Antigenic Fingerprinting following Primary RSV Infection in Young Children Identifies Novel Antigenic Sites and Reveals Unlinked Evolution of Human Antibody Repertoires to Fusion and Attachment Glycoproteins.
Respiratory Syncytial Virus (RSV) is the major cause of pneumonia among infants. Here we elucidated the antibody repertoire following primary RSV infection and traced its evolution through adolescence and adulthood. Whole genome-fragment phage display libraries (GFPDL) expressing linear and conformational epitopes in the RSV fusion protein (F) and attachment protein (G) were used for unbiased epitope profiling of infant sera prior to and following RSV infection. F-GFPDL analyses demonstrated modest changes in the anti-F epitope repertoires post-RSV infection, while G-GFPDL analyses revealed 100-fold increase in number of bound phages. The G-reactive epitopes spanned the N- and C-terminus of the G ectodomain, along with increased reactivity to the central conserved domain (CCD). Panels of F and G antigenic sites were synthesized to evaluate sera from young children (<2 yr), adolescents (14-18 yr) and adults (30-45 yr) in SPR real-time kinetics assays. A steady increase in RSV-F epitope repertoires from young children to adults was observed using peptides and F proteins. Importantly, several novel epitopes were identified in pre-fusion F and an immunodominant epitope in the F-p27. In all age groups, antibody binding to pre-fusion F was 2-3 folds higher than to post-fusion form. For RSV-G, antibody responses were high following early RSV infection in children, but declined significantly in adults, using either G proteins or peptides. This study identified unlinked evolution of anti-F and anti G responses and supportive evidence for immune pressure driven evolution of RSV-G. These findings could help development of effective countermeasures including vaccines.
Division of Viral Products, Center for Biologics Evaluation and Research (CBER), FDA, Silver Spring, Maryland, United States of America.
Sandra
S
Fuentes
Division of Viral Products, Center for Biologics Evaluation and Research (CBER), FDA, Silver Spring, Maryland, United States of America.
Elizabeth M
EM
Coyle
Division of Viral Products, Center for Biologics Evaluation and Research (CBER), FDA, Silver Spring, Maryland, United States of America.
Judy
J
Beeler
Division of Viral Products, Center for Biologics Evaluation and Research (CBER), FDA, Silver Spring, Maryland, United States of America.
Hana
H
Golding
Division of Viral Products, Center for Biologics Evaluation and Research (CBER), FDA, Silver Spring, Maryland, United States of America.
Surender
S
Khurana
D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology*; D002648:Child; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D007223:Infant; D008297:Male; D019151:Peptide Library; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology*; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology*; D020349:Surface Plasmon Resonance; D014759:Viral Envelope Proteins / Q000276:immunology; D014760:Viral Fusion Proteins / Q000276:immunology
D000914:Antibodies, Viral; D000956:Antigens, Viral; D018985:Epitopes, B-Lymphocyte; D006023:Glycoproteins; D016056:Immunodominant Epitopes; D019151:Peptide Library; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins; C116204:attachment protein G