A recombinant vesicular stomatitis-based Lassa fever vaccine elicits rapid and long-term protection from lethal Lassa virus infection in guinea pigs

Lassa virus (LASV) is a mammarenavirus (arenavirus) that causes zoonotic infection in humans that can lead to fatal hemorrhagic Lassa fever (LF) disease. Currently, there are no FDA-approved vaccines or therapeutics against LASV. Development of treatments against LF and other related arenavirus-induced hemorrhagic fevers (AHFs) requires relevant animal models that can recapitulate clinical and pathological features of AHF diseases in humans. Laboratory mice are generally resistant to LASV infection, and non-human primates, while being a good animal model for LF, are limited by their high cost. Here, we describe a small, affordable, and convenient animal model that is based on outbred Hartley guinea pigs infected with Pichinde virus (PICV), a mammarenavirus that is non-pathogenic in humans, for use as a surrogate model of human LF. We conducted a detailed analysis of tissue histopathology and immunohistochemical analysis of different organs of outbred Hartley guinea pigs infected with different PICV strains that show differential disease phenotypes and pathologies. Comparing to infection with the avirulent PICV strain (P2 or rP2), animals infected with the virulent strain (P18 or rP18) show extensive pathological changes in different organs that sustain high levels of virus replication. The similarity of tissue pathology and viral antigen distribution between the virulent PICV–guinea pig model and lethal human LASV infection supports a role of this small animal model as a surrogate model of studying human LF in order to understand its pathogenesis and for evaluating potential preventative and therapeutic options against AHFs.

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A Recombinant Vesicular Stomatitis Virus-Based Lassa Fever Vaccine Protects Guinea Pigs and Macaques against Challenge with Geographically and Genetically Distinct Lassa Viruses

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0003736 ◽

2015 ◽

Vol 9 (4) ◽

pp. e0003736 ◽

Cited By ~ 56

Author(s):

David Safronetz ◽

Chad Mire ◽

Kyle Rosenke ◽

Friederike Feldmann ◽

Elaine Haddock ◽

...

Keyword(s):

Vesicular Stomatitis Virus ◽

Guinea Pigs ◽

Lassa Fever ◽

Vesicular Stomatitis

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Long-Term Persistent Vesicular Stomatitis Virus and Rabies Virus Infection of Cells In Vitro

Journal of General Virology ◽

10.1099/0022-1317-33-2-193 ◽

1976 ◽

Vol 33 (2) ◽

pp. 193-211 ◽

Cited By ~ 48

Author(s):

J. J. Holland ◽

L. P. Villarreal ◽

R. M. Welsh ◽

M. B. A. Oldstone ◽

D. Kohne ◽

...

Keyword(s):

Virus Infection ◽

Rabies Virus ◽

Vesicular Stomatitis Virus ◽

Rabies Virus Infection ◽

Vesicular Stomatitis

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Acute Lassa Virus Encephalitis with Lassa Virus in the Cerebrospinal Fluid but Absent in the Blood: A Case Report with a Positive Outcome

Case Reports in Neurology ◽

10.1159/000490374 ◽

2018 ◽

Vol 10 (2) ◽

pp. 150-158 ◽

Cited By ~ 5

Author(s):

Peter O. Okokhere ◽

Cyril O. Erameh ◽

Francis Alikah ◽

Peter E. Akhideno ◽

Christopher O. Iruolagbe ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Neurological Complication ◽

Positive Outcome ◽

Lassa Fever ◽

Lassa Virus ◽

Rt Pcr ◽

Nigerian Woman ◽

The Central Nervous System ◽

High Index Of Suspicion

It is rare both to have the central nervous system (CNS) as the main focus in the acute phase of Lassa fever infection without associated bleeding, and to find Lassa virus (LAV) in the cerebrospinal fluid (CSF) but not in the serum. We report the case of a 38-year-old Nigerian woman with mainly CNS manifestation of Lassa fever. She was admitted twice within 11 days because of persistent fever. A clinical diagnosis of acute LAV encephalitis was made because of a high index of suspicion and CNS involvement confirmed by positive reverse transcriptase polymerase chain reaction (RT-PCR) for LAV in the CSF, while her blood was repeatedly negative for LAV by RT-PCR test. She recovered fully following supportive care coupled with treatment with an 18-day course of ribavirin, and suffered no long-term neurological complication or relapse. Post-treatment CSF examination by RT-PCR did not detect LAV.

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A Lassa Virus Live-Attenuated Vaccine Candidate Based on Rearrangement of the Intergenic Region

mBio ◽

10.1128/mbio.00186-20 ◽

2020 ◽

Vol 11 (2) ◽

Cited By ~ 3

Author(s):

Yingyun Cai ◽

Masaharu Iwasaki ◽

Daisuke Motooka ◽

David X. Liu ◽

Shuiqing Yu ◽

...

Keyword(s):

Intergenic Region ◽

Guinea Pigs ◽

Cultured Cells ◽

Vaccine Candidate ◽

Lassa Fever ◽

Lassa Virus ◽

Wild Type ◽

Live Attenuated Vaccine ◽

Attenuated Vaccine ◽

Western Africa

ABSTRACT Lassa virus (LASV) poses a significant public health problem within the regions of Lassa fever endemicity in Western Africa. LASV infects several hundred thousand individuals yearly, and a considerable number of Lassa fever cases are associated with high morbidity and lethality. No approved LASV vaccine is available, and current therapy is limited to an off-label usage of ribavirin that is only partially effective and associated with significant side effects. The impact of Lassa fever on human health, together with the limited existing countermeasures, highlights the importance of developing effective vaccines against LASV. Here, we present the development and characterization of a recombinant LASV (rLASV) vaccine candidate [rLASV(IGR/S-S)], which is based on the presence of the noncoding intergenic region (IGR) of the small (S) genome segment (S-IGR) in both large (L) and S LASV segments. In cultured cells, rLASV(IGR/S-S) was modestly less fit than wild-type rLASV (rLASV-WT). rLASV(IGR/S-S) was highly attenuated in guinea pigs, and a single subcutaneous low dose of the virus completely protected against otherwise lethal infection with LASV-WT. Moreover, rLASV(IGR/S-S) was genetically stable during serial passages in cultured cells. These findings indicate that rLASV(IGR/S-S) can be developed into a LASV live-attenuated vaccine (LAV) that has the same antigenic composition as LASV-WT and a well-defined mechanism of attenuation that overcomes concerns about increased virulence that could be caused by genetic changes in the LAV during multiple rounds of multiplication. IMPORTANCE Lassa virus (LASV), the causative agent of Lassa fever, infects several hundred thousand people in Western Africa, resulting in many lethal Lassa fever cases. No U.S. Food and Drug Administration-licensed countermeasures are available to prevent or treat LASV infection. We describe the generation of a novel LASV live-attenuated vaccine candidate rLASV(IGR/S-S), which is based on the replacement of the large genomic segment noncoding intergenic region (IGR) with that of the small genome segment. rLASV(IGR/S-S) is less fit in cell culture than wild-type virus and does not cause clinical signs in inoculated guinea pigs. Importantly, rLASV(IGR/S-S) protects immunized guinea pigs against an otherwise lethal exposure to LASV.

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Elevated l-threonine is a biomarker for Lassa fever and Ebola

Virology Journal ◽

10.1186/s12985-020-01459-y ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Trevor V. Gale ◽

John S. Schieffelin ◽

Luis M. Branco ◽

Robert F. Garry ◽

Donald S. Grant

Keyword(s):

Virus Infection ◽

Prognostic Value ◽

Ebola Virus ◽

Platelet Activating Factor ◽

Lassa Fever ◽

Lassa Virus ◽

Liquid Chromatography Mass Spectrometry ◽

Hemorrhagic Fevers ◽

Viral Hemorrhagic Fevers ◽

Ebola Virus Infection

Abstract Background Lassa fever and Ebola are characterized by non-specific initial presentations that can progress to severe multisystem illnesses with high fatality rates. Samples from additional subjects are examined to extend and corroborate biomarkers with prognostic value for these diseases. Methods Liquid Chromatography Mass Spectrometry metabolomics was used to identify and confirm metabolites disrupted in the blood of Lassa fever and Ebola patients. Authenticated standards are used to confirm the identify of key metabolites. Results We confirm prior results by other investigators that the amino acid l-threonine is elevated during Ebola virus infection. l-Threonine is also elevated during Lassa virus infection. We also confirmed that platelet-activating factor (PAF) and molecules with PAF moiety are reduced in the blood of patients with fatal Lassa fever. Similar changes in PAF and PAF-like molecules were not observed in the blood of Ebola patients. Conclusions Metabolomics may provide tools to identify pathways that are differentially affected during viral hemorrhagic fevers and guide development of diagnostics to monitor and predict outcome.

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Lassa Fever in Guinea: II. Distribution and Prevalence of Lassa Virus Infection in Small Mammals

Vector-Borne and Zoonotic Diseases ◽

10.1089/15303660160025912 ◽

2001 ◽

Vol 1 (4) ◽

pp. 283-297 ◽

Cited By ~ 68

Author(s):

Austin H. Demby ◽

Alphonse Inapogui ◽

Kandeh Kargbo ◽

James Koninga ◽

Kerfalla Kourouma ◽

...

Keyword(s):

Virus Infection ◽

Small Mammals ◽

Lassa Fever ◽

Lassa Virus

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Faculty Opinions recommendation of A Case of Human Lassa Virus Infection With Robust Acute T-Cell Activation and Long-Term Virus-Specific T-Cell Responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.730919539.793555409 ◽

2019 ◽

Author(s):

Igor Lukashevich

Keyword(s):

T Cell ◽

Virus Infection ◽

T Cell Activation ◽

Cell Activation ◽

T Cell Responses ◽

Lassa Virus ◽

Cell Responses

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CP100356 Hydrochloride, a P-Glycoprotein Inhibitor, Inhibits Lassa Virus Entry: Implication of a Candidate Pan-Mammarenavirus Entry Inhibitor

Viruses ◽

10.3390/v13091763 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1763

Author(s):

Toru Takenaga ◽

Zihan Zhang ◽

Yukiko Muramoto ◽

Sarah Katharina Fehling ◽

Ai Hirabayashi ◽

...

Keyword(s):

Virus Entry ◽

Lassa Fever ◽

Lymphocytic Choriomeningitis ◽

Entry Inhibitor ◽

Lassa Virus ◽

Glycoprotein P ◽

P Glycoprotein ◽

Vesicular Stomatitis ◽

Approved Drugs

Lassa virus (LASV)—a member of the family Arenaviridae—causes Lassa fever in humans and is endemic in West Africa. Currently, no approved drugs are available. We screened 2480 small compounds for their potential antiviral activity using pseudotyped vesicular stomatitis virus harboring the LASV glycoprotein (VSV-LASVGP) and a related prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV). Follow-up studies confirmed that CP100356 hydrochloride (CP100356), a specific P-glycoprotein (P-gp) inhibitor, suppressed VSV-LASVGP, LCMV, and LASV infection with half maximal inhibitory concentrations of 0.52, 0.54, and 0.062 μM, respectively, without significant cytotoxicity. Although CP100356 did not block receptor binding at the cell surface, it inhibited low-pH-dependent membrane fusion mediated by arenavirus glycoproteins. P-gp downregulation did not cause a significant reduction in either VSV-LASVGP or LCMV infection, suggesting that P-gp itself is unlikely to be involved in arenavirus entry. Finally, our data also indicate that CP100356 inhibits the infection by other mammarenaviruses. Thus, our findings suggest that CP100356 can be considered as an effective virus entry inhibitor for LASV and other highly pathogenic mammarenaviruses.

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