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.

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.

Publications

10 25 50
 
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 Learned Society
Country United States
Start 11/2017 
End 11/2017
 
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 09/2016 
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
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
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