The Meningococcal Vaccine Candidate GNA1870 Binds the Complement Regulatory Protein Factor H and Enhances Serum Resistance

Abstract

Neisseria meningitidis binds factor H (fH), a key regulator of the alternative complement pathway. A ∼29 kD fH-binding protein expressed in the meningococcal outer membrane was identified by mass spectrometry as GNA1870, a lipoprotein currently under evaluation as a broad-spectrum meningococcal vaccine candidate. GNA1870 was confirmed as the fH ligand on intact bacteria by 1) abrogation of fH binding upon deleting GNA1870, and 2) blocking fH binding by anti-GNA1870 mAbs. fH bound to whole bacteria and purified rGNA1870 representing each of the three variant GNA1870 families. We showed that the amount of fH binding correlated with the level of bacterial GNA1870 expression. High levels of variant 1 GNA1870 expression (either by allelic replacement of gna1870 or by plasmid-driven high-level expression) in strains that otherwise were low-level GNA1870 expressers (and bound low amounts of fH by flow cytometry) restored high levels of fH binding. Diminished fH binding to the GNA1870 deletion mutants was accompanied by enhanced C3 binding and increased killing of the mutants. Conversely, high levels of GNA1870 expression and fH binding enhanced serum resistance. Our findings support the hypothesis that inhibiting the binding of a complement down-regulator protein to the neisserial surface by specific Ab may enhance intrinsic bactericidal activity of the Ab, resulting in two distinct mechanisms of Ab-mediated vaccine efficacy. These data provide further support for inclusion of this molecule in a meningococcal vaccine. To reflect the critical function of this molecule, we suggest calling it fH-binding protein.

The Dual Role of Lipids of the Lipoproteins in Trumenba, a Self-Adjuvanting Vaccine Against Meningococcal Meningitis B Disease

“…fHbp is also an important virulence factor expressed by N. meningitidis to evade innate immune defenses by specifically binding to complement factor H (fH) (9). It was suggested that anti-fHbp antibodies can elicit protection by two mechanisms: direct complement-mediated killing of the bacterium and blocking fH binding to the bacteria to increase the susceptibility of the bacterium to killing by the alternative complement pathway (7,10).…”

Defining a protective epitope on factor H binding protein, a key meningococcal virulence factor and vaccine antigen

“…fHbp is a 28 kDa surface-exposed lipoprotein and an important component of two meningococcal vaccines currently in clinical development (6)(7)(8)(9). fHbp plays a prominent role in meningococcal pathogenesis by recruiting human factor H (hfH) to the bacterial surface, thus protecting the bacterium from complement-mediated killing (10)(11)(12). fHbp is expressed by the majority of virulent meningococcal strains; its sequence displays extensive variability, allowing classification into three main variant groups (var1, -2, and -3) or two subfamilies (A and B) sharing limited cross-protection (13).…”

Neisseria meningitidis NalP cleaves human complement C3, facilitating degradation of C3b and survival in human serum

“…Bacteria can escape recognition by the complement system through the actions of cell surface structures or secreted proteins (7)(8)(9). Nm has evolved several redundant mechanisms to evade the host innate responses at sites of colonization and during systemic growth, including expression of fHbp (10,11) and NspA (12,13), that facilitate binding of fH, lipooligosaccharide (LOS) sialic acid, which inhibits complement deposition (12), and Opc protein, which binds to vitronectin (2). In a recent functional genomic study, we identified factors involved in Nm survival in human blood (14).…”