Novel prime-boost immune-based therapy inhibiting both hepatitis B and D virus infections
Rani Burm 1 , Panagiota Maravelia 2 , Gustaf Ahlen 2 , Sandra Ciesek 3 4 5 , Noelia Caro Perez 2 , Anna Pasetto 2 , Stephan Urban 6 , Freya Van Houtte 1 , Lieven Verhoye 1 , Heiner Wedemeyer 7 , Magnus Johansson 8 , Lars Frelin 2 , Matti Sällberg 9 , Philip Meuleman 10
Affiliations
Affiliations
1
Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
2
Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
3
Institute for Medical Virology, University Hospital, Goethe University, Frankfurt am Main, Germany.
4
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany.
5
German Center for Infection Research, DZIF, External partner site, Frankfurt am Main, Germany.
6
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.
7
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
8
School of Medical Sciences, Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Orebro, Sweden.
9
Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden [email protected][email protected].
10
Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium [email protected][email protected].
PMID: 35977815 DOI: 10.1136/gutjnl-2022-327216
Abstract
Objective: Chronic HBV/HDV infections are a major cause of liver cancer. Current treatments can only rarely eliminate HBV and HDV. Our previously developed preS1-HDAg immunotherapy could induce neutralising antibodies to HBV in vivo and raise HBV/HDV-specific T-cells. Here, we further investigate if a heterologous prime-boost strategy can circumvent T-cell tolerance and preclude HDV superinfection in vivo.
Design: A DNA prime-protein boost strategy was evaluated for immunogenicity in mice and rabbits. Its ability to circumvent T-cell tolerance was assessed in immunocompetent hepatitis B surface antigen (HBsAg)-transgenic mice. Neutralisation of HBV and HDV was evaluated both in vitro and in immunodeficient human-liver chimeric mice upon adoptive transfer.
Results: The prime-boost strategy elicits robust HBV/HDV-specific T-cells and preS1-antibodies that can effectively prevent HBV and HDV (co-)infection in vitro and in vivo. In a mouse model representing the chronic HBsAg carrier state, active immunisation primes high levels of preS1-antibodies and HDAg-specific T-cells. Moreover, transfer of vaccine-induced antibodies completely protects HBV-infected human-liver chimeric mice from HDV superinfection.
Conclusion: The herein described preS1-HDAg immunotherapy is shown to be immunogenic and vaccine-induced antibodies are highly effective at preventing HBV and HDV (super)infection both in vitro and in vivo. Our vaccine can complement current and future therapies for the control of chronic HBV and HDV infection.