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.

Among several antigenic sites on RSV F associated with neutralizing activity [7] [8] [9] [10] [11] [12] , antigenic site Ø, located at the membrane distal end of pre-F (head region), is recognized by several of the most potent RSV-neutralizing antibodies thus far identified [9, 13, 14] and is a major target of neutralizing antibodies elicited in RSV-infected humans [15] . As antigenic site Ø is only present on the pre-F conformation of RSV F, and recombinant pre-F spontaneously rearranges to the post-fusion conformation [9] , several variants of RSV F stabilized in the pre-F form have been created for use as immunogens. DS-Cav1 [16] , DS-Cav1-Cys-zipper [17] , SC-TM [18] and SC-DM [18] , all of which preserve antigenic site Ø, have been shown to elicit high titers of neutralizing antibodies in mice, cotton rats, and macaques. However, antigenic site Ø comprises less than 10% of the surface area of the RSV F trimer glycoprotein [9] , providing ample opportunity for antigenic competition from irrelevant or less neutralization-sensitive epitopes on RSV F. A vaccine that were to more specifically present antigenic site Ø might thus have the potential to focus and to improve the quality of the antibody response.