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Review
. 2013 Aug;13(8):1109-24.
doi: 10.1517/14712598.2013.791277. Epub 2013 May 7.

Ever closer to a prophylactic vaccine for HCV

Leo Swadling  1 , Paul Klenerman, Eleanor Barnes
Affiliations
Free PMC article
Review

Ever closer to a prophylactic vaccine for HCV

Leo Swadling et al. Expert Opin Biol Ther. 2013 Aug.
Free PMC article

Abstract

Introduction: With 3 - 4 million new infections occurring annually, hepatitis C virus (HCV) is a major global health problem. There is increasing evidence to suggest that HCV will be highly amenable to a vaccine approach, and despite advances in treatment, a vaccine remains the most cost-effective and realistic means to significantly reduce the worldwide mortality and morbidity associated with persistent HCV infection.

Areas covered: In this review we discuss immune responses to HCV during natural infection, and describe how they may inform vaccine design. We introduce the current candidate vaccines for HCV and compare how these fare against the expected requirements of an effective prophylactic HCV vaccine in relation to the breadth, functionality, magnitude and phenotype of the vaccine-induced immune response.

Expert opinion: Although the correlates of immune protection against HCV are not completely defined, we now have vaccine technologies capable of inducing HCV-specific adaptive immune responses to an order of magnitude that are associated with protection during natural infection. The challenge next is to i) establish well-characterised cohorts of people at risk of HCV infection for vaccine efficacy testing and ii) to better understand the correlates of protection in natural history studies. If these can be achieved, a vaccine against HCV appears a realistic goal.

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Figures

Figure 1.
Figure 1.
HCV genome structure and vaccine immunogens. (A) Organisation of the HCV genome: HCV, a single-stranded RNA virus of ∼ 9.5 kb, consists of a single open-reading frame and two untranslated regions. HCV is transcribed as a single polyprotein, which is cleaved by a host signal protease in the structural region and the HCV-encoded serine protease in the NS region. The hypervariable regions of E2 (HVR1 + HVR2) are indicated by dashed arrows. The protein products of cleavage are shown. The structural regions consist of core and the two envelope proteins, gp35 and gp76. The NS proteins are shown and their functions are described where known. (B) Prophylactic vaccines for HCV tested in primates (including man) are listed according to the lead author of the paper in which they are described. The relative coverage of the HCV genome by vaccine immunogen is shown. The genotype of the immunogen encoded in each vaccine is shown in parenthesis with the paper reference [].
Figure 2.
Figure 2.
Magnitude of T-cell response to vaccination. A comparison of the magnitude of vaccine-induced T-cell responses in primates is shown (median of peak response after vaccination as measured by IFNγ ELISpot). Vaccines contained HCV antigens unless otherwise stated. Successive vaccinations are separated by a forward slash, e.g., DNA/MVA refers to a vaccine regimen using DNA priming followed by an MVA boost. References in parenthesis [].
Figure 3.
Figure 3.
Progress to an effective prophylactic vaccine against HCV. A summary of some of the key interactions between basic research and vaccine studies is shown. Natural history studies of HCV infection are used to better understand the immune correlates of protection against HCV infection; this understanding informs all levels of vaccine design, in particular the design of vaccines for preclinical and Phase I studies and at the selection stages when assessing efficacy of candidate vaccines. Cohorts of at-risk populations need to be characterised before candidate vaccines can be tested in Phase II/III studies and so this work should be done in parallel with early-stage vaccine assessment. Phase II/III studies of vaccine efficacy may be required to further define correlates of protection for optimal vaccine generation – a process termed “reverse vaccinology”. Basic research into vaccine modalities, adjuvants and the biology of T and B cells can be fed into the process of vaccine development at all stages to allow us to better design, assess and implement novel vaccines.
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