TY - JOUR

T1 - HCV p7 as a novel vaccine-target inducing multifunctional CD4+ and CD8+ T-cells targeting liver cells expressing the viral antigen

AU - Filskov, Jonathan

AU - Andersen, Peter

AU - Agger, Else Marie

AU - Bukh, Jens

PY - 2019

Y1 - 2019

N2 - Despite recent treatment advances for chronic hepatitis C virus (HCV) infection, a vaccine is urgently needed for global control of this important liver pathogen. The lack of robust immunocompetent HCV infection models makes it challenging to identify correlates of protection and test vaccine efficacy. However, vigorous CD4+ and CD8+ T-cell responses are detected in patients that spontaneously resolve acute infection, whereas dysfunctional T-cell responses are a hallmark of chronic infection. The HCV p7 protein, forming ion-channels essential for viral assembly and release, has not previously been pursued as a vaccine antigen. Herein, we demonstrated that HCV p7 derived from genotype 1a and 1b sequences are highly immunogenic in mice when employed as overlapping peptides formulated as nanoparticles with the cross-priming adjuvant, CAF09. This approach induced multifunctional cytokine producing CD4+ and CD8+ T-cells targeting regions of p7 that are subject to immune pressure during HCV infection in chimpanzees and humans. Employing a surrogate in vivo challenge model of liver cells co-expressing HCV-p7 and GFP, we found that vaccinated mice cleared transgene expressing cells. This study affirms the potential of a T-cell inducing nanoparticle vaccine platform to target the liver and introduces HCV p7 as a potential target for HCV vaccine explorations.

AB - Despite recent treatment advances for chronic hepatitis C virus (HCV) infection, a vaccine is urgently needed for global control of this important liver pathogen. The lack of robust immunocompetent HCV infection models makes it challenging to identify correlates of protection and test vaccine efficacy. However, vigorous CD4+ and CD8+ T-cell responses are detected in patients that spontaneously resolve acute infection, whereas dysfunctional T-cell responses are a hallmark of chronic infection. The HCV p7 protein, forming ion-channels essential for viral assembly and release, has not previously been pursued as a vaccine antigen. Herein, we demonstrated that HCV p7 derived from genotype 1a and 1b sequences are highly immunogenic in mice when employed as overlapping peptides formulated as nanoparticles with the cross-priming adjuvant, CAF09. This approach induced multifunctional cytokine producing CD4+ and CD8+ T-cells targeting regions of p7 that are subject to immune pressure during HCV infection in chimpanzees and humans. Employing a surrogate in vivo challenge model of liver cells co-expressing HCV-p7 and GFP, we found that vaccinated mice cleared transgene expressing cells. This study affirms the potential of a T-cell inducing nanoparticle vaccine platform to target the liver and introduces HCV p7 as a potential target for HCV vaccine explorations.

U2 - 10.1038/s41598-019-50365-z

DO - 10.1038/s41598-019-50365-z

M3 - Journal article

C2 - 31575882

AN - SCOPUS:85072848255

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 14085

ER -