Sequential Combination of a Strong Interferon Inducer Viral Vector With Low Doses of Nivolumab Plus Ipilimumab Could Provide Functional Cure in Chronic Hepatitis B Virus infections: Technical Report Proposing a New Modality

Bakács, Tibor; Safadi, Rifaat; Puskás, László G.; Feher, L; Kovesdi, Imre

doi:10.7759/cureus.22750

Cited by 5 publications

(5 citation statements)

References 20 publications

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“…Viruses have the unique ability to affect hundreds of genes with minimal genomic burden [ 26 ]. The small dsRNA genome of IBDV, for example, activates many IFN-related genes (toll-like receptor 3 (Tlr3), toll-like receptor 9 (Tlr9), Z-DNA binding protein 1 (Zbp1), IFN-activated gene 204 (Ifi204), IFN-gamma (IFN-g)) [ 8 ]. In the absence of adaptive immunity, the IFN system can control most, if not all, virus infections.…”

Section: Discussionmentioning

confidence: 99%

“…Most viruses produce dsRNA at some point during their replication cycle activating the IFN gene defense system. The IBDV genome is composed of dsRNA, which induces one of the strongest IFN responses among viruses [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Lee et al demonstrated crosstalk between TLR10 and TLR3, which opens up a new concept in the regulation of IFN response [ 15 ]. In this context, it is important to emphasize that IBDV therapy never induced an excessive release of pro-inflammatory cytokines, even in decompensated hepatitis patients with high-level viremia, which is one of the key drivers of cytokine storms [ 8 ]. It is tempting to speculate that the anti-inflammatory properties of TLR10 contribute to the safety of IBDV therapy.…”

Section: Introductionmentioning

confidence: 99%

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An Orally Administered Nonpathogenic Attenuated Vaccine Virus Can Be Used to Control SARS-CoV-2 Infection: A Complementary Plan B to COVID-19 Vaccination

Bakács¹,

Sandig²,

Kovesdi³

2022

Cureus

Self Cite

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Background Coronavirus disease 2019 (COVID-19) vaccination has substantially altered the course of the pandemic, saving tens of millions of lives globally. The problem is that despite such spectacular results, vaccination alone will not be able to control the COVID-19 pandemic because of the rapid evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) even in vaccinated human populations. Therefore, the development of a post-infection, broad-based, orally administered antiviral therapy that would complement vaccination efforts is urgently needed. Methodology The so-called viral superinfection therapy (SIT) administers a nonpathogenic attenuated double-stranded RNA (dsRNA) vaccine virus drug candidate, the infectious bursal disease virus serotype R903/78 (IBDV-R903/78) that activates the interferon (IFN) genes, which are the natural, antiviral defense system of host cells. Results Here we present two cases of properly vaccinated (with BNT162b2-Pfizer) and booster-dosed COVID-19 patients with vaccine breakthrough infections whose disease duration was shortened to a few days by oral SIT. Conclusions SIT has already been demonstrated to be safe and effective against five different families of viruses, hepatitis A virus, hepatitis B virus, hepatitis C virus, SARS-CoV-2, and herpes zoster virus. The R903/78 drug candidate is simple to manufacture and easy to administer in an outpatient setting. The expected cost of SIT will be affordable even in resource-limited countries.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An Orally Administered Nonpathogenic Attenuated Vaccine Virus Can Be Used to Control SARS-CoV-2 Infection: A Complementary Plan B to COVID-19 Vaccination

Bakács¹,

Sandig²,

Kovesdi³

2022

Cureus

Self Cite

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“…In stark contrast to the systemic toxic interferon-α-2b (IFNα2b) therapy, which may require dose modification or discontinuation, only minimal flu-like side effects were observed during IBDV superinfection therapy, even in parenchymally decompensated severe hepatitis patients [ 20 , 21 , 22 , 23 ]. One of the reasons for this difference could be that IFN receptors are virtually ubiquitously expressed in all cell membranes, and, following the interaction of IBDV with host cells, its dsRNA is recognized by specific receptors, which activate several gene families from within the cells.…”

Section: The Rationale Of Using Repurposed Ibdv Veterinary Vaccine To...mentioning

confidence: 99%

Combination Therapy for the Treatment of Shingles with an Immunostimulatory Vaccine Virus and Acyclovir

Bakács

Sandig²,

Kovesdi³

2023

Pharmaceuticals

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Practically the entire global population is infected by herpesviruses that establish lifelong latency and can be reactivated. Alpha-herpesviruses, herpes simplex viruses 1 and 2 (HSV-1/HSV-2) and varicella zoster virus (VZV), establish latency in sensory neurons and then reactivate to infect epithelial cells in the mucosa or skin, resulting in a vesicular rash. Licensed antivirals inhibit virus replication, but do not affect latency. On reactivation, VZV causes herpes zoster, also known as shingles. The 76-year-old first author of this paper published an autobiography of his own severe herpes zoster ophthalmicus (HZO) infection with orbital edema, which is considered an emergency condition. Acyclovir (ACV) treatment was complemented with an immunostimulatory viral therapy, which resolved most symptoms within a few days. The orally administered live-attenuated infectious bursal disease vaccine virus (IBDV) delivers its double-stranded RNA (dsRNA) cargo to host cells and activates the natural antiviral interferon (IFN) gene defense system from within the host cells. IBDV has already been demonstrated to be safe and effective against five different families of viruses, hepatitis A virus (HAV), hepatitis B and C virus (HBV/HCV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and varicella zoster virus (VZV). Here we propose a short phase I/II trial in elderly shingles patients who will be assigned to receive either ACV monotherapy or ACV combined with R903/78, an attenuated immunostimulatory IBDV strain. The primary endpoints will be safety, but the efficacy of the combination therapy against the ACV monotherapy also will be assessed.

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“…Many studies have observed that HBV infection upregulated one or more checkpoints expression on T cells or NK cells 21–23 . While still in early stages, basic and clinical data suggest that blockade of CTLA‐4 and PD‐1 can be beneficial in treating chronic HBV infection in some patients, but failed in others with unknown mechanisms 24–26 . Therefore, understanding the mechanism of immune checkpoint blockade therapies helps broaden the treatment options for chronic HBV infection.…”

Section: Introductionmentioning

confidence: 99%

IL‐21 collaborates with anti‐TIGIT to restore NK cell function in chronic HBV infection

Tang,

Li,

Chen

et al. 2023

Journal of Medical Virology

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Available therapies for chronic hepatitis B virus (HBV) infection are not satisfying, and interleukin‐21 (IL‐21) and checkpoint inhibitors are potential therapeutic options. However, the mechanism underlying IL‐21 and checkpoint inhibitors in treating chronic HBV infection is unclear. To explore whether IL‐21 and checkpoint inhibitors promote HBV clearance by modulating the function of natural killer (NK) cells, we measured the phenotypes and functions of NK cells in chronic HBV‐infected patients and healthy controls on mRNA and protein levels. We found that chronic HBV infection disturbed the transcriptome of NK cells, including decreased expression of KLRK1, TIGIT, GZMA, PRF1, and increased expression of CD69. We also observed altered phenotypes and functions of NK cells in chronic HBV‐infected patients, characterized by decreased NKG2D expression, increased TIGIT expression and impaired interferon‐gamma (IFN‐γ), tumor necrosis factor‐alpha (TNF‐α) production. Furthermore, these alterations cannot be restored by telbivudine treatment but can be partially restored by IL‐21 and anti‐TIGIT stimulation. IL‐21 upregulated the expression of activating receptor CD16, CD69, and NKG2D on NK cells, enhanced IFN‐γ production, cytolysis, and proliferation of NK cells, while anti‐TIGIT promoted IFN‐γ production in CD56dim subset exclusively in chronic HBV infected patients. Additionally, IL‐21 was indispensable for anti‐TIGIT in HBsAg clearance in mice bearing HBV. It enhanced IFN‐γ production in splenic NK cells rather than intrahepatic NK cells, indicating a brand‐new mechanism of IL‐21 in HBV clearance when combined with anti‐TIGIT. Overall, our findings contribute to the design of immunotherapy through enhancing the antiviral efficacy of NK cells in chronic HBV infection.

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Sequential Combination of a Strong Interferon Inducer Viral Vector With Low Doses of Nivolumab Plus Ipilimumab Could Provide Functional Cure in Chronic Hepatitis B Virus infections: Technical Report Proposing a New Modality

Cited by 5 publications

References 20 publications

An Orally Administered Nonpathogenic Attenuated Vaccine Virus Can Be Used to Control SARS-CoV-2 Infection: A Complementary Plan B to COVID-19 Vaccination

An Orally Administered Nonpathogenic Attenuated Vaccine Virus Can Be Used to Control SARS-CoV-2 Infection: A Complementary Plan B to COVID-19 Vaccination

Combination Therapy for the Treatment of Shingles with an Immunostimulatory Vaccine Virus and Acyclovir

IL‐21 collaborates with anti‐TIGIT to restore NK cell function in chronic HBV infection

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