Elsevier

Pathologie Biologie

Volume 58, Issue 4, August 2010, Pages 308-314
Pathologie Biologie

The woodchuck: A model for therapeutic vaccination against hepadnaviral infectionLa marmotte, un modèle pour la vaccination thérapeutique contre l’infection hepadnavirale

https://doi.org/10.1016/j.patbio.2010.04.005Get rights and content

Abstract

Interferon-α and nucleoside analogues are available for the treatment of chronic hepatitis B virus (HBV) infection but do not lead to a satisfactory result. New findings about the immunological control of HBV during acute infection suggest the pivotal role of T-cell mediated immune responses. Several preclinical and clinical trials were undertaken to explore the possibility of stimulating specific immune responses in chronically infected animals and patients by vaccination. However, vaccination with commercially available HBV vaccines in patients and immunization in woodchucks with core or surface proteins of woodchuck hepatitis virus (WHV) did not result in effective control of HBV and WHV infection, suggesting that new formulations of therapeutic vaccines are needed. Some new approaches combining antiviral treatments with nucleoside analogues, DNA vaccines and protein vaccines were tested in the woodchuck model. It could be shown that therapeutic vaccinations are able to stimulate specific B- and T-cell responses and to achieve transient suppression of viral replication. These results suggest the great potential of therapeutic vaccination in combination with antivirals to reach an effective and sustained control of HBV infection.

Résumé

L’interféron-α et les analogues de nucléosides sont disponibles pour le traitement de l’infection chronique due au virus de l’hépatite B. Des connaissances nouvelles sur le contrôle immunologique de VHB pendant une infection aiguë indiquent le rôle pivot des réponses immunitaires provoquées par les cellules T. Plusieurs expériences précliniques et cliniques ont été conduites pour explorer la possibilité d’exciter des réponses immunitaires spécifiques par la vaccination d’animaux et de patients chroniquement infectés. Cependant, la vaccination de patients par des vaccins VHB usuels et l’immunisation de marmottes par des protéines du core ou protéines de surface du virus de l’hépatite de la marmotte (WHV) n’ont pas comporté un contrôle effectif de l’infection par le VHB et le WHV, dénotant donc que des compositions de vaccins thérapeutiques nouvelles sont nécessaires. Des nouvelles approches qui combinent des traitements antivirales avec des analogues de nucléosides, des vaccins à ADN et des vaccins à protéine ont été testées par le modèle de la marmotte. Ces tests prouvent que les vaccinations thérapeutiques sont capables d’exciter des réponses spécifiques des cellules B et T et d’atteindre une suppression éphémère de la réplication virale. Ces résultats dénotent le haut potentiel d’une vaccination thérapeutique combinée avec des antiviraux afin d’obtenir un contrôle effectif et durable de l’infection par le VHB.

Section snippets

The woodchuck model for acute and chronic hepadnaviral infection

The woodchuck is an ideal model to evaluate therapeutic vaccines as WHV infection in woodchucks results in outcomes of infection, which is similar to HBV infection in humans, ranging from a subclinical or acute transient infection to chronic infection progressing to HCC. Unfortunately no inbred animals are available so far to standardize infection experiments. For the understanding of the underlying mechanisms responsible for different outcomes of infection, detailed in vivo studies on humoral

Development of immunological tool in the woodchuck model

In recent years, a number of immunological tools to determine T-cell responses in WHV infection have been introduced, allowing the evaluation of therapeutic vaccines against hepadnaviral infections in this animal model [23], [24]. Characterization of T-cell markers is a prerequisite to define T-cell subpopulations and to functionally analyze these cells in the course of acute and chronic infection. By designing primers chosen from regions conserved among humans and other mammalian species,

Monitoring T-cell response in the woodchuck model

For many years, studies on the cellular immune response to WHV were hampered by the lack of effective proliferations assay for peripheral blood mononuclear cells (PBMC). Thymidine uptake of woodchuck PBMC stimulated by mitogens or specific WHV proteins was very low as compared to other cell systems like mouse or human. The lack of incorporation of [3H]-thymidine into cellular DNA by PBMC was due to the absence of expression of thymidine kinase gene (TK) in the woodchuck lymphocytes. Using 2[3

Immunotherapeutic approaches in the woodchuck model

The woodchuck became an attractive animal model for the vaccine development with the progress in the characterization of the woodchuck immune system and the advancement in specific immunological assays [20], [24], [35].

The immunomodulatory approaches using therapeutic vaccines could be directly tested in chronic WHV carriers. Up to date, several studies of therapeutic vaccinations have been carried out in woodchucks (Table 1). Diverse therapeutic vaccines containing WHV core [20] or surface

Combination of antiviral treatment and vaccination

It is generally assumed that a reduction of viral load by antiviral treatments might enhance the efficacy of therapeutic vaccines. This idea is supported by Boni et al. reporting that the T-cell response to HBV was successfully restored in patients treated with lamivudine [41], [42]. In a combination therapy, chronic WHV carriers were treated with lamivudine at a relatively high dose of 200 mg/kg orally for 23 weeks, resulting in the decline of WHV DNA and WHsAg serum levels by 3–5 logs and 1 log,

New strategies for treatment of chronic hepadnaviral infection

It has been shown in other infectious systems that the degree of exhaustion of T-cells is dependent on the duration of infection, antigenic load, the presence of CD4 help, innate immunity, regulatory T-cells, the type of APCs, and the ratio of co-stimulatory molecules to inhibitor signals. Therefore it raises the question whether the substantial reduction of viral load by antiviral therapy with nucleoside analogues may influence the functionality of CD4 and CD8 cells in chronic HBV/WHV

Conclusion

The present work done in the woodchuck model has proven the feasibility of therapeutic vaccination against chronic hepadnaviral infection. It became clear that the induction of antibodies to WHsAg can be achieved in chronically infected individuals whereas the control of viral replication needs additional branches of immune responses, especially that of the T-cells. Particularly, immunizations with immune complexes and DNA vaccines in combination with antiviral drugs appear to be an effective

Conflict of interest statement

The authors have no conflict of interest to declare.

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