Two human antibodies to a meningococcal serogroup B vaccine antigen enhance binding of complement Factor H by stabilizing the Factor H binding site

Microbial pathogens bind host complement regulatory proteins to evade the immune system. The bacterial pathogen Neisseria meningitidis, or meningococcus, binds several complement regulators, including human Factor H (FH). FH binding protein (FHbp) is a component of two licensed meningococcal vaccines and in mice FHbp elicits antibodies that inhibit binding of FH to FHbp, which defeat the bacterial evasion mechanism. However, humans vaccinated with FHbp develop antibodies that enhance binding of FH to the bacteria, which could limit the effectiveness of the vaccines. In the present study, we show that two vaccine-elicited antibody fragments (Fabs) isolated from different human subjects increase binding of complement FH to meningococcal FHbp by ELISA. The two Fabs have different effects on the kinetics of FH binding to immobilized FHbp as measured by surface plasmon resonance. The 1.7- and 2.0-angstrom resolution X-ray crystal structures of the Fabs in complexes with FHbp illustrate that the two Fabs bind to similar epitopes on the amino-terminal domain of FHbp, adjacent to the FH binding site. Superposition models of ternary complexes of each Fab with FHbp and FH show that there is likely minimal contact between the Fabs and FH. Collectively, the structures reveal that the Fabs enhance binding of FH to FHbp by altering the conformations and mobilities of two loops adjacent to the FH binding site of FHbp. In addition, the 1.5 angstrom -resolution structure of one of the isolated Fabs defines the structural rearrangements associated with binding to FHbp. The FH-enhancing human Fabs, which are mirrored in the human polyclonal antibody responses, have important implications for tuning the effectiveness of FHbp-based vaccines. Author summary Microbial pathogens bind specific host proteins to invade the host or evade host immunity. The bacterial pathogen meningococcus causes sepsis and meningitis, and binds a protein in the human immune system known as Factor H (FH). FH binding protein (FHbp) is a component of two licensed vaccines and can produce antibodies that block this evasion mechanism. Surprisingly, humans vaccinated with FHbp develop antibodies that enhance FH binding. To understand the biological mechanism, here we show that two human antibody fragments (Fabs) increase binding of human FH to FHbp by changing the binding kinetics. The three-dimensional structures of the two Fabs bound to FHbp reveal that the Fabs enhance FH binding through structural rearrangement in a region of FHbp adjacent to the FH binding site. A better understanding of FH enhancement by human Fabs can inform the continued development of meningococcal vaccines by eliminating the binding sites for such antibodies.