title: Rational design of a meningococcal antigen inducing broad protective immunity.
abstract: The sequence variability of protective antigens is a major challenge to the development of vaccines. For Neisseria meningitidis, the bacterial pathogen that causes meningitis, the amino acid sequence of the protective antigen factor H binding protein (fHBP) has more than 300 variations. These sequence differences can be classified into three distinct groups of antigenic variants that do not induce cross-protective immunity. Our goal was to generate a single antigen that would induce immunity against all known sequence variants of N. meningitidis. To achieve this, we rationally designed, expressed, and purified 54 different mutants of fHBP and tested them in mice for the induction of protective immunity. We identified and determined the crystal structure of a lead chimeric antigen that was able to induce high levels of cross-protective antibodies in mice against all variant strains tested. The new fHBP antigen had a conserved backbone that carried an engineered surface containing specificities for all three variant groups. We demonstrate that the structure-based design of multiple immunodominant antigenic surfaces on a single protein scaffold is possible and represents an effective way to create broadly protective vaccines.
authors.affiliation: Novartis Vaccines and Diagnostics S.r.l., Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Scarselli
authors.forename: Beatrice
authors.initials: B
authors.lastname: Aricò
authors.forename: Brunella
authors.initials: B
authors.lastname: Brunelli
authors.forename: Silvana
authors.initials: S
authors.lastname: Savino
authors.forename: Federica
authors.initials: F
authors.lastname: Di Marcello
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Palumbo
authors.forename: Daniele
authors.initials: D
authors.lastname: Veggi
authors.forename: Laura
authors.initials: L
authors.lastname: Ciucchi
authors.forename: Elena
authors.initials: E
authors.lastname: Cartocci
authors.forename: Matthew James
authors.initials: MJ
authors.lastname: Bottomley
authors.forename: Enrico
authors.initials: E
authors.lastname: Malito
authors.forename: Paola
authors.initials: P
authors.lastname: Lo Surdo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Comanducci
authors.forename: Marzia Monica
authors.initials: MM
authors.lastname: Giuliani
authors.forename: Francesca
authors.initials: F
authors.lastname: Cantini
authors.forename: Sara
authors.initials: S
authors.lastname: Dragonetti
authors.forename: Annalisa
authors.initials: A
authors.lastname: Colaprico
authors.forename: Francesco
authors.initials: F
authors.lastname: Doro
authors.forename: Patrizia
authors.initials: P
authors.lastname: Giannetti
authors.forename: Michele
authors.initials: M
authors.lastname: Pallaoro
authors.forename: Barbara
authors.initials: B
authors.lastname: Brogioni
authors.forename: Marta
authors.initials: M
authors.lastname: Tontini
authors.forename: Markus
authors.initials: M
authors.lastname: Hilleringmann
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nardi-Dei
authors.forename: Lucia
authors.initials: L
authors.lastname: Banci
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Pizza
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000737:chemistry / Q000276:immunology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000276:immunology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007109:Immunity / Q000187:drug effects / Q000276:immunology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000276:immunology; D009154:Mutation / Q000235:genetics; D009345:Neisseria meningitidis / Q000187:drug effects / Q000276:immunology*; D015202:Protein Engineering; D017433:Protein Structure, Secondary
chemical_list: D000900:Anti-Bacterial Agents; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D050505:Mutant Proteins; C484699:factor H-binding protein, Neisseria meningitidis