Iterative structure-based improvement of a respiratory syncytial virus fusion glycoprotein vaccine

Structure-based design of vaccines has been a long-sought goal, especially the iterative optimization used so successfully with structure-based design of drugs. We previously developed a 1st-generation vaccine antigen called DS-Cav1, comprising a pre-fusion-stabilized form of the fusion (F) glycoprotein, which elicited high titers of protective responses against respiratory syncytial virus (RSV) in mice and macaques. Here we report the improvement of DS-Cav1 through iterative cycles of structure-based design that significantly increased the titer of RSV-protective responses. The resultant 2nd-generation “DS2”-stabilized immunogens have F subunits genetically linked, fusion peptide deleted, and interprotomer movements stabilized by an additional disulfide bond. These DS2-immunogens are promising vaccine candidates with superior attributes, such as the absence of a requirement for furin cleavage and increased antigenic stability to heat inactivation. The iterative structure-based improvement described here may have utility in the optimization of other vaccine antigens.