Modified vaccinia Ankara vaccine expressing Marburg virus-like particles protects guinea pigs from lethal Marburg virus infection

Delphine C. Malherbe,Farshad Guirakhoo,Michelle Meyer,Galit Alter,Mary J. Hauser,Alexander Bukreyev,Arban Domi,Bronwyn M. Gunn

doi:10.1038/s41541-020-00226-y

Abstract

We introduce a new vaccine platform against Marburg virus (MARV) combining the advantages of the immunogenicity of a highly attenuated vaccine vector (Modified Vaccinia Ankara, MVA) with the authentic conformation of virus-like particles (VLPs). Our vaccine, MVA–MARV–VLP, expresses the minimal components of MARV VLPs: the envelope glycoprotein GP and the matrix protein VP40. Electron microscopy confirmed self-assembly and budding of VLPs from infected cells. Prime/boost vaccination of guinea pigs with MVA–MARV–VLP-elicited MARV-specific binding and neutralizing antibody responses. Vaccination also induced Fc-mediated innate immune effector functions including activation of NK cells and antibody-dependent phagocytosis by neutrophils and monocytes. Inoculation of vaccinated animals with guinea pig-adapted MARV demonstrated 100% protection against death and disease with no viremia. Therefore, our vaccine platform, expressing two antigens resulting in assembly of VLPs in the native conformation in vaccinated hosts, can be used as a potent vaccine against MARV.

Highlights

Marburg virus (MARV) is a member of the Filoviridae family which causes a severe human disease with a 24–88% case fatality rate[1]
The modified vaccinia Ankara (MVA)–MARV–virus-like particles (VLPs) vaccine platform combines the advantages of the authentic conformation of VLPs with the immunogenicity of a replicating but a highly attenuated MVA vaccine vector (Fig. 1a)
Self-assembly of MARV VLPs in human HEK293 cells infected with MVA–MARV–VLP for 24 h was confirmed by thin section transmission electron microscopy which involved staining of GP with small gold particles (Fig. 1d)

Summary

Introduction

Marburg virus (MARV) is a member of the Filoviridae family which causes a severe human disease with a 24–88% case fatality rate[1]. The highly attenuated live vector modified vaccinia Ankara (MVA)-based vaccine expressing only the single glycoprotein (GP) protein of Ebola virus, another filovirus, was not protective in vivo[6] possibly due to non-authentic GP conformation (Fig. 1a). Another approach is to generate virus-like particles (VLPs)[7,8] in vitro to be used as subunit protein vaccines. VLPs mimic the native conformation of viral particles (Fig. 1a) and can be very immunogenic, but since they do not replicate in the host, they require multiple doses for complete protection These vaccines may need to be administered with adjuvants and are expensive to manufacture. Testing of MVA–MARV–VLP demonstrated induction of various levels of MARV-neutralizing antibodies and Fc-mediated antibody protective effects; all vaccinated animals were protected from death and disease against lethal MARV infection

Methods

Results

Conclusion