The global incidence and rise of severe S. aureus infections accompanied by an alarming increase in antibiotic resistance warrants the development of novel treatment and vaccination strategies. This proposal combines the expertise of Dr. Nina van Sorge (Fellow) from the United States and the Prof. Jos van Strijp lab at the University Medical Center Utrecht in the Netherlands (Host institute). The Van Strijp lab is world leading in the identification and characterization of many secreted immune evasion molecules in S. aureus that prevent clearance of the bacterium even in the presence of vaccine induced opsonic antibodies. In other words, immune evasion molecules are vaccine evasion molecules. Dr. Van Sorge has unique expertise and knowledge on high-throughput assays, transposon library screening, whole bacterium assays and in vivo models relevant to the battle with S. aureus. Van Sorge in collaboration with the Van Strijp lab proposes a novel approach to identify suitable vaccine candidates by screening for surface-exposed S. aureus immune evasion molecules. The vaccine-induced antibodies directed against these proteins act as a double edged sword: they block the immune evasive properties of the bacterium by “inhibiting the inhibitor” and facilitate bacterial clearance through efficient opsonization and phagocytosis. The proposed research represents the first comprehensive study to identify S. aureus surface proteins with immune evasive properties, elucidate their mechanism of action and role in disease pathogenesis and evaluate them in a combination vaccine. The project at hand concerns a highly synergistic approach by which unique expertise, tools and knowledge becomes available to the European community.