期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：12
页码：3680-3685
DOI：10.1073/pnas.1424924112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceStaphylococcus aureus is a human pathogen causing life-threatening infections. The high incidence of methicillin-resistant S. aureus isolates resistant to all antibiotics makes the development of anti-S. aureus vaccines an urgent medical need. However, the unique ability of S. aureus to produce virulent factors, which counteract virtually all pathways of innate and adaptive immunity, has hampered all vaccine discovery efforts. Starting from the assumption that to be effective a vaccine should induce highly functional antibodies and potentiate the killing capacity of phagocytic cells, we selected a cocktail of five conserved antigens involved in different mechanisms of pathogenesis, and we formulated them with a potent adjuvant. This vaccine provides an unprecedented protective efficacy against S. aureus infection in animal models. 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 -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.
