title: Vaccine composition formulated with a novel TLR7-dependent adjuvant induces high and broad protection against Staphylococcus aureus.
abstract: Both active and passive immunization strategies against Staphylococcus aureus have thus far failed to show efficacy in humans. With the attempt to develop an effective S. aureus vaccine, we selected five conserved antigens known to have different roles in S. aureus pathogenesis. They include the secreted factors α-hemolysin (Hla), ess extracellular A (EsxA), and ess extracellular B (EsxB) and the two surface proteins ferric hydroxamate uptake D2 and conserved staphylococcal antigen 1A. The combined vaccine antigens formulated with aluminum hydroxide induced antibodies with opsonophagocytic and functional activities and provided consistent protection in four mouse models when challenged with a panel of epidemiologically relevant S. aureus strains. The importance of antibodies in protection was demonstrated by passive transfer experiments. Furthermore, when formulated with a toll-like receptor 7-dependent (TLR7) agonist recently designed and developed in our laboratories (SMIP.7-10) adsorbed to alum, the five antigens provided close to 100% protection against four different staphylococcal strains. The new formulation induced not only high antibody titers but also a Th1 skewed immune response as judged by antibody isotype and cytokine profiles. In addition, low frequencies of IL-17-secreting T cells were also observed. Altogether, our data demonstrate that the rational selection of mixtures of conserved antigens combined with Th1/Th17 adjuvants can lead to promising vaccine formulations against S. aureus.
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Fabio
authors.initials: F
authors.lastname: Bagnoli
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Fontana
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Soldaini
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Ravi P N
authors.initials: RP
authors.lastname: Mishra
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Luigi
authors.initials: L
authors.lastname: Fiaschi
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: Cartocci
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nardi-Dei
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: Ruggiero
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Sarah
authors.initials: S
authors.lastname: Nosari
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: De Falco
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lofano
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Sara
authors.initials: S
authors.lastname: Marchi
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Bruno
authors.initials: B
authors.lastname: Galletti
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: Mariotti
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Marta
authors.initials: M
authors.lastname: Bacconi
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Antonina
authors.initials: A
authors.lastname: Torre
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Maccari
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Maria
authors.initials: M
authors.lastname: Scarselli
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: C Daniela
authors.initials: CD
authors.lastname: Rinaudo
authors.affiliation: Departments of Pediatrics and Microbiology, University of Chicago, Chicago, IL 60637; and.
authors.forename: Naoko
authors.initials: N
authors.lastname: Inoshima
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Silvana
authors.initials: S
authors.lastname: Savino
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: Mori
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi-Paccani
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Barbara
authors.initials: B
authors.lastname: Baudner
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Michele
authors.initials: M
authors.lastname: Pallaoro
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Erwin
authors.initials: E
authors.lastname: Swennen
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Roberto
authors.initials: R
authors.lastname: Petracca
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Cecilia
authors.initials: C
authors.lastname: Brettoni
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Sabrina
authors.initials: S
authors.lastname: Liberatori
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Norais
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Monaci
authors.affiliation: Departments of Pediatrics and Microbiology, University of Chicago, Chicago, IL 60637; and.
authors.forename: Juliane
authors.initials: J
authors.lastname: Bubeck Wardenburg
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL 60637.
authors.forename: Olaf
authors.initials: O
authors.lastname: Schneewind
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Derek T
authors.initials: DT
authors.lastname: O'Hagan
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Valiante
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Giuliano
authors.initials: G
authors.lastname: Bensi
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bertholet
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy;
authors.forename: Ennio
authors.initials: E
authors.lastname: De Gregorio
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy; rino.rappuoli@novartis.com grandiguido9@gmail.com.
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.affiliation: Novartis Vaccines Research Center, 53100 Siena, Italy; rino.rappuoli@novartis.com grandiguido9@gmail.com.
authors.forename: Guido
authors.initials: G
authors.lastname: Grandi
mesh_terms: D000038:Abscess / Q000473:pathology; D056704:Adaptive Immunity; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry; D000907:Antibodies, Bacterial / Q000276:immunology; D000941:Antigens / Q000276:immunology; D006801:Humans; D051379:Mice; D023421:Models, Animal; D013203:Staphylococcal Infections / Q000276:immunology / Q000517:prevention & control*; D013209:Staphylococcal Vaccines / Q000737:chemistry*; D013211:Staphylococcus aureus; D018417:Th1 Cells / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000737:chemistry*
chemical_list: D000276:Adjuvants, Immunologic; D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D000941:Antigens; D013209:Staphylococcal Vaccines; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7
keywords: Hla; Staphylococcus aureus; TLR7; adjuvant; vaccine