Additive and Synergistic Bactericidal Activity of Antibodies Directed against Minor Outer Membrane Proteins of
            <i>Neisseria meningitidis</i>

Weynants, Vincent; Feron, Christiane; Goraj, Karine; Bos, Martine P.; Denoël, Philippe; Verlant, Vincent; Tommassen, Jan; Peak, Ian R.; Judd, Ralph C.; Jennings, Michael P.; Poolman, Jan

doi:10.1128/iai.00411-07

Cited by 87 publications

(85 citation statements)

References 47 publications

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“…Previous studies indicated that for antibodies directed at "minor" protein antigens, a critical density of immune complexes on the bacterial surface was required to elicit bactericidal activity, and this threshold was reached only when more than one minor antigen was targeted (47). Evidence for cooperative serum bactericidal activity between antibodies to fHbp and Neisseria heparin binding antigen in adults immunized with a multicomponent recombinant vaccine was also recently reported (43).…”

Section: Resultsmentioning

confidence: 89%

A Critical Threshold of Meningococcal Factor H Binding Protein Expression Is Required for Increased Breadth of Protective Antibodies Elicited by Native Outer Membrane Vesicle Vaccines

Koeberling

Delany

Granoff³

2011

Clin. Vaccine Immunol.

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Native outer membrane vesicles (NOMV) (not detergent treated), which are prepared from recombinant strains with attenuated endotoxin activity and overexpressed factor H binding protein (fHbp), elicited broad serum bactericidal antibody responses in mice. The amount of overexpressed fHbp required for optimal immunogenicity is not known. In this study we prepared NOMV vaccines from LpxL1 knockout (⌬LpxL1) mutants with penta-acylated lipooligosaccharide and attenuated endotoxin activity. The recombinant strains had wild-type (1؋) fHbp expression or were engineered for 3-fold-or 10-fold-increased fHbp expression (3؋ or 10؋ fHbp). Control vaccines included NOMV from ⌬LpxL1/⌬fHbp mutants or recombinant fHbp. In mice, only the 10؋ fHbp NOMV vaccine elicited significantly higher serum IgG anti-fHbp antibody titers than the corresponding 1؋ fHbp NOMV or recombinant fHbp vaccine. The 10؋ fHbp NOMV vaccine also elicited higher bactericidal responses (P < 0.05) against five group B strains with heterologous PorA than the recombinant fHbp or 1؋ fHbp NOMV vaccine. The 3؋ fHbp NOMV vaccine gave higher bactericidal titers against only one strain. Serum bactericidal titers in mice immunized with the control ⌬fHbp NOMV vaccines were <1:10, and bactericidal titers in mice immunized with the 10؋ fHbp NOMV vaccine were <1:10 after adsorption of anti-fHbp antibodies. Mixing antiserum to NOMV vaccines from fHbp knockout mutants with antiserum to recombinant fHbp did not increase anti-fHbp bactericidal titers. Thus, a critical threshold of increased fHbp expression is required for NOMV vaccines to elicit broad serum bactericidal responses, and the antibodies conferring protection are directed primarily at fHbp.

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Section: Resultsmentioning

confidence: 89%

A Critical Threshold of Meningococcal Factor H Binding Protein Expression Is Required for Increased Breadth of Protective Antibodies Elicited by Native Outer Membrane Vesicle Vaccines

Koeberling

Delany

Granoff³

2011

Clin. Vaccine Immunol.

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“…Note that in our previous study, the binding of anti-fHbp MAbs to the bacterial surface was saturated through a wide range of MAb concentrations (29). Further, binding by an individual MAb did not result in sufficient immune complex to engage C1q and activate classical complement pathway bactericidal activity (18,30). However, if the amount of immune complex was increased on the bacterial surface by the binding of two anti-fHbp MAbs, or by binding by an individual antifHbp to a mutant strain of a strain that naturally expresses a low level of fHbp that was engineered to have increased expression of fHbp, there was an activation of the classical complement pathway and bacteriolysis (28).…”

Section: Discussionmentioning

confidence: 99%

Fine Antigenic Specificity and Cooperative Bactericidal Activity of Monoclonal Antibodies Directed at the Meningococcal Vaccine Candidate Factor H-Binding Protein

Beernink¹,

Welsch²,

Bar-Lev³

et al. 2008

Infect Immun

168

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“…If antibodies of two different specificities are involved, the removal of either of these antibody specificities could potentially result in loss of bactericidal activity. The cooperative (even synergistic) action of antibodies to two different OMPs has been reported (57). Certainly, LPS is often closely associated with outer membrane proteins, so it would not be hard to imagine cooperation in killing between bactericidal antibodies specific for LPS and OMPs.…”

Section: Discussionmentioning

confidence: 99%

Importance of Antibodies to Lipopolysaccharide in Natural and Vaccine-Induced Serum Bactericidal Activity against Neisseria meningitidis Group B

et al. 2011

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Analysis of the specificity of bactericidal antibodies in normal, convalescent, and postvaccination human sera is important in understanding human immunity to meningococcal infections and can aid in the design of an effective group B vaccine. A collection of human sera, including group C and group B convalescent-phase sera, normal sera with naturally occurring cross-reactive bactericidal activity, and some postvaccination sera, was analyzed to determine the specificity of cross-reactive bactericidal antibodies. Analysis of human sera using a bactericidal antibody depletion assay demonstrated that a significant portion of the bactericidal activity could be removed by purified lipopolysaccharide (LPS). LPS homologous to that expressed on the bactericidal test strain was most effective, but partial depletion by heterologous LPS suggested the presence of antibodies with various degrees of cross-reactivity. Binding of anti-L3,7 LPS bactericidal antibodies was affected by modification of the core structure, suggesting that these functional antibodies recognized epitopes consisting of both core structures and lacto-N-neotetraose (LNnT). When the target strain was grown with 5-cytidinemonophospho-N-acetylneuraminic acid (CMP-NANA) to increase LPS sialylation, convalescentphase serum bactericidal titers were decreased by only 2-to 4-fold, and most remaining bactericidal activity was still depleted by LPS. Highly sialylated LPS was ineffective in depleting bactericidal antibodies. We conclude that natural infections caused by strains expressing L3,7 LPS induce persistent, protective bactericidal antibodies and appear to be directed against nonsialylated bacterial epitopes. Additionally, subsets of these bactericidal antibodies are cross-reactive, binding to several different LPS immunotypes, which is a useful characteristic for an effective group B meningococcal vaccine antigen.

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Additive and Synergistic Bactericidal Activity of Antibodies Directed against Minor Outer Membrane Proteins of Neisseria meningitidis

Cited by 87 publications

References 47 publications

A Critical Threshold of Meningococcal Factor H Binding Protein Expression Is Required for Increased Breadth of Protective Antibodies Elicited by Native Outer Membrane Vesicle Vaccines

A Critical Threshold of Meningococcal Factor H Binding Protein Expression Is Required for Increased Breadth of Protective Antibodies Elicited by Native Outer Membrane Vesicle Vaccines

Fine Antigenic Specificity and Cooperative Bactericidal Activity of Monoclonal Antibodies Directed at the Meningococcal Vaccine Candidate Factor H-Binding Protein

Importance of Antibodies to Lipopolysaccharide in Natural and Vaccine-Induced Serum Bactericidal Activity against Neisseria meningitidis Group B

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