Immunogenicity of meningococcal PorA antigens in OMV vaccines

Abstract

For the prevention of meningococcal infection caused by group B meningococci, the Netherlands Vaccine Institute (NVI) has developed a hexavalent Porin A (PorA) based Outer Membrane Vesicle (OMV) vaccine (Hexamen). In various clinical studies with HexaMen, differences in the immune responses to the individual PorAs were observed. Factors involved in the development of the PorA specific immune response were studied, including the role of B and T cells. Also, alternative formulations or immunization schedules using the available monovalent and hexavalent candidate vaccines were investigated to optimize the immune response. To address these issues, studies were undertaken using P1.7-2,4 as a model for a weakly immunogenic PorA antigen, while P1.5-1,2-2 was used as a strongly immunogenic PorA model antigen. The influence of the composition of a PorA OMV vaccine on the immune response was limited, indicating that these are caused by intrinsic properties of the PorA antigen itself. We investigated the possibility to optimize the immune response against weakly immunogenic PorAs using immunization schedules with both monovalent OMVs and HexaMen. Priming with two different weakly immunogenic PorAs followed by two doses of HexaMen, induced good responses against all serosubtypes. The early immune responses against a strong (P1.5-1,2-2) and a weak PorA immunogen (P1.7-,2 4) after monovalent immunization, revealed a delayed onset of high affinity IgG and SBA titers for the weak immunogen. A PorA-specific B cell ELISPOT showed that the lower IgG and SBA titers were not reflected by a lack of specific B cells or plasma cells, but were instead higher after the boost. Apparently, the P1.7-2,4 specific B cells have difficulties to generate high affinity antibodies and require more proliferation to obtain sufficient antibody production. This higher number of P1.7-2,4 specific memory B cell pool remained constant for over a year. We also found that memory B cells were induced already after one HexaMen immunization, and were reactive upon both immunization and intranasal exposure to live bacteria, indicating that this memory B cell pool may contribute to vaccine-induced protection in the absence of PorA specific bactericidal titers. Finally, we studied the involvement of CD4 T cells in the PorA specific response by the generation of a PorA (P1.5-1,2-2) specific T cell hybridoma. The recognized epitope was located in a transmembrane region with limited strain variation. Still, one amino acid variation either inside or outside the CD4 T cell epitope could greatly reduce the efficiency of PorA specific CD4 T cell activation. In conclusion, a multivalent PorA OMV vaccine is to date the best vaccine to protect against meningococcal disease in an endemic situation. Differences in PorA specific immune responses are caused by intrinsic properties of PorA and the interaction with the complete immune system. Furthermore, our studies showed that the PorA specific immune responses may be enhanced by optimizing the vaccination schedule.