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Blockbuster expectations for hepatitis B therapeutic vaccine

Abivax CEO Hartmut Ehrlich

A French biotech has raised $63.4 million in an initial public offering to take a Cuban-made vaccine for treating hepatitis B virus (HBV) infections into phase 3 trials. Paris-based Abivax, acquired rights to ABX203, a vaccine designed to treat chronic HBV infection, from the Center for Genetic Engineering and Biotechnology in Havana. With these trials, Abivax joins a growing cadre of companies making strides in this space, as the dramatic success curing hepatitis C virus (HCV) with Sovaldi (sofosbuvir) has awakened interest in finding a similar cure for chronic HBV infection. Top developers, including Gilead and Roche, have entered collaborations with their sights set on the highly lucrative HBV therapeutic prize.

More than 240 million people worldwide are chronically infected with HBV, according to the World Health Organization, with some 650,000 deaths a year attributed to the virus. Infection levels are particularly high in the Asia-Pacific region. In China, 7% of the adult population is thought to be infected, partly because of a lack of childhood preventive vaccination with the long-approved prophylactic recombinant hepatitis B surface antigen vaccine programs and high rates of mother-to-newborn transmission.

Current best therapies are pegylated (PEG) recombinant subcutaneous interferon-α and viral DNA polymerase inhibitors. These agents decrease viral replication and slow disease progression, but cure only a minority of chronically infected individuals. Viral levels in blood plummet to almost undetectable levels in 90% of individuals receiving standard therapies, but intrahepatic viral DNA reductions are more modest. As a consequence, the virus rebounds soon after treatment stops and people with chronic HBV infections must stay on lifelong treatment. But even after ten years on antiviral therapy, drugs reduce liver failure by only 40–70%, and mortality from cirrhosis and liver cancer remains high.

Therapeutic vaccines could, in theory, reduce viremia and intrahepatic levels of HBV DNA to zero by inducing a T-cell response. The vaccine, designed in Cuba's laboratories and now in Abivax's hands, uses two viral recombinant proteins—the surface antigen HBsAg and the nucleocapsid core structure HBcAg (Vaccine 32, 4925–4931, 2014). A phase 2b/3 clinical trial is under way in several countries in the Asia-Pacific area to look at its ability to control and even clear the hepatitis B viral load in chronic infection. Early clinical studies carried out by the Center for Genetic Engineering and Biotechnology in Cuba and in Bangladesh showed that ABX203 triggered neutralizing serum antibodies against the virus and a cellular immune response at 30 days. The viral load fell to levels comparable to those after PEG-interferon-α treatment and are sustained for at least six months.

Basel-based Roche is also testing a recombinant DNA therapeutic vaccine based on Inovio Pharmaceuticals' SynCon platform. The Plymouth Meeting, Pennsylvania, biotech has started testing INO-1800 in phase 1 trials in the Asia-Pacific region as part of its collaboration with Roche. INO-1800 is a recombinant multi-antigen DNA immunotherapeutic targeting HBV clades A and C surface antigens and HBV core antigens. The vaccine has shown strong cytotoxic T-cell responses that kill target cells without causing considerable liver injury (Cancer Gene Ther. 19, 779–787, 2012). J. Joseph Kim, president and CEO at Inovio, says that because the company's approach uses DNA, it will likely be more effective than the vaccines based on proteins.

Louisville, Colorado–based GlobeImmune has licensed its therapeutic HBV vaccine to Gilead Sciences of Foster City, California. GlobeImmune's GS-4774 Tarmogen consists of heat-inactivated yeast cells that express a fusion protein including an HBV core and surface proteins to stimulate a T-cell response. The company intends to combine the Tarmogen with antiviral therapies to increase the chance of total clearance of the virus. A phase 1 trial showed an HBV-specific T-cell response (Vaccine 32, 4925–4931, 2014), but a phase 2 trial did not meet its primary endpoint of reducing serum HbsAg levels at week 24 in patients receiving ongoing antiviral therapy, though there was a nonsignificant reduction at the highest dose tested. Studies in treatment-naive patients are ongoing, and GlobeImmune is in discussion with Gilead Sciences over the next step.

Therapeutic infectious disease vaccines could have potential in other chronic infections, beyond HBV, particularly where the treatment is long and onerous, and/or it is difficult to fully eradicate the reservoir of infectious agent. In such cases, a successful strategy will likely combine a chemotherapeutic approach to reduce the viral load with a vaccine to clear the latent infection.

Some reasonably positive results with therapeutic vaccines have already emerged, says Tjip van der Werf, Pulmonary Physician and Professor of Medicine, Infectious Diseases, of the University of Groningen, the Netherlands, and he believes that the approach could improve adherence to treatment and increase survival rates, particularly in multidrug-resistant disease. He adds, “I only hope that we will have funding to explore this phenomenal option.”

Other therapeutic vaccines in clinical trials include HCV, human papillomavirus, tuberculosis and Middle East respiratory syndrome (MERS).

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Elvidge, S. Blockbuster expectations for hepatitis B therapeutic vaccine. Nat Biotechnol 33, 789 (2015). https://doi.org/10.1038/nbt0815-789

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