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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adjuvants, Immunologic / administration & dosage
  • Aluminum Compounds / immunology
  • Animals
  • Antibodies, Neutralizing / blood
  • Antibodies, Viral / blood
  • Antibody Affinity
  • Antiviral Agents / pharmacology
  • Drug Resistance, Viral
  • Epitopes / immunology
  • Female
  • Male
  • Mutation
  • Nanoparticles / administration & dosage
  • Palivizumab / pharmacology*
  • Phosphates / immunology
  • Rats
  • Respiratory Syncytial Virus Infections / prevention & control*
  • Respiratory Syncytial Virus Vaccines / immunology*
  • Respiratory Syncytial Virus, Human / drug effects*
  • Respiratory Syncytial Virus, Human / genetics
  • Sigmodontinae
  • Vaccination
  • Viral Fusion Proteins / immunology*

Substances

  • Adjuvants, Immunologic
  • Aluminum Compounds
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Antiviral Agents
  • Epitopes
  • F protein, human respiratory syncytial virus
  • Phosphates
  • Respiratory Syncytial Virus Vaccines
  • Viral Fusion Proteins
  • Palivizumab
  • aluminum phosphate