Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV.
Publication/Presentation Date
9-1-2016
Abstract
Structure-based design of vaccines, particularly the iterative optimization used so successfully in the structure-based design of drugs, has been a long-sought goal. We previously developed a first-generation vaccine antigen called DS-Cav1, comprising a prefusion-stabilized form of the fusion (F) glycoprotein, which elicits high-titer 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 second-generation 'DS2'-stabilized immunogens have their F subunits genetically linked, their fusion peptides deleted and their interprotomer movements stabilized by an additional disulfide bond. These DS2 immunogens are promising vaccine candidates with superior attributes, such as their lack of a requirement for furin cleavage and their increased antigenic stability against heat inactivation. The iterative structure-based improvement described here may have utility in the optimization of other vaccine antigens.
Volume
23
Issue
9
First Page
811
Last Page
820
ISSN
1545-9985
Published In/Presented At
Joyce, M. G., Zhang, B., Ou, L., Chen, M., Chuang, G. Y., Druz, A., Kong, W. P., Lai, Y. T., Rundlet, E. J., Tsybovsky, Y., Yang, Y., Georgiev, I. S., Guttman, M., Lees, C. R., Pancera, M., Sastry, M., Soto, C., Stewart-Jones, G. B. E., Thomas, P. V., Van Galen, J. G., … Kwong, P. D. (2016). Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV. Nature structural & molecular biology, 23(9), 811–820. https://doi.org/10.1038/nsmb.3267
Disciplines
Medicine and Health Sciences
PubMedID
27478931
Department(s)
Department of Medicine
Document Type
Article