Pre-fusion F glycoprotein is not displayed on the surface of formalin-inactivated respiratory syncytial virus

FARE Award Winner

Authors

• J Ngwuta
• S Moin
• K Morabito
• A Kumar
• M Kanekiyo
• BS Graham

Abstract

RSV infection causes serious airway problems in the young and elderly and is a leading cause of death in children under 4 months of age. A vaccine trial done in 1969 used formalin-inactivated RSV (FI-RSV) to immunize children aged 2-7 months and induced more frequent and severe illness in vaccinees, leading to two deaths. Further analysis shows immunization with FI-RSV induces high titres of antibodies with low neutralization activity. A major antibody target is the RSV surface glycoprotein (F) that triggers fusion between the viral and host membranes. Atomic level resolution structures have been solved of F in two distinct conformations: pre- and post-triggered. Despite RSV virions presenting a combination of pre- and post-F conformations on their surface, antibodies targeting pre-F account for >90% of neutralization activity. FI-RSV is produced by incubating RSV with formalin at 37C. To determine the composition of pre- and post-F on FI-RSV, we used a non-denaturing and non-reducing dot blot to detect F with a series of monoclonal antibodies targeting pre-F, post-F or both conformations. RSV incubated with formalin for 24hrs is still reactive with pre-F specific antibodies; however, RSV incubated with formalin for 72hrs looses its ability to react with pre-F specific antibodies. These data indicate that pre-F present on the surface of RSV transforms into a post-F conformation by incubation with formalin for 72hrs. This novel finding suggests that immunogens displaying a pre-F conformation would induce an immune response distinct from the vaccine-enhanced illness observed in the 1969 FI-RSV vaccine trials.

Scientific Focus Area: Virology

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