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Cell Reports May 2023Lassa 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...
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.
Topics: Humans; Lassa virus; Antibodies, Neutralizing; Lassa Fever; Glycoproteins; Antigens, Viral
PubMed: 37209096
DOI: 10.1016/j.celrep.2023.112524 -
Biotechnology and Bioengineering Mar 2021Lack of experimental human models hinders research on Lassa hemorrhagic fever and the development of treatment strategies. Here, we report the first chip-based model for...
Lack of experimental human models hinders research on Lassa hemorrhagic fever and the development of treatment strategies. Here, we report the first chip-based model for Lassa hemorrhagic syndrome. The chip features a microvessel interfacing collagen network as a simple mimic for extracellular matrix, allowing for quantitative and real-time vascular integrity assessment. Luminal infusion of Lassa virus-like particles led to a dramatic increase in vascular permeability in a viral load-dependent manner. Using this platform, we showed that Fibrin-derived peptide FX06 can be used to suppress the vascular integrity loss. This simple chip-based model proved promising in the assessment of disease severity and provides an easy-to-use platform for future investigation of Lassa pathogenesis and drug development in a human-like setting.
Topics: Human Umbilical Vein Endothelial Cells; Humans; Lab-On-A-Chip Devices; Lassa Fever; Lassa virus; Microfluidic Analytical Techniques; Models, Biological; Shock, Hemorrhagic; Syndrome
PubMed: 33241859
DOI: 10.1002/bit.27636 -
Nature Reviews. Microbiology Feb 2023Lassa virus (LASV) is endemic in the rodent populations of Sierra Leone, Nigeria and other countries in West Africa. Spillover to humans occurs frequently and results in... (Review)
Review
Lassa virus (LASV) is endemic in the rodent populations of Sierra Leone, Nigeria and other countries in West Africa. Spillover to humans occurs frequently and results in Lassa fever, a viral haemorrhagic fever (VHF) associated with a high case fatality rate. Despite advances, fundamental gaps in knowledge of the immunology, epidemiology, ecology and pathogenesis of Lassa fever persist. More frequent outbreaks, the potential for further geographic expansion of Mastomys natalensis and other rodent reservoirs, the ease of procurement and possible use and weaponization of LASV, the frequent importation of LASV to North America and Europe, and the emergence of novel LASV strains in densely populated West Africa have driven new initiatives to develop countermeasures for LASV. Although promising candidates are being evaluated, as yet there are no approved vaccines or therapeutics for human use. This Review discusses the virology of LASV, the clinical course of Lassa fever and the progress towards developing medical countermeasures.
Topics: Humans; Lassa Fever; Lassa virus; Africa, Western; Viral Vaccines
PubMed: 36097163
DOI: 10.1038/s41579-022-00789-8 -
Cell Host & Microbe Dec 2022The Lassa virus is endemic in parts of West Africa, and it causes hemorrhagic fever with high mortality. The development of a recombinant protein vaccine has been...
The Lassa virus is endemic in parts of West Africa, and it causes hemorrhagic fever with high mortality. The development of a recombinant protein vaccine has been hampered by the instability of soluble Lassa virus glycoprotein complex (GPC) trimers, which disassemble into monomeric subunits after expression. Here, we use two-component protein nanoparticles consisting of trimeric and pentameric subunits to stabilize GPC in a trimeric conformation. These GPC nanoparticles present twenty prefusion GPC trimers on the surface of an icosahedral particle. Cryo-EM studies of GPC nanoparticles demonstrated a well-ordered structure and yielded a high-resolution structure of an unliganded GPC. These nanoparticles induced potent humoral immune responses in rabbits and protective immunity against the lethal Lassa virus challenge in guinea pigs. Additionally, we isolated a neutralizing antibody that mapped to the putative receptor-binding site, revealing a previously undefined site of vulnerability. Collectively, these findings offer potential approaches to vaccine and therapeutic design for the Lassa virus.
Topics: Guinea Pigs; Rabbits; Animals; Lassa virus; Antibodies, Neutralizing; Lassa Fever; Glycoproteins; Vaccines, Synthetic; Nanoparticles
PubMed: 36400021
DOI: 10.1016/j.chom.2022.10.018 -
F1000Research 2019Lassa virus (LASV) is a highly prevalent mammarenavirus in West Africa and is maintained in nature in a persistently infected rodent host, , which is widely spread in... (Review)
Review
Lassa virus (LASV) is a highly prevalent mammarenavirus in West Africa and is maintained in nature in a persistently infected rodent host, , which is widely spread in sub-Saharan Africa. LASV infection of humans can cause Lassa fever (LF), a disease associated with high morbidity and significant mortality. Recent evidence indicates an LASV expansion outside its traditional endemic areas. In 2017, the World Health Organization (WHO) included LASV in top-priority pathogens and released a Target Product Profile (TPP) for vaccine development. Likewise, in 2018, the US Food and Drug Administration added LF to a priority review voucher program to encourage the development of preventive and therapeutics measures. In this article, we review recent progress in LASV vaccine research and development with a focus on the impact of LASV genetic and biological diversity on the design and development of vaccine candidates meeting the WHO's TPP for an LASV vaccine.
Topics: Africa, Western; Animals; Humans; Lassa Fever; Lassa virus; Murinae; Viral Vaccines
PubMed: 30774934
DOI: 10.12688/f1000research.16989.1 -
Nature Oct 2023Effective pandemic preparedness relies on anticipating viral mutations that are able to evade host immune responses to facilitate vaccine and therapeutic design....
Effective pandemic preparedness relies on anticipating viral mutations that are able to evade host immune responses to facilitate vaccine and therapeutic design. However, current strategies for viral evolution prediction are not available early in a pandemic-experimental approaches require host polyclonal antibodies to test against, and existing computational methods draw heavily from current strain prevalence to make reliable predictions of variants of concern. To address this, we developed EVEscape, a generalizable modular framework that combines fitness predictions from a deep learning model of historical sequences with biophysical and structural information. EVEscape quantifies the viral escape potential of mutations at scale and has the advantage of being applicable before surveillance sequencing, experimental scans or three-dimensional structures of antibody complexes are available. We demonstrate that EVEscape, trained on sequences available before 2020, is as accurate as high-throughput experimental scans at anticipating pandemic variation for SARS-CoV-2 and is generalizable to other viruses including influenza, HIV and understudied viruses with pandemic potential such as Lassa and Nipah. We provide continually revised escape scores for all current strains of SARS-CoV-2 and predict probable further mutations to forecast emerging strains as a tool for continuing vaccine development ( evescape.org ).
Topics: Humans; Drug Design; Evolution, Molecular; Forecasting; HIV Infections; Immune Evasion; Influenza, Human; Lassa virus; Mutation; Nipah Virus; Pandemics; SARS-CoV-2; Viral Vaccines; Viruses
PubMed: 37821700
DOI: 10.1038/s41586-023-06617-0 -
International Journal of Infectious... Jun 2022This summary on Lassa virus (LASV) infection and Lassa fever disease (LF) was developed from a clinical perspective to provide clinicians with a condensed, accessible... (Review)
Review
OBJECTIVES
This summary on Lassa virus (LASV) infection and Lassa fever disease (LF) was developed from a clinical perspective to provide clinicians with a condensed, accessible understanding of the current literature. The information provided highlights pathogenesis, clinical features, and diagnostics emphasizing therapies and vaccines that have demonstrated potential value for use in clinical or research environments.
METHODS
We conducted an integrative literature review on the clinical and pathological features, vaccines, and treatments for LASV infection, focusing on recent studies and in vivo evidence from humans and/or non-human primates (NHPs), when available.
RESULTS
Two antiviral medications with potential benefit for the treatment of LASV infection and 1 for post-exposure prophylaxis were identified, although a larger number of therapeutic candidates are currently being evaluated. Multiple vaccine platforms are in pre-clinical development for LASV prevention, but data from human clinical trials are not yet available.
CONCLUSION
We provide succinct summaries of medical countermeasures against LASV to give the busy clinician a rapid reference. Although there are no approved drugs or vaccines for LF, we provide condensed information from a literature review for measures that can be taken when faced with a suspected infection, including investigational treatment options and hospital engineering controls.
Topics: Animals; Antiviral Agents; Humans; Lassa Fever; Lassa virus; Viral Vaccines
PubMed: 35395384
DOI: 10.1016/j.ijid.2022.04.004 -
Emerging Infectious Diseases Nov 2023Lassa 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...
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.
Topics: Animals; Rats; Lassa virus; Lassa Fever; Disinfection; Sodium Hypochlorite; Africa, Western
PubMed: 37877545
DOI: 10.3201/eid2911.230678 -
Annals of Clinical Microbiology and... Apr 2021Lassa fever (LF), a zoonotic illness, represents a public health burden in West African countries where the Lassa virus (LASV) circulates among rodents. Human exposure... (Review)
Review
Lassa fever (LF), a zoonotic illness, represents a public health burden in West African countries where the Lassa virus (LASV) circulates among rodents. Human exposure hinges significantly on LASV ecology, which is in turn shaped by various parameters such as weather seasonality and even virus and rodent-host genetics. Furthermore, human behaviour, despite playing a key role in the zoonotic nature of the disease, critically affects either the spread or control of human-to-human transmission. Previous estimations on LF burden date from the 80s and it is unclear how the population expansion and the improvement on diagnostics and surveillance methods have affected such predictions. Although recent data have contributed to the awareness of epidemics, the real impact of LF in West African communities will only be possible with the intensification of interdisciplinary efforts in research and public health approaches. This review discusses the causes and consequences of LF from a One Health perspective, and how the application of this concept can improve the surveillance and control of this disease in West Africa.
Topics: Africa, Western; Animals; Disease Reservoirs; Humans; Lassa Fever; Lassa virus; One Health; Public Health; Rodentia
PubMed: 33894784
DOI: 10.1186/s12941-021-00431-0 -
Current Opinion in Virology Aug 2019Lassa fever is a unique viral hemorrhagic fever that is endemic in parts of West Africa, primarily Sierra Leone, Guinea, Liberia, and Nigeria. The disease is caused by... (Review)
Review
Lassa fever is a unique viral hemorrhagic fever that is endemic in parts of West Africa, primarily Sierra Leone, Guinea, Liberia, and Nigeria. The disease is caused by the Lassa virus, an Old World arenavirus that has as primary reservoir host the multimammate rodent Mastomys nataliensis, which lives in association with humans. Recent estimates suggest LF causes two million cases and 5000-10000 deaths annually, mainly in West Africa. Clinical diagnosis and laboratory confirmation have always been major challenges for effective management and control of the disease in afflicted areas of West Africa. Recent advancements in molecular biology, recombinant DNA technology, and genomics sequencing has facilitated major advancement in development of better diagnostic and surveillance tools for Lassa fever virus. These include, the multiplex, magnetic bead-based immunodiagnostics for both Lassa virus antigens and antibodies; molecular probe-based quantitative real-time PCR for genomic signatures; rapid diagnostics tests that detects the most prevalent West African lineages; and the successful utilization of next-generation sequencing technology to diagnose and characterize Lassa virus in West Africa. These advances will continue to improve disease treatment, control, and prevention. In this review we will discuss progression of Lassa virus diagnostics from the past and into the future.
Topics: Africa, Western; Antigens, Viral; Clinical Laboratory Techniques; Genomics; Humans; Lassa Fever; Lassa virus; Molecular Diagnostic Techniques; Serologic Tests
PubMed: 31518896
DOI: 10.1016/j.coviro.2019.08.002