Structural Biology in Vaccine Research
Danilo Donnarumma, Matthew J. Bottomley, Enrico Malito, Ethan Settembre, Ilaria Ferlenghi and Roberta Cozzi
from: Advanced Vaccine Research Methods for the Decade of Vaccines (Edited by: Fabio Bagnoli and Rino Rappuoli). Caister Academic Press, U.K. (2015) Pages: 103-132.
The emerging strategy for next-generation vaccine development is the structure-based antigen design approach. To enhance vaccine efficacy the atomic-resolution structural approach, able to generate information on the overall antigen structure, becomes the driving force in the production of engineered antigens with improved immunological properties and biophysical attributes that facilitate manufacturing. The first and most important step of the structure-based approach is the definition of the regions of an antigen that are bound by protective antibodies: the epitopes, core elements in the molecular nature of the host-pathogen interaction. The definition of naturally-occurring epitopes (also called ‘epitope mapping') provides insight into the molecular features recognized by the host immune response upon infection by the pathogen. Information available about such interactions can help in the selection and in the rational-design of an antigen that elicits the desired neutralizing or bactericidal response upon immunization. Moreover, epitope-mapping data defines which parts of an antigen are exposed and accessible on the surface of the pathogen, and thus provides insights into the functional regions of the protein. Going beyond vaccine research, epitope mapping has several applications in development of disease diagnostics and immune-therapeutics. Many different epitope mapping studies have been performed in the last 3 decades, generating a wealth of information that has been analyzed and interpreted in many ways. Although these data are beginning to provide clues about the common themes of antigen-antibody interactions, most recently analyzed via computational studies, an empirical approach is still essential in order to generate reliable information about any specific antibody-antigen interaction. Herein we review different strategies to identify and characterize protective epitopes, from the simplest epitope mapping approach, such as the synthetic library approach, through to well-established approaches like X-ray crystallography, NMR and negative stain single-particle electron microscopy. We also discuss the emerging applications of mass spectrometry and finally the computational prediction of epitopes. We highlight several examples revealing how the combination of epitope mapping and structural biology has already enabled improved antigen design and discuss how such structure-guided antigen design approaches may evolve further in the future read more ...