Induction of cross-neutralizing antibodies by a permuted hepatitis C virus glycoprotein nanoparticle vaccine candidate

Abstract

Hepatitis C virus (HCV) infection affects approximately 58 million people and causes ~300,000 deaths yearly. The only target for HCV neutralizing antibodies is the highly sequence diverse E1E2 glycoprotein. Eliciting broadly neutralizing antibodies that recognize conserved cross-neutralizing epitopes is important for an effective HCV vaccine. However, most recombinant HCV glycoprotein vaccines, which usually include only E2, induce only weak neutralizing antibody responses. Here, we describe recombinant soluble E1E2 immunogens that were generated by permutation of the E1 and E2 subunits. We displayed the E2E1 immunogens on two-component nanoparticles and these nanoparticles induce significantly more potent neutralizing antibody responses than E2. Next, we generated mosaic nanoparticles co-displaying six different E2E1 immunogens. These mosaic E2E1 nanoparticles elicit significantly improved neutralization compared to monovalent E2E1 nanoparticles. These results provide a roadmap for the generation of an HCV vaccine that induces potent and broad neutralization.

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

“…Another potential avenue of exploration with E1E2 NPs is the potential to create mosaic and cocktail mixtures as a means to enhance neutralisation breadth as in the E2E1 NP study. 155 It is not clear, nor has it been systematically investigated, whether the best choice for an HCV vaccine will be a single patient-derived strain derived from an elite neutraliser or a mixture of representative strains from multiple genotypes, perhaps varying based on the geographical distribution of genotypes and population to be vaccinated. The successful development of mosaic NP vaccine candidates against SARS-CoV-2 148 suggests that once a NP-based E1E2 vaccine system is established, the mosaic versus single-strain immunogen design can be more thoroughly investigated.…”

“…The third NP study 155 utilised a permuted version of E1E2 in which the order of the antigens in the open reading frame was reversed (i.e. E2E1) and the I53‐50 platform for NP display.…”

“…For HCV E1E2, this represents an experimental challenge waiting to be met. Another potential avenue of exploration with E1E2 NPs is the potential to create mosaic and cocktail mixtures as a means to enhance neutralisation breadth as in the E2E1 NP study 155 . It is not clear, nor has it been systematically investigated, whether the best choice for an HCV vaccine will be a single patient‐derived strain derived from an elite neutraliser or a mixture of representative strains from multiple genotypes, perhaps varying based on the geographical distribution of genotypes and population to be vaccinated.…”

De Novo Design of Polyhedral Protein Assemblies: Before and After the AI Revolution

“…Computationally designed polyhedral assemblies displaying antigens are promising vaccine candidates, triggering robust immune responses. [103][104][105][106][107][108][109][110][111][112][113][114][115][116] Indeed several candidates have advanced to clinical trials, [116][117][118] and more recently a nanoparticle vaccine for COVID-19 has demonstrated the safety and immunogenicity of this technology platform in a phase 1/2 clinical trial, achieving approval for use in South Korea. [119] These protein assemblies have also been used as fluorescence standards, through the display of a defined number of green fluorescent protein molecules, [40,120] and as scaffolds for cryogenic electron microscopy (cryo-EM), through the rigid helical fusion of specific DARPin domains, enabling the analysis of proteins that would otherwise be too small to achieve near-atomic resolution.…”

“…First, the exterior surface of the designed polyhedral assemblies can be decorated with a variety of molecules through genetic fusion. Computationally designed polyhedral assemblies displaying antigens are promising vaccine candidates, triggering robust immune responses [103–116] . Indeed several candidates have advanced to clinical trials, [116–118] and more recently a nanoparticle vaccine for COVID‐19 has demonstrated the safety and immunogenicity of this technology platform in a phase 1/2 clinical trial, achieving approval for use in South Korea [119] .…”