Hepatitis C Virus is a major public health problem with over 71 million people infected globally causing 400,000 deaths each year. Although effective treatments are available, 1.7 million people are newly infected each year and could be prevented by a vaccine. Viral clearance is associated with the rapid induction of neutralising antibodies. Cross-genotype neutralising monoclonal antibodies that recognise the E2 envelope glycoprotein of HCV protect against heterologous viral infection and suggest that a HCV vaccine may be achievable.
We have previously shown that a soluble recombinant form of glycoprotein E2, that lacks three variable regions (D123) is able to elicit a higher titre of broadly neutralizing antibodies in comparison to the parental wild type form (RBD).
In this study we engineered a nanoparticle that displays HCV glycoprotein E2 on a Duck hepatitis B virus S (DHBVS) antigen scaffold. Four variants of E2-DHBVS VLP’s were constructed; D123 and RBD, and D123A7 and RBDA7 in which 7 cysteines were replaced with alanine. While all four E2-DHBVS VLP’s display E2 as a surface antigen, the D123A7 and RBDA7 secreted VLPs most efficiently from transfected mammalian cells, and displayed epitopes recognized by cross-genotype neutralizing monoclonal antibodies. Both D123A7-DHBVS and RBDA7-DHBVS VLPs were immunogenic in small animals generating high titre antibodies reactive to native E2, and able to prevent the interaction between E2 and the cellular receptor CD81. However, only animals immunized with D123A7-DHBVS elicited cross-genotype neutralizing antibodies to all 7 genotypes of HCV. Immune serum generated by animals with neutralizing antibodies mapped to a major neutralization epitope located at residues 412-420 (epitope I) and antigenic region 3. Nanoparticles that display E2 glycoproteins represent a promising vaccine platform for HCV. Future studies will investigate production of VLPs in yeast for high yield manufacture.