Proof of concept for rational design of hepatitis C virus E2 core nanoparticle vaccines

He, Linling; Tzarum, Netanel; Lin, Xiaohe; Shapero, Benjamin; Sou, Cindy; Mann, Colin J.; Stano, Armando; Zhang, Lei; Nagy, Kenna; Giang, Erick; Law, Mansun; Wilson, Ian A.; Zhu, Jiang

doi:10.1126/sciadv.aaz6225

Proof of concept for rational design of hepatitis C virus E2 core nanoparticle vaccines

Journal Article · Wed Apr 01 04:00:00 EDT 2020 · Science Advances

DOI:https://doi.org/10.1126/sciadv.aaz6225· OSTI ID:1816263

^[1]; ^[2]; Lin, Xiaohe ^[2]; ^[2]; Sou, Cindy ^[2]; ^[2]; Stano, Armando ^[2]; Zhang, Lei ^[2]; ^[3]; Giang, Erick ^[3]; ^[3]; ^[4]; ^[5]

The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology; OSTI
The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology
The Scripps Research Inst., La Jolla, CA (United States). Dept. of Immunology and Microbiology
The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology; The Scripps Research Inst., La Jolla, CA (United States). Skaggs Inst. for Chemical Biology
The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology; The Scripps Research Inst., La Jolla, CA (United States). Dept. of Immunology and Microbiology

Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are responsible for cell entry, with E2 being the major target of neutralizing antibodies (NAbs). Here, we present a comprehensive strategy for B cell–based HCV vaccine development through E2 optimization and nanoparticle display. We redesigned variable region 2 in a truncated form (tVR2) on E2 cores derived from genotypes 1a and 6a, resulting in improved stability and antigenicity. Crystal structures of three optimized E2 cores with human cross-genotype NAbs (AR3s) revealed how the modified tVR2 stabilizes E2 without altering key neutralizing epitopes. We then displayed these E2 cores on 24- and 60-meric nanoparticles and achieved substantial yield and purity, as well as enhanced antigenicity. In mice, these nanoparticles elicited more effective NAb responses than soluble E2 cores. Next-generation sequencing (NGS) defined distinct B cell patterns associated with nanoparticle-induced antibody responses, which target the conserved neutralizing epitopes on E2 and cross-neutralize HCV genotypes.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1816263

Alternate ID(s):: OSTI ID: 1833647
OSTI ID: 1837288

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 16 Vol. 6; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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