title: Prefusion F-specific antibodies determine the magnitude of RSV neutralizing activity in human sera.
abstract: Respiratory syncytial virus (RSV) is estimated to claim more lives among infants <1 year old than any other single pathogen, except malaria, and poses a substantial global health burden. Viral entry is mediated by a type I fusion glycoprotein (F) that transitions from a metastable prefusion (pre-F) to a stable postfusion (post-F) trimer. A highly neutralization-sensitive epitope, antigenic site Ø, is found only on pre-F. We determined what fraction of neutralizing (NT) activity in human sera is dependent on antibodies specific for antigenic site Ø or other antigenic sites on F in healthy subjects from ages 7 to 93 years. Adsorption of individual sera with stabilized pre-F protein removed >90% of NT activity and depleted binding antibodies to both F conformations. In contrast, adsorption with post-F removed ~30% of NT activity, and binding antibodies to pre-F were retained. These findings were consistent across all age groups. Protein competition neutralization assays with pre-F mutants in which sites Ø or II were altered to knock out binding of antibodies to the corresponding sites showed that these sites accounted for ~35 and <10% of NT activity, respectively. Binding competition assays with monoclonal antibodies (mAbs) indicated that the amount of site Ø-specific antibodies correlated with NT activity, whereas the magnitude of binding competed by site II mAbs did not correlate with neutralization. Our results indicate that RSV NT activity in human sera is primarily derived from pre-F-specific antibodies, and therefore, inducing or boosting NT activity by vaccination will be facilitated by using pre-F antigens that preserve site Ø.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Joan O
authors.initials: JO
authors.lastname: Ngwuta
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Man
authors.initials: M
authors.lastname: Chen
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Kayvon
authors.initials: K
authors.lastname: Modjarrad
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: M Gordon
authors.initials: MG
authors.lastname: Joyce
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Masaru
authors.initials: M
authors.lastname: Kanekiyo
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Azad
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hadi M
authors.initials: HM
authors.lastname: Yassine
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Syed M
authors.initials: SM
authors.lastname: Moin
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: April M
authors.initials: AM
authors.lastname: Killikelly
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Gwo-Yu
authors.initials: GY
authors.lastname: Chuang
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Aliaksandr
authors.initials: A
authors.lastname: Druz
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ivelin S
authors.initials: IS
authors.lastname: Georgiev
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Rundlet
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Mallika
authors.initials: M
authors.lastname: Sastry
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Guillaume B E
authors.initials: GB
authors.lastname: Stewart-Jones
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Baoshan
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Martha C
authors.initials: MC
authors.lastname: Nason
authors.affiliation: The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Capella
authors.affiliation: The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Peeples
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Ledgerwood
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: McLellan
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. bgraham@nih.gov.
authors.forename: Barney S
authors.initials: BS
authors.lastname: Graham
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D057134:Antibodies, Neutralizing / Q000097:blood / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D000914:Antibodies, Viral / Q000097:blood / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D002648:Child; D006801:Humans; D008875:Middle Aged; D022261:Respiratory Syncytial Virus Vaccines / Q000276:immunology; D012136:Respiratory Syncytial Viruses / Q000737:chemistry / Q000276:immunology*; D014760:Viral Fusion Proteins / Q000737:chemistry / Q000276:immunology*; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D022261:Respiratory Syncytial Virus Vaccines; D014760:Viral Fusion Proteins