A Single Dose of Modified Vaccinia Ankara Expressing Lassa Virus-like Particles Protects Mice from Lethal Intra-cerebral Virus Challenge.

Maria S Salvato,Arban Domi,Sandra Medina-Moreno,Nathanael Mccurley,Rahul Basu,Haoting Hsu,Camila Guzmán-Cardozo,Michael Hellerstein,Farshad Guirakhoo,Juan Carlos Zapata,Mary Hauser

doi:10.3390/pathogens8030133

Abstract

Lassa fever surpasses Ebola, Marburg, and all other hemorrhagic fevers except Dengue in its public health impact. Caused by Lassa virus (LASV), the disease is a scourge on populations in endemic areas of West Africa, where reported incidence is higher. Here, we report construction, characterization, and preclinical efficacy of a novel recombinant vaccine candidate GEO-LM01. Constructed in the Modified Vaccinia Ankara (MVA) vector, GEO-LM01 expresses the glycoprotein precursor (GPC) and zinc-binding matrix protein (Z) from the prototype Josiah strain lineage IV. When expressed together, GP and Z form Virus-Like Particles (VLPs) in cell culture. Immunogenicity and efficacy of GEO-LM01 was tested in a mouse challenge model. A single intramuscular dose of GEO-LM01 protected 100% of CBA/J mice challenged with a lethal dose of ML29, a Mopeia/Lassa reassortant virus, delivered directly into the brain. In contrast, all control animals died within one week. The vaccine induced low levels of antibodies but Lassa-specific CD4+ and CD8+ T cell responses. This is the first report showing that a single dose of a replication-deficient MVA vector can confer full protection against a lethal challenge with ML29 virus.

Highlights

Lassa fever (LF), a zoonotic disease caused by Lassa virus (LASV), can lead to acute hemorrhagic fever with a case fatality rate (CFR) of up to 50% [1]
GEO-LM01 is replication-competent in avian cells but is replication-deficient in mammalian cells (Figure 1c) due to six deletions in the Modified Vaccinia Ankara (MVA) genome which together resulted in high attenuation and mammalian cell host restriction [21]
In contrast to other LF vaccines in development that rely on a single glycoprotein antigen, GEO-LM01 includes an additional matrix protein that forms Virus-Like Particles (VLPs) with the LASV glycoproteins

Summary

Introduction

Lassa fever (LF), a zoonotic disease caused by Lassa virus (LASV), can lead to acute hemorrhagic fever with a case fatality rate (CFR) of up to 50% [1]. African countries including Ghana, Guinea, Mali, Benin, Liberia, Sierra Leone, Togo, and Nigeria has been reported as high as 300,000 infections and 5000–10,000 deaths, but these figures are most likely underestimates due to inadequate diagnosis and surveillance [2,3,4,5]. Based on prospective studies performed in Guinea, Sierra Leone, Liberia, and Nigeria, it was estimated that 59 million people are at risk of LASV infections, with as many as 67,000 deaths per year [6]. The 2018 outbreak in Nigeria resulted in 3498 suspected cases in 22 states and 171 deaths with a CFR of 27% based on confirmed cases [7]. The fact that a virus that was first discovered in 1969 in Lassa village in Nigeria is still capable of causing outbreaks in the same geographical regions indicates challenges in eradicating its animal reservoir.

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