Prospects for developing an Hepatitis C virus E1E2-based nanoparticle vaccine

Abstract

Globally, more than 58 million people are chronically infected with Hepatitis C virus (HCV) with 1.5 million new infections occurring each year. An effective vaccine for HCV is therefore a major unmet medical and public health need. Since HCV rapidly accumulates mutations, vaccines must elicit the production of broadly neutralising antibodies (bnAbs) in a reproducible fashion. Decades of research have generated a number of HCV vaccine candidates. Based on the available data and research through clinical development, a vaccine antigen based on the E1E2 glycoprotein complex appears to be the best choice, but robust induction of humoral and cellular responses leading to virus neutralisation has not yet been achieved. One issue that has arisen in developing an HCV vaccine (and many other vaccines as well) is the platform used for antigen delivery. The majority of viral vaccine trials have employed subunit vaccines. However, subunit vaccines often have limited immunogenicity, as seen for HCV, and thus multiple formats must be examined in order to elicit a robust anti-HCV immune response. Nanoparticle vaccines are gaining prominence in the field due to their ability to facilitate a controlled multivalent presentation and trafficking to lymph nodes, where they can interact with both arms of the immune system. This review discusses the potential for development of a nanoparticle-based HCV E1E2 vaccine, with an emphasis on the potential benefits of such an approach along with the major challenges facing the incorporation of E1E2 into nanoparticulate delivery systems and how those challenges can be addressed.

Keywords: HCV E1E2; nanoparticles; nanoparticulate delivery systems; vaccine.

Figure 1.. Conserved antigenic domains on the E1E2 complex.

The E1E2 complex (RCSB ID 8FSJ) is represented as a solvent-excluded surface. The antigenic domains in the E1 ectodomain are the N-terminal residues 192–202 (dark red) and a conserved α-helix (α2, residues 314–327).This helix appears to have a role in viral entry as mutants in this region result in structurally intact but noninfectious virions . For the E2 ectodomain, the conserved antigenic domains are domain A (red, residues 581–584 and 627–634), domain B/AR3 (yellow, residues 431–439 and 529–535), domain D (green, residues 420–428, 441–443, and 616), and domain E (blue, residues 412–423). The AR4/5 region, which requires the presence of both E1 and E2 is colored dark purple and comprises residues 635, 646, 649, 652, 657, 658, 667, 671, 676, 677, and 696.

Figure 2.. Overview of polymer, emulsion and vesicle-based delivery systems

(Reprinted with permission from Andrianov AK, Fuerst TR. Immunopotentiating and Delivery Systems for HCV Vaccines. Viruses. 2021;13(6).)

Figure 3.. The SpyCatcher-SpyTag system as a potential platform for making an E1E2-based nanoparticle.

The sE1E2 construct with the SpyTag at the C-terminus of one of the subunits (SpyTag attachment to the E2 subunit is shown) and the Spycatcher nanoparticle can be purified separately. The two components can then be coupled by leveraging the spontaneous formation of an isopeptide bond upon the interaction of SpyCatcher and SpyTag, creating an E1E2 nanoparticle assembly.

Figure 4.. E1E2-based nanoparticles modeled for three common platforms.

A model of sE1E2 derived from a recent cryo-EM structure was superposed onto the attachment points of each monomer for the associated model platforms. Both the full particle and cross-section are shown to provide a view of the approximate size and antigen density on each type of nanoparticle.