New generation vaccines are in demand to include only the key antigens 
sufficient to confer protective immunity among the plethora of pathogen 
molecules. In the last decade, large-scale genomics-based technologies have 
emerged. Among them, the Reverse Vaccinology approach was successfully applied 
to the development of an innovative vaccine against Neisseria meningitidis 
serogroup B, now available on the market with the commercial name BEXSERO® 
(Novartis Vaccines). The limiting step of such approaches is the number of 
antigens to be tested in in vivo models. Several laboratories have been trying 
to refine the original approach in order to get to the identification of the 
relevant antigens straight from the genome. Here we report a new bioinformatics 
tool that moves a first step in this direction. The tool has been developed by 
identifying structural/functional features recurring in known bacterial 
protective antigens, the so called "Protectome space," and using such 
"protective signatures" for protective antigen discovery. In particular, we 
applied this new approach to Staphylococcus aureus and Group B Streptococcus and 
we show that not only already known protective antigens were re-discovered, but 
also two new protective antigens were identified.