Immunogenicity of a protective intradermal DNA vaccine against lassa virus in cynomolgus macaques

Jingjing Jiang,Preeti Banglore,Kathleen A Cashman,Connie S Schmaljohn,Katherine Schultheis,Holly Pugh,Jacklyn Nguyen,Laurent M Humeau,Kate E Broderick,Stephanie J Ramos

doi:10.1080/21645515.2019.1616499

Abstract

ABSTRACT Lassa virus (LASV) is a hemorrhagic fever virus of the Arenaviridae family with high rates of mortality and co-morbidities, including chronic seizures and permanent bilateral or unilateral deafness. LASV is endemic in West Africa and Lassa fever accounts for 10–16% of hospitalizations annually in parts of Sierra Leone and Liberia according to the CDC. An ongoing outbreak in Nigeria has resulted in 144 deaths in 568 cases confirmed as LASV as of November 2018, with many more suspected, highlighting the urgent need for a vaccine to prevent this severe disease. We previously reported on a DNA vaccine encoding a codon-optimized LASV glycoprotein precursor gene, pLASV-GPC, which completely protects Guinea pigs and nonhuman primates (NHPs) against viremia, clinical disease, and death following lethal LASV challenge. Herein we report on the immunogenicity profile of the LASV DNA vaccine in protected NHPs. Antigen-specific binding antibodies were generated in 100% (6/6) NHPs after two immunizations with pLASV-GPC. These antibodies bound predominantly to the assembled LASV glycoprotein complex and had robust neutralizing activity in a pseudovirus assay. pLASV-GPC DNA-immunized NHPs (5/6) also developed T cell responses as measured by IFNγ ELISpot assay. These results revealed that the pLASV-GPC DNA vaccine is capable of generating functional, LASV-specific T cell and antibody responses, and the assays developed in this study will provide a framework to identify correlates of protection and characterize immune responses in future clinical trials.

Highlights

Lassa virus (LASV) is an Old World Arenavirus and the known cause of hemorrhagic Lassa fever.[1]
Expression of LASV glycoprotein complex (GPC) antigen following intradermal electroporation delivery We have previously reported on in vivo intradermal electroporation (ID-EP) delivery of plasmid DNA resulting in robust plasmid gene expression within treated skin,[20] and that ID-EP delivery of a plasmid DNA vaccine encoding LASV GPC antigen results in 100% protective immunity against lethal LASV challenge to Guinea pigs and nonhuman primates (NHPs).[18,19]
We previously demonstrated the direct transfection of both keratinocytes and dendritic cells in the epidermis with the ID-EP device used to deliver the pLASV-GPC DNA vaccine,[20,21] suggesting the same populations of cells were targeted by the vaccine in the current study

Summary

Introduction

Lassa virus (LASV) is an Old World Arenavirus and the known cause of hemorrhagic Lassa fever.[1] It is endemic in West Africa with an estimated 100,000 to 300,000 cases of Lassa fever occurring each year and is classified as a Category A pathogen with pandemic potential by the CDC.[2] LASV is transmitted via ingestion or inhalation exposure to excretions by its primary reservoir, the Mastomys rat, as well as through person-to-person transmission following exposure to blood, tissue, secretions, or excretions of LASV-infected individuals.[3] Imported cases of Lassa fever have been reported in the United States[4] and Europe,[5] and nosocomial infections have occurred in nearly every recorded outbreak.[6] The clinical symptoms of Lassa infection include fever, malaise, severe edema, blood loss, and acute hemorrhagic fever which are associated with a high mortality rate. Development of an effective vaccine and vaccine delivery technologies to protect those living in Lassa endemic areas are of extreme importance and could prevent this deadly infectious disease from becoming a global health emergency

Methods

Results

Conclusion