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Clinical and Vaccine Immunology, February 2009, p. 156-162, Vol. 16, No. 2
1071-412X/09/$08.00+0     doi:10.1128/CVI.00403-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Meningococcal Outer Membrane Vesicle Vaccines Derived from Mutant Strains Engineered To Express Factor H Binding Proteins from Antigenic Variant Groups 1 and 2{triangledown}

Oliver Koeberling,1 Serena Giuntini,1 Anja Seubert,1 and Dan M. Granoff2*

Novartis Vaccines, Siena, Italy,1 Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California 946092

Received 6 November 2008/ Returned for modification 8 December 2008/ Accepted 16 December 2008

Meningococcal outer membrane vesicle (OMV) vaccines, which are treated with detergents to decrease endotoxin activity, are safe and effective in humans. However, the vaccines elicit serum bactericidal antibody responses largely directed against PorA, which is antigenically variable. We previously prepared a native (non-detergent-treated) OMV vaccine from a mutant of group B strain H44/76 in which the lpxL1 gene was inactivated, which resulted in penta-acylated lipid A with attenuated endotoxin activity. To enhance protection, we overexpressed factor H binding protein (fHbp) from the antigenic variant 1 group. The vaccine elicited broad serum bactericidal antibody responses in mice against strains with fHbp variant 1 (~70% of group B isolates) but not against strains with variant 2 or 3. In the present study, we constructed a mutant of group B strain NZ98/254 with attenuated endotoxin that expressed both endogenous variant 1 and heterologous fHbp variant 2. A mixture of the two native OMV vaccines from the H44/76 and NZ98/254 mutants stimulated proinflammatory cytokine responses by human peripheral blood mononuclear cells similar to those stimulated by control, detergent-treated OMV vaccines from the wild-type strains. In mice, the mixture of the two native OMV vaccines elicited broad serum bactericidal antibody responses against strains with heterologous PorA and fHbp in the variant 1, 2, or 3 group. By adsorption studies, the principal bactericidal antibody target was determined to be fHbp. Thus, native OMV vaccines from mutants expressing fHbp variants have the potential to be safe for humans and to confer broad protection against meningococcal disease from strains expressing fHbp from each of the antigenic variant groups.

* Corresponding author. Mailing address: Children's Hospital Oakland Research Institute, 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 24 December 2008.

Clinical and Vaccine Immunology, February 2009, p. 156-162, Vol. 16, No. 2
1071-412X/09/$08.00+0     doi:10.1128/CVI.00403-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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