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1.
J Immunol ; 167(11): 6487-96, 2001 Dec 01.
Article in English | MEDLINE | ID: mdl-11714816

ABSTRACT

Molecular mimetic Ags are of considerable interest as vaccine candidates. Yet there are few examples of mimetic Ags that elicit protective Ab against a pathogen, and the functional activity of anti-mimetic Abs has not been studied in detail. As part of the Neisseria meningitidis serogroup B genome sequencing project, a large number of novel proteins were identified. Herein, we provide evidence that genome-derived Ag 33 (GNA33), a lipoprotein with homology to Escherichia coli murein transglycosylase, elicits protective Ab to meningococci as a result of mimicking an epitope on loop 4 of porin A (PorA) in strains with serosubtype P1.2. Epitope mapping of a bactericidal anti-GNA33 mAb using overlapping peptides shows that the mAb recognizes peptides from GNA33 and PorA that share a QTP sequence that is necessary but not sufficient for binding. By flow cytometry, mouse antisera prepared against rGNA33 and the anti-GNA33 mAb bind as well as an anti-PorA P1.2 mAb to the surface of eight of nine N. meningitidis serogroup B strains tested with the P1.2 serosubtype. Anti-GNA33 Abs also are bactericidal for most P1.2 strains and, for susceptible strains, the activity of an anti-GNA33 mAb is similar to that of an anticapsular mAb but less active than an anti-P1.2 mAb. Anti-GNA Abs also confer passive protection against bacteremia in infant rats challenged with P1.2 strains. Thus, GNA33 represents one of the most effective immunogenic mimetics yet described. These results demonstrate that molecular mimetics have potential as meningococcal vaccine candidates.


Subject(s)
Antibodies, Bacterial/biosynthesis , Antigens, Bacterial/immunology , Meningococcal Infections/immunology , Molecular Mimicry/immunology , Neisseria meningitidis/immunology , Adult , Animals , Animals, Suckling , Antibodies, Bacterial/therapeutic use , Antigens, Bacterial/genetics , Binding Sites, Antibody , Blood Bactericidal Activity , Blotting, Western , Cell Membrane/chemistry , Cell Membrane/immunology , Cell Membrane/microbiology , Female , Flow Cytometry , Fluorescent Antibody Technique, Indirect , Genome, Bacterial , Glycosyltransferases/immunology , Humans , Meningococcal Infections/prevention & control , Mice , Molecular Mimicry/genetics , Neisseria meningitidis/genetics , Neisseria meningitidis/metabolism , Peptide Mapping , Porins/immunology , Rats , Receptors, Antigen, B-Cell/metabolism
2.
Infect Immun ; 69(6): 3762-71, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11349041

ABSTRACT

Neisserial surface protein A (NspA) is currently being investigated with humans as a candidate vaccine for the prevention of meningococcal disease. Although NspA is highly conserved, the ability of anti-NspA antibodies to bind to or elicit complement-mediated bactericidal activity against diverse Neisseria meningitidis serogroup B strains is controversial. To evaluate strain differences in NspA surface accessibility and susceptibility to bactericidal activity, we prepared murine immunoglobulin G2a anti-NspA monoclonal antibodies (MAbs) and evaluated their functional activity against 10 genetically diverse N. meningitidis serogroup B strains. By colony Western blot, all 10 strains expressed NspA as detected by one or more MAbs. By flow cytometry, two MAbs were found to bind to the bacterial surface of 6 of the 10 strains. In addition, two strains showed variable NspA surface accessibility for the MAbs despite being uniformly positive for NspA expression by colony Western blotting. Only 4 of the 10 strains were susceptible to anti-NspA complement-mediated bacteriolysis. Passively administered MAb protected infant rats from developing bacteremia after challenge with N. meningitidis serogroup B strain 8047 (surface binding positive, susceptible to anti-NspA bacteriolysis), was poorly protective against strain BZ232 (surface binding variable, resistant to bacteriolysis), and did not protect against strain M986 (surface binding negative, resistant to bacteriolysis). Finally, NspA does not appear to be critical for causing bacteremia, as an NspA knockout from strain 8047 was highly virulent in infant rats. Taken together, these findings suggest that an NspA-based vaccine will need to incorporate additional antigens to elicit broad protection against N. meningitidis serogroup B.


Subject(s)
Antibodies, Monoclonal/immunology , Bacterial Outer Membrane Proteins/immunology , Bacterial Vaccines/immunology , Neisseria meningitidis/classification , Neisseria meningitidis/immunology , Animals , Antibodies, Bacterial/immunology , Antibodies, Bacterial/metabolism , Antibodies, Monoclonal/metabolism , Antigens, Bacterial/immunology , Bacteremia/microbiology , Bacteremia/prevention & control , Bacterial Outer Membrane Proteins/genetics , Bacteriolysis , Female , Humans , Immune Sera , Meningococcal Infections/immunology , Meningococcal Infections/microbiology , Meningococcal Infections/prevention & control , Mice , Neisseria meningitidis/metabolism , Neisseria meningitidis/pathogenicity , Rats , Rats, Wistar , Serotyping , Virulence
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