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Hepatitis B & D

Background

Despite the availability of prophylactic vaccines > 250 million patients are chronic carriers of Hepatitis B virus (HBV) and there are no curative treatments available today. The risk of developing liver cirrhosis and cancer are greatly increased in these patients compared to non-carriers, and the conditions are accompanied by much suffering and with high healthcare costs. To combat HBV, both prophylactic and curative treatments will be required.


Hepatitis D is a rare disease and the most severe form of viral hepatitis and represents a major unmet medical need, with no curative treatments available.


Over 12 million patients infected with chronic HDV globally. HDV can only replicate in subjects already infected with HBV as HDV steels the outer envelope from HBV. The major medical problem is the superinfection with HDV infection in patients with chronic HBV as this significantly worsens the liver damage.


HDV heightens the likelihood of adverse outcomes, compared to mono-infection with HBV:

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  • 3.9 X risk of cirrhosis

  • 2.0 X risk of Hepatocellular Carcinoma

  • 2.1 X risk for death

  • More rapid disease progression

Vaccine Immunotherapy Objective

The objective of our vaccine is to prevent infection of liver cells and eliminate those already infected.


How does SVF-001 work?


SVF-001 helps the body fight chronic Hepatitis D Virus (HDV) infections by:

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  • Inducing antibodies and T cells targeting HDV that:

    • Prevent HDV from entering liver cells

    • Eliminate HDV infected cells

Which leads to…

  • Reduced HDV levels

  • Normalizing liver function

 

​SVF-001 poses a possible solution to the Hepatitis D Challenge:


Existing prophylactic vaccines have no therapeutic effect on HBV or HBV/HDV and other therapeutic vaccine candidates have failed to due to lack of immunogenicity in a chronically infected patients. SVF-001 circumvents these problems through its unique design.

SVF-001 contains a unique combination of antigens selected to activate immune functional responses in a patient with chronic infection.

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Vaccine Design

The design of our vaccine targets the essential components of both viruses and direct the immune system to target the essential region of the surface antigen found on both HBV and HDV (i.e. PreS1). The PreS1 contains the receptor binding activity of the surface antigen, and is therefore essential for viral entry into liver cells. Antibodies targeting PreS1 are known to neutralize HBV and HDV, and can protect HBV carriers against HDV infection. PreS1-specific B cells take up HBV and HDV particles, process and present to activate T cells.

The vaccine design also direct the immune system to target the HDV large antigen (LAg), which represents the whole HDV proteome (i.e. all HDV epitopes are therefore included). The inclusion of HDV LAg directs T-cell responses to HBV/HDV co-infected cell alongside the PreS1 response. Thus, this approach will bypass immune tolerance in chronic HBV mono-infection.

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Our research have so far shown that:

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  • SVF-001 activates antibodies and T cells to HDV

  • SVF-001 activates antibodies and T cells to HDV in a model of chronic HBV infection and prevent superinfection

  • SVF-001 antibodies can protect against, and treat, HDV in vivo in mice with human livers

Publications

Hawman DW, Ahlén G, Appelberg S, Meade-White K, Hanley P, Scott D, Monteil D, Devignot D, Weber F, Feldmann H*, Sällberg M*, Mirazimi A*. 2021 A DNA-based vaccine protects against Crimean-Congo hemorrhagic fever virus disease in a Cynomolgus macaque model. Nat Microbiol. 2021 Feb;6(2):187-195. doi: 10.1038/s41564-020-00815-6.


Maravelia P, Frelin L, Ni Y, Noelia Caro Pérez 1 , Ahlén G, Jagya N, Verch G, Verhoye L, Pater L, Johansson M, Pasetto A, Meuleman P, Urban S, and Sällberg M. 2021. Blocking entry of hepatitis B and D viruses to hepatocytes as a novel immunotherapy for treating chronic infections. Journal of Infectious Diseases, 2021 Jan 4;223(1):128-138. doi: 10.1093/infdis/jiaa036.


Appelberg S, John L,  Pardi N,  Végvári A,  Bereczky S,  Ahlén G,  Monteil V,  Abdurahman S,  Mikaeloff F,  Beatti M,  Tam Y, Sällberg M, Neogi U,  Weissman D,  Mirazimi A Nucleoside-modified mRNA vaccines protect IFNAR  -/- mice against Crimean Congo hemorrhagic fever virus infection J Virology, 2021 https//doi.org/10.1128/JVI.01568-21.


Burm R, Maravelia P, Ahlén G, Ciesek S, Perez NC, Pasetto A, Urban S, van Houtte F, Verhoye L, Wedemeyer H, Johansson M, Frelin L, Sallberg M*, and Meuleman P*. 2022. Novel prime-boost immune-basedd therapy inhibiting both hepatitis B and D virus infections. Gut DOI: 10.1136/gutjnl- 2022-327216.


Appelberg S, Ahlén G, Yan J, Nikouyan N, Weber S, Larsson O, Höglund U, Aleman S, Weber F, Perlhamre E, Apro J, Gidlund EK, Tuvesson O, Salati S, Cadossi M, Tegel H, Hober S, Frelin L, Mirazimi A, and Sallberg M. 2022. A universal SARS-CoV DNA vaccine inducing highly crossreactive neutralizing antibodies and T cells. EMBO Molecular Medicine DOI: 10.15252/emmm.202215821.


Hawman DW, Meade-White K, Leventhal S, Appelberg S, Ahlén G, Nikoyan N, Clancy C, Smith B, Hanley P, Lovaglio J, Mirazimi A, Sällberg M*, Feldmann H*. 2023. A two dose DNA vaccine regimen expressing the Crimean-Congo hemorrhagic fever virus nucleoprotein and glycoproteins provides robust protection in a macaque model. Molecular Therapy. 2023 Feb 1;31(2):387-397. doi: 10.1016/j.ymthe.2022.09.016. Epub 2022 Oct 3.*equal contribution.


Yan J, Bangalore CR, Nikouyan N, Appelberg S, Pasetto A, Weber F, Weber S, Larsson O, Höglund U, Bogdanovic G, Grabbe M, Aleman S, Szekely L, Szakos A, Tuvesson O, Gidlund EK, Cadossi M, Salati S, Tegel H, Hober S, Frelin L, Mirazimi A, Ahlén G, and Sallberg M. Distinct roles of vaccine induced SARS-CoV-2-specific neutralizing antibodies and T cells in protection and disease. Molecular Therapy 2024. 32(2):540-555. doi: 10.1016/j.ymthe.2024.01.007.

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