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Immunization with a synthetic consensus hepatitis C virus E2 glycoprotein ectodomain elicits virus-neutralizing antibodies

Tarr, Alexander W.; Backx, Matthijs; Hamed, Mohamed R.; Urbanowicz, Richard A.; McClure, C. Patrick; Brown, Richard J.P.; Ball, Jonathan K.

Authors

Alexander W. Tarr

Matthijs Backx

Mohamed R. Hamed

Richard A. Urbanowicz

C. Patrick McClure

Richard J.P. Brown

Jonathan K. Ball



Abstract

Global eradication of hepatitis C virus (HCV) infection will require an efficacious vaccine capable of eliciting protective immunity against genetically diverse HCV strains. Natural spontaneous resolution of HCV infection is associated with production of broadly neutralizing antibodies targeting the HCV glycoproteins E1 and E2. As such, production of cross-neutralizing antibodies is an important endpoint for experimental vaccine trials. Varying success generating cross-neutralizing antibodies has been achieved with immunogens derived from naturally-occurring HCV strains. In this study the challenge of minimising the genetic diversity between the vaccine strain and circulating HCV isolates was addressed. Two novel synthetic E2 glycoprotein immunogens (NotC1 and NotC2) were derived from consensus nucleotide sequences deduced from samples of circulating genotype 1 HCV strains. These two synthetic sequences differed in their relative positions in the overall genotype 1a/1b phylogeny. Expression of these constructs in Drosophila melanogaster S2 cells resulted in high yields of correctly-folded, monomeric E2 protein, which were recognised by broadly neutralizing monoclonal antibodies. Immunization of guinea pigs with either of these consensus immunogens, or a comparable protein representing a circulating genotype 1a strain resulted in high titres of cross-reactive anti-E2 antibodies. All immunogens generated antibodies capable of neutralizing the H77 strain, but NotC1 elicited antibodies that more potently neutralized virus entry. These vaccine-induced antibodies neutralized some viruses representing genotype 1, but not strains representing genotype 2 or genotype 3. Thus, while this approach to vaccine design resulted in correctly folded, immunogenic protein, cross-neutralizing epitopes were not preferentially targeted by the host immune response generated by this immunogen. Greater immunofocussing by vaccines to common epitopes is necessary to successfully elicit broadly neutralizing antibodies.

Journal Article Type Article
Publication Date 2018-09
Journal Antiviral Research
Print ISSN 0166-3542
Electronic ISSN 1872-9096
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 160
Pages 25-37
APA6 Citation Tarr, A. W., Backx, M., Hamed, M. R., Urbanowicz, R. A., McClure, C. P., Brown, R. J., & Ball, J. K. (2018). Immunization with a synthetic consensus hepatitis C virus E2 glycoprotein ectodomain elicits virus-neutralizing antibodies. Antiviral Research, 160, 25-37. doi:10.1016/j.antiviral.2018.09.005
DOI https://doi.org/10.1016/j.antiviral.2018.09.005
Keywords Hepatitis C; Vaccine; Consensus; Neutralization
Publisher URL https://www.sciencedirect.com/science/article/pii/S0166354218303243?via%3Dihub

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