scholarly journals A Single Dose of Modified Vaccinia Ankara Expressing Lassa Virus-like Particles Protects Mice from Lethal Intra-cerebral Virus Challenge

Pathogens ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 133 ◽  
Author(s):  
Maria S. Salvato ◽  
Arban Domi ◽  
Camila Guzmán-Cardozo ◽  
Sandra Medina-Moreno ◽  
Juan Carlos Zapata ◽  
...  
Keyword(s):  
Single Dose ◽  
Matrix Protein ◽  
Lethal Dose ◽  
Health Impact ◽  
Lassa Virus ◽  
Protein Z ◽  
Glycoprotein Precursor ◽  
Lethal Challenge ◽  
Virus Like Particles ◽  
Virus Challenge

Lassa fever surpasses Ebola, Marburg, and all other hemorrhagic fevers except Dengue in its public health impact. Caused by Lassa virus (LASV), the disease is a scourge on populations in endemic areas of West Africa, where reported incidence is higher. Here, we report construction, characterization, and preclinical efficacy of a novel recombinant vaccine candidate GEO-LM01. Constructed in the Modified Vaccinia Ankara (MVA) vector, GEO-LM01 expresses the glycoprotein precursor (GPC) and zinc-binding matrix protein (Z) from the prototype Josiah strain lineage IV. When expressed together, GP and Z form Virus-Like Particles (VLPs) in cell culture. Immunogenicity and efficacy of GEO-LM01 was tested in a mouse challenge model. A single intramuscular dose of GEO-LM01 protected 100% of CBA/J mice challenged with a lethal dose of ML29, a Mopeia/Lassa reassortant virus, delivered directly into the brain. In contrast, all control animals died within one week. The vaccine induced low levels of antibodies but Lassa-specific CD4+ and CD8+ T cell responses. This is the first report showing that a single dose of a replication-deficient MVA vector can confer full protection against a lethal challenge with ML29 virus.

scholarly journals ChAdOx1-vectored Lassa fever vaccine elicits a robust cellular and humoral immune response and protects guinea pigs against lethal Lassa virus challenge

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Robert J. Fischer ◽  
Jyothi N. Purushotham ◽  
Neeltje van Doremalen ◽  
Sarah Sebastian ◽  
Kimberly Meade-White ◽  
...  
Keyword(s):  
Single Dose ◽  
Guinea Pigs ◽  
Lassa Fever ◽  
Therapeutic Interventions ◽  
Lassa Virus ◽  
Glycoprotein Precursor ◽  
Lethal Challenge ◽  
Virus Challenge ◽  
Humoral Immune ◽  
Vectored Vaccine

AbstractLassa virus (LASV) infects hundreds of thousands of individuals each year, highlighting the need for the accelerated development of preventive, diagnostic, and therapeutic interventions. To date, no vaccine has been licensed for LASV. ChAdOx1-Lassa-GPC is a chimpanzee adenovirus-vectored vaccine encoding the Josiah strain LASV glycoprotein precursor (GPC) gene. In the following study, we show that ChAdOx1-Lassa-GPC is immunogenic, inducing robust T-cell and antibody responses in mice. Furthermore, a single dose of ChAdOx1-Lassa-GPC fully protects Hartley guinea pigs against morbidity and mortality following lethal challenge with a guinea pig-adapted LASV (strain Josiah). By contrast, control vaccinated animals reached euthanasia criteria 10–12 days after infection. Limited amounts of LASV RNA were detected in the tissues of vaccinated animals. Viable LASV was detected in only one animal receiving a single dose of the vaccine. A prime-boost regimen of ChAdOx1-Lassa-GPC in guinea pigs significantly increased antigen-specific antibody titers and cleared viable LASV from the tissues. These data support further development of ChAdOx1-Lassa-GPC and testing in non-human primate models of infection.

Characterization of the Lassa virus matrix protein Z: electron microscopic study of virus-like particles and interaction with the nucleoprotein (NP)

2004 ◽  
Vol 100 (2) ◽  
pp. 249-255 ◽  
Author(s):  
Robert Eichler ◽  
Thomas Strecker ◽  
Larissa Kolesnikova ◽  
Jan ter Meulen ◽  
Winfried Weissenhorn ◽  
...  
Keyword(s):  
Microscopic Study ◽  
Electron Microscopic Study ◽  
Matrix Protein ◽  
Lassa Virus ◽  
Electron Microscopic ◽  
Protein Z ◽  
Virus Like Particles

scholarly journals Lassa Virus Z Protein Is a Matrix Protein Sufficient for the Release of Virus-Like Particles

2003 ◽  
Vol 77 (19) ◽  
pp. 10700-10705 ◽  
Author(s):  
Thomas Strecker ◽  
Robert Eichler ◽  
Jan ter Meulen ◽  
Winfried Weissenhorn ◽  
Hans Dieter Klenk ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Viral Proteins ◽  
Lassa Virus ◽  
Glycoprotein Precursor ◽  
Particle Release ◽  
Virus Like Particles ◽  
Enveloped Virus ◽  
Viral Particles ◽  
Z Protein ◽  
Late Domains

ABSTRACT Lassa virus is an enveloped virus with glycoprotein spikes on its surface. It contains an RNA ambisense genome that encodes the glycoprotein precursor GP-C, the nucleoprotein NP, the polymerase L, and the Z protein. Here we demonstrate that the Lassa virus Z protein (i) is abundant in viral particles, (ii) is strongly membrane associated, (iii) is sufficient in the absence of all other viral proteins to release enveloped particles, and (iv) contains two late domains, PTAP and PPXY, necessary for the release of virus-like particles. Our data provide evidence that Z is the Lassa virus matrix protein that is the driving force for virus particle release.

scholarly journals Adenovirus vectored IFN-α protects mice from lethal challenge of Chikungunya virus infection

2020 ◽  
Vol 14 (12) ◽  
pp. e0008910
Author(s):  
Huixin Chen ◽  
Nyo Min ◽  
Luyao Ma ◽  
Chee-Keng Mok ◽  
Justin Jang Hann Chu
Keyword(s):  
Single Dose ◽  
Chikungunya Virus ◽  
Lethal Dose ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Chikv Infection ◽  
Lethal Challenge ◽  
Virus Challenge ◽  
Multiple Organs

Chikungunya virus (CHIKV) is a mosquito-borne pathogen that is responsible for numerous large and geographical epidemics, causing millions of cases. However, there is no vaccine or therapeutics against CHIKV infection available. Interferon-alpha (IFN-α) has been shown to produce potent antiviral responses during viral infection. Herein we demonstrated the use of an adenovirus-vectored expressed mouse IFN-α (mDEF201) as a prophylactic and therapeutic treatment against CHIKV in vivo. 6-day-old BALB/c mice were pre- or post-treated intranasally with single dose of mDEF201 at 5 x 106 PFU per mouse and challenged with lethal dose of CHIKV. Complete survival protection was observed in mice upon a single dose of mDEF201 administration 1 days prior to virus challenge. Viral load in the serum and multiple organs were significantly reduced upon mDEF201 administration in a dose dependent manner as compare with adenovirus 5 vector placebo set. Histological analysis of the mice tissue revealed that mDEF201 could significantly reduce the tissue morphological abnormities, mainly infiltration of immune cells and muscle fibre necrosis caused by CHIKV infection. In addition, administration of mDEF201 at 6 hours post CHIKV challenge also showed promising inhibitory effect against viral replication and dissemination. In conclusion, single-dose of intranasal administration with mDEF201 as a prophylactic or therapeutic agent within 6 hours post CHIKV infection is highly protective against a lethal challenge of CHIKV in the murine model.

scholarly journals Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge

2019 ◽  
Vol 11 (494) ◽  
pp. eaau9242 ◽  
Author(s):  
Michael K. Lo ◽  
Friederike Feldmann ◽  
Joy M. Gary ◽  
Robert Jordan ◽  
Roy Bannister ◽  
...  
Keyword(s):  
Virus Disease ◽  
Antiviral Treatment ◽  
Lethal Dose ◽  
Nipah Virus ◽  
Case Fatality ◽  
Emerging Pathogen ◽  
Lethal Challenge ◽  
Once Daily ◽  
Virus Challenge ◽  
Green Monkeys

Nipah virus is an emerging pathogen in the Paramyxoviridae family. Upon transmission of Nipah virus from its natural reservoir, Pteropus spp. fruit bats, to humans, it causes respiratory and neurological disease with a case-fatality rate about 70%. Human-to-human transmission has been observed during Nipah virus outbreaks in Bangladesh and India. A therapeutic treatment for Nipah virus disease is urgently needed. Here, we tested the efficacy of remdesivir (GS-5734), a broad-acting antiviral nucleotide prodrug, against Nipah virus Bangladesh genotype in African green monkeys. Animals were inoculated with a lethal dose of Nipah virus, and a once-daily intravenous remdesivir treatment was initiated 24 hours later and continued for 12 days. Mild respiratory signs were observed in two of four treated animals, whereas all control animals developed severe respiratory disease signs. In contrast to control animals, which all succumbed to the infection, all remsdesivir-treated animals survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment for Nipah virus infection.

scholarly journals Lassa Virus Z Protein Is a Matrix Protein and Sufficient for the Release of Virus-Like Particles

2003 ◽  
Vol 77 (23) ◽  
pp. 12927-12927 ◽  
Author(s):  
Thomas Strecker ◽  
Robert Eichler ◽  
Jan ter Meulen ◽  
Winfried Weissenhorn ◽  
Hans Dieter Klenk ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Lassa Virus ◽  
Virus Like Particles ◽  
Z Protein

scholarly journals Intranasal Vaccination with 1918 Influenza Virus-Like Particles Protects Mice and Ferrets from Lethal 1918 and H5N1 Influenza Virus Challenge

2009 ◽  
Vol 83 (11) ◽  
pp. 5726-5734 ◽  
Author(s):  
Lucy A. Perrone ◽  
Attiya Ahmad ◽  
Vic Veguilla ◽  
Xiuhua Lu ◽  
Gale Smith ◽  
...  
Keyword(s):  
Influenza Virus ◽  
H5n1 Virus ◽  
Influenza Pandemic ◽  
Human Case ◽  
Lethal Challenge ◽  
Virus Like Particles ◽  
Virus Challenge ◽  
H5n1 Influenza ◽  
Pandemic Virus ◽  
Homologous Virus

ABSTRACT Influenza vaccines capable of inducing cross-reactive or heterotypic immunity could be an important first line of prevention against a novel subtype virus. Influenza virus-like particles (VLPs) displaying functional viral proteins are effective vaccines against replication-competent homologous virus, but their ability to induce heterotypic immunity has not been adequately tested. To measure VLP vaccine efficacy against a known influenza pandemic virus, recombinant VLPs were generated from structural proteins of the 1918 H1N1 virus. Mucosal and traditional parenteral administrations of H1N1 VLPs were compared for the ability to protect against the reconstructed 1918 virus and a highly pathogenic avian H5N1 virus isolated from a fatal human case. Mice that received two intranasal immunizations of H1N1 VLPs were largely protected against a lethal challenge with both the 1918 virus and the H5N1 virus. In contrast, mice that received two intramuscular immunizations of 1918 VLPs were only protected against a homologous virus challenge. Mucosal vaccination of mice with 1918 VLPs induced higher levels of cross-reactive immunoglobulin G (IgG) and IgA antibodies than did parenteral vaccination. Similarly, ferrets mucosally vaccinated with 1918 VLPs completely survived a lethal challenge with the H5N1 virus, while only a 50% survival rate was observed in parenterally vaccinated animals. These results suggest a strategy of VLP vaccination against a pandemic virus and one that stimulates heterotypic immunity against an influenza virus strain with threatening pandemic potential.

scholarly journals Analysis of Assembly and Budding of Lujo Virus

2015 ◽  
Vol 90 (6) ◽  
pp. 3257-3261 ◽  
Author(s):  
Shuzo Urata ◽  
Jacqueline Weyer ◽  
Nadia Storm ◽  
Yukiko Miyazaki ◽  
Petrus Jansen van Vuren ◽  
...  
Keyword(s):  
Cell Surface ◽  
Matrix Protein ◽  
Hemorrhagic Fever ◽  
Surface Glycoprotein ◽  
Protein Z ◽  
Glycoprotein Precursor ◽  
Cell Surface Glycoprotein ◽  
Particle Release ◽  
Viral Release ◽  
Virus Like Particle

The recently identified arenavirus Lujo virus (LUJV) causes fatal hemorrhagic fever in humans. We analyzed its mechanism of viral release driven by matrix protein Z and the cell surface glycoprotein precursor GPC. The L domains in Z are required for efficient virus-like particle release, but Tsg101, ALIX/AIP1, and Vps4A/B are unnecessary for budding. LUJV GPC is cleaved by site 1 protease (S1P) at the RKLM motif, and treatment with the S1P inhibitor PF-429242 reduced LUJV production.

scholarly journals Efficient Budding of the Tacaribe Virus Matrix Protein Z Requires the Nucleoprotein

2010 ◽  
Vol 84 (7) ◽  
pp. 3603-3611 ◽  
Author(s):  
Allison Groseth ◽  
Svenja Wolff ◽  
Thomas Strecker ◽  
Thomas Hoenen ◽  
Stephan Becker
Keyword(s):  
Essential Role ◽  
New World ◽  
Matrix Protein ◽  
Protein Z ◽  
Virus Like Particles ◽  
Endosomal Sorting ◽  
Virus Particles ◽  
Tacaribe Virus ◽  
C Terminus ◽  
Z Protein

ABSTRACT The Z protein has been shown for several arenaviruses to serve as the viral matrix protein. As such, Z provides the principal force for the budding of virus particles and is capable of forming virus-like particles (VLPs) when expressed alone. For most arenaviruses, this activity has been shown to be linked to the presence of proline-rich late-domain motifs in the C terminus; however, for the New World arenavirus Tacaribe virus (TCRV), no such motif exists within Z. It was recently demonstrated that while TCRV Z is still capable of functioning as a matrix protein to induce the formation of VLPs, neither its ASAP motif, which replaces a canonical PT/SAP motif in related viruses, nor its YxxL motif is involved in budding, leading to the suggestion that TCRV uses a novel budding mechanism. Here we show that in comparison to its closest relative, Junin virus (JUNV), TCRV Z buds only weakly when expressed in isolation. While this budding activity is independent of the ASAP or YxxL motif, it is significantly enhanced by coexpression with the nucleoprotein (NP), an effect not seen with JUNV Z. Interestingly, both the ASAP and YxxL motifs of Z appear to be critical for the recruitment of NP into VLPs, as well as for the enhancement of TCRV Z-mediated budding. While it is known that TCRV budding remains dependent on the endosomal sorting complex required for transport, our findings provide further evidence that TCRV uses a budding mechanism distinct from that of other known arenaviruses and suggest an essential role for NP in this process.

scholarly journals Protective Immunity against Tularemia Provided by an Adenovirus-Vectored Vaccine Expressing Tul4 of Francisella tularensis

2012 ◽  
Vol 19 (3) ◽  
pp. 359-364 ◽  
Author(s):  
Ravinder Kaur ◽  
Shan Chen ◽  
Maria T. Arévalo ◽  
Qingfu Xu ◽  
Yanping Chen ◽  
...  
Keyword(s):  
Single Dose ◽  
Francisella Tularensis ◽  
Virulent Strain ◽  
Lethal Dose ◽  
Protein Vaccine ◽  
Lethal Challenge ◽  
Live Attenuated Vaccine ◽  
Content Type ◽  
Skin Contact ◽  
Vectored Vaccine

ABSTRACTFrancisella tularensis, a category A bioterrorism agent, is a highly infectious organism that is passed on via skin contact and inhalation routes. A live attenuated vaccine strain (LVS) has been developed, but it has not been licensed for public use by the FDA due to safety concerns. Thus, there exists a need for a safer and improved vaccine. In this study, we have constructed a replication-incompetent adenovirus, Ad/opt-Tul4, carrying a codon-optimized gene for expression of a membrane protein, Tul4, ofF. tularensisLVS. Its ability to protect against lethal challenge and its immunogenicity were evaluated in a murine model. An intramuscular injection of a single dose (1 × 107PFU) of Ad/opt-Tul4 elicited a robust Tul4-specific antibody response. Assays suggest a Th1-driven response. A single dose elicited 20% protection against challenge with 100 × 50% lethal dose (LD50)F. tularensisLVS; two additional booster shots resulted in 60% protection. In comparison, three doses of 5 μg recombinant Tul4 protein did not elicit significant protection against challenge. Therefore, the Ad/opt-Tul4 vaccine was more effective than the protein vaccine, and protection was dose dependent. Compared to LVS, the protection rate is lower, but an adenovirus-vectored vaccine may be more attractive due to its enhanced safety profile and mucosal route of delivery. Furthermore, simple genetic modification of the vaccine may potentially produce antibodies protective against a fully virulent strain ofF. tularensis. Our data support the development and further research of an adenovirus-vectored vaccine against Tul4 ofF. tularensisLVS.

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