Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in young children and the elderly. There are currently no licensed RSV vaccines, and passive prophylaxis with the monoclonal antibody palivizumab is restricted to high-risk infants in part due to its modest efficacy. Although it is widely agreed that an effective RSV vaccine will require the induction of a potent neutralizing antibody response against the RSV fusion (F) glycoprotein, little is known about the specificities and functional activities of RSV F-specific antibodies induced by natural infection. We have comprehensively profiled the human antibody response to RSV F by isolating and characterizing 364 RSV F-specific monoclonal antibodies from the memory B cells of three healthy adult donors. In all donors, the antibody response to RSV F was composed of a broad diversity of clones that targeted several antigenic sites. Nearly half of the most potent antibodies targeted a previously undefined site of vulnerability near the apex of the prefusion conformation of RSV F (preF). Additionally, the antibodies targeting this new site displayed convergent sequence features, thus providing a future means to rapidly detect the presence of these antibodies in human vaccine samples. Many of the antibodies that bind preF-specific surfaces were >100 times more potent than palivizumab and several cross-neutralized human metapneumovirus. Together, the results have implications for the design and evaluation of RSV vaccine candidates and offer new options for passive prophylaxis.