VADER · Vaccine Design and Immune Responses

Vaccine Design and Immune Responses

Final Publishable Summary Report http://www.vadereugrant.com/index.html The primary objective of the VADER (VAccine DEsign and immune Responses) project was the creation of a training programme between the GlaxoSmithKline Vaccines Institute for Global Health (GVGH) and the University of Birmingham (UoB) in vaccinology, immunology and microbiology for four Early Stage Researcher fellows. The fellows were to have the opportunity to conduct scientific projects in an environment that combines industrial excellence in vaccinology with complementary academic excellence in immunology and microbiology, with the rigor and discipline required to obtain a PhD. Each fellow was to have her own project, linked to one or more vaccine projects at GVGH, and to benefit from close interaction with other fellows and other vaccine projects at GVGH, and research groups at UoB. Scientific Results and Conclusions Project 1. Improving immunity to typhoid through novel polysaccharide-conjugate vaccines. This project was linked to the glycoconjugate typhoid fever vaccine project at GVGH. The fellow conducted a systematic investigation of the effect of different variables on the immunogenicity of glycoconjugate vaccines against typhoid fever, a major cause of morbidity and mortality, particularly in Southern and South-East Asia. This involved the design and synthesis of panels of candidate vaccines, differing by one parameter at a time. These new vaccines were then tested in mice for immunogenicity, and careful characterisation of the immune responses elicited were undertaken at UoB. Saccharide size and carrier protein were found to be the parameters with the greatest impact on immunogenicity, and use of fragmented polysaccharide was found to have added benefits in relation to ease of manufacture. The project facilitated the development of the GVGH typhoid vaccine and established a systematic approach for rational design of glycoconjugate vaccines that can be applied to the development of other vaccines. Project 2. Manipulating outer membrane particles to enhance immunogenicity of factor H binding protein for low-cost novel vaccines against Neisseria meningitidis. This project was linked to the pan-African GMMA (Generalized Modules for Membrane Antigens) meningococcal vaccine project at GVGH. The fellow explored the opportunity presented by GMMA vaccine technology to generate a vaccine that can protect against different types of Neisseria meningitidis (meningococcus) responsible for epidemics of meningitis in Africa. The work focused on the key antigen, factor H binding protein (fHbp), beginning with an analysis of its variability across different strains of meningococcus. This information was used to design a panel of vesicle vaccines, differing only in relation to the exact fHbp molecule expressed at high levels on the vesicle surface, and a panel of matched recombinant fHbp vaccines. When tested in mice, the amino acid sequence of fHbp was found to influence the specificity of the antibody response, with vesicle vaccines providing greater breadth of strain coverage than recombinant vaccines. Careful study of the immune responses at UoB showed that the vesicle vaccines induce a fast, long-lasting antibody response, with germinal centre induction, suggesting that they are well suited for further development. Project 3. OmpD in GMMA as a vaccine candidate against nontyphoidal Salmonella for sub-Saharan Africa. This project was linked to the GMMA nontyphoidal Salmonella (NTS) project at GVGH. The fellow focused on GMMA vaccines against Salmonella Typhimurium, the major cause of NTS bloodstream infections in Africa, and the expression in GMMA of the promising vaccine antigen OmpD, a porin molecule present in the bacterial outer membrane. Genetic manipulation was used to modulate porin expression in Salmonella GMMA and the immune responses to candidate GMMA vaccines were studied in detail. As well as demonstrating the ability of these vaccines to protect mice against Salmonella infections, strong antibody responses were characterised to two immunodominant antigens: lipopolysaccharide and porins. These were found to differ in their kinetics, but both showed good persistence indicating the potential of this vaccine approach and the utility of the vaccines as a tool to understand B cell responses. Project 4. Recombinant protein production using bacteria autotransporter technology for the development of vaccines. This project was linked to the ETEC vaccine project at GVGH. The fellow investigated the potential of the Pet Autotransporter system (proposed as a streamlined means of recombinant protein production) for production of a ‘difficult’ E. coli protein with commercial vaccine potential. Through genetic manipulation of the Pet Autotransporter, the protein was synthesised and the final product found to have equivalent purity, stability and immunogenicity to that produced using conventional technology. The system was subsequently shown to be suitable for process scale-up. The Pet Autotransporter system was then used to express the E. coli protein on the surface of bacterial outer membrane vesicles in an ‘antigen display’ mode. After confirming expression, the vesicles were tested in mice and shown to induce a specific immune response to the protein as well as the vesicles themselves, indicating a promising new strategy for vaccine development. Research Training The four early stage researcher fellows undertook a comprehensive programme of training during the VADER project in order to equip them for a future career at the interface of academia and industry. This programme included three planned Scientific Research and Laboratory Skills Courses focusing on 1. vaccine design and engineering, 2. immunity to infection and 3. molecular microbiology. The fellows also undertook three Transferrable Skills Courses on 1. commercialisation of research (Medici Enterprise Training Programme), 2. working with animals (course for Personal Licence from UK Home Office), and 3. scientific writing. Socio-economic impacts Socio-economic impacts from the VADER project are short-term and longer term. In the short term, all four fellows have been successfully trained in vaccine design and immune responses and all have decided to continue in related areas of research within the EU. This transition to becoming Experience Researchers, able to work in both academia and industry and move between the two sectors, serves as an important justification for the investment made by the EU into the careers of each fellow. Therefore, the research skills acquired as part of the VADER project are being reinvested in the EU and will provide socio-economic impact through enhanced research capacity at the critical academia/industry interface. The research conducted within the VADER project will also serve to provide more direct, but longer term socio-economic impact through the advancement of each of the Global Health vaccine projects that the fellows were involved with (see above for details). This will have socio-economic impact well beyond the boundaries of the EU, with each vaccine project aimed at alleviating suffering from infectious diseases in developing countries. Finally, the more academic-related aspects of the work have provided new data to support the application of follow-on funding from sources beyond the European Commission. Conclusions The VADER project can be judged to have been a success by the following criteria: 1. the completing of the three-year fellowship/PhD by all four early stage researchers and their progression to the next stage of their careers, both in academia and industry, and 2. the socio-economic impacts of the work including that resulting from the scientific advances made by each fellow. (a pdf of this Summary Report has been included as an attachment)

Data: CORDIS, © European Union