3. Prof. Fatma Amer Medical Microbiology and Immunology, ZAGAZIG FACULTY OF Medicine, Egypt President of ISC/HWG President of ArAPUA In the Era of Direct Acting Antivials; is There a Need for an HCV Vaccine

4.  Global distribution of HCV  Treatment of HCV infection  The need for an HCV vaccine  Challenges for developing an HCV vaccine  A successful HCV vaccine  Vaccine target  Promising outcomes of HCV vaccine modalities  Future vaccination approaches Overview of the presentation

5. Global distribution of HCV

6. BOC TVR SOC PEG-INF + Ribavirin the first- generation direct-acting antivirals 2011 + SOC FDA, 2013 Sofospivir Semiprivir FDA for type I FDA, 10/2014 Ledipasvir/Sofosbuvir Once/D, G1 Treatment of HCV infection

7. The need for an HCV vaccine

8. Managemant of HCV infection challenges Genetic determinants of host & virus can prevent 100% efficacy Resistance Very high cost Low rate of diagnosis Reinfection SOC with many side effects. DAAs problems

9. So, development of safe, effective, and affordable vaccines against HCV remain the best long-term hope for bringing the global epidemic under control. Prophylactic vaccine Current data indicate that vaccine – induced immunity may not prevent completely HCV infection, but rather prevent persistence of the virus Acceptable goal. Chronic persistence main cause of pathogenesis & development of serious conditions. High risk groups and

10. Therapeutic vaccine The need for an HCV vaccine has been emphasized in 2011 when the US Department of Health and Human Services issued the Viral Hepatitis Action Plan. Replace/ enhance teatment Benefits in expenses & logistics if patients treated with 2–3 doses of vaccine with/without SOC, opposed to months of combination.

11. The genetic heterogeneity which is a hallmark of HCV as RNA virus Technical limitations in the study of HCV Difficulty of growing the virus in cell culture, a problem which has been recently overcome. Challenges for developing an HCV vaccine

12.  Should address viral heterogeneity,  Should cover the various genotypes and quasispecies of HCV,  Should elicit desired immune response. A successful HCV vaccine

14. 1.Envelope region: - Hypervariability is an obstacle. 2. Core protein: - Interfere with innate and adaptive immunity - Viral replication inefficiently controlled. A key question, which HCV antigen a vaccine should target ??

15. Inducing T-cell responses to NS HCV antigens - Relatively, genetically conserved, - Known to contain multiple CD4+ & CD8+ T- cell epitopes. Targeting more than one Ag is most efficient strategy. Recent strategies have focused on

16. Terresi et al. (2011) Progress in the development of preventive and therapeutic vaccines for hepatitis C virus. JH; 54(6): 1273-1285.

26.  Applications for VLPs.  Combination modality. Future vaccination approaches

27. Beaumont E, et al. Chimeric hepatitis B virus/hepatitis C virus envelope proteins elicit broadly neutralizing antibodies and constitute a potential bivalent prophylactic vaccine. Hepatology.2013 Apr;57(4):1303-13.

28. T cell Response Anti-E1 and Anti-E2 Cross- neutralizing Abs A Prime Boost Strategy Adenovirus Bivalent HBV-HCV Prophylacti c Vaccine Vaccines with Highly Protective, Long Lasting Immunity to HCV and HBV

29.  There have been tremendous advances in the development of antiviral therapy to treat chronic HCV infections. However, there still remains the problem of treating chronically infected persons for whom the use of antiviral drugs is impractical because of cost and logistics. Availability of therapeutic and prophylactic vaccine can provide more cost-effective alternatives. Conclusions