Induction of broadly neutralizing antibodies

Hepatitis C virus chronically infects approximately 1% of the world's population, making an effective hepatitis C virus vaccine a significant unmet public health need. The membrane-associated envelope glycoprotein E1E2 has been used in clinical studies as a vaccine candidate. However, the limited breadth of neutralization and the difficulty in producing large quantities of homogeneous membrane-associated E1E2 have hampered efforts to develop an E1E2-based vaccine.

Our previous work described the design and biochemical validation of a native-like soluble secreted form of E1E2 (sE1E2). Here, we describe the immunogenic characterization of the sE1E2 complex. sE1E2 elicited broadly neutralizing antibodies in immunized mice, with a higher amplitude of neutralization relative to membrane-associated E1E2, thus validating this platform as a promising model system for vaccine development.

Hepatitis C virus (HCV) is a global disease burden and a preventive vaccine is needed to control or eradicate the virus. Despite the advent of effective antiviral therapy, this treatment is not accessible to many patients and does not prevent reinfection, making chronic hepatitis C an ongoing global health problem. Therefore, the development of a prophylactic vaccine will represent an important step towards the global eradication of HCV. HCV exhibits high genetic variability, often leading to immune escape. However, a considerable challenge facing HCV vaccine development is designing an antigen that elicits broadly neutralizing antibodies. Here, we characterize the immunogenicity of a vaccine based on a soluble secreted form of the E1E2 envelope heterodimer (sE1E2.LZ).

Sera from mice immunized with sE1E2.LZ exhibited a comparable anti-E1E2 specific response to mice immunized with membrane-bound E1E2 (mbE1E2) or a soluble E2 ectodomain (sE2). In competition inhibition ELISA using antigenic domain-specific neutralizing and non-neutralizing antibodies, sera from mice immunized with sE1E2.LZ showed almost identical or stronger competition towards neutralizing antibodies compared to mbE1E2. In contrast

sera from mice immunized with sE2 and, to a lesser extent, mbE1E2, competed more effectively with non-neutralizing antibodies. An evaluation of neutralizing activity using HCV pseudoparticles and cell culture-derived infectious HCV showed that immunization with sE1E2.LZ elicited the broadest neutralizing activity of the three antigens, and sE1E2.LZ induced neutralizing activity against all genotypes. . These results indicate that our native-like soluble glycoprotein design, sE1E2.LZ, induces broadly neutralizing antibodies and serves as a promising vaccine candidate for further development.