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Lassa fever virus (LASV) can cause life-threatening hemorrhagic fevers for which there are currently no vaccines or targeted treatments. The late Prof. Stefan Kunz, along with others, showed that the high-affinity host receptor for LASV, and other Old World and clade-C New World mammarenaviruses, is matriglycan—a linear repeating disaccharide of alternating xylose and glucuronic acid that is polymerized uniquely on α-dystroglycan by like-acetylglucosaminyltransferase-1 (LARGE1). Although α-dystroglycan is ubiquitously expressed, LASV preferentially infects vascular endothelia and professional phagocytic cells, which suggests that viral entry requires additional cell-specific factors. In this review, we highlight the work of Stefan Kunz detailing the molecular mechanism of LASV binding and discuss the requirements of receptors, such as tyrosine kinases, for internalization through apoptotic mimicry.

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 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.

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 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.

Lassa fever (LF), caused by the Lassa virus and transmitted primarily by Mastomys natalensis rodents, is a severe hemorrhagic disease endemic to West Africa, particularly Nigeria, with significant morbidity and mortality rates. This study develops dynamic models for LF, incorporating crucial but often overlooked factors such as vertical transmission (i.e., transmission from parents to their offsprings) in rodents, surface contamination, and asymptomatic human carriers. The persistence of the disease is shown analytically. Using data from Nigeria to train the models, the impact of various control and mitigation measures is assessed. The results of the study reveal that asymptomatic individuals are key drivers of LF and that including additional LF virus transmission pathways, e.g., vertical transmission and environmental contamination, increases the estimated reproduction number threefold compared to previous studies. Models incorporating rodent dynamics show the highest disease prevalence, highlighting the critical role of rodent control. Specifically, effective interventions using only rodent control measures require maintaining rodent populations below a specific threshold. In addition, a multifaceted approach, combining antiviral treatment, environmental disinfection, and personal protective equipment, significantly enhances disease control, while the introduction of a competitor rodent species can drastically reduce human and rodent infections. Ultimately, the study underscores the need for integrated, multifaceted strategies, including targeting rodents, asymptomatic cases, and comprehensive treatment and disinfection protocols, for effective LF management.

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.

Lassa fever (LF) is a zoonotic viral hemorrhagic disease endemic to several West African countries. Approximately 300–500,000 cases occur annually across all ages with 10–20% case fatality rates. A LF vaccine is a recognized public health priority, with several candidates entering clinical trials. However, the perspectives of regional experts regarding critical vaccine properties, ideal delivery methods, and priority target populations remain unclear. Using a mixed methods approach with a standardized questionnaire, we individually interviewed 8 West African stakeholders, each with extensive knowledge and experience of LF. They strongly favored the use of a mass, proactive campaign strategy to immunize a wide age range of people in high-risk areas, including pregnant women and health care workers. We estimated that these and other plausible delivery scenarios could result in an initial demand of anywhere from 1 to 100 million doses, with most demand coming from Nigeria. These findings may help inform LF vaccine development and deployment efforts.

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).

Lassa fever virus (LASV) is the causative agent of Lassa fever, a disease endemic in West Africa. Exploring the relationships between environmental factors and LASV transmission across ecologically diverse regions can provide crucial information for the design of appropriate interventions and disease monitoring. We investigated LASV exposure in 2 ecologically diverse regions of Guinea. Our results showed that exposure to LASV was heterogenous between and within sites. LASV IgG seropositivity was 11.9% (95% CI 9.7%-14.5%) in a coastal study site in Basse-Guinée, but it was 59.6% (95% CI 55.5%-63.5%) in a forested study site located in Guinée Forestière. Seropositivity increased with age in the coastal site. We also found significant associations between exposure risk for LASV and landscape fragmentation in coastal and forested regions. Our study highlights the potential link between environmental change and LASV emergence and the urgent need for research on land management practices that reduce disease risks.