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Vaccine. 2018 Dec 18;36(52):8069-8078. doi: 10.1016/j.vaccine.2018.10.073. Epub 2018 Oct 30.

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.

Author information

1
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA. Electronic address: bgilbert@bcm.edu.
2
Novavax, Inc., Gaithersburg, MD, USA. Electronic address: npatel@novavax.com.
3
Novavax, Inc., Gaithersburg, MD, USA. Electronic address: hlu@novavax.com.
4
Regenxbio, Inc., Rockville, MD, USA(1). Electronic address: yliu@regenxbio.com.
5
Novavax, Inc., Gaithersburg, MD, USA. Electronic address: mguebre-xabier@novavax.com.
6
Department of Molecular Virology and Microbiology and Pediatrics, Baylor College of Medicine, Houston, TX, USA. Electronic address: ppiedra@bcm.edu.
7
Novavax, Inc., Gaithersburg, MD, USA. Electronic address: gglenn@novavax.com.
8
Novavax, Inc., Gaithersburg, MD, USA. Electronic address: lellingsworth@novavax.com.
9
Novavax, Inc., Gaithersburg, MD, USA. Electronic address: gsmith@novavax.com.

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.

KEYWORDS:

Cotton rat; Fusion glycoprotein; Nanoparticle vaccine; Palivizumab-resistant mutant RSV; Respiratory syncytial virus

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