Understanding and harnessing the power of the legendary yellow fever 17D vaccine

With more than 240 million people that are persistently infected with the hepatitis B virus (HBV), chronic hepatitis B (CHB) remains the main and leading cause of liver cirrhosis and cancer. CHB is in fact a direct consequence of a failure of the adaptive immune system to eliminate HBV from the infected liver. Most potent state-of-the-art antiviral therapy can only suppress viral loads but will never cure chronic CHB. Cure of CHB may be achieved if a vigorous cytotoxic T cell (CTL) responses against the HBV is restored e.g. by therapeutic vaccination. We use a novel and proprietary vaccine platform to generate live-attenuated viral vaccines expressing relevant HBV T cell antigens. The platform is based on a recombinant yellow fever vaccine virus that is launched directly from a plasmid (plasmid-launched live-attenuated vaccine, PLLAV technology). These HBV PLLAV vaccines can easily and cheaply be produced in fermenters and are thermostable, yet fully preserve the extraordinary immunogenicity and efficacy of the powerful yellow fever vaccine. The therapeutic potency of HBV PLLAV will be tested in a stringent mouse model of CHB. Here three major questions will be addressed: (i) Are those CTL responses we generate in mice by HBV PLLAV polyfunctional as required for therapeutic efficacy? (ii) Can similarly potent responses also be elicited in immune tolerant HBV transgenic mice? And finally (iii) does HBV PLLAV outperform existing approaches in breaking CTL anergy towards a cure for CHB?