New vaccine adjuvants from metal organic frameworks

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.

- 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.