Complement-dependent synergistic bactericidal activity of antibodies against factor H-binding protein, a sparsely distributed meningococcal vaccine antigen.
BACKGROUND
Antibodies to factor H (fH)-binding protein (fHBP), a meningococcal vaccine antigen, activate classical complement pathway serum bactericidal activity (SBA) and block binding of the complement inhibitor fH.


METHODS
To understand these 2 functions in protection, we investigated the interactions of human complement and 2 anti-fHBP monoclonal antibodies (MAbs) with encapsulated Neisseria meningitidis.


RESULTS
JAR 3 (IgG3) blocks fH binding and elicits SBA against 2 strains with naturally high fHBP expression and a low-expressing strain genetically engineered to express high fHBP levels. JAR 4 (IgG2a) does not block fH binding or elicit SBA. Neither MAb alone elicits SBA against 2 other strains with low fHBP expression, but together the MAbs increase C4b binding and elicit SBA; JAR 3 alone also is bactericidal in whole blood. In nonimmune blood, fHBP knockout mutants from high-expressing stains do not survive, but mutants of low-expressing strains do.


CONCLUSIONS
Expression of fHBP is a prerequisite for bacterial survival in blood only by strains with naturally high fHBP expression. In low-expressing strains, combinations of 2 nonbactericidal anti-fHBP MAbs can bind to nonoverlapping epitopes, engage C1q, activate C4, and mediate classical complement pathway SBA. In the absence of sufficient C4b binding for SBA, an individual MAb can have opsonophagocytic bactericidal activity.
Welsch
Jo Anne
JA
Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California, USA.
Ram
Sanjay
S
Koeberling
Oliver
O
Granoff
Dan M
DM
D000907:Antibodies, Bacterial / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D015169:Colony Count, Microbial; D003165:Complement System Proteins / Q000276:immunology* / Q000378:metabolism; D017353:Gene Deletion; D005798:Genes, Bacterial; D006801:Humans; D050296:Microbial Viability; D009345:Neisseria meningitidis / Q000276:immunology*; D011485:Protein Binding
D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D003165:Complement System Proteins