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. Here, 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 is comprised of a broad diversity of clones that target several antigenic sites. Nearly half of the most potent
antibodies target a previously undefined site of vulnerability near the apex of the prefusion conformation of RSV F (preF), providing strong support for the development of
RSV vaccine candidates that preserve the membrane-distal hemisphere of the preF
protein. Additionally, the
antibodies targeting this new site display 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 are over 100 times more potent than
palivizumab, and several cross-neutralize human metapneumovirus (HMPV). Taken together, the results have implications for the design and evaluation of
RSV vaccine candidates and offer new options for passive prophylaxis.