The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance.
Neisseria meningitidis binds factor H (fH), a key regulator of the alternative complement pathway. A approximately 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.
Madico
Guillermo
G
Section of Infectious Diseases, Boston University School of Medicine, Boston, MA 02118, USA.
Welsch
Jo Anne
JA
Lewis
Lisa A
LA
McNaughton
Anne
A
Perlman
David H
DH
Costello
Catherine E
CE
Ngampasutadol
Jutamas
J
Vogel
Ulrich
U
Granoff
Dan M
DM
Ram
Sanjay
S
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D001422:Bacterial Adhesion / Q000276:immunology; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D001666:Binding Sites, Antibody; D001667:Binding, Competitive / Q000276:immunology; D001770:Blood Bactericidal Activity / Q000235:genetics / Q000276:immunology*; D017242:Complement Factor H / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D003170:Complement Pathway, Alternative / Q000235:genetics / Q000276:immunology; D017353:Gene Deletion; D014644:Genetic Variation; D006801:Humans; D008024:Ligands; D022401:Meningococcal Vaccines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009345:Neisseria meningitidis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018272:Porins / Q000378:metabolism; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D008024:Ligands; D022401:Meningococcal Vaccines; D018272:Porins; D019444:Vaccines, DNA; C488465:antigen 1870, Neisseria meningitidis; C057699:porin protein, Neisseria; D017242:Complement Factor H