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Role of the E2 hypervariable region (HVR1) in the immunogenicity of a recombinant HCV vaccine.

Role of the E2 hypervariable region (HVR1) in the immunogenicity of a recombinant HCV vaccine.
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Law JLM, Logan M, Wong J, Kundu J, Hockman D, Landi A, Chen C, Crawford K, Wininger M, Johnson J, Mesa Prince C, Dudek E, Mehta N, Tyrrell DL, Houghton M,


Law JLM, Logan M, Wong J, Kundu J, Hockman D, Landi A, Chen C, Crawford K, Wininger M, Johnson J, Mesa Prince C, Dudek E, Mehta N, Tyrrell DL, Houghton M, (click to view)

Law JLM, Logan M, Wong J, Kundu J, Hockman D, Landi A, Chen C, Crawford K, Wininger M, Johnson J, Mesa Prince C, Dudek E, Mehta N, Tyrrell DL, Houghton M,

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Journal of virology 2018 03 14() pii JVI.02141-17
Abstract

Current evidence supports a protective role for virus neutralizing antibodies in immunity against HCV infection. Many cross-neutralizing monoclonal antibodies have been identified. These antibodies have been shown to protect or clear infection in animal models. Previous clinical trials have shown a gpE1/gpE2 vaccine can induce antibodies that neutralize theinfectivity of all the major HCVcc genotypes around the world. However, cross-neutralization appeared to favour certain genotypes with significant but lower neutralization against others. HCV may employ epitope masking to avoid antibody-mediated neutralization. The hypervariable region-1 (HVR1) at the amino-terminus of glycoprotein E2 has been shown to restrict access to many neutralizing antibodies. Consistent with this, other groups have reported that recombinant viruses lacking the HVR1 are hypersensitive to neutralization. It has been proposed that gpE1/gpE2 lacking this domain could be a better vaccine antigen to induce broadly neutralizing antibodies. In this study, we examined the immunogenicity of recombinant gpE1/gpE2 lacking the HVR1 (ΔHVR1). Our results indicate that WT and ΔHVR1 gpE1/gpE2 induced antibodies targeting many well-characterized cross-genotype neutralizing epitopes. However, while WT gpE1/gpE2 vaccine can induce cross-genotype protection against various genotypes of HCVcc and/or HCVpp, antisera from ΔHVR1 gpE1/gpE2 immunized animals exhibited either reduced homologous neutralization activity or similar heterologous neutralization activity compared to WT. This data suggests ΔHVR1 gpE1/gpE2 is not a superior vaccine antigen. Based on chimpanzee protection data reported previously using WT gpE1/gpE2 and our current findings, we are preparing a combination vaccine including a wild type recombinant gpE1/gpE2 for clinical testing in the future.An HCV vaccine is an unmet medical need. Current evidence suggests neutralizing antibodies play an important role in viral clearance along with cellular immune responses. Previous clinical data showed gpE1/gpE2 can effectively induce cross neutralizing antibodies although they favour certain genotypes. HCV employs the hypervariable HVR1 region within gpE2 to evade host immune control. It has been hypothesized that removal of this domain would improve the production of cross-neutralizing antibodies. In this study, we compared the immunogenicity of WT and ΔHVR1 gpE1/gpE2 antigens as vaccine candidates. Our results indicate that ΔHVR1 gpE1/gpE2 antigen confers no advantages in the neutralization of HCV when compared with WT antigen. Previously we have shown that this WT antigen remains the only vaccine candidate to protect chimpanzees from chronic infection, contains multiple cross-neutralizing epitopes, and is well-tolerated and immunogenic in humans. The current data supports the further clinical development of this vaccine antigen component.

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