title: A novel pre-fusion conformation-specific neutralizing epitope on the respiratory syncytial virus fusion protein.
abstract: Respiratory syncytial virus (RSV) remains a major human pathogen, infecting the majority of infants before age two and causing re-infection throughout life. Despite decades of RSV research, there is no licensed RSV vaccine. Most candidate vaccines studied to date have incorporated the RSV fusion (F) surface glycoprotein, because the sequence of F is highly conserved among strains of RSV. To better define the human B cell response to RSV F, we isolated from a single donor 13 new neutralizing human monoclonal antibodies (mAbs) that recognize the RSV F protein in the pre-fusion conformation. Epitope binning studies showed that the majority of neutralizing mAbs targeted a new antigenic site on the globular head domain of F, designated here antigenic site VIII, which occupies an intermediate position between the previously defined major antigenic sites II and site Ø. Antibodies to site VIII competed for binding with antibodies to both of those adjacent neutralizing sites. The new mAbs exhibited unusual breadth for pre-fusion F-specific antibodies, cross-reacting with F proteins from both RSV subgroups A and B viruses. We solved the X-ray crystal structure of one site VIII mAb, hRSV90, in complex with pre-fusion RSV F protein. The structure revealed a large footprint of interaction for hRSV90 on RSV F, in which the heavy chain and light chain both have specific interactions mediating binding to site VIII, the heavy chain overlaps with site Ø, and the light chain interacts partially with site II.
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Jarrod J
authors.initials: JJ
authors.lastname: Mousa
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Nurgun
authors.initials: N
authors.lastname: Kose
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Pranathi
authors.initials: P
authors.lastname: Matta
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Pavlo
authors.initials: P
authors.lastname: Gilchuk
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.|Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA.|Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D000914:Antibodies, Viral / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D003429:Cross Reactions; D018360:Crystallography, X-Ray; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D014760:Viral Fusion Proteins / Q000737:chemistry / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; C526850:F protein, human respiratory syncytial virus; D014760:Viral Fusion Proteins