Chimeric Pneumoviridae fusion proteins as immunogens to induce cross-neutralizing antibody responses.

Eduardo Olmedillas,Olga Cano,Daniel Luque,José A Melero,Vicente Más,Jason S Mclellan,María C Terrón,Isidoro Martínez

doi:10.15252/emmm.201708078

Abstract

Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV), two members of the Pneumoviridae family, account for the majority of severe lower respiratory tract infections worldwide in very young children. They are also a frequent cause of morbidity and mortality in the elderly and immunocompromised adults. High levels of neutralizing antibodies, mostly directed against the viral fusion (F) glycoprotein, correlate with protection against either hRSV or hMPV. However, no cross‐neutralization is observed in polyclonal antibody responses raised after virus infection or immunization with purified F proteins. Based on crystal structures of hRSV F and hMPV F, we designed chimeric F proteins in which certain residues of well‐characterized antigenic sites were swapped between the two antigens. The antigenic changes were monitored by ELISA with virus‐specific monoclonal antibodies. Inoculation of mice with these chimeras induced polyclonal cross‐neutralizing antibody responses, and mice were protected against challenge with the virus used for grafting of the heterologous antigenic site. These results provide a proof of principle for chimeric fusion proteins as single immunogens that can induce cross‐neutralizing antibody and protective responses against more than one human pneumovirus.

Highlights

Human respiratory syncytial virus is the leading cause worldwide of severe acute lower respiratory tract infections (ALRI, mainly bronchiolitis and pneumonia) in infants and very young children
The concept of “universal” vaccines (Nabel & Fauci, 2010) has recently attracted much attention. In some cases, such as influenza virus (Kanekiyo et al, 2013; Krammer & Palese, 2014; Yassine et al, 2015) or human immunodeficiency virus (HIV) (Kwong et al, 2013), a universal vaccine is sought to overcome strain variability so that a single immunogen designed to reorient the antibody response toward relatively conserved antigenic regions would protect against infections with highly divergent antigenic variants
A Each mouse serum was tested in Enzyme-linked immunosorbent assay (ELISA) for antibody binding to the F proteins indicated at the bottom of each panel. *P = 0.00046 and **P = 0.02459

Summary

Introduction

Human respiratory syncytial virus (hRSV) is the leading cause worldwide of severe acute lower respiratory tract infections (ALRI, mainly bronchiolitis and pneumonia) in infants and very young children. Human metapneumovirus (hMPV) is a virus of clinical significance (van den Hoogen et al, 2001), second only to hRSV as a cause of ALRI in young children (Edwards et al, 2013; Schuster & Williams, 2013). HRSV and hMPV share clinical and biological features, they have important differences, for example, in the number of genes or in the proteolytic processing of their respective fusion (F) glycoproteins (van den Hoogen et al, 2002). Both hRSV and hMPV genomes encode three glycoproteins (SH, G, and F) that are inserted in the viral membrane. F is a type I glycoprotein that fuses the viral and cell membranes at the initial stages of an infectious cycle and is the main target of neutralizing antibodies (for a recent review Melero & Mas, 2015)

Methods

Results

Conclusion