scholarly journals Treatment of Yellow Fever Virus with an Adenovirus-Vectored Interferon, DEF201, in a Hamster Model

2011 ◽  
Vol 55 (5) ◽  
pp. 2067-2073 ◽  
Author(s):  
Justin G. Julander ◽  
Jane Ennis ◽  
Jeffrey Turner ◽  
John D. Morrey
Keyword(s):  
Yellow Fever ◽  
Viral Infections ◽  
Yellow Fever Virus ◽  
Adenovirus Type ◽  
Fever Virus ◽  
Hamster Model ◽  
Virus Challenge ◽  
Infection Treatment ◽  
Effective Prophylaxis ◽  
Adenovirus Type 5

ABSTRACTInterferon (IFN) is an innate immune response protein that is involved in the antiviral response during viral infection. Treatment of acute viral infections with exogenous interferon may be effective but is generally not feasible for clinical use due to many factors, including cost, stability, and availability. To overcome these limitations, an adenovirus type 5-vectored consensus alpha IFN, termed DEF201, was constructed as a potential way to deliver sustained therapeutic levels of systemic IFN. To demonstrate the efficacy of DEF201 against acute flaviviral disease, various concentrations of the construct were administered as a single intranasal dose prior to virus infection, which resulted in a dose-responsive, protective effect in a hamster model of yellow fever virus (YFV) disease. A DEF201 dose of 5 × 107PFU/animal administered intranasally just prior to YFV challenge protected 100% of the animals, while a 10-fold lower DEF201 dose exhibited lower, although significant, levels of protection. Virus titers in the liver and serum and levels of serum alanine aminotransferase were all significantly reduced as a result of DEF201 administration at all doses tested. No toxicity, as indicated by weight loss or gross morbidity, was observed in non-YFV-infected animals treated with DEF201. Protection of YFV-infected animals was observed when DEF201 was delivered as early as 7 days prior to virus challenge and as late as 2 days after virus challenge, demonstrating effective prophylaxis and therapy in a hamster model of disease. Overall, it appears that DEF201 is effective in the treatment of YFV in a hamster model.

scholarly journals Activity of T-705 in a Hamster Model of Yellow Fever Virus Infection in Comparison with That of a Chemically Related Compound, T-1106

2008 ◽  
Vol 53 (1) ◽  
pp. 202-209 ◽  
Author(s):  
Justin G. Julander ◽  
Kristiina Shafer ◽  
Donald F. Smee ◽  
John D. Morrey ◽  
Yousuke Furuta
Keyword(s):  
Cell Culture ◽  
Yellow Fever ◽  
Related Compound ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Yield Reduction ◽  
Hamster Model ◽  
Virus Challenge ◽  
Antiviral Efficacy ◽  
Disease Parameters

ABSTRACT Treatment with the nucleoside analog T-1106 was previously shown to be effective in a hamster model of yellow fever virus (YFV) disease, even though it had only slight activity in cell culture. In the study described in this report, the activity of T-705, a chemically related compound currently undergoing clinical trials for the treatment of influenza (FDANews 4:1, 2007), was tested against YFV in cell culture and in the hamster model. The antiviral efficacy of T-705 in cell culture occurred at a concentration of 330 μM, which was more than threefold lower than the concentration at which T-1106 had antiviral efficacy, as determined by a virus yield reduction assay and confirmed by a luciferase-based ATP detection assay. Time-of-addition studies revealed that addition of T-705, T-1106, or ribavirin at 0, 4, 8, or 12 h after virus challenge was effective in inhibiting virus in Vero cells, suggesting that these three agents have similar mechanisms of action in cell culture. Because of its more potent activity in cell culture, it was anticipated that T-705 treatment of hamsters infected with YFV would result in protection from disease. Significant improvements in survival and disease parameters were seen in infected animals when T-705 was administered orally at a dose of 200 or 400 mg/kg of body weight per day when it was given twice a day for 8 days. Significant improvements were also observed with a dose of 400 mg/kg/day when treatment initiation was delayed as late as 3 days after virus inoculation. Although the dose of T-705 required for efficacy in hamsters is higher than that of T-1106 required for efficacy, T-705 treatment is effective in significantly improving disease parameters in YFV-infected hamsters, which may indicate its potential utility in the treatment of YFV disease in humans.

scholarly journals Activity of T-1106 in a Hamster Model of Yellow Fever Virus Infection

2007 ◽  
Vol 51 (6) ◽  
pp. 1962-1966 ◽  
Author(s):  
Justin G. Julander ◽  
Yousuke Furuta ◽  
Kristiina Shafer ◽  
Robert W. Sidwell
Keyword(s):  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Virus Titer ◽  
Fever Virus ◽  
Virus Inoculation ◽  
Hamster Model ◽  
Minimal Effective Dose ◽  
Virus Challenge ◽  
Cell Culture Assay ◽  
Favorable Safety

ABSTRACT Yellow fever virus (YFV) causes 30,000 deaths worldwide, despite the availability of a vaccine. There are no approved antiviral therapies for the treatment of YFV disease in humans, and, therefore, these studies were designed to investigate the anti-YFV properties of T-1106, a substituted pyrazine, in a hamster model of YFV disease. Intraperitoneal (i.p.) treatment with 100 mg/kg of body weight/day of T-1106 starting 4 h prior to virus inoculation and continuing twice daily through 7 days post-virus inoculation (dpi) resulted in significantly improved survival, alanine aminotransferase levels in the serum, weight gain, and mean day to death. Virus titer in the liver at 4 dpi was significantly reduced in treated animals, as determined by both quantitative real-time PCR and infectious cell culture assay. No toxicity (weight loss or mortality) was observed at a dose of 100 mg/kg/day in sham-infected control animals. The observed minimal effective dose of T-1106 was 32 mg/kg/day administered either by oral or i.p. treatment. Therapeutic treatment was effective in significantly improving survival when T-1106 was administered beginning as late as 4 days after virus challenge with twice-daily treatment for 8 days at a dose of 100 mg/kg/day. With favorable safety, bioavailability, and postviral challenge treatment efficacy, T-1106 was effective in the treatment of disease in hamsters infected with YFV and should be further studied for potential use as a therapy for human YFV disease.

scholarly journals Comparison of the inhibitory effects of interferon alfacon-1 and ribavirin on yellow fever virus infection in a hamster model

2007 ◽  
Vol 73 (2) ◽  
pp. 140-146 ◽  
Author(s):  
Justin G. Julander ◽  
John D. Morrey ◽  
Lawrence M. Blatt ◽  
Kristiina Shafer ◽  
Robert W. Sidwell
Keyword(s):  
Virus Infection ◽  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Inhibitory Effects ◽  
Hamster Model

scholarly journals Experience of application of IgY-technology for laboratory diagnostics of viral infections

2020 ◽  
Vol 65 (1) ◽  
pp. 21-26 ◽  
Author(s):  
A. P. Ivanov ◽  
T. D. Klebleeva ◽  
O. E. Ivanova
Keyword(s):  
Yellow Fever ◽  
Viral Infections ◽  
Yellow Fever Virus ◽  
Laboratory Diagnosis ◽  
Encephalitis Virus ◽  
Fever Virus ◽  
Laboratory Animals ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus

Introduction. The well-known advantages of class Y antibodies (IgY) from egg yolks of immunized hens in comparison with class G antibodies (IgG) of laboratory animals traditionally used in laboratory diagnosis of infectious diseases determine the stable interest of researchers in using IgY for these purposes (IgY technology) . Over the past 20 years, the obvious benefits of IgY technology have been demonstrated for a number of viral and bacterial infections. Goals and objectives. Construction of ELISA systems based on specific IgY for laboratory diagnosis of infections caused by tick-borne encephalitis virus, yellow fever virus, poliovirus.Material and methods. Obtaining yolk preparations of immunized chickens, obtaining highly purified IgY preparations (salting out, affinity chromatography), constructing ELISA systems for determining virus-specific antigens, testing the parameters of ELISA systems.Results and discussion. For the first time in laboratory practice, ELISA systems based on the use of specific polyclonal IgY were designed for laboratory diagnosis of topical human viral infections caused by flaviviruses and enteroviruses: determination of antigens of tick-borne encephalitis virus, yellow fever virus, 3 types of poliovirus. It was experimentally shown that these ELISA systems have high sensitivity and specificity, which allows them to be used for the semiquantitative and quantitative determination of antigens of these viruses in various materials (infected cell cultures, vaccines, etc.).Conclusion. The ELISA systems developed on the basis of specific IgY for determination of viral antigens can be effectively used for laboratory diagnosis of a number of viral infections, for the validation and control of vaccine preparations.

scholarly journals AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model

2021 ◽  
Author(s):  
Kai Lin ◽  
Steven S Good ◽  
Justin G. Julander ◽  
Abbie Weight ◽  
Adel Moussa
Keyword(s):  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Limit Of Detection ◽  
Virus Titer ◽  
Fever Virus ◽  
Effective Vaccine ◽  
Hamster Model ◽  
Nucleotide Analog

Yellow fever virus (YFV) is a zoonotic pathogen re-emerging in parts of the world, causing a viral hemorrhagic fever associated with high mortality rates. While an effective vaccine is available, having an effective antiviral against YFV is critical against unexpected outbreaks, or when vaccination is not recommended. We have previously identified AT-281, the free base of AT-752, an orally available double prodrug of a guanosine nucleotide analog, as a potent inhibitor of YFV in vitro , with a 50% effective concentration (EC 50 ) of 0.31 µM. In hamsters infected with YFV (Jimenez strain), viremia rose about 4 log 10 -fold and serum alanine aminotransferase (ALT) 2-fold compared to sham-infected animals. Treatment with 1000 mg/kg AT-752 for 7 days, initiated 4 h prior to viral challenge, reduced viremia to below the limit of detection by day 4 post infection (pi) and returned ALT to normal levels by day 6 pi. When treatment with AT-752 was initiated 2 days pi, the virus titer and ALT dropped >2 log 10 and 53% by day 4 and 6 pi, respectively. In addition, at 21 days pi, 70 – 100% of the infected animals in the treatment groups survived compared to 0% of the untreated group (p<0.001). Moreover, in vivo formation of the active triphosphate metabolite AT-9010 was measured in the animal tissues, with the highest concentrations in liver and kidney, organs that are vulnerable to the virus. The demonstrated in vivo activity of AT-752 suggests that it is a promising compound for clinical development in the treatment of YFV infection.

scholarly journals Efficacy of 2′-C-methylcytidine against yellow fever virus in cell culture and in a hamster model

2010 ◽  
Vol 86 (3) ◽  
pp. 261-267 ◽  
Author(s):  
Justin G. Julander ◽  
Ashok K. Jha ◽  
Jung-Ae Choi ◽  
Kie-Hoon Jung ◽  
Donald F. Smee ◽  
...  
Keyword(s):  
Cell Culture ◽  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Hamster Model

scholarly journals Yellow Fever Virus Exhibits Slower Evolutionary Dynamics than Dengue Virus

2009 ◽  
Vol 84 (2) ◽  
pp. 765-772 ◽  
Author(s):  
Amadou A. Sall ◽  
Ousmane Faye ◽  
Mawlouth Diallo ◽  
Cadhla Firth ◽  
Andrew Kitchen ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Yellow Fever ◽  
Central African Republic ◽  
Evolutionary Dynamics ◽  
Nucleotide Substitution ◽  
Viral Infections ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Limited Information ◽  
Reduced Rate

ABSTRACT Although yellow fever has historically been one of the most important viral infections of humans, relatively little is known about the evolutionary processes that shape its genetic diversity. Similarly, there is limited information on the molecular epidemiology of yellow fever virus (YFV) in Africa even though it most likely first emerged on this continent. Through an analysis of complete E gene sequences, including a newly acquired viral collection from Central and West Africa (Senegal, Cameroon, Central African Republic, Côte d'Ivoire, Mali, and Mauritania), we show that YFV exhibits markedly lower rates of evolutionary change than dengue virus, despite numerous biological similarities between these two viruses. From this observation, along with a lack of clock-like evolutionary behavior in YFV, we suggest that vertical transmission, itself characterized by lower replication rates, may play an important role in the evolution of YFV in its enzootic setting. Despite a reduced rate of nucleotide substitution, phylogenetic patterns and estimates of times to common ancestry in YFV still accord well with the dual histories of colonialism and the slave trade, with areas of sylvatic transmission (such as Kedougou, Senegal) acting as enzootic/epidemic foci.

scholarly journals BCX4430, a Novel Nucleoside Analog, Effectively Treats Yellow Fever in a Hamster Model

2014 ◽  
Vol 58 (11) ◽  
pp. 6607-6614 ◽  
Author(s):  
Justin G. Julander ◽  
Shanta Bantia ◽  
Brian R. Taubenheim ◽  
Dena M. Minning ◽  
Pravin Kotian ◽  
...  
Keyword(s):  
Weight Loss ◽  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Neutralizing Antibody ◽  
Therapeutic Index ◽  
Nucleoside Analog ◽  
Hamster Model ◽  
Virus Challenge ◽  
Highly Active ◽  
Improvement In Survival

ABSTRACTNo effective antiviral therapies are currently available to treat disease after infection with yellow fever virus (YFV). A Syrian golden hamster model of yellow fever (YF) was used to characterize the effect of treatment with BCX4430, a novel adenosine nucleoside analog. Significant improvement in survival was observed after treatment with BCX4430 at 4 mg/kg of body weight per day dosed intraperitoneally (i.p.) twice daily (BID). Treatment with BCX4430 at 12.5 mg/kg/day administered i.p. BID for 7 days offered complete protection from mortality and also resulted in significant improvement of other YF disease parameters, including weight loss, serum alanine aminotransferase levels (6 days postinfection [dpi]), and viremia (4 dpi). In uninfected hamsters, BCX4430 at 200 mg/kg/day administered i.p. BID for 7 days was well tolerated and did not result in mortality or weight loss, suggesting a potentially wide therapeutic index. Treatment with BCX4430 at 12 mg/kg/day i.p. remained effective when administered once daily and for only 4 days. Moreover, BCX4430 dosed at 200 mg/kg/day i.p. BID for 7 days effectively treated YF, even when treatment was delayed up to 4 days after virus challenge, corresponding with peak viral titers in the liver and serum. BCX4430 treatment did not preclude a protective antibody response, as higher neutralizing antibody (nAb) concentrations corresponded with increasing delays of treatment initiation, and greater nAb responses resulted in the protection of animals from a secondary challenge with YFV. In summary, BCX4430 is highly active in a hamster model of YF, even when treatment is initiated at the peak of viral replication.

scholarly journals PO 8559 ASSESSMENT OF THE EFFECT OF RVSV REPLICATION ON NON-EBOLA CIRCULATING ANTIBODIES IN RVSV-ZEBOV-GP-VACCINATED INDIVIDUALS IN LAMBARÉNÉ, GABON

2019 ◽  
Vol 4 (Suppl 3) ◽  
pp. A53.1-A53
Author(s):  
Armel V Ndong Mbouna ◽  
Selidji T Agnandji
Keyword(s):  
Dengue Virus ◽  
Yellow Fever ◽  
Ebola Virus ◽  
Viral Infections ◽  
Yellow Fever Virus ◽  
Virus Disease ◽  
Fever Virus ◽  
Serum Samples ◽  
Elisa Technique ◽  
Circulating Antibodies

BackgroundThe West Africa Ebola virus disease (EVD) outbreak between 2015 and 2016 accelerated the need for safe and effective vaccines. Among candidate vaccines in clinical development, the recombinant Vesicular stomatitis virus (VSV) vectored with the Ebola virus (EBOV) glycoprotein (rVSV-ZEBOV-GP) vaccine showed acceptable safety and promising immunogenicity results across diverse settings.Baseline screening data from the phase I trial of this vaccine in Lambaréné, Gabon, established that prior to vaccination about 21% (33/155) and 8% (12/155) of adults had naturally acquired antibodies to infectious ZEBOV particle and ZEBOV-GP, respectively. In participants with prior ZEBOV(-GP) antibodies, post-vaccination antibodies titres were significantly higher 56 days following vaccination with doses of 3×103, 3×104, and 3×106 PFU compared to those without.Our study seeks to investigate rVSV vector non-specific boosting of naturally acquired antibodies to other viral infections (dengue virus 1–4, and yellow fever virus).MethodsWe measured antibodies titres to Dengue (serotypes 1–4) and yellow fever infection at baseline, 28 and 56 days after injection in a total of 155 serum samples from vaccinees receiving various doses of rVSV-ZEBOV-GP using ELISA technique.ResultsPreliminary results were presented at the meeting.ConclusionOur results confirm rVSV vector non-specific replication on non ZEBOV-GP circulating antibodies in Lambaréné vaccinees and potential boosting action on naturally acquired dengue virus (serotypes 1–4) and yellow fever virus antibodies.

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