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Dikici, Bünyamin; Kalaycı, Ayhan Gazi; Özgenç, Funda; Boşnak, Mehmet; DAVUTOGLU, MEHMET; Aydin, Ece; Özkan, Tanju; Özeke, Turgut; Yağcı, Raşit Vural; HASPOLAT, KENAN

doi:10.1097/00006454-200304000-00011

Cited by 11 publications

(7 citation statements)

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“…Therefore, when viral load is high and T cell dysfunction is severe, therapeutic vaccination alone can not induce a strong HBV-specific T cell response. Actually, poor responses and limited antiviral effects have been reported for the therapeutic vaccination of chronic HBV patients [7], [34], [35], [36]. In contrast, T cell exhaustion may be less severe at lower viral loads, and subsequent therapeutic vaccination may be more effective [9].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, therapeutic vaccination, which aims to enhance the patient's own antiviral cellular immune response, has been considered as an alternative therapy. However, the efficacy of such strategies in patients has so far been disappointing [6], [7], [8]. Recent work suggests that the high viral load at the time of vaccination might explain the inefficient responses to therapeutic vaccination [9], [10].…”

Section: Introductionmentioning

confidence: 99%

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Enhancing Virus-Specific Immunity In Vivo by Combining Therapeutic Vaccination and PD-L1 Blockade in Chronic Hepadnaviral Infection

et al. 2014

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Hepatitis B virus (HBV) persistence is facilitated by exhaustion of CD8 T cells that express the inhibitory receptor programmed cell death-1 (PD-1). Improvement of the HBV-specific T cell function has been obtained in vitro by inhibiting the PD-1/PD-ligand 1 (PD-L1) interaction. In this study, we examined whether in vivo blockade of the PD-1 pathway enhances virus-specific T cell immunity and leads to the resolution of chronic hepadnaviral infection in the woodchuck model. The woodchuck PD-1 was first cloned, characterized, and its expression patterns on T cells from woodchucks with acute or chronic woodchuck hepatitis virus (WHV) infection were investigated. Woodchucks chronically infected with WHV received a combination therapy with nucleoside analogue entecavir (ETV), therapeutic DNA vaccination and woodchuck PD-L1 antibody treatment. The gain of T cell function and the suppression of WHV replication by this therapy were evaluated. We could show that PD-1 expression on CD8 T cells was correlated with WHV viral loads during WHV infection. ETV treatment significantly decreased PD-1 expression on CD8 T cells in chronic carriers. In vivo blockade of PD-1/PD-L1 pathway on CD8 T cells, in combination with ETV treatment and DNA vaccination, potently enhanced the function of virus-specific T cells. Moreover, the combination therapy potently suppressed WHV replication, leading to sustained immunological control of viral infection, anti-WHs antibody development and complete viral clearance in some woodchucks. Our results provide a new approach to improve T cell function in chronic hepatitis B infection, which may be used to design new immunotherapeutic strategies in patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhancing Virus-Specific Immunity In Vivo by Combining Therapeutic Vaccination and PD-L1 Blockade in Chronic Hepadnaviral Infection

et al. 2014

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“…Indeed, poor responses have been reported for the therapeutic vaccination of human HBV carriers (8). Conversely, at lower viral loads, when T cell exhaustion is less severe, therapeutic vaccination may be more effective (11).…”

Section: Discussionmentioning

confidence: 99%

“…However, the efficacy of such strategies has so far been disappointing (6–9). Recent work suggests that the decreased proliferative potential of virus-specific CD8 + T cells generated during chronic infection, and high viral load at the time of vaccination might explain the inefficient responses to therapeutic vaccination (6, 8, 10–12). Thus, it is important to develop a therapeutic vaccine strategy to more effectively boost endogenous T cell responses to control persistent viral infections.…”

mentioning

confidence: 99%

Enhancing therapeutic vaccination by blocking PD-1–mediated inhibitory signals during chronic infection

Mueller

Wherry

et al. 2008

The Journal of Experimental Medicine

194

181

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Therapeutic vaccination is a potentially promising strategy to enhance T cell immunity and viral control in chronically infected individuals. However, therapeutic vaccination approaches have fallen short of expectations, and effective boosting of antiviral T cell responses has not always been observed. One of the principal reasons for the limited success of therapeutic vaccination is that virus-specific T cells become functionally exhausted during chronic infections. We now provide a novel strategy for enhancing the efficacy of therapeutic vaccines. In this study, we show that blocking programmed death (PD)-1/PD-L1 inhibitory signals on exhausted CD8+ T cells, in combination with therapeutic vaccination, synergistically enhances functional CD8+ T cell responses and improves viral control in mice chronically infected with lymphocytic choriomeningitis virus. This combinatorial therapeutic vaccination was effective even in the absence of CD4+ T cell help. Thus, our study defines a potent new approach to augment the efficacy of therapeutic vaccination by blocking negative signals. Such an approach may have broad applications in developing treatment strategies for chronic infections in general, and perhaps also for tumors.

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“…Yet, HBV-DNA “negativization” rates were somewhat higher in the Pre-S2/S vaccine recipient (15 %) as compared to the control group (2.7 %), but this effect was not sustained following cessation of vaccination. Regardless of several failures in using GenHevac B® as a therapeutic vaccine [ 5 , 72 ], these investigators could demonstrate a specific CD4 T cell response against viral envelope epitopes in some of the vaccinees [ 58 ]. A similar observation was reported from Japan where Ren et al [ 73 ] evaluated a transfected hepatoma cell line-derived product containing glycosylated and non-glycosylated SHBs with a small amount of MHBs.…”

Section: Prospects Of Sci-b-vac™ As a Therapeutic Vaccinementioning

confidence: 99%

Enhanced immune response to hepatitis B vaccination through immunization with a Pre-S1/Pre-S2/S Vaccine

Shouval

Roggendorf

2015

Med Microbiol Immunol

124

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Efficacy and safety of recombinant yeast-derived hepatitis B vaccines for prevention of hepatitis B have been demonstrated unequivocally worldwide as reflected in reduction in HBsAg carrier rates and hepatocellular carcinoma. A new generation of recombinant HBV vaccines expressed in mammalian cells containing Pre-S/S epitopes has been developed in several countries. Such vaccines are useful in special risk groups, i.e., in non-responders to conventional HBV vaccines including older adults, obese people, health care workers, patients with renal failure and on dialysis, transplant patients, patients with HIV as well as travelers on short notice to HBV endemic regions. The future of such vaccines depends on their enhanced immunogenicity and cost profile. Sci-B-Vac™ is a mammalian cell-derived recombinant Pre-S1/Pre-S2/S hepatitis B vaccine which has been shown to be highly immunogenic, inducing faster and higher seroprotection rates against HBV with higher anti-HBs levels at lower HBsAg doses as compared to conventional yeast-derived vaccines. Recently, it has been suggested that such Pre-S/S vaccines against HBV might be efficacious not only for prevention but also for intervention in persistent HBV infection. Data obtained in a recent clinical trial conducted in Vietnam in patients with chronic hepatitis B suggest that repeated monthly i.m. injections of the Sci-B-Vac™ co-administered with daily oral lamivudine treatment can suppress HBV replication and lead to anti-HBs seroconversion in ~50 % of treated patients. Optimization of protocols and efficacy of such an intervention, intended to bypass T cell exhaustion and immune tolerance to HBV remains to be explored.

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Cited by 11 publications

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Enhancing Virus-Specific Immunity In Vivo by Combining Therapeutic Vaccination and PD-L1 Blockade in Chronic Hepadnaviral Infection

Enhancing Virus-Specific Immunity In Vivo by Combining Therapeutic Vaccination and PD-L1 Blockade in Chronic Hepadnaviral Infection

Enhancing therapeutic vaccination by blocking PD-1–mediated inhibitory signals during chronic infection

Enhanced immune response to hepatitis B vaccination through immunization with a Pre-S1/Pre-S2/S Vaccine

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