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Lassa virus spreads from a rodent to humans and can lead to lethal hemorrhagic fever. Despite its broad tropism, chicken cells were reported 30 years ago to resist infection. We found that Lassa virus readily engaged its cell-surface receptor α-dystroglycan in avian cells, but virus entry in susceptible species involved a pH-dependent switch to an intracellular receptor, the lysosome-resident protein LAMP1. Iterative haploid screens revealed that the sialyltransferase ST3GAL4 was required for the interaction of the virus glycoprotein with LAMP1. A single glycosylated residue in LAMP1, present in susceptible species but absent in birds, was essential for interaction with the Lassa virus envelope protein and subsequent infection. The resistance of Lamp1-deficient mice to Lassa virus highlights the relevance of this receptor switch in vivo.

Glycosylated α-dystroglycan (α-DG) serves as cellular entry receptor for multiple pathogens, and defects in its glycosylation cause hereditary Walker-Warburg syndrome (WWS). At least eight proteins are critical to glycosylate α-DG, but many genes mutated in WWS remain unknown. To identify modifiers of α-DG, we performed a haploid screen for Lassa virus entry, a hemorrhagic fever virus causing thousands of deaths annually that hijacks glycosylated α-DG to enter cells. In complementary screens, we profiled cells for absence of α-DG carbohydrate chains or biochemically related glycans. This revealed virus host factors and a suite of glycosylation units, including all known Walker-Warburg genes and five additional factors critical for the modification of α-DG. Our findings accentuate the complexity of this posttranslational feature and point out genes defective in dystroglycanopathies.

Lassa virus (LASV) belongs to the Arenavirus family. LASV is endemic in several West Africa countries and causes viral hemorrhagic fevers. The Nigeria CDC has reported that an outbreak in 2024 in 28 states has resulted in 7767 suspected cases of Lassa fever, 971 confirmed cases and 166 confirmed deaths up to 11 August. Since infection with LASV can result in sensorineural hearing loss (SNHL) in up to 30% of patients, there are questions about whether triggering the immune response by immunization with LASV vaccines could potentially cause SNHL, although this has not been shown in clinical trials to date. To address this issue, the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration (BC) Safety Platform for Emergency vACcines (SPEAC) convened a three-hour webinar on 22 September 2023 to review what is known from both animal studies and human clinical trials and how hearing assessments in future clinical trials can help to assess the risk. This report summarizes the evidence presented and provides considerations for hearing assessment in expanded human trials of LASV vaccine candidates in children and adults.

Lassa fever is a serious epidemic viral disease in West Africa affecting an estimated 2 million people annually with about 5000–10,000 deaths, although supporting data is sparse. Lassa fever significantly affects neonates, children, and pregnant women, however, comprehensive data on its impact in these populations are lacking. We reviewed the available literature on Lassa fever to assess its prevalence and impact in these populations and implications for vaccine development. Clinical features in children were similar to those observed in adults, with complications such as bleeding. Altered mental status, anasarca (swollen baby syndrome), bleeding, and poor urine output were risk factors for death. The case fatality rate (CFR) in 16 paediatric studies ranged from 6 % to 63 % and was 66.7 % and 75.0 % in two neonatal studies. In a systematic review of studies on pregnant women the CFR was 33.73 %. The adverse foetal outcomes included miscarriage, stillbirth, and intrauterine death associated with maternal death. Since Lassa fever significantly affects neonates, children, and pregnant women, developing a safe and effective, single-dose vaccine for these high-risk populations is vital. Currently, there are four clinical trials assessing Lassa virus vaccines. Only one of these trials is enrolling children aged ≥18 months, and exclude pregnant and breast-feeding women. It is essential that pregnant and breast-feeding women and young children are included in clinical trials that incorporate robust safety surveillance and risk mitigation measures. In our review, potential approaches to address the specific gaps in the areas of diagnosis, management, and prevention of Lassa fever in these specific populations, such as disease surveillance systems and vaccine development, were identified. A comprehensive strategy with investment focused on addressing specific knowledge gaps will be essential in protecting the health of these specific populations in Lassa virus endemic regions.

There are currently no prophylactic vaccines licensed to protect against Lassa fever caused by Lassa virus (LASV) infection. The Emergent BioSolutions (EBS) vaccine candidate, EBS-LASV, is being developed for the prevention of Lassa fever. EBS-LASV is a live-attenuated recombinant Vesicular Stomatitis Virus (rVSV)-vectored vaccine encoding the surface glycoprotein complex (GPC) from LASV and has two attenuating vector modifications: a gene shuffle of the VSV N gene and a deletion of the VSV G gene. Several preclinical safety studies demonstrate that EBS-LASV is safe when administered to animals. Likewise, in non-human primate immunogenicity and efficacy studies, administration of EBS-LASV produces a cellular and humoral immune response that fully protects NHPs from a lethal Lassa virus challenge. Together, these studies supported a first-in-human dose-escalation, safety, and immunogenicity clinical study. This paper uses a viral vector vaccine safety template developed by the Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group to review the features of the rVSV-vectored EBS-LASV vaccine candidate and provides a high-level summary of safety findings from preclinical studies and the Phase 1 clinical study.

Lassa fever virus, a member of the family Arenaviridae, is a highly endemic category A pathogen that causes 300,000-500,000 infections per year in Western Africa. The arenaviral nucleoprotein NP has been implicated in suppression of the host innate immune system, but the mechanism by which this occurs has remained elusive. Here we present the crystal structure at 1.5 Å of the immunosuppressive C-terminal portion of Lassa virus NP and illustrate that, unexpectedly, its 3D fold closely mimics that of the DEDDh family of exonucleases. Accompanying biochemical experiments illustrate that NP indeed has a previously unknown, bona fide exonuclease activity, with strict specificity for double-stranded RNA substrates. We further demonstrate that this exonuclease activity is essential for the ability of NP to suppress translocation of IFN regulatory factor 3 and block activation of the innate immune system. Thus, the nucleoprotein is a viral exonuclease with anti-immune activity, and this work provides a unique opportunity to combat arenaviral infections.

Lassa virus, the cause of deadly Lassa fever, is endemic in West Africa, where thousands of cases occur on an annual basis. Nigeria continues to report increasingly severe outbreaks of Lassa Fever each year and there are currently no approved vaccines or therapeutics for the prevention or treatment of Lassa Fever. Given the high burden of disease coupled with the potential for further escalation due to climate change the WHO has listed Lassa virus as a priority pathogen with the potential to cause widespread outbreaks. Several candidate vaccines have received support and have entered clinical trials with promising early results. This review focuses on the current state of vaccine and therapeutic development for LASV disease and the potential of these interventions to advance through clinical trials. The growing burden of LASV disease in Africa highlights the importance of advancing preclinical and clinical testing of vaccines and therapeutics to respond to the growing threat of LASV disease.

Viral hemorrhagic Lassa fever (LF), caused by Lassa virus (LASV), is a significant public health concern endemic in West Africa with high morbidity and mortality rates, limited treatment options, and potential for international spread. Despite advances in interrogating its epidemiology and clinical manifestations, the molecular mechanisms driving pathogenesis of LASV and other arenaviruses remain incompletely understood. This review synthesizes current knowledge regarding the role of LASV host-virus interactions in mediating the pathogenesis of LF, with emphasis on interactions between viral and host proteins. Through investigation of these critical protein–protein interactions, we identify potential therapeutic targets and discuss their implications for development of medical countermeasures including antiviral drugs. This review provides an update in recent literature of significant LASV host-virus interactions important in informing the development of targeted therapies and improving clinical outcomes for LF patients. Knowledge gaps are highlighted as opportunities for future research efforts that would advance the field of LASV and arenavirus pathogenesis.

Lassa fever (LF) is a rodent-borne disease that threatens human health in the sub-region of West Africa where the zoonotic host of Lassa virus (LASV) is predominant. Currently, treatment options for LF are limited and since no preventive vaccine is approved for its infectivity, there is a high mortality rate in endemic areas. This narrative review explores the transmission, pathogenicity of LASV, advances, and challenges of different treatment options. Our findings indicate that genetic diversity among the different strains of LASV and their ability to circumvent the immune system poses a critical challenge to the development of LASV vaccines/therapeutics. Thus, understanding the biochemistry, physiology and genetic polymorphism of LASV, mechanism of evading host immunity are essential for development of effective LASV vaccines/therapeutics to combat this lethal viral disease. The LASV nucleoprotein (NP) is a novel target for therapeutics as it functions significantly in several aspects of the viral life cycle. Consequently, LASV NP inhibitors could be employed as effective therapeutics as they will potentially inhibit LASV replication. Effective preventive control measures, vaccine development, target validation, and repurposing of existing drugs, such as ribavirin, using activity or in silico-based and computational bioinformatics, would aid in the development of novel drugs for LF management.

Defective interfering particles (DIPs) are naturally occurring products during virus replication in infected cells. DIPs contain defective viral genomes (DVGs) and interfere with replication and propagation of their corresponding standard viral genomes by competing for viral and cellular resources, as well as promoting innate immune antiviral responses. Consequently, for many different viruses, including mammarenaviruses, DIPs play key roles in the outcome of infection. Due to their ability to broadly interfere with viral replication, DIPs are attractive tools for the development of a new generation of biologics to target genetically diverse and rapidly evolving viruses. Here, we provide evidence that in cells infected with the Lassa fever (LF) vaccine candidate ML29, a reassortant that carries the nucleoprotein (NP) and glycoprotein (GP) dominant antigens of the pathogenic Lassa virus (LASV) together with the L polymerase and Z matrix protein of the non-pathogenic genetically related Mopeia virus (MOPV), L-derived truncated RNA species are readily detected following infection at low multiplicity of infection (MOI) or in persistently-infected cells originally infected at high MOI. In the present study, we show that expression of green fluorescent protein (GFP) driven by a tri-segmented form of the mammarenavirus lymphocytic choriomeningitis virus (r3LCMV-GFP/GFP) was strongly inhibited in ML29-persistently infected cells, and that the magnitude of GFP suppression was dependent on the passage history of the ML29-persistently infected cells. In addition, we found that DIP-enriched ML29 was highly attenuated in immunocompetent CBA/J mice and in Hartley guinea pigs. Likewise, STAT-1-/- mice, a validated small animal model for human LF associated hearing loss sequelae, infected with DIP-enriched ML29 did not exhibit any hearing abnormalities throughout the observation period (62 days).