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Hepatitis C virus modified sE2F442NYT as an antigen in candidate vaccine facilitates human immune cell activation
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DOI：10.1128/jvi.01809-23.png)
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Abstract
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The rational selection of hepatitis C virus (HCV) vaccine antigen will aid in the prevention of future chronic liver disease burden and associated healthcare costs. We have previously shown that HCV E2 glycoprotein is not highly immunogenic, and the modification of E2 reduced CD81 binding and displayed altered cytokine and protective immune responses in vitro and in a surrogate mouse model. Here, we compared the influence of a parental and a modified sE2(F442NYT) glycoprotein region from HCV genotype 1a for the activation of peripheral blood mononuclear cell (PBMC)-derived dendritic cells (DCs), CD4(+)T cells, and B cells. Modified sE2(F442NYT), when incubated with DCs, induced a higher number of CD86-positive cells. The sE2(F442NYT) or parental sE2 encapsulated as mRNA-lipid nanoparticle (sE2(F442NYT) mRNA-LNP) primed DCs co-cultured with autologous CD4(+)T cells did not induce CD25 or forkhead box P3 expression. PBMC-derived CD4(+)T cells treated with sE2(F442NYT) exhibited enhanced signal transducer and activator of transcription (Stat)1/Stat4 phosphorylation in response to anti-CD3/CD28 stimulation in comparison to parental sE2 treatment and facilitated isotype switching in B cells, leading to the generation of a broader subclass of antibodies. Cells treated with modified sE2(F442NYT) displayed an increase in activated Stat3 and extracellular signal-regulated kinase (ERK). Likewise, PBMC-derived na & iuml;ve B cells upon in vitro stimulation with sE2(F442NYT) induced an increased proliferation, Stat3 and ERK activation, and protein kinase B (Akt) suppression. Thus, the modified sE2(F442NYT) antigen from HCV facilitates improved DC, CD4(+)T, and B cell activation compared to parental sE2 to better induce a robust protective immune response, supporting its selection as an HCV candidate vaccine antigen for preclinical and clinical HCV vaccine trials.
Keywords:
HCV
modified E2
DCs
CD4(+)T cells
B cell response
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