Respiratory syncytial virus fusion nanoparticle vaccine immune responses target multiple neutralizing epitopes that contribute to protection against wild-type and palivizumab-resistant mutant virus challenge. Issue 52 (18th December 2018)

• Record Type: Journal Article
• Authors: Gilbert, Brian E.; Patel, Nita; Lu, Hanxin; Liu, Ye; Guebre-Xabier, Mimi; Piedra, Pedro A.; Glenn, Gregory; Ellingsworth, Larry; Smith, Gale
• Is Part Of: Vaccine. Volume 36:Issue 52(2018)
• Page Start: 8069
• Page End: 8078
• Publication Date: 2018-12-18
• Subjects: Respiratory syncytial virus -- Palivizumab-resistant mutant RSV -- Fusion glycoprotein -- Nanoparticle vaccine -- Cotton rat; Vaccines -- Periodicals; 615.372
• DOI: 10.1016/j.vaccine.2018.10.073
• Languages: English
• ISSNs: 0264-410X

Abstract

Highlights: RSV F nanoparticle vaccine elicits protection against palivizumab-resistant RSV. Adjuvanted vaccine elicits anti-F IgG that binds F protein with higher affinity. Nanoparticle vaccine elicits antibodies targeting multiple neutralizing epitopes. Abstract: Human respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in newborns, young children, elderly, and immune-compromised. The RSV fusion (F) glycoprotein is a major focus of vaccine development and the target of palivizumab (Synagis®) which is licensed as an immuno-prophylactic for use in newborn children at high risk of infection. However, clinical use of a narrowly targeted monoclonal antibodies leads to the generation of escape mutant strains that are fully resistant to neutralization by the antibody. Herein, we evaluated the RSV F nanoparticle vaccine (RSV F vaccine), produced as near-full-length, pre-fusogenic F trimers that form stable protein-detergent nanoparticles. The RSV F vaccine induces polyclonal antibodies that bind to antigenic site II as well as other epitopes known to be broadly neutralizing. Cotton rats immunized with the RSV F vaccine produced antibodies that were both neutralizing and protected against wild-type RSV infection, as well as against a palivizumab-resistant mutant virus. Use of aluminum phosphate adjuvant with the RSV F vaccine increased site II antibody avidity 100 to 1000-fold, which correlated with enhanced protection against challenge. The breadth of the vaccine-induced antibody response was demonstrated using competitive binding with monoclonal antibodies targeting antigenic sites Ø, II, IV, and VIII found on pre-fusion and post-fusion conformations of RSV F. In summary, we found the RSV F vaccine induced antibodies that bind to conserved epitopes including those defined as pre-fusion F specific; that use of adjuvant increased antibody avidity that correlated with enhanced protection in the cotton rat challenge model; and the polyclonal, high-avidity antibodies neutralized and protected against both wild-type and palivizumab-resistant mutant virus. These data support the ongoing clinical development of the aluminum phosphate adjuvanted RSV F nanoparticle vaccine.