we are building a collaboration such that UCL can get access to this library to explore for adjuvanticity. This will enable us to significantly expand the range of MOFs we have been able to explore to date, and strengthen our structure-property models. |
Impact | None as yet. |
Start Year | 2019 |
Description | Hanoi University of Science and Technology collaboration |
Organisation | Hanoi University |
Country | Viet Nam |
Sector | Academic/University |
PI Contribution | Design and synthesis of novel inorganic adjuvants. |
Collaborator Contribution | Combinations of adjuvants with antigens, and disease models for testing the resultant vaccines (currently being planned). |
Impact | None yet. |
Start Year | 2018 |
Description | New collaboration with Prof Russell Morris, University of St Andrews |
Organisation | University of St Andrews |
Department | School of Chemistry St Andrews |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Dr Ilona Kubajewska, the PDRA employed on this project has undertaken the vast majority of work in the preparation of metal organic framework (MOF) adjuvants and their testing in vitro. She has also provided instruction and guidance in in vitro techniques, aiding with a related project using MOFs in biomedicine led by Prof Morris. She and GRW provided assistance with data analysis and manuscript preparation. GRW also directed the adjuvant project and the work of the visiting student (see below) while she was at UCL. |
Collaborator Contribution | Ms Kasia Mocniak, a PhD student from Prof Morris' group has spent 18 months as a visiting student in UCL. Ms Mocniak has experience in MOF synthesis and provided assistance to Dr Kubajewska in the initial stages of her work, with regard to MOF synthesis and characterisation. She has prepared a number of MOF materials for our project and learning and performing immunoassay experiments. |
Impact | So far, one publication, with a PhD thesis being written up. |
Start Year | 2014 |
Description | A unique class of organic-inorganic hybrid polymers with adjuvant properties: an emerging platform for vaccines and immunotherapies |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Dr Kubajewska delivered an oral presentation describing the key findings from our EPSRC funded work on MOFs as adjuvants. |
Year(s) Of Engagement Activity | 2016 |
Description | Invited presentation (Donghua University) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited talk given to ca. 30 staff and students at Donghua University. Several interesting discussions had afterwards which might lead to future collaborations. |
Year(s) Of Engagement Activity | 2015 |
Description | Invited presentation (J Heyrovsky Institure of Physical Chemistry, Prague) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited talk given to ca. 40 staff and students at the J Heyrovsky Insitute. Several interesting discussions had afterwards which might lead to future collaborations. |
Year(s) Of Engagement Activity | 2015 |
Description | Invited presentation (Open University) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Gave an invited talk on our research on inorganic adjuvants, including metal organic frameworks, to the Dept of Life, Health & Chemical Sciences at the Open University, talking to some 20 members of academic staff/postgraduate students. Following this, I have had discussions as to a potential new collaboration which we will take forward soon. |
Year(s) Of Engagement Activity | 2015 |
Description | Invited presentation to Vaccine Antigen Delivery: New Approaches to Vaccine Development conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Dr Kubajewska (ex-post doc on the project) gave an invited talk on our work to a virtual conference, reaching researchers all around the world. This raised a number of interesting discussion points, as well as raising awareness of our findings. |
Year(s) Of Engagement Activity | 2016 |
URL | http://lifescienceevents.com/speakers-vaccine-antigen-delivery-approaches-vaccine-development/ |
Description | Poster presenation at the UCL IIT Immunology Symposium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Poster presented at the UCL IIT Immunology Symposium. A number of colleagues expressed interest in the work. |
Year(s) Of Engagement Activity | 2015 |
Description | Poster presentation at AAPS meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Poster presentation entitled "New Application Of Metal Organic Frameworks As Adjuvants With Antigen Delivery Capacity For More Effective Vaccines and Immunotherapies" given by Dr Ilona Kubajewska to the AAPS Annual Meeting & Exposition 2017. |
Year(s) Of Engagement Activity | 2017 |
Description | UK-Indonesia Conference on Porous Materials |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Talk and poster presented at the UK-Indonesia Conference on Porous Materials, in addition to participation by Dr Ilona Kubajewska (PDRA on the grant) in a number of workshops with UK and Indonesian early career researchers, helping her to expand her network. A number of people expressed interest in the work. |
Year(s) Of Engagement Activity | 2015 |