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Infection and Immunity, September 2008, p. 4232-4240, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.00367-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Peter T. Beernink,1 Jo Anne Welsch,1 Michal Bar-Lev,1 Oliver Koeberling,1 Maurizio Comanducci,2 and Dan M. Granoff1*

Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California,1 Novartis Vaccines, Siena, Italy2

Received 21 March 2008/ Returned for modification 19 May 2008/ Accepted 19 June 2008

No broadly protective vaccine is available for the prevention of group B meningococcal disease. One promising candidate is factor H-binding protein (fHbp), which is present in all strains but often sparsely expressed. We prepared seven murine immunoglobulin G monoclonal antibodies (MAbs) against fHbp from antigenic variant group 2 (v.2) or v.3 (~40% of group B strains). Although none of the MAbs individually elicited bactericidal activity with human complement, all had activity in different combinations. We used MAb reactivity with strains expressing fHbp polymorphisms and site-specific mutagenesis to identify residues that are important for epitopes recognized by six of the v.2 or v.3 MAbs and by two v.1 MAbs that were previously characterized. Residues affecting v.2 or v.3 epitopes resided between amino acids 174 and 216, which formed an eight-stranded beta-barrel in the C domain, while residues affecting the v.1 epitopes included amino acids 121 and 122 of the B domain. Pairs of MAbs were bactericidal when their respective epitopes involved residues separated by 16 to 20 Å and when at least one of the MAbs inhibited the binding of fH, a downregulatory complement protein. In contrast, there was no cooperative bactericidal activity when the distance between residues was ≥27 Å or ≤14 Å, which correlated with the inhibition of the binding of one MAb by the other MAb. Thus, a model for anti-fH MAb bactericidal activity against strains expressing low levels of fHbp requires the binding of two MAbs directed at nonoverlapping epitopes, which activates the classical complement pathway as well as inhibits fH binding. The latter increases the susceptibility of the organism to complement-mediated bacteriolysis.

* Corresponding author. Mailing address: 5700 Martin Luther King Jr. Way, Oakland, CA 94609. Phone: (510) 450-7640. Fax: (510) 450-7915. E-mail: dgranoff{at}chori.org

{triangledown} Published ahead of print on 30 June 2008.

Editor: J. N. Weiser

Infection and Immunity, September 2008, p. 4232-4240, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.00367-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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  • Koeberling, O., Giuntini, S., Seubert, A., Granoff, D. M. (2009). Meningococcal Outer Membrane Vesicle Vaccines Derived from Mutant Strains Engineered To Express Factor H Binding Proteins from Antigenic Variant Groups 1 and 2. CVI 16: 156-162 [Abstract] [Full Text]  
  • Seib, K. L., Serruto, D., Oriente, F., Delany, I., Adu-Bobie, J., Veggi, D., Arico, B., Rappuoli, R., Pizza, M. (2009). Factor H-Binding Protein Is Important for Meningococcal Survival in Human Whole Blood and Serum and in the Presence of the Antimicrobial Peptide LL-37. Infect. Immun. 77: 292-299 [Abstract] [Full Text]  


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