In vivo immunization by vaccine therapy following virus suppression by lamivudine: a novel approach for treating patients with chronic hepatitis B

Horiike, Norio; Akbar, Sk. Md. Fazle; Michitaka, Kojiro; Joukou, Kouji; Yamamoto, Kazuhisa; Kojima, Naohiko; Hiasa, Yoichi; Abe, Masanori; Onji, Morikazu

doi:10.1016/j.jcv.2004.07.004

Cited by 79 publications

(58 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therapy with interferon or nucleoside/tide analogs is not satisfactory due to the low responder rate and resistance development (16,18,20,33). To date, immunotherapy against chronic hepatitis B has not yet achieved satisfactory results (7,14,17,31,32,41,44). Given the crucial role of cytotoxic T lymphocytes in the control of HBV infections, new therapeutic vaccines with the ability to stimulate vigorous, broad HBV-specific cytotoxic T lymphocyte responses are needed (3,11,26,38,39).…”

mentioning

confidence: 99%

Combination of an Antiviral Drug and Immunomodulation against Hepadnaviral Infection in the Woodchuck Model

Yao

et al. 2008

J Virol

View full text Add to dashboard Cite

Approximately 400 million people worldwide are chronically infected with hepatitis B virus (HBV). Therapy with interferon or nucleoside/tide analogs is not satisfactory due to the low responder rate and resistance development (16,18,20,33). To date, immunotherapy against chronic hepatitis B has not yet achieved satisfactory results (7,14,17,31,32,41,44). Given the crucial role of cytotoxic T lymphocytes in the control of HBV infections, new therapeutic vaccines with the ability to stimulate vigorous, broad HBV-specific cytotoxic T lymphocyte responses are needed (3,11,26,38,39).Several studies of therapeutic vaccinations have been carried out in the woodchuck model (reviewed in references 24, 25, 34, and 35) and demonstrated collectively that B-or T-cell responses to viral antigens could be induced in chronic woodchuck hepatitis virus (WHV) carriers (12,13,23,30). Yet, none of these studies have demonstrated the capability of vaccines to suppress viral replication. Here, we carried out a proof-of-principle experiment using DNA vaccines alone and DNA vaccines combined with immune complexes (IC) in the woodchuck model. IC of HBsAg and anti-HBs have been tested in patients and in transgenic mice (42,43,45,46). IC are more efficiently taken up by antigen-presenting cells than free antigens, leading to an improved presentation to T cells. DNA vaccines are potent inducers of T-cell responses. They could stimulate HBV-specific immune responses in humans and prevent hepadnaviral infections in the animal model (21,22,37). In addition, woodchucks were pretreated with lamivudine, a potent antiviral drug against HBV with the ability to enhance T-cell responses in chronically HBV-infected patients (1, 2).A total of 10 chronically WHV-infected woodchucks (from Northeastern Wildlife, Ithaca, NY) were first treated with 15 mg of lamivudine daily and randomly divided into three groups: the control group (n ϭ 2), a group vaccinated with WHV surface antigen (WHsAg)-IC and DNA (n ϭ 4), and a group vaccinated with DNA (n ϭ 4). The immunization schedule is presented in Fig. 1.The DNA vaccines consisted of an equimolar mixture of three plasmids, pWHsIm, pWHcIm, and pWIFN, expressing WHsAg, WHV core antigen (WHcAg), and woodchuck gamma interferon, respectively, as described previously (21, 37). To produce IC for woodchucks, antibodies to WHs (antiWHs) and WHsAg were titrated by the checkerboard method to determine the stoichiometry of the antigen and antibodies. The appropriate concentration of WHsAg was chosen and incubated with antibodies at 37°C for 30 min and then incubated overnight at 4°C, resulting in a preparation with a final concentration of 80 g WHsAg/ml in complex with anti-WHs. The vaccine consisted of 20 g WHsAg-IC and 250 g plasmid pWHsIm DNA per 0.5-ml dose. The DNA vaccines and IC-DNA vaccines were administered by intramuscular injections (21,22).The following parameters were determined by the indicated methods: serum WHV DNA concentrations as genome equivalents (GE) by real-time PCR with the LightCycler DNA Master S...

show abstract

mentioning

confidence: 99%

Combination of an Antiviral Drug and Immunomodulation against Hepadnaviral Infection in the Woodchuck Model

Yao

et al. 2008

J Virol

View full text Add to dashboard Cite

show abstract

“…LAM is known to directly reduce the viral load, while cytokines released following vaccine therapy may enhance the cellular immune response to suppress viral replication or to clear the virus. The limited combination therapy studies of CHB patients using HBV vaccine and LAM conducted to date have shown differing results for HBeAg seroconversion and viral suppression (12,18,41). Very few reports have noted any antiHBs response after vaccine therapy or its effect on viral clearance.…”

Section: Discussionmentioning

confidence: 99%

“…Studies investigating combined vaccine and lamivudine (LAM) treatment have also been reported (12,18,36,41). The effects of combination treatment compared to those of LAM monotherapy appear to be quite variable, a result that is thought to be due to differences in the timing of the vaccination, the type and dose of vaccine, the duration of vaccine intervention, and even the selection criteria for the study population.…”

mentioning

confidence: 99%

Randomized Controlled Study Investigating Viral Suppression and Serological Response following Pre-S1/Pre-S2/S Vaccine Therapy Combined with Lamivudine Treatment in HBeAg-Positive Patients with Chronic Hepatitis B

Hoa¹,

Huy²,

Nga³

et al. 2009

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The aim of the current study was to evaluate viral suppression following combined treatment with an S/pre-S1/pre-S2 vaccine and lamivudine in patients with chronic hepatitis B. We established a randomized, controlled clinical trial to compare the responses of three different treatment groups: those receiving vaccine monotherapy, lamivudine monotherapy, or combination treatment. Viral response was evaluated via hepatitis B virus (HBV) DNA suppression using different levels of classification. Seroconversion was evaluated via HBeAg loss, HBeAg seroconversion, HBsAg loss, and anti-HBs response. We found that the group receiving combination treatment demonstrated a significant increase in viral suppression over that for the lamivudine or vaccine monotherapy group, although the HBeAg seroconversion rate was not different. This enhanced suppression effect in the combination group was reversed after the discontinuation of vaccine treatment, suggesting that booster doses are required for a sustained viral response. Anti-HBs was detected in 55/120 vaccine recipients, but only 3 patients demonstrated HBsAg loss, indicating that the vaccine-induced anti-HBs was unable to completely neutralize HBsAg in the serum. At the study end point, anti-HBs responders showed significantly higher HBeAg seroconversion rates, greater suppression of HBV DNA levels, and a lower median reduction in HBV DNA levels than those of anti-HBs nonresponders. Our results suggest that combined treatment with the vaccine and lamivudine was significantly more effective than lamivudine monotherapy in the short term and was especially successful in producing viral suppression and an enhanced anti-HBs antibody response.

show abstract

“…The nature of antigen and adjuvants, dose of vaccine, and duration of therapy underwent considerable alterations during the last 18 years. Wen and her group used an antigen-antibody complex vaccine containing HBsAg and anti-HBs as a therapeutic vaccine (67), whereas others used a HBsAg-based vaccine with antiviral agents or other immune modulators to increase the therapeutic potential of these vaccines (68)(69)(70)(71)(72). Also, a DNA-based vaccine expressing HBsAg was used in CHB patients (73).…”

Section: Additional Tips In Hbsag-based Therapeutic Vaccination In Chmentioning

confidence: 99%

Immune therapy for hepatitis B

et al. 2016

View full text Add to dashboard Cite

Although several antiviral drugs are now available for treatment of patients with chronic hepatitis B (CHB), sustained off-treatment clinical responses and containment of CHB-related complications are not achieved in majority of CHB patients by antiviral therapy. In addition, use of these drugs is endowed with substantial long term risk of viral resistance and drug toxicity. The infinite treatment regimens of antiviral drugs for CHB patients are also costly and usually unbearable by most patients of developing and resource-constrained countries.Taken together, there is a pressing need to develop new and innovative therapeutic approaches for CHB patients.

show abstract

In vivo immunization by vaccine therapy following virus suppression by lamivudine: a novel approach for treating patients with chronic hepatitis B

Cited by 79 publications

References 19 publications

Combination of an Antiviral Drug and Immunomodulation against Hepadnaviral Infection in the Woodchuck Model

Combination of an Antiviral Drug and Immunomodulation against Hepadnaviral Infection in the Woodchuck Model

Randomized Controlled Study Investigating Viral Suppression and Serological Response following Pre-S1/Pre-S2/S Vaccine Therapy Combined with Lamivudine Treatment in HBeAg-Positive Patients with Chronic Hepatitis B

Immune therapy for hepatitis B

Contact Info

Product

Resources

About