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Vaccine composition formulated with a novel TLR7-dependent adjuvant induces high and broad protection against Staphylococcus aureus

2015; National Academy of Sciences; Volume: 112; Issue: 12 Linguagem: Inglês

10.1073/pnas.1424924112

1091-6490

Fábio Bagnoli, Maria Rita Fontana, Elisabetta Soldaini, Ravi P.N. Mishra, Luigi Fiaschi, Elena Cartocci, Vincenzo Nardi‐Dei, Paolo Ruggiero, Sarah Nosari, Maria Grazia De Falco, Giuseppe Lofano, Sara Marchi, Bruno Galletti, Paolo Mariotti, Marta Bacconi, Antonina Torre, Silvia Maccari, Maria Scarselli, C. Daniela Rinaudo, Naoko Inoshima, Silvana Savino, Elena Mori, Silvia Rossi-Paccani, Barbara C. Baudner, Michele Pallaoro, Erwin Swennen, Roberto Petracca, Cecilia Brettoni, Sabrina Liberatori, Nathalie Norais, Elisabetta Monaci, Juliane Bubeck Wardenburg, Olaf Schneewind, Derek T. O’Hagan, Nicholas M. Valiante, Giuliano Bensi, Sylvie Bertholet, Ennio De Gregorio, Rino Rappuoli, Guido Grandi,

Antimicrobial Peptides and Activities

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.