Quantifying the risk of spillover reduction programs for human health.

Reducing spillover of zoonotic pathogens is an appealing approach to preventing human disease and minimizing the risk of future epidemics and pandemics. Although the immediate human health benefit of reducing spillover is clear, over time, spillover reduction could lead to counterintuitive negative consequences for human health. Here, we use mathematical models and computer simulations to explore the conditions under which unanticipated consequences of spillover reduction can occur in systems where the severity of disease increases with age at infection. Our results demonstrate that, because the average age at infection increases as spillover is reduced, programs that reduce spillover can actually increase population-level disease burden if the clinical severity of infection increases sufficiently rapidly with age. If, however, immunity wanes over time and reinfection is possible, our results reveal that negative health impacts of spillover reduction become substantially less likely. When our model is parameterized using published data on Lassa virus in West Africa, it predicts that negative health outcomes are possible, but likely to be restricted to a small subset of populations where spillover is unusually intense. Together, our results suggest that adverse consequences of spillover reduction programs are unlikely but that the public health gains observed immediately after spillover reduction may fade over time as the age structure of immunity gradually re-equilibrates to a reduced force of infection.

Deciphering the enigma of Lassa virus transmission dynamics and strategies for effective epidemic control through awareness campaigns and rodenticides.

This study aims to formulate a mathematical framework to examine how the Lassa virus spreads in humans of opposite genders. The stability of the model is analyzed at an equilibrium point in the absence of the Lassa fever. The model's effectiveness is evaluated using real-life data, and all the parameters needed to determine the basic reproduction number are estimated. Sensitivity analysis is performed to pinpoint the crucial parameters significantly influencing the spread of the infection. The interaction between threshold parameters and the basic reproduction number is simulated. Control theory is employed to devise and evaluate strategies, such as awareness campaigns, advocating condom usage, and deploying rodenticides to reduce the possibility of virus transmission efficiently.

Potent immunogenicity and protective efficacy of a multi-pathogen vaccination targeting Ebola, Sudan, Marburg and Lassa viruse.

Viral haemorrhagic fevers (VHF) pose a significant threat to human health. In recent years, VHF outbreaks caused by Ebola, Marburg and Lassa viruses have caused substantial morbidity and mortality in West and Central Africa. In 2022, an Ebola disease outbreak in Uganda caused by Sudan virus resulted in 164 cases with 55 deaths. In 2023, a Marburg disease outbreak was confirmed in Equatorial Guinea and Tanzania resulting in over 49 confirmed or suspected cases; 41 of which were fatal. There are no clearly defined correlates of protection against these VHF, impeding targeted vaccine development. Any vaccine developed should therefore induce strong and preferably long-lasting humoral and cellular immunity against these viruses. Ideally this immunity should also cross-protect against viral variants, which are known to circulate in animal reservoirs and cause human disease. We have utilized two viral vectored vaccine platforms, an adenovirus (ChAdOx1) and Modified Vaccinia Ankara (MVA), to develop a multi-pathogen vaccine regime against three filoviruses (Ebola virus, Sudan virus, Marburg virus) and an arenavirus (Lassa virus). These platform technologies have consistently demonstrated the capability to induce robust cellular and humoral antigen-specific immunity in humans, most recently in the rollout of the licensed ChAdOx1-nCoV19/AZD1222. Here, we show that our multi-pathogen vaccines elicit strong cellular and humoral immunity, induce a diverse range of chemokines and cytokines, and most importantly, confers protection after lethal Ebola virus, Sudan virus and Marburg virus challenges in a small animal model.

A systematic review of mathematical models of Lassa fever.

This systematic review, conducted following the PRISMA guidelines, scrutinizes mathematical models employed in the study of Lassa fever. The analysis revealed the inherent heterogeneity in both models and data, posing significant challenges to parameter estimation. While health and behavioral interventions exhibit promise in mitigating the disease's spread, their efficacy is contingent upon contextual factors. Identified through this review are critical gaps, limitations, and avenues for future research, necessitating increased harmonization and standardization in modeling approaches. The considerations of seasonal and spatial variations emerge as crucial elements demanding targeted investigation. The perpetual threat of emerging diseases, coupled with the enduring public health impact of Lassa fever, underscores the imperative for sustained research endeavors and investments in mathematical modeling. The conclusion underscored that while mathematical modeling remains an invaluable tool in the combat against Lassa fever, its optimal utilization mandates multidisciplinary collaboration, refined data collection methodologies, and an enriched understanding of the intricate disease dynamics. This comprehensive approach is essential for effectively reducing the burden of Lassa fever and safeguarding the health of vulnerable populations.

Analysing the association between perceived knowledge, and attitudes on Lassa Fever infections and mortality risk factors in lower Bambara Chiefdom.

BACKGROUND: Lassa fever (LF) presents significant public health challenges in Sierra Leone, particularly in the Lower Bambara Chiefdom. This study aims to deeply understand how knowledge and attitudes towards LF correlate with community-driven prevention and control measures. METHODS: A descriptive cross-sectional quantitative approach was used to conduct the research. Data from 2167 participants were collected using an Android-based survey from 1st February 2022 to 14th February 2022. Respondents' knowledge of LF causes, risk factors, transmission modes, and preventive measures were evaluated through a multiple-choice questionnaire, and attitudes toward prevention and control were measured on a 5-point Likert scale. Quantitative data were analyzed using SPSS version 26.0 and frequencies were presented in count, percentage, and table. Chi-square statistics were used to test for associations. RESULTS: Among the 2167 participants, over half were males (1184, 54.60%), farmers (1406, 64.90%), married (monogamous) (1428, 65.90%), and had never attended school (1336, 61.70%). Respondents demonstrated high knowledge levels of LF across socio-demographic groups (33% to 100%) and shared a positive attitude towards prevention and control (mean score of 26.77 on a 5-40 scale). Educational level, religious beliefs, and occupational status significantly influenced LF knowledge (p < 0.05). Specifically, illiterates had a high knowledge score of 48.24%, while those with tertiary education had the highest score at 83.33%. Additionally, a Pearson correlation analysis revealed a positive linear relationship between the degree of knowledge and positive attitude towards LF infection and mortality risk factors (r = 0.090, p = 0.02). CONCLUSION: High LF knowledge in Lower Bambara Chiefdom positively influences prevention attitudes. Education, religion, and occupation are key factors. Tailored interventions enhance public health efforts.

An mRNA-LNP-based Lassa virus vaccine induces protective immunity in mice.

The mammarenavirus Lassa virus (LASV) causes the life-threatening hemorrhagic fever disease, Lassa fever. The lack of licensed medical countermeasures against LASV underscores the urgent need for the development of novel LASV vaccines, which has been hampered by the requirement for a biosafety level 4 facility to handle live LASV. Here, we investigated the efficacy of mRNA-lipid nanoparticle (mRNA-LNP)-based vaccines expressing the LASV glycoprotein precursor (LASgpc) or nucleoprotein (LCMnp) of the prototypic mammarenavirus, lymphocytic choriomeningitis virus (LCMV), in mice. Two doses of LASgpc- or LCMnp-mRNA-LNP administered intravenously (i.v.) protected C57BL/6 mice from a lethal challenge with a recombinant (r) LCMV expressing a modified LASgpc (rLCMV/LASgpc2m) inoculated intracranially. Intramuscular (i.m.) immunization with two doses of LASgpc- or LCMnp-mRNA-LNP significantly reduced the viral load in C57BL/6 mice inoculated i.v. with rLCMV/LASgpc2m. High levels of viremia and lethality were observed in CBA mice inoculated i.v. with rLCMV/LASgpc2m, which were abrogated by i.m. immunization with two doses of LASgpc-mRNA-LNP. The protective efficacy of two i.m. doses of LCMnp-mRNA-LNP was confirmed in a lethal hemorrhagic disease model of FVB mice i.v. inoculated with wild-type rLCMV. In all conditions tested, negligible and high levels of LASgpc- and LCMnp-specific antibodies were detected in mRNA-LNP-immunized mice, respectively, but robust LASgpc- and LCMnp-specific CD8+ T cell responses were induced. Accordingly, plasma from LASgpc-mRNA-LNP-immunized mice did not exhibit neutralizing activity. Our findings and surrogate mouse models of LASV infection, which can be studied at a reduced biocontainment level, provide a critical foundation for the rapid development of mRNA-LNP-based LASV vaccines.IMPORTANCELassa virus (LASV) is a highly pathogenic mammarenavirus responsible for several hundred thousand infections annually in West African countries, causing a high number of lethal Lassa fever (LF) cases. Despite its significant impact on human health, clinically approved, safe, and effective medical countermeasures against LF are not available. The requirement of a biosafety level 4 facility to handle live LASV has been one of the main obstacles to the research and development of LASV countermeasures. Here, we report that two doses of mRNA-lipid nanoparticle-based vaccines expressing the LASV glycoprotein precursor (LASgpc) or nucleoprotein (LCMnp) of lymphocytic choriomeningitis virus (LCMV), a mammarenavirus genetically closely related to LASV, conferred protection to recombinant LCMV-based surrogate mouse models of lethal LASV infection. Notably, robust LASgpc- and LCMnp-specific CD8+ T cell responses were detected in mRNA-LNP-immunized mice, whereas no virus-neutralizing activity was observed.

Rodent control strategies and Lassa virus: some unexpected effects in Guinea, West Africa.

The Natal multimammate mouse (Mastomys natalensis) is the host of Lassa mammarenavirus, causing Lassa haemorrhagic fever in West Africa. As there is currently no operational vaccine and therapeutic drugs are limited, we explored rodent control as an alternative to prevent Lassa virus spillover in Upper Guinea, where the disease is highly endemic in rural areas. In a seven-year experiment, we distributed rodenticides for 10-30 days once a year and, in the last year, added intensive snap trapping for three months in all the houses of one village. We also captured rodents both before and after the intervention period to assess their effectiveness by examining alterations in trapping success and infection rates (Lassa virus RNA and IgG antibodies). We found that both interventions reduced the rodent population by 74-92% but swiftly rebounded to pre-treatment levels, even already six months after the last snap-trapping control. Furthermore, while we observed that chemical control modestly decreased Lassa virus infection rates annually (a reduction of 5% in seroprevalence per year), the intensive trapping unexpectedly led to a significantly higher infection rate (from a seroprevalence of 28% before to 67% after snap trapping control). After seven years, we conclude that annual chemical control, alone or with intensive trapping, is ineffective and sometimes counterproductive in preventing Lassa virus spillover in rural villages. These unexpected findings may result from density-dependent breeding compensation following culling and the survival of a small percentage of chronically infected rodents that may spread the virus to a new susceptible generation of mice.

The Importance of Lassa Fever and Its Disease Management in West Africa.

Lassa virus (LASV) is a zoonotic pathogen endemic throughout western Africa and is responsible for a human disease known as Lassa fever (LF). Historically, LASV has been emphasized as one of the greatest public health threats in West Africa, with up to 300,000 cases and 5000 associated deaths per year. This, and the fact that the disease has been reported in travelers, has driven a rapid production of various vaccine candidates. Several of these vaccines are currently in clinical development, despite limitations in understanding the immune response to infection. Alarmingly, the host immune response has been implicated in the induction of sensorineural hearing loss in LF survivors, legitimately raising safety questions about any future vaccines as well as efficacy in preventing potential hearing loss. The objective of this article is to revisit the importance and prevalence of LF in West Africa, with focus on Nigeria, and discuss current therapeutic approaches and ongoing vaccine development. In addition, we aim to emphasize the need for more scientific studies relating to LF-associated hearing loss, and to promote critical discussion about potential risks and benefits of vaccinating the population in endemic regions of West Africa.

Lassa fever vaccine use cases and demand: Perspectives from select West African experts.

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.

Monoclonal antibody therapy protects nonhuman primates against mucosal exposure to Lassa virus.

Lassa fever (LF) is an acute viral illness that causes thousands of deaths annually in West Africa. There are currently no Lassa virus (LASV) vaccines or antivirals approved for human use. Recently, we showed that combinations of broadly neutralizing human monoclonal antibodies (BNhuMAbs) known as Arevirumab-2 or Arevirumab-3 protected up to 100% of cynomolgus macaques against challenge with diverse lineages of LASV when treatment was initiated at advanced stages of disease. This previous work assessed efficacy against parenteral exposure. However, transmission of LASV to humans occurs primarily by mucosal exposure to virus shed from Mastomys rodents. Here, we describe the development of a lethal intranasal exposure macaque model of LF. This model is employed to show that Arevirumab cocktails rescue 100% of macaques from lethal LASV infection when treatment is initiated 8 days after LASV exposure. Our work demonstrates BNhuMAbs have utility in treating LASV infection acquired through mucosal exposure.

[Recent advances in the development of vaccines against hemorrhagic fevers caused by arenaviruses]. / Les fièvres hémorragiques causées par les arénavirus : de récentes avancées vaccinales.

Arenaviruses are a global threat, causing thousands of deaths each year in several countries around the world. Despite strong efforts in the development of vaccine candidates, vaccines against Lassa fever or Bolivian and Venezuelan hemorrhagic fevers are yet to be licensed for a use in humans. In this synthesis, we present the arenaviruses causing fatal diseases in humans and the main vaccine candidates that have been developed over the past decades with an emphasis on the measles-Lassa vaccine, the first Lassa vaccine ever tested in humans, and on the MOPEVAC platform that can potentially be used as a pan-arenavirus vaccine platform.

Title: Les fièvres hémorragiques causées par les arénavirus : de récentes avancées vaccinales. Abstract: Le développement de vaccins contre les arénavirus est un enjeu global. En effet, plusieurs milliers de personnes meurent chaque année de la fièvre de Lassa en Afrique occidentale et les virus Machupo, Guanarito ou Chapare continuent de ré-émerger en Amérique du Sud. Pourtant, il n'existe à ce jour aucun vaccin validé pour une utilisation dans l'espèce humaine pour lutter contre ces arénavirus. Dans cette synthèse, nous présentons les différents arénavirus causant des maladies mortelles chez l'espèce humaine et les principaux candidats vaccins développés au cours des dernières décennies contre ces virus. Nous décrivons plus particulièrement le vaccin rougeole-Lassa, premier vaccin contre la fièvre de Lassa à avoir été testé dans l'espèce humaine, et la plateforme MOPEVAC qui permet de générer avec succès des vaccins mono- ou multivalents contre potentiellement tous les arénavirus pathogènes connus.

Environmental Persistence and Disinfection of Lassa Virus.

Lassa fever, caused by Lassa virus (LASV), is endemic to West Africa, where ≈300,000 illnesses and ≈5,000 deaths occur annually. LASV is primarily spread by infected multimammate rats via urine and fomites, highlighting the need to understand the environmental fate of LASV. We evaluated persistence of LASV Josiah and Sauerwald strains on surfaces, in aqueous solutions, and with sodium hypochlorite disinfection. Tested strains were more stable in deionized water (first-order rate constant [k] for Josiah, 0.23 days; for Sauerwald, k = 0.34 days) than primary influent wastewater (Josiah, k = 1.3 days; Sauerwald, k = 1.9 days). Both strains had similar decay rates on high-density polyethylene (Josiah, k = 4.3 days; Sauerwald, k = 2.3 days) and stainless steel (Josiah, k = 5.3 days; Sauerwald, k = 2.7 days). Sodium hypochlorite was highly effective at inactivating both strains. Our findings can inform future risk assessment and management efforts for Lassa fever.

A human monoclonal antibody combination rescues nonhuman primates from advanced disease caused by the major lineages of Lassa virus.

There are no approved treatments for Lassa fever (LF), which is responsible for thousands of deaths each year in West Africa. A major challenge in developing effective medical countermeasures against LF is the high diversity of circulating Lassa virus (LASV) strains with four recognized lineages and four proposed lineages. The recent resurgence of LASV in Nigeria caused by genetically distinct strains underscores this concern. Two LASV lineages (II and III) are dominant in Nigeria. Here, we show that combinations of two or three pan-lineage neutralizing human monoclonal antibodies (8.9F, 12.1F, 37.D) known as Arevirumab-2 or Arevirumab-3 can protect up to 100% of cynomolgus macaques against challenge with both lineage II and III LASV isolates when treatment is initiated at advanced stages of disease on day 8 after LASV exposure. This work demonstrates that it may be possible to develop postexposure interventions that can broadly protect against most strains of LASV.

Efficacy of microbicidal actives and formulations for inactivation of Lassa virus in suspension.

The World Health Organization's R&D Blueprint list of priority diseases for 2022 includes Lassa fever, signifying the need for research and development in emergency contexts. This disease is caused by the arenavirus Lassa virus (LASV). Being an enveloped virus, LASV should be susceptible to a variety of microbicidal actives, although empirical data to support this expectation are needed. We evaluated the virucidal efficacy of sodium hypochlorite, ethanol, a formulated dual quaternary ammonium compound, an accelerated hydrogen peroxide formulation, and a p-chloro-m-xylenol formulation, per ASTM E1052-20, against LASV engineered to express green fluorescent protein (GFP). A 10-µL volume of virus in tripartite soil (bovine serum albumin, tryptone, and mucin) was combined with 50 µL of disinfectant in suspension for 0.5, 1, 5, or 10 min at 20-25 °C. Neutralized test mixtures were quantified by GFP expression to determine log10 reduction. Remaining material was passaged on Vero cells to confirm absence of residual infectious virus. Input virus titers of 6.6-8.0 log10 per assay were completely inactivated by each disinfectant within 1-5 min contact time. The rapid and substantial inactivation of LASV suggests the utility of these microbicides for mitigating spread of infectious virus during Lassa fever outbreaks.

Inter-State Transmission of Lassa Fever during the 2015-2016 Lassa Outbreak in Nigeria: An Implication for Infection Prevention and Control Practices.

BACKGROUND: Lassa fever is an acute hemorrhagic viral disease caused by the Lassa virus. The Lassa virus belongs to the Arenaviridae family of RNA viruses. On 05/04/2016; two cases of Lassa fever were reported from Katsina State with the date of presentation of the first case on 23/03/2016 and 27/03/ 2016 for the second case. We investigated the outbreak to identify the agent and the source and propose recommendations as well as to assess the practice of infection, prevention and control (IPC). METHODS: We used descriptive study to describe contact tracing and facility assessment. We described the outbreak by time, place, and person. We defined a case using established guidelines and line-listed the contacts. We conducted IPC facility check in the state. Blood specimens were collected for Lassa fever detection. Microsoft Excel and Epi-info version 7.1.6 were used for data analysis. RESULTS: The index case of Lassa fever in Katsina State was seen on 23/03/2016 with a travel history from Kaduna State. The second case had contact with a positive Lassa fever case from Gwagwalada, Federal Capital Territory (FCT). A total of 82 contacts were line listed (9 developed Lassa fever). The case fatality rate was 27.3%. IPC checklist revealed 37.5% of the health facilities lacked personal protective equipment and safety boxes, 25% lacked isolation wards, and none had chlorine solution. Overall, 61% of personnel had poor knowledge of Lassa fever, 31% had fair knowledge and 8% had good knowledge. CONCLUSION: A multiple-source epidemic with sources of primary infection from outside Katsina state was noted. Most of the health facilities assessed lack basic IPC materials and knowledge on Lassa fever which should be addressed.

CONTEXTE: La fièvre de Lassa est une maladie virale hémorragique aiguë causée par le virus de Lassa. Le virus Lassa appartient à la famille des Arenaviridae, des virus à ARN. Le 05/04/2016 ; deux cas de fièvre de Lassa ont été signalés dans l'État de Katsina avec la date de présentation du premier cas le 23/03/2016 et le 27/03/2016 pour le second cas. Nous avons enquêté sur cette épidémie pour identifier l'agent et la source et proposer des recommandations ainsi que pour évaluer la pratique de l'infection, de la prévention et du contrôle (IPC). MÉTHODES: Nous avons utilisé une étude descriptive pour décrire la recherche des contacts et l'évaluation des installations. Nous avons décrit l'épidémie en fonction de la date, du lieu et de la personne. Nous avons défini un cas à l'aide de lignes directrices établies et dressé une liste des contacts. Nous avons vérifié les installations de CIP dans l'État. Des échantillons de sang ont été prélevés pour la détection de la fièvre de Lassa. Microsoft Excel et Epi-info version 7.1.6 ont été utilisés pour l'analyse des données. RÉSULTATS: Le cas index de fièvre de Lassa dans l'État de Katsina a été observé le 23/03/2016 avec des antécédents de voyage en provenance de l'État de Kaduna. Le deuxième cas a été en contact avec un cas positif de fièvre de Lassa à Gwagwalada, dans le Territoire de la capitale fédérale (FCT). Au total, 82 contacts ont été répertoriés (9 ont développé une fièvre de Lassa). Le taux de létalité était de 27,3%. La liste de contrôle IPC a révélé que 37,5 % des établissements de santé manquaient d'équipements de protection individuelle et de boîtes de sécurité, que 25 % n'avaient pas de salles d'isolement et qu'aucun n'avait de solution chlorée. Dans l'ensemble, 61 % du personnel avait une mauvaise connaissance de la fièvre de Lassa, 31 % une connaissance moyenne et 8 % une bonne connaissance. CONCLUSION: Une épidémie à sources multiples avec des sources d'infection primaire en dehors de l'État de Katsina a été observée. La plupart des établissements de santé évalués manquent de matériel IPC de base et de connaissances sur la fièvre de Lassa, ce qui devrait être corrigé. Mots clés: Épidémiologie, Contrôle des infections, Katsina, Épidémie, Fièvre de Lassa.

Structural conservation of Lassa virus glycoproteins and recognition by neutralizing antibodies.

Lassa fever is an acute hemorrhagic fever caused by the zoonotic Lassa virus (LASV). The LASV glycoprotein complex (GPC) mediates viral entry and is the sole target for neutralizing antibodies. Immunogen design is complicated by the metastable nature of recombinant GPCs and the antigenic differences among phylogenetically distinct LASV lineages. Despite the sequence diversity of the GPC, structures of most lineages are lacking. We present the development and characterization of prefusion-stabilized, trimeric GPCs of LASV lineages II, V, and VII, revealing structural conservation despite sequence diversity. High-resolution structures and biophysical characterization of the GPC in complex with GP1-A-specific antibodies suggest their neutralization mechanisms. Finally, we present the isolation and characterization of a trimer-preferring neutralizing antibody belonging to the GPC-B competition group with an epitope that spans adjacent protomers and includes the fusion peptide. Our work provides molecular detail information on LASV antigenic diversity and will guide efforts to design pan-LASV vaccines.

Lassa fever vaccine candidates: A scoping review of vaccine clinical trials.

OBJECTIVE: Lassa fever (LF) is caused by a viral pathogen with pandemic potential. LF vaccines have the potential to prevent significant disease in individuals at risk of infection, but no such vaccine has been licensed or authorised for use thus far. We conducted a scoping review to identify and compare registered phase 1, 2 or 3 clinical trials of LF vaccine candidates, and appraise the current trajectory of LF vaccine development. METHOD: We systematically searched 24 trial registries, PubMed, relevant conference abstracts and additional grey literature sources up to 27 October 2022. After extracting key details about each vaccine candidate and each eligible trial, we qualitatively synthesised the evidence. RESULTS: We found that four LF vaccine candidates (INO-4500, MV-LASV, rVSV∆G-LASV-GPC, and EBS-LASV) have entered the clinical stage of assessment. Five phase 1 trials (all focused on healthy adults) and one phase 2 trial (involving a broader age group from 18 months to 70 years) evaluating one of these vaccines have been registered to date. Here, we describe the characteristics of each vaccine candidate and trial and compare them to WHO's target product profile for Lassa vaccines. CONCLUSION: Though LF vaccine development is still in early stages, current progress towards a safe and effective vaccine is encouraging.

Lassa Virus Structural Biology and Replication.

Lassa virus (LASV) is the causative agent of Lassa fever, an often-fatal hemorrhagic fever that is endemic in West Africa. LASV virions are enveloped and contain two single-stranded RNA genome segments. Both segments are ambisense and encode two proteins. The nucleoprotein associates with viral RNAs forming ribonucleoprotein complexes. The glycoprotein complex mediates viral attachment and entry. The Zinc protein serves as the matrix protein. Large is a polymerase that catalyzes viral RNA transcription and replication. LASV virion entry occurs via a clathrin-independent endocytic pathway usually involving alpha-dystroglycan and lysosomal associated membrane protein 1 as surface and intracellular receptors, respectively. Advances in understanding LASV structural biology and replication have facilitated development of promising vaccine and drug candidates.

Deletion of the first glycosylation site promotes Lassa virus glycoprotein-mediated membrane fusion.

The Lassa virus (LASV) is endemic in West Africa and causes severe hemorrhagic Lassa fever in humans. The glycoprotein complex (GPC) of LASV is highly glycosylation-modified, with 11 â€‹N-glycosylation sites. All 11 N-linked glycan chains play critical roles in GPC cleavage, folding, receptor binding, membrane fusion, and immune evasion. In this study, we focused on the first glycosylation site because its deletion mutant (N79Q) results in an unexpected enhanced membrane fusion, whereas it exerts little effect on GPC expression, cleavage, and receptor binding. Meanwhile, the pseudotype virus bearing GPCN79Q was more sensitive to the neutralizing antibody 37.7H and was attenuated in virulence. Exploring the biological functions of the key glycosylation site on LASV GPC will help elucidate the mechanism of LASV infection and provide strategies for the development of attenuated vaccines against LASV infection.