Alphavirus vector-based replicon particles expressing multivalent cross-protective Lassa virus glycoproteins

Vaccine
Min WangIgor S Lukashevich

Abstract

Lassa virus (LASV) is the most prevalent rodent-borne arenavirus circulated in West Africa. With population at risk from Senegal to Nigeria, LASV causes Lassa fever and is responsible for thousands of deaths annually. High genetic diversity of LASV is one of the challenges for vaccine R&D. We developed multivalent virus-like particle vectors (VLPVs) derived from the human Venezuelan equine encephalitis TC-83 IND vaccine (VEEV) as the next generation of alphavirus-based bicistronic RNA replicon particles. The genes encoding VEEV structural proteins were replaced with LASV glycoproteins (GPC) from distantly related clades I and IV with individual 26S promoters. Bicistronic RNA replicons encoding wild-type LASV GPC (GPCwt) and C-terminally deleted, non-cleavable modified glycoprotein (ΔGPfib), were encapsidated into VLPV particles using VEEV capsid and glycoproteins provided in trans. In transduced cells, VLPVs induced simultaneous expression of LASV GPCwt and ΔGPfib from 26S alphavirus promoters. LASV ΔGPfib was predominantly expressed as trimers, accumulated in the endoplasmic reticulum, induced ER stress and apoptosis promoting antigen cross-priming. VLPV vaccines were immunogenic and protective in mice and upregulated CD11c+/C...Continue Reading

Citations

Feb 2, 2019·Expert Review of Vaccines·Hannah G KellyAdam K Wheatley
Jan 18, 2019·Pathogens·Dylan M JohnsonIgor S Lukashevich
Feb 19, 2019·F1000Research·Igor S LukashevichJuan Carlos de la Torre
Jul 24, 2020·International Journal of Molecular Sciences·Kenneth Lundstrom
Mar 29, 2019·Frontiers in Immunology·Morgan E Brisse, Hinh Ly

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Methods Mentioned

BETA
PCR
flow cytometry
ELISA
genetic modification

Software Mentioned

Immunospot ®
OriginLab

Related Concepts

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis