Staphylococcus aureus is a commensal of the human skin and nares, and a major cause of skin, and soft tissue as well as invasive infections. Bacterial pathogenicity results from a complex interplay of virulence factors with regulatory systems that respond to multiple external signals from the host environment and the bacterial population. Currently no vaccine against S. aureus is available. Novartis Vaccines and Diagnostics (NVD) has employed the reverse vaccinology approach to identify a list of novel antigens which are now under further analysis for inclusion in a vaccine. RESTAVAC will investigate the regulatory mechanisms involved in controlling expression of these vaccine antigen candidates. By analysing the temporal expression of novel antigens and characterised reference virulence factors, through reporter fusions, in various in vitro, ex vivo and animal models, RESTAVAC will uncover regulatory responses to environmental stimuli, diverse niches or disease settings as well as the molecular mechanisms involved in their fine-tuning. This will aid in predicting the efficacy of the candidate proteins as vaccine antigens and contribute to understanding their roles in the pathogenesis of the bacterium. Secondly, analysis of global gene expression profiles in ex vivo and animal models will greatly assist in identifying critical genes important for the different disease outcomes and the regulatory networks that may be involved. Such analysis will help to unravel the complex interactions between S. aureus and its host environmental niches during disease development. And thirdly, comparative analysis of reporter gene expression in both HA- and CA- isolates from geographic, temporal and sequence-type diverse origins along with genome-wide expression profiling will shed light on fundamental differences of this emerging group of pathogens as well as understanding the patterns of gene expression of the vaccine antigen genes across diverse staphylococcal disease isolates.