VACCINE - Development of novel picornavirus virus-like particle vaccines

The strategy of the Medical Research Council is to improve the progress of international health research worldwide. Vaccination has had an enormous impact on human and animal health and is therefore one of the most important and effective medical interventions. However, there are still many examples of diseases for which we do not have effective vaccines. Furthermore, much of our current vaccine production involves the production of disease-causing agents (e.g. viruses) which are subsequently inactivated during the production process. In their simplest terms, viruses can be thought of as protein containers that protect the viral genetic material inside. The container is inert - it is the viral genetic material inside which is responsible for causing disease. However, the container (capsid) is of key importance in the process of developing immunity through vaccination. Here, the body's immune system recognises the capsid proteins and generates antibodies to these, which then give the body protection against the disease. Therefore, production of just the capsid as a virus-like particle (VLP) should elicit a protective immune response, yet be totally safe. Furthermore, such production could be undertaken under low containment, which is both easier and cheaper, thus making such virus-like particle vaccines more accessible to developing countries. However, there are problems to be overcome, as many VLPs are unstable. We have a large amount of proof-of-principle data with the production of VLPs for poliovirus and have generated stabilised VLPs that offer better protection than the current polio vaccine (in animal models). We now we wish to apply our strategy to other viruses, focussing on the causative agents of hand, foot and mouth disease. This is a disease of growing concern due to outbreaks particularly in the SE Asia region, associated with hospitalisation and death. According to the World Health Organisation, this affected 1,520,274 people by the end of July in 2012 in China, with 431 reported deaths, and outbreaks are now reported in Europe.

Virus-like particles (VLPs) are of interest as novel vaccines. They can present antigenic features of a viral pathogen in a safe and highly immunogenic form. The hepatitis B and human papillomavirus vaccines are well-established examples. Some viruses e.g. the picornavirus, poliovirus, produce empty particles as part of the natural lifecycle. Although these empty particles could be VLP vaccine candidates, they are very unstable and readily undergo an antigenic conversion to a non-native state and therefore would not elicit a protective immune response. Over the past 5 years, we have generated VLPs of poliovirus that are now being expressed in recombinant systems as novel vaccine candidates. By selecting viruses at elevated temperatures and by identifying reversion of temperature-sensitive mutants, we have identified a number of residues in the capsid which renders this stable, even when empty. We now propose to extend our studies to other picornaviruses and thus develop a generic approach to VLP vaccine development. The focus of the current application is the causative agents of human hand, foot and mouth disease (HFMD), enterovirus 71 (EV71) and Coxsackie virus A16 (CVA16). HFMD is a disease of growing concern due to outbreaks affecting children in the SE Asia region, associated with hospitalisation and death. Outbreaks have recently been reported in Europe.

The initial fundamental and exploratory phases of the study will be of interest and value to academic investigators in the fields of protein expression, structure and assembly and to vaccinologists, as outlined in the 'academic beneficiaries' section. Delivery of impact during the grant to non-academic beneficiaries will be pursued in four main areas. Firstly, the UK/global economy will benefit through the development of highly skilled researchers, with high level scientific and transferable skills equipping him/her to continue on the pathway to an independent research career. Secondly, the general public (both adults and children) will benefit through a range of public engagement events, leading to improved understanding of the science of infectious diseases, viruses and their control by vaccination. In addition, the research community beyond academia (for example pharmaceutical companies) will benefit from this research through having access to the exploitation of techniques/approaches with potential for wide application in the area of vaccine development. Finally, government organisations in developing countries may benefit from this research through new approaches for the development of vaccines to counter diseases prevalent or emerging in these regions. In the medium and longer term, there is significant potential for impact to pharmaceutical companies and governments to be realised through further development and uptake of the research carried out in this project. As an example, the development of technology which reduces the cost of production of vaccines through the use of appropriate technology and low containment facilities has the potential to greatly benefit companies in developing countries, and ultimately to benefit healthcare professionals and patients through availability of lower cost vaccines.