title: One Dose of Staphylococcus aureus 4C-Staph Vaccine Formulated with a Novel TLR7-Dependent Adjuvant Rapidly Protects Mice through Antibodies, Effector CD4+ T Cells, and IL-17A.
abstract: A rapidly acting, single dose vaccine against Staphylococcus aureus would be highly beneficial for patients scheduled for major surgeries or in intensive care units. Here we show that one immunization with a multicomponent S. aureus candidate vaccine, 4C-Staph, formulated with a novel TLR7-dependent adjuvant, T7-alum, readily protected mice from death and from bacterial dissemination, both in kidney abscess and peritonitis models, outperforming alum-formulated vaccine. This increased efficacy was paralleled by higher vaccine-specific and α-hemolysin-neutralizing antibody titers and Th1/Th17 cell responses. Antibodies played a crucial protective role, as shown by the lack of protection of 4C-Staph/T7-alum vaccine in B-cell-deficient mice and by serum transfer experiments. Depletion of effector CD4+ T cells not only reduced survival but also increased S. aureus load in kidneys of mice immunized with 4C-Staph/T7-alum. The role of IL-17A in the control of bacterial dissemination in 4C-Staph/T7-alum vaccinated mice was indicated by in vivo neutralization experiments. We conclude that single dose 4C-Staph/T7-alum vaccine promptly and efficiently protected mice against S. aureus through the combined actions of antibodies, CD4+ effector T cells, and IL-17A. These data suggest that inclusion of an adjuvant that induces not only fast antibody responses but also IL-17-producing cell-mediated effector responses could efficaciously protect patients scheduled for major surgeries or in intensive care units.
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.|Department of Biomedical Sciences, University of Padua, Padua, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mancini
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Monaci
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.|Department of Biology and Biotechnologies "Charles Darwin", University of Rome "La Sapienza", Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lofano
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Antonina
authors.initials: A
authors.lastname: Torre
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.|Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Bacconi
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Tavarini
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Sammicheli
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Arcidiacono
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Galletti
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Donatello
authors.initials: D
authors.lastname: Laera
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Pallaoro
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tuscano
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Fontana
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Bensi
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Grandi
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi-Paccani
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Nuti
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Ennio
authors.initials: E
authors.lastname: De Gregorio
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Bagnoli
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Soldaini
authors.affiliation: Novartis Vaccines and Diagnostics, S.r.l., Research Center, Siena, Italy.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bertholet
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013203:Staphylococcal Infections / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D013209:Staphylococcal Vaccines / Q000276:immunology*; D013211:Staphylococcus aureus / Q000235:genetics / Q000276:immunology*; D015996:Survival Rate; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000276:immunology / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D057134:Antibodies, Neutralizing; D016207:Cytokines; C098680:Il17a protein, mouse; D020381:Interleukin-17; D013209:Staphylococcal Vaccines; D051199:Toll-Like Receptor 7
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