Polymer adjuvants for innate and cellular based vaccination

In the early days of commercial vaccine manufacture, significant variation between the effectiveness of different batches of the same vaccine were correctly ascribed to contamination of the reaction vessels. However, more scrupulous attention to cleanliness seemed to reduce the effectiveness of the vaccines, suggesting the contaminants actually enhanced immunogenicity. These contaminants were described as 'adjuvants'; agents which stimulate the immune system and increase the response to a vaccine, without having any intrinsic antigenic effect. They do this by creating a non-specific pro-inflammatory environment, where presentation of specific antigens leading to a vaccine response is much more efficient. Experience shows that adjuvants make a crucial contribution to the development of effective vaccines, and many adjuvants are now in widespread use, including oils, aluminium salts and virosomes.The field of vaccination is of ever-increasing importance, ranging from successful eradication of Smallpox in 1977 (estimated to have saved 30 m lives) through to the pressing need for prophylactic (and ideally therapeutic) vaccines for HIV, malaria, TB and cancer. New adjuvants will make an important contribution to the development of new vaccines, as some of the most effective adjuvants to date (such as Freund's adjuvants) cannot be manufactured to cGMP and are not suitable for clinical use. One way to address this shortfall is to design and produce potent and specific synthetic molecular adjuvants which are suitable for cGMP manufacture.We will synthesize polymer-TLR ligands conjugates which are capable of binding their receptor and activate a programmed cytokine response. Multivalent reactive polymers will be synthesized using controlled radical polymerization to obtain polymers which have a narrow molecular weight distribution. Hydrophilic monomers such as polyethylene glycol methacrylate, or N,(2-hydroxypropylmethacrylamide) will be co-polymerized with either an activated ester bearing monomer or an azide bearing monomer for subsequent modification. Three parameters of polymer structure will be examined in order to determine optimum capacity of the materials to induce an immune response: Firstly the molecular weight and polydispersity of the polymer; secondly the number of TLR ligands per polymer and finally the spacer length and properties. All of these parameters will be adjusted in parallel and are important in understanding how features of the material alter the immune response.Biological activity will be initially assessed using reporter cells which are activated upon stimulation of any TLR ligands. A reporter protein is expressed and reflects the level of activation of the cells and thus an indicator of stimulation. Secondly, the specific activity of the ligand-polymer conjugates will be assessed to determine whether the materials stimulate either a cell based or antibody based immune response by measuring the relative quantities of the cytokines released following activation.

Potential Impact on Public Health Throughout the history of medicine adjuvants have played an important role in vaccination. However the lack of innovation of 'adjuvantology' alongside vaccinology is now restricting progress in the field and threatens to limit the future involvement of adjuvants in new vaccines. Additionally the difficulty of cGMP preparation of safe and well defined adjuvants is also hampering progress. An effective adjuvant will minimise the amount of vaccine material required for each dose, and maximise worldwide protection. The science of 'adjuvantology' is therefore a very important component of emerging vaccines and the poor supply of high quality, molecular-defined and safe adjuvants presents a significant public health issue. Demonstrating that new materials which act as PAMPs, with high avidity interaction with TLR 'pattern receptors', will provide a whole new field of defined adjuvants, tuneable to specific biological outcomes and easily scaled for cGMP production. This family of agents can be readily combined with a broad range of existing and new vaccines, to give improved protection (and possible treatment) of a several important diseases - notably HIV, malaria, TB, influenza, and hepatitis A-E. Among many beneficiaries worldwide is the UK Dept Health/National Health Service. At present the Dept Health spends some 150m p.a. on childhood vaccines, and introduction of effective adjuvants could dramatically decrease this cost. In addition the pandemic swine flu vaccine has cost the UK approaching 7 Euros per dose for some 60-132m doses of GSK's H1N1 influenza vaccine, a total cost of approximately 400-800m. Again, efficient adjuvants could dramatically decrease these costs. Benefits are even more important in the developing world, where efficient adjuvants could make the difference between availability of effective pandemic flu vaccines or not. Knowledge Interdisciplinary work such as that proposed in this project impacts on many subject areas. Firstly, polymer chemistry and in particular biomedical polymer synthesis will be advanced by novel synthetic strategies and conjugation methodologies which can be applied to drug delivery and modification of surfaces. Development of new adjuvants will lead to the improved design and rationale for new vaccines with improved potency. For example, antigens which are weakly immunogenic will be capable of eliciting strong response when delivered with suitable adjuvants. As a result we will see a new wave materials becoming available for clinical trials. Dissemination of information The University of Oxford requires that its members publish their work in a manner which allows for greatest accessibility and dissemination of research information and has introduced the Oxford University Research Archive (ORA). ORA contains research publications and other research output produced by members of the University of Oxford and includes copies of journal articles, conference papers, theses and other types of research publications. The full text of many of these items is freely available to be used in accordance with copyright and end-user permissions. Public engagement is also extremely important, and for studies funded from the public purse it is vital to display our progress in a transparent and engaging way. To do otherwise runs the risk of losing public support, and eventually finance. The Department of Clinical Pharmacology and other University of Oxford Departments are actively engaged in promoting the scientific work which is carried out to the general public. There have been a number of successful open days at the Old Road Campus Research Building, which have been aimed at providing information about the science and the potential impact on the future of medicine.