Abstract
Hepatitis C virus (HCV) persistently infects approximately 71 million people globally. To prevent infection a vaccine which elicits neutralizing antibodies against the virus envelope proteins (E1/E2) which are required for entry into host cells is desirable. DNA vaccines are cost-effective to manufacture globally and despite recent landmark studies highlighting the therapeutic efficacy of DNA vaccines in humans against cervical cancer, DNA vaccines encoding E1/E2 developed thus far are poorly immunogenic. We now report a novel and highly immunogenic DNA vaccination strategy that incorporates secreted E1 and E2 (sE1 and sE2) into oligomers by fusion with the oligomerization domain of the C4b-binding protein, IMX313P. The FDA approved plasmid, pVax, was used to encode sE1, sE2, or sE1E2 with or without IMX313P, and intradermal prime-boost vaccination studies in BALB/c mice showed that vaccines encoding IMX313P were the most effective in eliciting humoral and cell-mediated immunity against the envelope proteins. Further boosting with recombinant E1E2 proteins but not DNA nor virus-like particles (VLPs) expressing E1E2 increased the immunogenicity of the DNA prime-boost regimen. Nevertheless, the antibodies generated by the homologous DNA prime-boost vaccinations more effectively inhibited the binding of VLPs to target cells and neutralized transduction with HCV pseudoparticles (HCVpp) derived from different genotypes including genotypes 1, 2, 3, 4, 5, and 6. This report provides the first evidence that IMX313P can be used as an adjuvant for E1/E2-based DNA vaccines and represents a translatable approach for the development of a HCV DNA vaccine.
Highlights
Current estimates have shown that more than 71 million people are living with chronic hepatitis C and a large proportion of these individuals are at risk of developing cirrhosis that may progress to hepatocellular carcinoma [1, 2]
DNA vaccines, each encoding a different form of sE1 and/or sE2, were constructed in pVAX: p-sE1, p-sE2, p-sE1E2, p-sE1IMX313P, p-sE2-IMX313P, and p-sE1E2-IMX313P (Figure 1A)
Oligomers of sE1- and/or sE2-IMX313P were only detectable in non-reducing conditions and under reducing conditions, proteins that migrated as monomers of 37 kDa for E1 and ∼68 kDa for E2 were detected using E1 and E2-specific antibodies (Figure 1B)
Summary
Current estimates have shown that more than 71 million people are living with chronic hepatitis C and a large proportion of these individuals are at risk of developing cirrhosis that may progress to hepatocellular carcinoma [1, 2]. In 2015, viral hepatitis caused 1.34 million deaths and surpassed human immunodeficiency virus (HIV) as a cause of mortality worldwide [1]. The introduction of direct acting antivirals (DAA), developed to disrupt the function of critical non-structural (NS) HCV proteins involved in viral replication, has been highly effective, resulting in a reduced duration of treatment and high cure rates in most patients, compared to pegylated interferon plus ribavirin [3]. An additional challenge to DAA treatment includes the potential for reinfection after treatment [7]. For these reasons, the development of an inexpensive, safe and effective HCV vaccine is required to control the HCV epidemic worldwide and reduce the financial stress on healthcare systems
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