Alternative conformations of a major antigenic site on RSV F

Jones, Harrison G.; Battles, Michael B.; Lin, Chun-Chi; Bianchi, Siro; Corti, Davide; McLellan, Jason S.

The majority of RSV-neutralizing activity in human sera is due to antibodies specific for the prefusion conformation of F [17, 18] , and recent characterizations of the human antibody response to RSV F has revealed that prefusion-specific antigenic sites, including site Ø ("zero"), are the major target of neutralizing antibodies [18, 32, 33] . Antigenic site Ø is located at the membrane-distal apex of the trimer and includes the α4-helix and the loop connecting α4 to α5 (α4-α5 loop) of F1, and the F2 loop between β2 and α1. Upon triggering, site Ø undergoes an extensive structural rearrangement in which α4 and the α4-α5 loop refold to form the continuous α5-helix observed in the postfusion F conformation [8] . Comparison of the neutralization potency of two site Ø antibodies, D25 [34] and 5C4 [35] , with palivizumab, a site II-directed conformation-independent antibody [36] , demonstrated that the prefusionspecific antibodies are 10-100 times more potent [8] . Other potent prefusion-specific human antibodies that bind to the apex of the trimer, such as AM22 and RSD5, have also been isolated in recent years [8, 37, 38] , and one of them (MEDI8897) is now in advanced stages of clinical development [39] .