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Collectively, malaria, TB & HIV/AIDS cause more than five million deaths per year - nearly the entire population of the state of Washington - and represent one of the world's major public health challenges as we move into the second decade of the 21st century. In the May 26, 2011, edition of scientific journal Nature, Seattle BioMed Director Alan Aderem, Ph.D., along with Rino Rappuoli, Ph.D., Global Head of Vaccines Research for Novartis Vaccines & Diagnostics, discuss recent advances in vaccine development, along with new tools including systems biology and structure-based antigen design that could lead to a deeper understanding of mechanisms of protection. This, in turn, will illuminate the path to rational vaccine development to lift the burden of the world's most devastating infectious diseases.