Effective multiple oral administration of reverse genetics engineered infectious bursal disease virus in mice in the presence of neutralizing antibodies

Hornyák, Ákos; Lipinski, Kai S.; Bakonyi, Tamás; Forgách, Petra; Horváth, Ernő; Farsang, Attila; Hedley, Susan J.; Palya, Vilmos; Bakács, Tibor; Kovesdi, Imre

doi:10.1002/jgm.2830

Cited by 16 publications

(20 citation statements)

References 55 publications

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“…Also, different formulations were tested for stability and a formulation that was stable at 5°C for 6 months was developed. These preclinical data support the development of an orally or nasally delivered anti-viral agent for human use (Hornyak, et al, 2015).…”

Section: Testing the R903/78 Drug Candidate In Severe 2019-ncov Patiementioning

confidence: 53%

“…3 While generating small animal models of coronavirus disease can be difficult, SARS-CoV passaged to adapt to the mouse host caused significant disease in mice (Frieman, et al, 2012) (Gralinski and Menachery, 2020). In our mice studies (Hornyak, et al, 2015), we demonstrated that using high doses of R903/78 inoculums repeatedly is feasible. Therefore, we hope to demonstrate that breakthrough infection and sustained viremia can be achieved and maintained in small animal models, in spite of the presence of anti-IBDV antibodies.…”

Section: Extending Our Knowledge On Virus Induced Changes and Mechanimentioning

confidence: 81%

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The Clinically Validated Viral Superinfection Therapy (SIT) Platform Technology May Mitigate Severe Cases of 2019-nCoV Infections

Kovesdi¹,

Mv²,

Pm³

et al. 2020

Preprint

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Stochastic simulations of early outbreak trajectories found that the basic reproduction number, R0, of the Wuhan new coronavirus (2019-nCoV) is around 2.2, which indicates the potential for sustained human-to-human transmission. In fact, this transmission characteristic is a similar magnitude to severe acute respiratory syndrome-related coronavirus (SARS-CoV) and the 1918 pandemic influenza. Cases have now spread to at least 4 continents, currently with 43,108 cases and 1,018 lives lost. The World Health Organization (WHO) declared the outbreak a public health emergency of international concern. There is no current evidence from random clinical trials (RCTs) to recommend any specific anti-nCoV treatment for patients with suspected or confirmed 2019-nCoV infection. In order to mitigate the impact of the 2019-nCoV outbreak, here we propose an innovative superinfection therapeutic (SIT) strategy, which could complement the development of prophylactic vaccines. SIT is based on clinical observations that unrelated viruses might interact in co-infected patients. During SIT, the patient benefit from superinfection with an apathogenic dsRNA virus such as the infectious bursal disease virus (IBDV), which is a powerful activator of the interferon-dependent antiviral gene program. An attenuated vaccine strain of IBDV was already successfully administered to resolve acute and persistent infections induced by two completely different viruses, the hepatitis B (DNA) and C (RNA) viruses (HBV/HCV). Importantly, IBDV is also a potential prophylactic vaccine vector drug candidate, since a recombinant IBDV was previously generated that displays exogenous viral peptides from a replication-competent IBDV.

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Section: Testing the R903/78 Drug Candidate In Severe 2019-ncov Patiementioning

confidence: 53%

Section: Extending Our Knowledge On Virus Induced Changes and Mechanimentioning

confidence: 81%

The Clinically Validated Viral Superinfection Therapy (SIT) Platform Technology May Mitigate Severe Cases of 2019-nCoV Infections

Kovesdi¹,

Mv²,

Pm³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…These preclinical data support the development of an orally or nasally delivered anti-viral agent for human use (Hornyak, et al, 2015).…”

Section: Testing the R903/78 Drug Candidate In Severe Covid-19 Patienmentioning

confidence: 53%

“…5 While generating small animal models of coronavirus disease can be difficult, SARS-CoV passaged to adapt to the mouse host caused significant disease in mice (Frieman, et al, 2012) (Gralinski and Menachery, 2020). In our mice studies (Hornyak, et al, 2015), we demonstrated that using high doses of R903/78 inoculums repeatedly is feasible. Therefore, we hope to demonstrate that breakthrough infection and sustained viremia can be achieved and maintained in small animal models, in spite of the presence of anti-IBDV antibodies.…”

Section: Extending Our Knowledge On Virus Induced Changes and Mechanimentioning

confidence: 81%

“…Presently, a new Phase 1 trial is planed using a well-characterized drug candidate, which is constructed by reverse genetics and can be manufactured reproducibly. Our preclinical data indicates that R903/78 is a potent activator of the interferon-dependent innate antiviral gene program which could explain its strong interference with unrelated viruses (Hornyak, et al, 2015). Importantly, IBDV is one of the most stable viruses known that can survive significant temperature variations, which allows for transportation and storage without dry ice.…”

Section: A Testable Hypothesismentioning

confidence: 83%

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The Clinically Validated Viral Superinfection Therapy (SIT) Platform Technology May Mitigate Severe Cases of COVID-19 Infections

Kovesdi¹,

Ranst²,

Chumakov³

et al. 2020

Preprint

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The transmission characteristic of COVID-19 is of similar magnitude to severe acute respiratory syndrome-related coronavirus (SARS-CoV) and the 1918 pandemic influenza. The virus is now in 50 countries and on nearly all continents. The World Health Organization (WHO) says to prepare for a pandemic. There is no current evidence from random clinical trials (RCTs) to recommend any specific anti-COVID-19 treatment for patients with suspected or confirmed COVID-19 infection. In order to mitigate the impact of the COVID-19 outbreak, here we propose an innovative superinfection therapeutic (SIT) strategy, which could complement the development of prophylactic vaccines. SIT is based on clinical observations that unrelated viruses might interact in co-infected patients. During SIT, the patient benefit from superinfection with an apathogenic dsRNA virus such as the infectious bursal disease virus (IBDV), which is a powerful activator of the interferon-dependent antiviral gene program. An attenuated vaccine strain of IBDV was already successfully administered to resolve acute and persistent infections induced by two completely different viruses, the hepatitis B (DNA) and C (RNA) viruses (HBV/HCV). Importantly, the epidemiological efficacy of a similar strategy to SIT had already been successfully tested in large controlled trials. Standard live orally administered enterovirus vaccines that stimulate the production of endogenous interferon of the host mitigated the seasonal outbreaks of influenza and other associated acute respiratory infections in 152,042 individuals without adverse reactions.

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Post-infection viral superinfection technology could treat HBV and HCV patients with unmet needs

Bakács

Safadi

Kovesdi

2018

Hepatology Medicine Policy

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BackgroundViral hepatitis deaths from acute infection, cirrhosis, and liver cancer have risen from the tenth to the seventh leading cause of death worldwide between 1990 and 2013. Even in the oral direct acting antiviral (DAA) agent era there are still large numbers of patients with unmet needs. Medications approved for treatment of chronic hepatitis B virus (HBV) infection do not eradicate HBV often requiring treatment for life associated with risks of adverse reactions, drug resistance, nonadherence, and increased cost. Although DAAs increased virologic cure rates well over 90% in all hepatitis C virus (HCV) genotypes, HCV infection still cannot be cured in a small but significant minority of patients. While most of the medical issues of HCV treatment have been solved, the current costs of DAAs are prohibitive.ResultsThe post-infection viral superinfection treatment (SIT) platform technology has been clinically proven to be safe and effective to resolve acute and persistent viral infections in 42 HBV and HCV patients (20 HBV, 22 HCV), and in 4 decompensated patients (2 HBV, 2 HCV). SIT employs a non-pathogenic avian double stranded RNA (dsRNA) virus, a potent activator of antiviral gene responses. Unexpectedly, SIT is active against unrelated DNA (HBV) and RNA (HCV) viruses. SIT does not require lifelong therapy, which is a major advantage considering present HBV treatments. The new viral drug candidate (R903/78) is homogeneously produced by reverse genetics in Vero cells. R903/78 has exceptional pH and temperature stability and also excellent long-term stability; therefore, it can be orally administered, stored and shipped without freezing. Since R903/78 is easy to stockpile, the post-infection SIT could also alleviate the logistic hurdles of surge capacity in vaccine production during viral pandemics.ConclusionTo help large number of HBV and HCV patients with unmet needs, broad-spectrum antiviral drugs effective against whole classes of viruses are urgently needed. The innovative SIT technological platform will be a great additional armament to conquer viral hepatitis, which is still a major cause of death and disability worldwide.

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Effective multiple oral administration of reverse genetics engineered infectious bursal disease virus in mice in the presence of neutralizing antibodies

Cited by 16 publications

References 55 publications

The Clinically Validated Viral Superinfection Therapy (SIT) Platform Technology May Mitigate Severe Cases of 2019-nCoV Infections

The Clinically Validated Viral Superinfection Therapy (SIT) Platform Technology May Mitigate Severe Cases of 2019-nCoV Infections

The Clinically Validated Viral Superinfection Therapy (SIT) Platform Technology May Mitigate Severe Cases of COVID-19 Infections

Post-infection viral superinfection technology could treat HBV and HCV patients with unmet needs

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