Structure-Based Design of Head-Only Fusion Glycoprotein Immunogens for Respiratory Syncytial Virus

Boyington, Jeffrey C.; Joyce, M. Gordon; Sastry, Mallika; Stewart-Jones, Guillaume B. E.; Chen, Man; Kong, Wing-Pui; Ngwuta, Joan O.; Thomas, Paul V.; Tsybovsky, Yaroslav; Yang, Yongping; Zhang, Baoshan; Chen, Lei; Druz, Aliaksandr; Georgiev, Ivelin S.; Ko, Kiyoon; Zhou, Tongqing; Mascola, John R.; Graham, Barney S.; Kwong, Peter D.

We assessed these size-exclusion purified immunogens by biolayer interferometry for recognition by site Ø-directed antibodies D25 and AM22 as well as by the site II-directed antibody motavizumab. D25 and AM22 recognized all four immunogens with nanomolar affinity, though i-273 monomer and i-693 dimer displayed slightly lower affinity than the trimeric immunogens i-210 and i-447 ( S3 Fig and Table 1 ). Although the antigenic site II-directed antibody motavizumab recognized both the i-447 trimer and the i-693 dimer with nanomolar affinity, the i-273 monomer and i-210 trimer each displayed only micromolar affinity. This was unsurprising as both i-273 and i-210 contained a L258K surface mutation in the middle of Head-Only RSV F Immunogens the motavizumab epitope and the immunogen with the lowest motavizumab affinity, i-273, had an additional epitope mutation of L273K (S2 Fig). Moreover, the four top scoring designs were chosen because of their recognition by site Ø-directed antibodies, with no consideration given to their recognition by site II-directed antibodies.