Baseline mapping of Lassa fever virology, epidemiology and vaccine research and development

Hallam, Hoai J.; Hallam, Steven J.; Rodriguez, Sergio E.; Barrett, Alan D.T.; Beasley, David W.C.; Chua, Arlene; Ksiazek, Thomas G.; Milligan, Gregg N.; Sathiyamoorthy, Vaseeharan; Reece, Lisa M.

doi:10.1038/s41541-018-0049-5

Cited by 94 publications

(84 citation statements)

References 136 publications

(176 reference statements)

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“…To demonstrate the application of V ALL in the case of an outbreak, we applied it to samples of clinically confirmed (by qRT-PCR) Lassa fever cases from Nigeria. In 2018, Nigeria experienced a sharp increase in cases of Lassa fever, a severe hemorrhagic disease caused by LASV 45 , leading the World Health Organization and the Nigeria Centre for Disease Control to declare it an outbreak 46, 47 . Previous genome sequencing of LASV has revealed its extensive genetic diversity, with distinct lineages circulating in different parts of the endemic region 3,48 , and ongoing sequencing can enable rapid identification of changes in this genetic landscape.…”

Section: Rescuing Lassa Virus Genomes In Patient Samples From Nigeriamentioning

confidence: 99%

Capturing diverse microbial sequence with comprehensive and scalable probe design

Gladden-Young

et al. 2018

Preprint

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Metagenomic sequencing has the potential to transform microbial detection and characterization, but new tools are needed to improve its sensitivity. We developed CATCH (Compact Aggregation of Targets for Comprehensive Hybridization), a computational method to enhance nucleic acid capture for enrichment of diverse microbial taxa, and implemented it in a publicly available software package. CATCH designs compact probe sets that achieve full coverage of known microbial sequence diversity and that scale well with this diversity. Using CATCH, we designed and synthesized multiple probe sets, including one to capture whole genomes of the 356 viral species known to infect humans, and conducted a rigorous evaluation of their performance. Capture with these probe sets enriched unique viral content on average 18× in sequencing libraries from patient and environmental samples and allowed us to assemble viral genomes that we could not otherwise recover. We show that capture accurately reflects co-infections and within-host nucleotide variation, enriches sequence with substantial divergence from the probe sets, and improves detection of viral infections in samples with unknown microbial content. Our work provides a new approach to probe design and evaluation, and demonstrates a path toward more sensitive, cost-effective metagenomic sequencing.

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Section: Rescuing Lassa Virus Genomes In Patient Samples From Nigeriamentioning

confidence: 99%

Capturing diverse microbial sequence with comprehensive and scalable probe design

Gladden-Young

et al. 2018

Preprint

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“…As the most clinically significant member of this large family, LASV is a major pathogen in West Africa, where it infects an estimated 300,000 people each year. LASV has also been responsible for a number of imported cases of Lassa hemorrhagic fever (LHF) in Europe and North America in recent years (1). The 2018 outbreak of LHF in Nigeria was particularly severe, with over 430 confirmed positive cases and a case fatality rate of ϳ25% (2).…”

mentioning

confidence: 99%

“…Arbidol suppresses LASV GP-mediated cell-cell fusion (CCF). Effector cells were generated by transfecting HEK293T/17 cells with plasmids encoding DSP[1][2][3][4][5][6][7] (the N-terminal split luciferase plasmid) and either LASV GP (A) or WSN influenza HA and NA (B). Target cells were generated by transfecting HEK293T/17 cells with plasmids encoding DSP[8][9][10][11] (the C-terminal split luciferase plasmid) and pmLamp1.…”

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confidence: 99%

Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses

Hulseberg

Fénéant

Wijs

et al. 2019

J Virol

130

138

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Antiviral therapies that impede virus entry are attractive because they act on the first phase of the infectious cycle. Drugs that target pathways common to multiple viruses are particularly desirable when laboratory-based viral identification may be challenging, e.g., in an outbreak setting. We are interested in identifying drugs that block both Ebola virus (EBOV) and Lassa virus (LASV), two unrelated but highly pathogenic hemorrhagic fever viruses that have caused outbreaks in similar regions in Africa and share features of virus entry: use of cell surface attachment factors, macropinocytosis, endosomal receptors, and low pH to trigger fusion in late endosomes. Toward this goal, we directly compared the potency of eight drugs known to block EBOV entry with their potency as inhibitors of LASV entry. Five drugs (amodiaquine, apilimod, arbidol, niclosamide, and zoniporide) showed roughly equivalent degrees of inhibition of LASV and EBOV glycoprotein (GP)-bearing pseudoviruses; three (clomiphene, sertraline, and toremifene) were more potent against EBOV. We then focused on arbidol, which is licensed abroad as an anti-influenza drug and exhibits activity against a diverse array of clinically relevant viruses. We found that arbidol inhibits infection by authentic LASV, inhibits LASV GP-mediated cell-cell fusion and virus-cell fusion, and, reminiscent of its activity on influenza virus hemagglutinin, stabilizes LASV GP to low-pH exposure. Our findings suggest that arbidol inhibits LASV fusion, which may partly involve blocking conformational changes in LASV GP. We discuss our findings in terms of the potential to develop a drug cocktail that could inhibit both LASV and EBOV. IMPORTANCE Lassa and Ebola viruses continue to cause severe outbreaks in humans, yet there are only limited therapeutic options to treat the deadly hemorrhagic fever diseases they cause. Because of overlapping geographic occurrences and similarities in mode of entry into cells, we seek a practical drug or drug cocktail that could be used to treat infections by both viruses. Toward this goal, we directly compared eight drugs, approved or in clinical testing, for the ability to block entry mediated by the glycoproteins of both viruses. We identified five drugs with approximately equal potencies against both. Among these, we investigated the modes of action of arbidol, a drug licensed abroad to treat influenza infections. We found, as shown for influenza virus, that arbidol blocks fusion mediated by the Lassa virus glycoprotein. Our findings encourage the development of a combination of approved drugs to treat both Lassa and Ebola virus diseases. FIG 2 Comparative effects of arbidol on infection by MLV pseudoviruses bearing LASV or other viral glycoproteins: LASV, LCMV, and Junin GP (A) and LASV GP and influenza virus HA (B). MLV pseudoviruses bearing LASV GP, LCMV GP, Junin GP, or WSN influenza HA and NA were prepared as described in Materials and Methods. BSC-1 cells were pretreated with the indicated concentrations of arbidol and then processed an...

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“…Given the annual incidence of Lassa fever, vaccine licensure will likely proceed via a traditional approval pathway and multi-site efficacy trials in West Africa, rather than through the US Food and Drug Administration's "Animal Rule" [59]. Moreover, as the molecular pathogenesis of LASV infection and immune correlates of protection are not fully understood, the value of animal models in predicting clinical outcomes to vaccination may be limited.…”

Section: Animal Models For Lassa Fever Vaccine Developmentmentioning

confidence: 99%

Vaccine platforms for the prevention of Lassa fever

2019

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A B S T R A C TLassa fever is an acute viral haemorrhagic illness caused by Lassa virus (LASV), which is endemic throughout much of West Africa. The virus primarily circulates in the Mastomys natalensis reservoir and is transmitted to humans through contact with infectious rodents or their secretions; human-to-human transmission is documented as well. With the exception of Dengue fever, LASV has the highest human impact of any haemorrhagic fever virus. On-going outbreaks in Nigeria have resulted in unprecedented mortality. Consequently, the World Health Organization (WHO) has listed LASV as a high priority pathogen for the development of treatments and prophylactics. Currently, there are no licensed vaccines to protect against LASV infection. Although numerous candidates have demonstrated efficacy in animal models, to date, only a single candidate has advanced to clinical trials. Lassa fever vaccine development efforts have been hindered by the high cost of biocontainment requirements, the absence of established correlates of protection, and uncertainty regarding the extent to which animal models are predictive of vaccine efficacy in humans. This review briefly discusses the epidemiology and biology of LASV infection and highlights recent progress in vaccine development.

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Baseline mapping of Lassa fever virology, epidemiology and vaccine research and development

Cited by 94 publications

References 136 publications

Capturing diverse microbial sequence with comprehensive and scalable probe design

Capturing diverse microbial sequence with comprehensive and scalable probe design

Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses

Vaccine platforms for the prevention of Lassa fever

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