Pre-fusion RSV F strongly boosts pre-fusion specific neutralizing responses in cattle pre-exposed to bovine RSV

Ann-Muriel Steff,Thi Lien-Anh Nguyen,Sai Tian,Andrea Carfi,Sarah Vandepaer,Sumana Chandramouli,James Monroe,Kristian Friedrich,Jean-François Toussaint

doi:10.1038/s41467-017-01092-4

Abstract

Human respiratory syncytial virus (hRSV) is responsible for serious lower respiratory tract disease in infants and in older adults, and remains an important vaccine need. RSV fusion (F) glycoprotein is a key target for neutralizing antibodies. RSV F stabilized in its pre-fusion conformation (DS-Cav1 F) induces high neutralizing antibody titers in naïve animals, but it remains unknown to what extent pre-fusion F can boost pre-existing neutralizing responses in RSV seropositive adults. We here assess DS-Cav1 F immunogenicity in seropositive cattle pre-exposed to bovine RSV, a virus closely related to hRSV. A single immunization with non-adjuvanted DS-Cav1 F strongly boosts RSV neutralizing responses, directed towards pre-fusion F-specific epitopes, whereas a post-fusion F is unable to do so. Vaccination with pre-fusion F thus represents a promising strategy for maternal immunization and for other RSV vaccine target populations such as older adults.

Highlights

Human respiratory syncytial virus is responsible for serious lower respiratory tract disease in infants and in older adults, and remains an important vaccine need
In the pre-fusion conformation, the heptad repeat A (HRA) region is associated with the globular head while in the postfusion conformation HRA has extended from the head and the heptad repeat B (HRB) region has rearranged to associate with the HRA region, forming a very stable 6-helix bundle
To assess the effect of mutations on epitopes recognized by Human respiratory syncytial virus (hRSV) Fneutralizing antibodies (Fig. 1b), we generated a homology model of pre-fusion bovine RSV (bRSV) F based on the crystal structure of pre-F DSCav[1]

Summary

Introduction

Human respiratory syncytial virus (hRSV) is responsible for serious lower respiratory tract disease in infants and in older adults, and remains an important vaccine need. Maternal hRSV neutralizing antibodies transferred to the fetus through the placenta during pregnancy confer some level of protection during the first 1-2 months of life[7–10]. As these passively transferred antibodies wane, babies become more susceptible to hRSV infection[11]. One strategy to increase and extend protection during the first 4-6 months of life, the most critical for severe hRSV infections, is to vaccinate pregnant women during the third trimester of pregnancy, effectively boosting the pre-existing hRSV immune response and increasing neutralizing antibody titers in the newborn[12, 13]. Researchers in other laboratories have succeeded in generating RSV F molecules, such as PreF-GCN4, DS-Cav[1] and SC-TM that are stabilized in the pre-fusion conformation by introducing mutations that prevent rearrangement of HRA and by adding a trimerization sequence at the C-terminal end of HRB21, 22–24

Methods

Results

Conclusion