Adjuvant formulated virus-like particles expressing native-like forms of the Lassa virus envelope surface glycoprotein are immunogenic and induce antibodies with broadly neutralizing activity

Helena Müller,Larissa Kolesnikova,Lisa Oestereich,N’Faly Magassouba,Martin Schauflinger,Andreas Kaufmann,Verena Krähling,Jens Dorna,Yvonne Krebs,Stephan Becker,Jonathan K Ball,Stefan Bauer,Sarah Katharina Fehling,Thomas Strecker,Richard A Urbanowicz,Elisabeth Fichet-Calvet,Veronika Von Messling

doi:10.1038/s41541-020-00219-x

Abstract

Lassa mammarenavirus (LASV) is a rodent-borne arenavirus endemic to several West African countries. It is the causative agent of human Lassa fever, an acute viral hemorrhagic fever disease. To date, no therapeutics or vaccines against LASV have obtained regulatory approval. Polyclonal neutralizing antibodies derived from hyperimmunized animals may offer a useful strategy for prophylactic and therapeutic intervention to combat human LASV infections. The LASV envelope surface glycoprotein complex (GP) is the major target for neutralizing antibodies, and it is the main viral antigen used for the design of an LASV vaccine. Here, we assessed the immunogenic potential of mammalian cell-derived virus-like particles (VLPs) expressing GP from the prototypic LASV strain Josiah in a native-like conformation as the sole viral antigen. We demonstrate that an adjuvanted prime-boost immunization regimen with GP-derived VLPs elicited neutralizing antibody responses in rabbits, suggesting that effective antigenic epitopes of GP were displayed. Notably, these antibodies exhibited broad reactivity across five genetic lineages of LASV. VLP-based immunization strategies may represent a powerful approach for generating polyclonal sera containing cross-reactive neutralizing antibodies against LASV.

Highlights

Lassa mammarenavirus (LASV), an Old World member of the family Arenaviridae, is the zoonotic agent of human Lassa fever (LF), which is endemic to several West African countries and affects an estimated 100,000–300,000 people annually[1,2]
As canine-derived Madin–Darby canine kidney strain II (MDCK II) cells do not represent a natural host cell type for LASV, and recombinantly generated glycoprotein complex (GP) may not resemble native-like glycosylation of infectious LASV particles, we analyzed the glycosylation status of GP expressed on the surface of virus-like particles (VLPs) in comparison with GP present on authentic LASV virions purified from infected MDCK II cells
We assessed the glycosylation profile of GP from purified LASV virions released from infected human-derived HuH7 cells as well as Baby hamster kidney (BHK) cells that mimic virus shedding from rodents

Summary

Introduction

Lassa mammarenavirus (LASV), an Old World member of the family Arenaviridae, is the zoonotic agent of human Lassa fever (LF), which is endemic to several West African countries and affects an estimated 100,000–300,000 people annually[1,2]. While most cases of LF are asymptomatic or have mild symptoms, 20% of infections result in clinical manifestations varying from flu-like syndromes to fatal hemorrhagic fevers. Since no licensed therapeutic approaches or protective vaccines are yet available, LASV represents a severe public health problem in the affected regions. Ongoing large LF outbreaks associated with high case fatality rates in Nigeria underscore the critical need for accelerated research activities toward approved therapeutics and vaccines[5]. LASV is one of the most common viral hemorrhagic fever agents in risk group 4 exported to countries outside the endemic areas

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