Challenges for HCV Vaccine Development in HIV–HCV Coinfection

Mélanie Lambotin; Heidi Barth; Christiane Moog; François Habersetzer; Thomas F Baumert; Françoise Stoll-Keller; Samira Fafi-Kremer

Disclosures

Expert Rev Vaccines. 2012;11(7):791-804.

Abstract and Introduction

Abstract

It is estimated that 4–5 million HIV-infected patients are coinfected with HCV. The impact of HIV on the natural course of HCV infection is deleterious. This includes a higher rate of HCV persistence and a faster rate of fibrosis progression. Coinfected patients show poor treatment outcome following standard HCV therapy. Although direct antiviral agents offer new therapeutic options, their use is hindered by potential drug interactions and toxicity in HIV-infected patients under HAART. Overtime, a large reservoir of HCV genotype 1 patients will accumulate in resource poor countries where the hepatitis C treatment is not easily affordable and HIV therapy remains the primary health issue for coinfected individuals. HCV vaccines represent a promising strategy as an adjunct or alternative to current HCV therapy. Here, the authors review the pathogenesis of hepatitis C in HIV-infected patients, with a focus on the impact of HIV on HCV-specific immune responses and discuss the challenges for vaccine development in HIV–HCV coinfection.

Introduction

HIV-1 and HCV may cause persistent infections with long-term high-level viremia in spite of a specific immune response.^[1] Both infections progress silently over several years, leading to the destruction of the immune system in the case of HIV-1 and liver cirrhosis in the case of HCV. Unlike HIV infection, HCV is spontaneously cleared in 25% of cases and curable in more than 50% of patients when treated with interferon (IFN)-based combination therapies.^[2,3] Coinfection is frequent because of the shared risk factors for viral transmission, as HCV and HIV are both transmitted through exposure to blood and sexual exposure, although with different efficiencies. Recent epidemiologic and clinical studies showed that the introduction of HAART has improved the survival of HIV-infected patients, while HCV-associated liver diseases have become a leading cause of death in the coinfected population. The standard treatment for HCV infection in HIV–HCV-coinfected patients is similar to that of HCV-monoinfected patients, although significant toxicity is associated with pegylated IFN-α and ribavirin in coinfected patients.^[4] Therefore, the development of new therapeutic and preventive strategies against HCV in HIV-infected individuals has become a priority. This review summarizes the current knowledge on the pathogenesis of hepatitis C in HIV-infected patients, with a focus on the impact of HIV on HCV-specific immune responses and discusses the challenges for HCV vaccine development in HIV–HCV coinfection.

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Table 1. Summary of prophylactic HCV vaccine assays in animal models and in human according to target type of immune response to be induced by vaccination.
Study (year)	HCV vaccine strategy	Animal model/patients	Immunogenicity observed and HCV outcome	Potential impact of HIV infection on HCV vaccine response	Ref.
*HCV-specific CD4⁺ and/or CD8⁺ T-cell response*
Chiron/Novartis	Yeast-derived fusion HCV polyprotein comprising HCV core, NS3 to NS5, with ISCOMATRIX®	Chimpanzees	Vigourous HCV multispecific T-cell response No HCV clearance		[94]
Folgori et al. (2006)	DNA encoding for HCV NS proteins. Administration by combination of two injections of adenoviral vectors followed by electroporation of plasmid DNA	Chimpanzees	Multispecific HCV CD4⁺ and CD8⁺ T cells Protection from acute HCV infection after challenge with heterologous virus	Increased risk of HCV escape mutants Enhancement of HIV replication	[95]
Barnes et al. (2012)	HCV NS proteins expressed by adenoviral vectors	Healthy human individuals	HCV-specific T-cell response targeting multiple HCV proteins from different genotypes	No/lower induction of HCV-specific CD4⁺ T-cell response	[96,203]
*HCV-neutralizing antibodies*
Chiron/Novartis	Recombinant HCV gpE1/gpE2	Chimpanzees	Antibody response and protection against homologous virus No cross-neutralizing antibodies Protection against development of chronic infection	Increased risk of HCV escape mutants	[97,98]
Stamataki et al. (2007)	Recombinant HCV gpE1/gpE2	Guinea pigs	Antibody titers able to neutralize in vitro HCV pseudoparticles and cell culture-derived HCV derived from heterologous viral strains	Impairment of HCV cross-neutralizing antibody induction	[99]
*Combination of HCV-specific T-cell response and HCV-neutralizing antibodies*
NIAID and Chiron/Novartis	MF59-adjuvanted recombinant gpE1/gpE2	Healthy human volunteers	Induction of anti-gpE1/gpE2 antibodies T-cell-proliferative response	Increased risk of HCV escape mutants	[94,104,204]
NIAID and Chiron/Novartis	ISCOMATRIX-adjuvanted recombinant HCV core protein	Healthy human volunteers	Induction of anti-core antibodies T-cell-proliferative response	Impairment of HCV cross-neutralizing antibody induction	[94,106]
Garrone et al. (2011)	Prime–boost strategy: prime using adenovirus encoding HCV E1E2 proteins; boost with HCV E1 and/or E2 VLPs	Macaques/mice	Multispecific HCV T-cell responses HCV cross-neutralizing antibodies	Enhancement of HIV replication No/lower induction of HCV-specific CD4⁺ T-cell response	[107]

Table 2. Summary of therapeutic HCV vaccine clinical trials in human according to target type of immune response to be induced by vaccination.
Study (year)	HCV vaccine strategy	Patients	Immunogenicity observed and HCV outcome	Potential impact of HIV infection on HCV vaccine response	Ref.
*HCV-specific CD4⁺ and/or CD8⁺ T-cell response*
Transgene	TG4040: highly modified vaccinia Ankara virus encoding for HCV NS3, NS4 and NS5B proteins	Treatment-naive HCV patients	Decrease of HCV viral load associated with a boost of HCV-specific T-cell response		[108,205]
Intercell AG	IC41: poly-l-arginine-adjuvanted synthetic peptides encoding highly conserved epitopes in HCV core, NS3 and NS4 proteins	HCV patients who are nonresponders to standard treatment	HCV-specific T-cell response No impact on HCV viral load		[109,206]
Tripep AB	ChronVac-C®: in vivo electroporation of HCV plasmid DNA expressing HCV NS3/4A proteins	Patients infected with genotype 1 HCV	Decrease of HCV viral load associated with a boost of HCV-specific T-cell response	Increase in HCV escape mutant numbers	[110,207]
Globe Immune	GI-5005: recombinant yeast expressing a HCV core–NS3 fusion protein	HCV-infected volunteers	Decrease of HCV viral load HCV-specific CD8⁺ T-cell response	Enhancement of HIV replication	[112,113,208]
Globe Immune	GI-5005 in combination with standard PEG-IFN/RBV treatment	HCV-infected volunteers	Increased SVR compared with standard therapy	No/lower induction of HCV-specific CD4⁺ T-cell response	[102,209]
Transgene	TG4040 in combination with standard PEG-IFN/RBV treatment	HCV-infected volunteers	Increased SVR compared with standard therapy		[114,210]
*Combination of HCV-specific T-cell response and HCV neutralizing antibodies*
NIAID and Chiron/Novartis	MF59-adjuvanted recombinant gpE1/gpE2	HCV-infected volunteers	Failure to induce decrease in HCV viral load	Increase in HCV escape mutants numbers	[94]
NIAID and Chiron/Novartis	Iscomatrix-adjuvanted recombinant HCV core protein	HCV-infected volunteers	Failure to induce decrease in HCV viral load	Impairment of HCV cross-neutralizing antibody induction	[94]
Alvarez-Lajonchere et al. (2009)	CIGB-203: HCV structural protein-encoding DNA-based vaccine combined with recombinant HCV core protein	HCV-patients who are nonresponders to standard treatment	HCV core-specific T-cell response Neutralizing antibodies No decrease in HCV viral load Reduction of liver fibrosis	Enhancement of HIV replication No/lower induction of HCV-specific CD4⁺ T-cell response	[111,211]