Journal of virology 2017 05 24() pii 10.1128/JVI.00176-17
Palivizumab, a humanized murine monoclonal antibody that recognizes antigenic site II on both the prefusion (pre-F) and postfusion (post-F) conformations of the RSV F glycoprotein, is the only prophylactic agent approved for RSV. However, its relatively low neutralizing potency and high cost has limited its use to a restricted population of infants at high risk of severe disease. Previously, we isolated a high potency neutralizing antibody, 5C4, that specifically recognizes antigenic site Ø at the apex of the pre-F trimer. We compared-in vitro and in vivo-the potency and protective efficacy of 5C4 and the murine precursor of palivizumab, antibody 1129. Both antibodies were synthesized on identical murine backbones as either an IgG1 or IgG2a subclass and evaluated for binding to multiple F protein conformations, in vitro inhibition of RSV infection and propagation, and protective efficacy in mice. Although 1129 and 5C4 have similar pre-F binding affinities, 5C4 neutralizing activity is nearly 50-fold greater than that of 1129 in vitro In BALB/c mice, 5C4 reduced peak RSV titers 1000-fold more than 1129 in both upper and lower respiratory tracts. These data indicate that antibodies specific for antigenic site Ø are more efficacious at preventing RSV infection than antibodies specific for antigenic site II. Our data also suggest that site Ø-specific antibodies may be useful for RSV prevention or therapy and support the use of pre-F as a vaccine antigen.IMPORTANCE There is no vaccine yet available to prevent RSV. The licensed antibody, palivizumab, which recognizes site II on both pre-F and post-F, is restricted to prophylaxis in neonates at high-risk of severe RSV disease. Recommendations for using passive immunization in the general population or for therapy in immunocompromised persons with persistent infection is limited because of cost, determined inhigh doses needed to compensate for relatively low neutralizing potency. Prior efforts to improve in vitro potency of site II antibodies did not translate to significant in vivo dose-sparing. We isolated a pre-F-specific, high-potency neutralizing antibody (5C4) that recognizes antigenic site Ø, and compared its efficacy to the murine precursor of palivizumab (1129) matched for isotype and pre-F binding affinities. Our findings demonstrate that epitope specificity is an important determinant of antibody neutralizing potency, and defining mechanisms of neutralization has the potential to identify improved products for RSV prophylaxis and therapy.