RT Journal Article SR Electronic T1 Rational Design of a Meningococcal Antigen Inducing Broad Protective Immunity JF Science Translational Medicine FD American Association for the Advancement of Science SP 91ra62 OP 91ra62 DO 10.1126/scitranslmed.3002234 VO 3 IS 91 A1 Scarselli, Maria A1 Aricò, Beatrice A1 Brunelli, Brunella A1 Savino, Silvana A1 Di Marcello, Federica A1 Palumbo, Emmanuelle A1 Veggi, Daniele A1 Ciucchi, Laura A1 Cartocci, Elena A1 Bottomley, Matthew James A1 Malito, Enrico A1 Lo Surdo, Paola A1 Comanducci, Maurizio A1 Giuliani, Marzia Monica A1 Cantini, Francesca A1 Dragonetti, Sara A1 Colaprico, Annalisa A1 Doro, Francesco A1 Giannetti, Patrizia A1 Pallaoro, Michele A1 Brogioni, Barbara A1 Tontini, Marta A1 Hilleringmann, Markus A1 Nardi-Dei, Vincenzo A1 Banci, Lucia A1 Pizza, Mariagrazia A1 Rappuoli, Rino YR 2011 UL http://stm.sciencemag.org/content/3/91/91ra62.abstract AB 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.