Reverse vaccinology 2.0: Human immunology instructs vaccine antigen design

Rappuoli, Rino; Bottomley, Matthew J.; D’Oro, Ugo; Finco, Oretta; De Gregorio, Ennio

Recent technological advances in human immunology and structural biology have provided new reagents and improved tools that allow a better understanding of the basic biological and molecular mechanisms leading to a protective human immune response to pathogens, inspiring new strategies for vaccine design. For some of these approaches (e.g., stabilization of RSV prefusion F antigen and discovery of the HCMV pentamer complex), a solid preclinical proof of principle has been obtained supporting a clinical development. However, additional preclinical work is still required to demonstrate the validity of other rationally designed vaccines (e.g., universal flu or HIV germlinetargeting antigens). Nevertheless, further investigations of the basic mechanisms regulating the human immune response to pathogens will continue to facilitate the design of new and more efficacious vaccines against infectious diseases. The combined application of the described new tools in human immunology and structural biology with microbial genomics will establish a new multidisciplinary approach to vaccine antigen discovery and design that may be termed reverse vaccinology 2.0.