Hepatitis C vaccine

Abstract

Hepatitis C virus (HCV) was first identified in 1989. HCV is a small, enveloped RNA virus. Globally, 3–4 million persons are infected with HCV each year, and are at risk of developing liver cirrhosis and/or liver cancer. The common modalities of the spread of hepatitis C infection are blood transfusions, injection drug use, unsafe therapeutic injections, and healthcare-related procedures. The standard treatment for hepatitis C has been combination antiviral therapy with interferon (IFN) and ribavirin, which are effective against all the genotypes of hepatitis viruses (pan-genotypic). A 12-month course of Peg-IFN/ribavirin treatment costs > $20 000. New HCV-specific antiviral drugs, especially in combination, have shown very high cure rates; however, the annual cost for a single subject ($82 000) make these unaffordable in most of the world. There is no hepatitis C vaccine. However, several vaccines in development, and some have shown promising preclinical results. Over the last few years, numerous HCV vaccine approaches have been assessed in mice and primates, but only a few vaccines have progressed to human trials. The challenge to develop HCV vaccine is to move into larger at-risk or infected populations to test efficacy.

Hepatitis C virus was first identified in 1989 using molecular biology techniques after extensive testing of serum from experimentally infected animals. HCV is a small, enveloped, single-stranded, positive-sense RNA virus, a member of the Hepacivirus genus in the family Flaviviridae.¹ The half-life of the virus particles in serum is ~3 h and may be as short as 45 min. In an infected person, about 10¹² virus particles are produced each day. In addition to replicating in the liver, the virus can multiply in lymphocytes.²

Globally, 3–4 million people are infected with HCV every year. About 150 million people are chronically infected with HCV, and ~350 000 people die annually from hepatitis C-related liver diseases.³ Most developed countries report a prevalence of HCV 0.5–2% in the general population. In the United States and western Europe, ~150 000 new cases occur annually, while in Japan this figure is more than double, i.e., ~350 000 new cases annually. Of these cases ~25% are symptomatic, but 60–80% may progress to chronic liver disease, 20% of these develop cirrhosis, and ~57% ultimately die of the consequences of infection. The WHO South-East Asia Region has ~30 million carriers, which is > 1.6% of the population, and > 120 000 people in the region are estimated to die annually due to cirrhosis and liver cancer associated with hepatitis C.⁴ The countries with the high prevalence rates include Egypt (14.7%), Pakistan (4.8%), and China (3.2%). The main mode of transmission in these countries is the use of unsafe syringes and needles. In India, several studies on voluntary or mixed donors have noted prevalence < 2%.^5-10 About 12 million people may be chronically infected in India, and most are unaware of the infection.¹¹ The common modalities of spread of hepatitis C are blood transfusions, injection drug use, unsafe therapeutic injections, and healthcare-related procedures. In developed countries, the predominant cause of hepatitis C infection is intravenous drug use, whereas in India blood transfusions and unsafe therapeutic injections are the predominant ways of transmitting hepatitis C.

HCV is not known to infect animals other than chimpanzees. Most descriptions of global HCV epidemiology rely on HCV sero-prevalence studies. These studies are typically cross-sectional in design and are done in a selected population, e.g., blood donors or patients with chronic liver disease, which are not a true representation of the community or region in which they reside. Population-based studies representative of an entire community are far more useful and accurate in capturing the real scenario of the disease. Different HCV genomes have been isolated from different geographical regions, and HCV has been classified into six major genotypes (genotype 1–6). Although the genotype of the virus does not influence disease presentation or severity, it is a major predictor of the response to antiviral therapy.

Hepatitis C does not always require treatment in that the immune response in some people will clear the infection. When treatment is necessary, the goal of treatment is cure. The cure rate depends on several factors including the strain of the virus and the type of treatment given. Careful screening is necessary before starting the treatment to determine the most appropriate approach for the patient.

The standard treatment for hepatitis C has been combination antiviral therapy with IFN + ribavirin, which is moderately effective against all HCV genotypes (pan-genotypic) even though these drugs are not HCV-specific. Unfortunately, IFN is not widely available globally and it is poorly tolerated in some patients. This means that management of the treatment is complex, and many patients do not finish their treatment. Despite these limitations, IFN / ribavirin treatment can be life-saving. Recent scientific advances have led to the development of new antiviral drugs for hepatitis C, which are much more effective, safer and better-tolerated than IFN-based therapy. These therapies, known as oral directly acting antiviral agent (DAAs) therapies, simplify hepatitis C treatment by significantly decreasing monitoring requirements and by providing very high cure rates (generally 90–100%). Although the production costs of DAAs are relatively low, the initial prices set by companies in light of their development costs are very high and likely to make access to these drugs difficult even in high-income countries. A one-year course of combination Peg-IFN/ribavirin treatment costs > $20 000. The initial combination DAA regimen costs $82 000 for a 3-mo regimen, and even though this price will decrease due to competitive combinations expected to be licensed during the new two years, the price likely will remain higher than the > $20 000 for the IFN-based therapy. An estimate in the Veterans Affairs health care system was that, if all veterans were to be screened in order to identify the carriers, and if 20% of the hepatitis C carriers were eligible for treatment with IFN / ribavirin, the cost would be > $600M.¹²

The response to IFN / ribavirin treatment, which is lower than that to the new DAAs, is measured by sustained viral response and varies by HCV genotype. A sustained response occurs in ~40–50% in people with HCV genotype 1 given 48 wk of IFN / ribavirin treatment, ~70–80% of people with HCV genotypes 2 and 3 with 24 wk of treatment.¹³ A sustained response occurs ~65% in those with genotype 4 after 48 wk of treatment. The evidence for treatment in genotype 6 disease is sparse, and what evidence there is supports 48 wk of treatment at the same doses used for genotype 1 disease. Successful treatment decreases the future risk of hepatocellular carcinoma by 75%.^14,15

No vaccine is available against hepatitis C. However, some vaccines under development have shown encouraging results. Over the last decade, numerous HCV vaccine approaches have been assessed in mice and primates. Only a small fraction of HCV vaccines tested in preclinical models have progressed to human trials. The majority of these trials have evaluated potential therapeutic vaccines in HCV-infected patients. A smaller number have assessed vaccines in healthy volunteers, with the aim of developing a prophylactic HCV vaccine or as a bridge to evaluate vaccine in HCV-infected patients.

Most vaccines target the virus surface and elicit antibody responses. However, HCV is highly variable among strains and mutates rapidly, making the development of an effective vaccine very difficult.¹⁶ The detailed structure of E2 envelope glycoprotein, believed to be the key protein the virus uses to invade liver cells, was reported by scientists at Scripps Research Institute in November 2013. Due to the relatively conserved binding region of E2 to the CD81 receptor on the liver cells, this discovery may enable the design of an HCV vaccine that will stimulate neutralizing antibody responses to a broad range of virus strains.

Another vaccine strategy is to induce cell-mediated immunity using viral vectors, e.g., adenoviral vectors that contain large parts of the HCV genome itself, to induce a T-cell response against HCV-infected cells.¹⁶ Most of the work to date to develop a vaccine for inducing cell-mediated immune responses has been done against a particular genotype. The six genotypes reflect differences in virus structure. Initial vaccines might target only genotypes 1a and 1b, which account for > 60% of chronic HCV infections worldwide, while follow-on vaccines might target other genotypes by prevalence.¹⁷

Other new HCV vaccine approaches, including peptide, recombinant protein, DNA and vector-based vaccines, have reached Phase 1/2 clinical trials. Some of these technologies have generated robust antiviral immunity in healthy volunteers and infected patients. Novel future vaccine approaches include virus-like particle-based vaccines that have been successfully employed for hepatitis B virus and human papilloma virus. Additional strategies include molecules that induce innate immune responses, with secondary effects on adaptive responses (such as TLR-9 ligands) that are either encoded within a vaccine construct or used as a vaccine adjuvant.

The challenge is to move forward into larger at-risk or infected populations to truly test efficacy.

10.4161/hv.29033