How Computational and Structural Biology Are Changing Vaccine Design

Structural biology and next-generation sequencing are two of the most data-rich areas in biology, with structure and sequence data bases expanding exponentially. Can this remarkable expansion be harnessed for vaccine design?  At the Vaccine Research Center, NIAID/NIH and in close collaboration with CHAVI and IAVI investigators, we have been attempting to apply the atomic-level tools of structural biology and the bioinformatics tools of next-generation sequencing to the design of effective vaccines against HIV-1 and other human pathogens, against which traditional vaccinology has failed. We recently developed a four step paradigm involving (i) identification of effective neutralizing antibody response to natural infection by a pathogen, (ii) determination of the atomic-level structure of an antibody in complex with a pathogen site of vulnerability, (iii) engineering of the stable presentation of the pathogen site of vulnerability in the absence of antibody, and (iv) optimization of the elicited neutralizing response by the stabilized immunogen. Implementation of this paradigm against respiratory syncytial virus, a major childhood pathogen, induced the elicitation of highly effective RSV-neutralizing antibodies in macaques. We are now working to implement this paradigm against HIV-1, which – in additional to conformational stabilization – may require B cell ontogeny-specific design. Progress on both RSV and HIV-1 vaccine design will be discussed.