Vaccine Candidates against Arenavirus Infections

Abstract

The viral family Arenaviridae contains several members that cause severe, and often lethal, diseases in humans. Several highly pathogenic arenaviruses are classified as Risk Group 4 agents and must be handled in the highest biological containment facility, biosafety level-4 (BSL-4). Vaccines and treatments are very limited for these pathogens. The development of vaccines is crucial for the establishment of countermeasures against highly pathogenic arenavirus infections. While several vaccine candidates have been investigated, there are currently no approved vaccines for arenavirus infection except for Candid#1, a live-attenuated Junin virus vaccine only licensed in Argentina. Current platforms under investigation for use include live-attenuated vaccines, recombinant virus-based vaccines, and recombinant proteins. We summarize here the recent updates of vaccine candidates against arenavirus infections.

Keywords: Junin virus; Lassa virus; arenavirus; vaccine; virus attenuation.

Figure 1

Phylogenetic relationships and classification of arenaviruses. The New World (NW) arenaviruses are subdivided into clade A (light green), clade A/Rec (green), clade B (orange), and clade C (blue). The phylogenetic tree is based on a nucleotide comparison of the NP genes. Red stars following virus names indicates the ability to infect humans. The virus names in boldface indicate Lymphocytic choriomeningitis virus and those that cause fatal hemorrhagic fevers in humans. The phylogenetic tree was drawn using MEGA11: Molecular Evolutionary Genetics Analysis version 1 [24]. The scale bar indicates substitutions per site. Accession numbers for reference sequences are: NC_010253.1 (Allpahuayo virus), NC_006447.1 (Pichinde virus), NC_010757.1 (Flexal virus), NC_010756.1 (Parana virus), NC_005894.1 (Pirital virus), NC_010256.1 (Bear Canyon virus), NC_010701.1 (Tamiami virus), EU123328.1 (Skinner Tank virus), EF619034.1 (Tonto Creek virus), EF619035.1 (Big Brushy Tank virus), NC_010700.1 (Whitewater Arroyo virus), NC_005081.1 (Junin virus, XJ13), D10072.2 (Junin virus, MC2), NC_005078.1 (Machupo virus, Carvallo), AY624355.1 (Machupo virus, Chicava), JN897398.1 (Ocozocoautla de Espinosa virus), NC_004293.1 (Tacaribe virus), NC_010254.1 (Cupixi virus), NC_010247.1 (Amapari virus), NC_005077.1 (Guanarito virus), NC_010562.1 (Chapare virus), NC_006317.1 (Sabia virus), MG976578.1 (Xapuri virus), NC_010758.1 (Latino virus), NC_010248.1 (Oliveros virus), AY847350.1 (Lymphocytic choriomeningitis virus), EU136038.1 (Dandenong virus), NC_039009.1 (Ryukyu mammarenavirus), NC_018710.1 (Lunk virus), NC_039012.1 (Souris virus), NC_023764.1 (Merino Walk virus), NC_027135.1 (Okahandja virus), NC_027134.1 (Mariental virus), NC_007905.1 (Ippy virus), NC_038367.1 (Solwezi virus), NC_026018.1 (Wenzhou virus), KC669694.1 (Cardamones virus), NC_004296.1 (Lassa virus, Josiah), GU481078.1 (Lassa virus, Nig08_A47), GU830848.1 (Gbagroube virus), GU830862.1 (Menekre virus), NC_026246.1 (Gairo virus), NC_007903.1 (Mobala virus), NC_016152.1 (Luna virus), DQ328874.1 (Mopeia virus), NC_013057.1 (Morogoro virus), and NC_012776.1 (Lujo virus).

Figure 2

Geographic distribution of human pathogenic arenaviruses. The OW arenaviruses are mainly distributed in the African continent, with the exception of LCMV, which is found worldwide. LASV is endemic in West African countries including Guinea, Liberia, Sierra Leone, and Nigeria, and LUJV is endemic in Zambia and South Africa. The NW arenaviruses are distributed mainly in South America, with JUNV in Argentina, MACV in Bolivia, GTOV in Venezuela and Colombia, CHAPV in Bolivia, and SABV in Brazil. WWAV is found in North America.

Figure 3

Structure of arenavirus virion and genome. (a) Structure of arenavirus virion showing surface glycoprotein complex (GPC,), nucleoprotein (NP), Zinc finger matrix protein (Z), and RNA-dependent RNA polymerase (L). (b) The genome of arenaviruses is bi-segmented, single-stranded, negative-sense RNA. The segmented genomes consist of small- (S) and large (L)-segments flanked by 5′ untranslated regions (UTRs) and 3′ UTRs. The L segment encodes Z and L, and the S segment encodes GPC and NP. The S- and L-segment encode their respective proteins using an ambisense encoding strategy, with the coding regions separated by the noncoding intergenic regions (IGRs). Figure created with BioRender (https://app.biorender.com, (accessed on 9 March 2023)).

Figure 4

Life cycle of arenavirus. Virus entry into cells is initiated by binding GP1 to cellular receptors (1). Following attachment to the cell surface, viruses are mainly internalized by endocytosis (2). Conformational change of GPC triggered by acidic condition in the late endosomes promotes fusion between the virus and endosome membrane, leading to the release of viral genomes and replication complexes into cytosols (3 and 4). Replication complexes are released into the cytoplasm and initiate replication, transcription, and translation of the viral genome with NP and L. The transcription of viral genes begins at the 3′ ends of sense genomic vRNA and complementary anti-sense vRNA. NP and L coding regions are transcribed directly from the vRNA. GPC and Z are translated from anti-sense vRNA. A secondary stem-loop structure within IGRs of the S and L segments is responsible for transcription termination. The anti-sense vRNA serves as a template for newly synthesized vRNA (5). GPC is translated in the endoplasmic reticulum and undergoes N-linked glycosylation and cleavage of SSP by cellular signal peptidase (SPase). GPC is further cleaved into GP1 and GP2 by Subtilisin Kexin Isozyme 1/Site 1 Protease (SKI-1/S1P), and finally matured into SSP, GP1, and GP2 in the trans-Golgi network (6). Z protein utilizes the ESCRT pathway to drive transportation and assembly of viral components such as NP, L, and replication complexes at the plasma membrane. Z protein also interacts with GPC, mediating the incorporation of viral RNP complexes into GPC containing particles, leading to the release of the progeny virus from infected cells (7 and 8). Figure created with BioRender (https://app.biorender.com, (accessed on 9 March 2023)).