Abstract
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.
Author Summary
Respiratory syncytial virus (RSV) is the major cause of pneumonia and bronchiolitis among infants and children globally. In the United States, RSV infections lead to 57,000 hospitalizations among young children, especially in those less than one year old. Furthermore, despite the development of immunity following RSV infection during childhood, individuals remain susceptible to RSV upper respiratory tract reinfection. In the current study we explored the antibody repertoires following primary RSV infection and their evolution in adolescents and adults. Whole genome-fragment phage display libraries (GFPDL) expressing linear and conformational epitopes from RSV fusion protein (F) and attachment protein (G) were used for unbiased epitope profiling of sera prior to and following RSV infection. In addition, Plasmon Surface Resonance (SPR) was used to measure antibody binding to F and G peptides and proteins. A steady increase in RSV-F epitope repertoires from young children to adults was observed. Several novel epitopes were identified in pre-fusion F and an immunodominant epitope in F0-p27. For RSV-G, antibody responses were high following RSV infection in children, but declined in adults. This study identified unlinked evolution of anti-F and anti G responses that could help development of better RSV vaccines and therapies.
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