Self-replicating RNA Vaccine against Hepatitis C Virus Genotype 2, targeted to dendritic cells
The aim of this project is to develop a novel hepatitis C virus (HCV) vaccine based on RNA-replicon technology delivered by targeted nanogel vaccine-delivery vehicles. For successful induction of immunity, vaccines must interact with dendritic cells (DCs). Hence, the nanogels are both delivery and targeting vehicles, the later employing modified nanogel surfaces carrying oligosaccharide ligands specifically targeting DC receptors. This is combined with novel adjuvants providing the “danger” signals to promote DC activation and maturation, ensuring efficacious immune defense development.It is currently estimated that HCV has infected approximately 170 million people worldwide; it has been described by the World Health Organisation (WHO) as a “viral time bomb”. In the former Soviet Union, HCV is a particular problem, with approximately 4% of the population infected. For this reason, this project will focus on HCV genotype 2 (HCVg2), the prevalent genotype in Russia, although the synthetic vaccine can be readily adapted for other genotypes.
We propose a unique combination of techniques to develop vaccines against HCV: RNA-replicon constructs encoding antigenic structures; replicon characteristics proven capable of inducing strong immune responses; a nanogel delivery system both to protect the RNA and target it to cells of the immune system; glycoconjugate ligands for receptors on DC to decorate the nanogel surface and enhance this targeting; novel adjuvants to enhance development of efficacious immune defenses.RNA replicons encoding genes from HCVg2 will be generated using replicon constructs that induce protective immunity and cell-mediated defenses. These will be incorporated into oligosaccharide surface decorated nanogel vaccine delivery vehicles, which target C-type lectin receptors on DCs. The DC activation, a vital component for successful induction of efficacious immune defenses, will apply new synthetic adjuvants of proven capacity in this area. Both the targeting ligands and adjuvants will be optimized for synergistic use with the nanogels for replicon delivery to and activation of the DCs.Initial evaluation of the synthetic HCVg2 vaccine will be in vitro with respect to interaction with and activation of DCs. This will also assess the replicon translation and antigen expression in the DCs. Finally, immunological correlates in mice will be measured, particularly with respect to the influence of the adjuvants and targeting moieties in combination.
This project is highly innovative considering that it blends different technologies in a multidisciplinary approach to produce a synthetic HCVg2 vaccine. These technologies have not been combined before in such a manner, but our current research is demonstrating a high potential for success. Moreover, we believe that the new innovative vaccine generation technology will be adaptable to deal with any new HCV genotype that presents a threat in the future, and also other vaccine targets.
Dr Kenneth C. McCullough (coordinator)
Institute of Virology and Immunoprophylaxis
Prof Nicolai Bovin
Synthaur LLC (Ltd)
Prof Carlos A. Guzmán
Helmholtz Centre of Infection Research