Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV.

Joyce MG, Zhang B, Ou L, Chen M, Chuang GY, Druz A, Kong WP, Lai YT, Rundlet EJ, Tsybovsky Y, Yang Y, Georgiev IS, Guttman M, Lees CR, Pancera M, Sastry M, Soto C, Stewart-Jones GBE, Thomas PV, Van Galen JG, Baxa U, Lee KK, Mascola JR, Graham BS, Kwong PD
Nat Struct Mol Biol. 2016 23 (9): 811-820

PMID: 27478931 · PMCID: PMC5016229 · DOI:10.1038/nsmb.3267

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.

MeSH Terms (16)

Animals Crystallography, X-Ray Female Glycoproteins HEK293 Cells Humans Male Mice, Inbred C57BL Models, Molecular Protein Engineering Protein Stability Respiratory Syncytial Viruses Respiratory Syncytial Virus Infections Vaccination Viral Fusion Proteins Viral Vaccines

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