Towards an improved Neisseria meningitidis B vaccine: vesicular PorA formulations

Abstract

There is a great need for vaccines against Neisseria meningitidis serogroup B. This is especially important in Western European countries, were approximately two thirds of the cases of meningococcal disease can be attributed to serogroup B strains. Against this serogroup, traditional vaccines based on capsular polysaccharides are not effective. The immunogenicity of the capsular polysaccharide of group B meningococci is low, due to structural similarity with epitopes expressed by host neural tissue. During the search for vaccine candidates against serogroup B meningococci, a great interest has been focused on PorA, a porin located in the outer membrane of the bacteria. PorA is one of the immunodominant antigens expressed by Neisseria meningitidis. Monoclonal antibodies directed against PorA have shown to have a high bactericidal activity and are protective in an infant rat meningitis model. The vaccine potential of PorA embedded in outer membrane vesicles (OMV) developed by different groups has been studied in various clinical trials. The vaccine presently being developed by the Netherlands Vaccine Institute (NVI) is based on OMV purified from genetically modified meningococcal strains expressing three different PorA serosubtypes (trivalent OMV). The vaccine contains a mixture of two different trivalent OMV are mixed, which together represent the majority of PorA serosubtypes circulating in the Netherlands and other European countries. Among the PorA serosubtypes included in the NVI vaccine, the serosubtype P1.7-2,4 is present in up to 40% of the serogroup B strains causing bacterial meningitis. Thus, a PorA-based vaccine should cover at least this subtype. On the other hand, the immunogenicity of PorA P1.7-2,4 is not yet optimal in its present formulation as OMV vaccine. For these reasons, PorA P1.7-2,4 was chosen as a model protein for our studies. The objective this thesis was to improve the immunogenicity of PorA. The research was exclusively focused on the study of the effect of the presentation form on the immunogenicity of PorA P1.7-2,4. For this purpose, three lines of investigation were followed: ? Detailed study of physicochemical and immunochemical characteristics of PorA and its presentation form. Also, study of the effects of different storage conditions on the physicochemical stability and immunogenicity of PorA formulated in different types of OMV. ? Preparation of well-defined liposomal PorA formulations and study of the effect of various targeting strategies for dendritic cells (DC) on the immunogenicity of PorA. ? Addition of adjuvants to liposomal PorA formulations and study of their effect on the PorA-specific immune response.