Adenovector 26 encoded prefusion conformation stabilized RSV-F protein induces long-lasting Th1-biased immunity in neonatal mice

Leslie Van Der Fits,Jan Serroyen,Hanneke Schuitemaker,Yolinda Van Polanen,Roland Zahn,Marjolein Heemskerk-Van Der Meer,Renske Bolder,Joke Drijver,Johannes P M Langedijk,Eirikur Saeland

doi:10.1038/s41541-020-0200-y

Abstract

While RSV is a major cause of respiratory morbidity in infants, vaccine development is hindered by the immaturity and Th2-bias of the infant immune system and the legacy of enhanced respiratory disease (ERD) after RSV infection following immunization with formalin inactivated (FI)-RSV vaccine in earlier clinical trials. Preclinical studies have demonstrated that an adenoviral vector-based RSV F vaccine candidate (Ad26.RSV.FA2) induces Th1-biased protective immune responses, without signs of ERD upon subsequent RSV challenge. We here developed an Ad26 vector encoding the RSV F protein stabilized in its prefusion conformation (Ad26.RSV.preF). In adult mice, Ad26.RSV.preF induced superior, Th1-biased IgG2a-dominated humoral responses as compared to Ad26.RSV.FA2, while maintaining the strong Th1-biased cellular responses. Similar to adult mice, Ad26.RSV.preF induced robust and durable humoral immunity in neonatal mice, again characterized by IgG2a-dominated RSV F-binding antibodies, and high and stable virus-neutralizing titers. In addition, vaccine-elicited cellular immune responses were durable and characterized by IFN-γ-producing CD4+ and CD8+ T cells, with a profound Th1 bias. In contrast, immunization of neonatal mice with FI-RSV resulted in IgG1 RSV F-binding antibodies associated with a Th2 phenotype, no detectable virus-neutralizing antibodies, and a Th2-biased cellular response. These results are supportive for the clinical development of Ad26.RSV.preF for use in infants.

Highlights

Respiratory syncytial virus (RSV) is an orthopneumovirus of the Pneumoviridae family that causes annual epidemics of acute lower respiratory tract infections, while in addition, reinfection is common[1]
Single intramuscular immunization with Ad26.RSV.preF resulted in higher Virus neutralization assay (VNA) titers against RSV A Long and RSV B1 when compared to Ad26.RSV.FA2 in an across dose statistical comparison
Levels of IgG-binding antibodies against the preF protein were higher in Ad26.RSV.preF-immunized animals, whereas titers of postF-binding antibodies were similar between Ad26.RSV.preF and Ad26.RSV.FA2 immunized groups (Fig. 1b, d), resulting in a significantly increased ratio between preF-binding and postF-binding antibodies in the former group

Summary

Introduction

Respiratory syncytial virus (RSV) is an orthopneumovirus of the Pneumoviridae family that causes annual epidemics of acute lower respiratory tract infections, while in addition, reinfection is common[1]. To assess the relative Th1/Th2 skewing, we compared Ad26.RSV.preF-induced immune responses in adult mice to those npj Vaccines (2020) 49 Stimulation of splenocytes with RSV F peptides resulted in significantly increased numbers of IFN-γpositive cells in Ad26.RSV.preF-immunized neonatal mice (Fig. 4a), when compared to the non-immunized control group (p = 0.0087).

Results

Conclusion