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.

The design of even smaller RSV F head-derived immunogens with less extraneous non-neutralizing epitopes could potentially focus the RSV F immune response still further. However, such immunogen designs could be complicated if both non-proximal antigenic sites Ø and II were retained or if increased T cell help from the addition of universal T cell epitope peptides [58, 59] is required for the smallest immunogens. Although we did not observe a consistent correlation between oligomer size (i.e. monomer, dimer and trimer) and neutralization titers or immune focusing, increasing the immunogen oligomerization state in an ordered manner might also be expected to improve immune focusing since it would provide more opportunities for irrelevant epitopes to be masked by neighbor-neighbor interactions and the additional multivalency of the target epitope could lead to increased B cell avidity through antibody crosslinking, resulting in increased immunogenicity for the epitope [41, 60] . Therefore, additional multimerization by incorporation into nanoparticles [53, 61] might further improve both immune focusing and overall immunogenicity of the head-only RSV F immunogens.