The Effect of Human Factor H on Immunogenicity of Meningococcal Native Outer Membrane Vesicle Vaccines with Over-Expressed Factor H Binding Protein

The binding of human complement inhibitors to vaccine antigens in vivo could diminish their immunogenicity. A meningococcal ligand for the complement down-regulator, factor H (fH), is fH-binding protein (fHbp), which is specific for human fH. Vaccines containing recombinant fHbp or native outer membrane vesicles (NOMV) from mutant strains with over-expressed fHbp are in clinical development. In a previous study in transgenic mice, the presence of human fH impaired the immunogenicity of a recombinant fHbp vaccine. In the present study, we prepared two NOMV vaccines from mutant group B strains with over-expressed wild-type fHbp or an R41S mutant fHbp with no detectable fH binding. In wild-type mice in which mouse fH did not bind to fHbp in either vaccine, the NOMV vaccine with wild-type fHbp elicited 2-fold higher serum IgG anti-fHbp titers (P = 0.001) and 4-fold higher complement-mediated bactericidal titers against a PorA-heterologous strain than the NOMV with the mutant fHbp (P = 0.003). By adsorption, the bactericidal antibodies were shown to be directed at fHbp. In transgenic mice in which human fH bound to the wild-type fHbp but not to the R41S fHbp, the NOMV vaccine with the mutant fHbp elicited 5-fold higher serum IgG anti-fHbp titers (P = 0.002), and 19-fold higher bactericidal titers than the NOMV vaccine with wild-type fHbp (P = 0.001). Thus, in mice that differed only by the presence of human fH, the respective results with the two vaccines were opposite. The enhanced bactericidal activity elicited by the mutant fHbp vaccine in the presence of human fH far outweighed the loss of immunogenicity of the mutant protein in wild-type animals. Engineering fHbp not to bind to its cognate complement inhibitor, therefore, may increase vaccine immunogenicity in humans

Meningococcal Factor H Binding Proteins in Epidemic Strains from Africa: Implications for Vaccine Development

Epidemics of meningococcal meningitis are common in sub-Saharan Africa. Most are caused by encapsulated serogroup A strains, which rarely cause disease in industrialized countries. A serogroup A polysaccharide protein conjugate vaccine recently was introduced in some countries in sub-Saharan Africa. The antibodies induced, however, may allow replacement of serogroup A strains with serogroup W-135 or X strains, which also cause epidemics in this region. Protein antigens, such as factor H binding protein (fHbp), are promising for prevention of meningococcal serogroup B disease. These proteins also are present in strains with other capsular serogroups. Here we report investigation of the potential of fHbp vaccines for prevention of disease caused by serogroup A, W-135 and X strains from Africa. Four fHbp amino acid sequence variants accounted for 81% of the 106 African isolates studied. While there was little cross-protective activity by antibodies elicited in mice by recombinant fHbp vaccines from each of the four sequence variants, a prototype native outer membrane vesicle (NOMV) vaccine from a mutant with over-expressed fHbp elicited antibodies with broad protective activity. A NOMV vaccine has the potential to supplement coverage by the group A conjugate vaccine and help prevent emergence of disease caused by non-serogroup A strains

Porin of Shigella dysenteriae enhances Toll-like receptors 2 and 6 of mouse peritoneal B-2 cells and induces the expression of immunoglobulin M, immunoglobulin G2a and immunoglobulin A

Porin of Shigella dysenteriae type 1 increased the mRNA levels for Toll-like receptors TLR2 and TLR6, by 1·8-fold and twofold, respectively, in peritoneal cavity B-2 cells from C57BL/6 mice, implicating that the co-expression of TLR2 and TLR6 occurs as a combinatorial repertoire in response to porin. Among the two key TLRs, TLR2 and TLR4, which are primarily responsible for recognizing the majority of bacterial products, TLR2 alone participates in porin recognition. TLR2 expression was increased on B-2 cells, whereas the expression of TLR4 remained unaffected. Besides TLRs, mRNA for myeloid differentiation factor 88 (MyD88), an effector molecule associated with the TLR-mediated response, was enhanced by twofold, suggesting its involvement in the activity of porin. The B-2 cells showed a 1·8-fold increase in mRNA expression of the signalling molecule, nuclear factor-kappa B (NF-κB), in the presence of porin. Porin treatment of B-2 cells selectively up-regulated the expression of the costimulatory molecule, CD86, by 4·4-fold. Porin induced the cell-surface expression of immunoglobulin (Ig)M, of IgG2a preferentially among the IgG subclasses, and of IgA, on B-2 cells. The porin-mediated inductions of IgG2a and IgA were augmented by interleukin-6 on B-2 cells, by 2·7- and 1·6-fold, respectively