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.

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.

Modeling maternal fetal RSV F vaccine induced antibody transfer in guinea pigs.

BACKGROUND: Protection of newborns and young infants against RSV disease via maternal immunization mediated by transplacental transfer of antibodies is under evaluation in third-trimester pregnant women with the RSV recombinant F nanoparticle vaccine (RSV F vaccine). Since the hemichorial placental architecture in guinea pigs and humans is similar, the guinea pig model was employed to assess RSV F vaccine immunogenicity in pregnant sows and to compare RSV-specific maternal antibody levels in their pups. METHODS: Thirty (30) presumptive pregnant guinea pigs were immunized on gestational day 25 and 46 with placebo (PBS), 30µg RSV F, or 30µg RSV F+400µg aluminum phosphate. Sera at delivery/birth (sows/pups) and 15 and 30 days post-partum (pups) were analyzed for the presence of anti-F IgG, palivizumab-competitive antibody (PCA) and RSV/A microneutralization (MN). RESULTS: The rates of pregnancy and stillbirth were similar between controls and vaccinees. The vaccine induced high levels of anti-F IgG, PCA and MN in sows, with the highest levels observed in adjuvanted vaccinees. Placental transfer to pups was proportional to the maternal antibody levels, with concentration effects observed for all immune measures. CONCLUSIONS: The RSV F vaccine was safe and immunogenic in pregnant guinea pigs and supported robust transplacental antibody transfer to their pups. Relative concentration of antibodies in the pups was observed even in the presence of high levels of maternal antibody. Guinea pigs may be an important safety and immunogenicity model for preclinical assessment of candidate vaccines for maternal immunization.