Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 197, Issue 7, Pages 1053-1061Publisher
OXFORD UNIV PRESS INC
DOI: 10.1086/528994
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Funding
- NCRR NIH HHS [C06 RR-16226] Funding Source: Medline
- NIAID NIH HHS [R01 AI046464, AI054544, AI32725, R21 AI061533, R01 AI46464] Funding Source: Medline
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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.
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