Hepatitis Vaccine

Viral hepatitis

Viral hepatitis is liver inflammation due to a viral infection. It may present in acute form as a recent infection with relatively rapid onset, or in chronic form. The most common causes of viral hepatitis are the five unrelated hepatotropic viruses hepatitis A, B, C, D, and E.

• Hepatitis A virus

HAV is a positive-strand RNA virus. The hepatitis A infection is transmitted through the fecal-oral route, and the infection cycle starts with the ingestion of naked particles. These particles are highly stable in the environment, for instance high infectious titers can still be detected after 60 days of desiccation on surfaces at room temperature or in soils and water after several weeks, and in the harsh conditions during the transit through the stomach to the gut. The clinical manifestations of HAV infection range from asymptomatic infection to ALF (Figure 1) ^{[4, 5]}. HAV exists in a dual phenotype, naked and quasi-enveloped virions. The Quasi-enveloped virions are present in the blood and are responsible for the cell to cell transmission and occasionally parenteral host-to-host transmission. Naked virions are shed in the feces of infected patients and are responsible for the fecal host-to-host transmission. Particles in the exosomes are immature and contain the VP1-pX protein; instead, naked virions in feces are mature and contain the fully processed VP1 protein ^[4-6].

Figure 1. A typical course of hepatitis A. After a 3- to 5-week incubation period following hepatitis A virus (HAV) infection, patients develop symptoms of hepatitis with elevation of serum alanine aminotransferase (ALT) levels. Fecal virus shedding and viremia are present and peak during the incubation period. Anti-HAV antibodies appear in serum first as immunoglobulin (Ig)M and subsequently as IgG. Virus-specific T-cell responses coincide with the elevation of serum ALT levels.

• Hepatitis B virus

Hepatitis B virus (HBV) is a hepatotropic virus that can cause severe liver diseases including acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC).

HBV has three important proteins, HBsAg, HBcAg and HBeAg. The viral envelope proteins known as surface antigens (HBsAgs) which is the main virulence factor of the virus. The core protein packages its own mRNA, also known as the pregenomic RNA (pgRNA), to form the core particle that displays the core antigenic determinant (i.e., the core antigen, HBcAg) ^[7]. The e antigen (HBeAg) is not essential for HBV replication, as mutations that abolish its expression do not negatively affect viral replication. HBeAg seroconversion, have been observed in many chronic HBV patients and are often preceded by flares of hepatitis due to enhanced cytotoxic T lymphocyte (CTL) responses. For that reason, HBeAg is thought to have immunomodulatory functions ^[7].

• Hepatitis C virus

Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. The virus persists in the liver, becoming chronic, in about 70% of those initially infected. The key role of lipids in the HCV life cycle and pathogenesis has been researched, but dynamic models to address the role of the lipid environment for structural rearrangements in HCV proteins are still in their infancy (Figure 2) ^[8].

The HCV RNA genome contains three major parts: a single open reading frame (ORF) flanked by 5' and 3' untranslated regions (UTRs). The ORF encdes a viral poly-protein, which comprises a total of ten structural and nonstructural NNS) proteins cleaved by viral and host Structural proteins of the 'assembly' module include core protein, building up the viral capsid, and envelope glycoproteins E1 and E2, inserted into the surrounding capsid membrane. The NS protein p7 is a viroporin that forms an intracellular proton-conducting transmembrane channel, supporting virus assembly and release by shunting the pH of intracellular compartments. NS2 flanks the 'assembly' module on the 3'-end and is responsible for the poly-protein cleavage on the NS2 and NS3 junction and serves as a hub for the infectious viral particles assembly. Viral nonstructural proteins are important targets for specific antiviral drugs. Lipid exposed surfaces of these proteins play an important, albeit poorly understood, role in the development of drug resistance. The NS3–4A protease/helicase plays an essential role in the HCV replication cycle and is a prime target site for direct antiviral therapy. NS5A is a multifunctional phospho- and metalloprotein. NS5A is capable of triggering DMVs formation and, possibly, acting as a master regulator of viral RNA translation, replication and assembly of infectious viral particles. NS5A inhibitors are central to most direct-acting antiviral agent (DAA)-treatment approaches and retreatment options against HCV ^[8].

Figure 2 Schematic representation of the HCV life cycle. Steps of the HCV genome replication cycle involving interactions between nonstructural viral proteins and host phospholipids are shown in red.

• Other hepatitis viruses

HDV is the only member of the Deltavirus genus. The core of the HDV virion is a single-stranded RNA molecule complexed with both the small and large forms of hepatitis D antigen (HDAg), the only protein encoded by HDV. HDAg is ultimately translated into two isoforms: small HDAg (S-HDAg) and large HDAg (L-HDAg). Treatment for HDV is very promising in spite of the lack of virus-specific enzymes, which prevent it from being directly targeted to inhibit its replication. The primary goal of treatment is the suppression of HDV replication (or even eradication) and/or accompanying improvements in ALT and reduction in hepatic necroinflammation ^[9].

In developing countries, HEV has caused multiple outbreaks where the virus is transmitted via the fecal-oral route by drinking contaminated water. The genome of HEV has a short 5′ untranslated region (5′ UTR) capped at its 5′ end and a short 3′ UTR terminated by the poly(A) tract. ORF1 is translated from genomic RNA, while ORF2 and ORF3 are translated from a subgenomic RNA strand. The HEV particles in bile and those shed in the feces are non-enveloped. Meanwhile, the particles in circulating blood and culture supernatants are in membrane-associated form, in which membrane-associated HEV particles seem to be completely covered with a lipid membrane. HEV replicates primarily in the liver (not in the gut) and that the non-enveloped virions entering via the gastrointestinal tract will be neutralized by immune sera before reaching the liver via the portal vein ^[10].

Vaccine for viral hepatitis

Given that viral hepatitis A, B, C, D, and E together constitute the eighth leading cause of mortality worldwide. It is clear that safe and effective vaccines for all of these viruses as well as enlightened and enforced public policy to insure widespread dissemination could dramatically reduce the morbidity and mortality associated with these serious infections of the liver.

• HAV vaccine

Since the late 1970s, the development of the formalin-inactivated hepatitis A vaccine, resulted in the commencement of Phase I clinical studies in 1989 and progressed to Phase III clinical trials. These trials demonstrated efficacy of a single dose of the vaccine in preventing clinical HAV disease in pediatric populations in Monroe, NY. Inactivated HAV vaccines have proven to be among the most immunogenic, safe, and well-tolerated vaccines. Since the 1990s, several vaccines against HAV have been commercially available, including both an inactivated and live attenuated vaccine. The first inactivated HAV vaccine was produced from a strain of the virus propagated in cell culture. This vaccine was clear of any remaining infective capability in vitro. The persistence of antibody in adults more than 25 years after vaccination is estimated to be >95 percent. The HAV vaccine has also proved to be an extremely safe vaccination ^{[1, 11]}.

• HBV vaccine

HBV is a major cause of morbidity and mortality worldwide. About two billion people have been infected by HBV at some time; 370 million are currently chronically infected and around one million die each year from HBV-related liver diseases, particularly liver cancer. HBV contains eight different genotypes (A–H) ^[2]. The most effective way of reducing global incidence is vaccination supported by effective enforceable public health policies. The first HBV vaccine to be developed was a subviral particle (hepatitis B surface antigen) purified from the inactivated plasma of asymptomatic carriers of HBV ^[11]. This was followed by a vaccine developed from cloned HBV DNA fragments encoding the S protein, first in mouse L cells and then in yeast cells. Both plasma-derived and cell-based vaccines are safe and effective and have been utilized since the 1990s in some but not all parts of the world ^[12].

• HCV vaccine

An effective vaccine against HCV would aim to replicate or accelerate the immune pathway during natural infection to prevent disease chronicity. With prior evidence of other vaccines almost completely eradicating serious endemic diseases such as smallpox and polio, vaccine development for HCV remains a hopeful option. However, vaccine development has been especially challenging for HCV due to several reasons. The most difficult reason is the vast diversity among the genetic sequence of the seven different known genotypes of HCV. Other barriers include the lack of appropriate animal models since the use of non-human primate models is challenging to obtain. The numerous mechanisms used by the HCV to avoid detection by the innate immune system have also been highly challenging in addition to its extreme genetic diversity ^[11].

• HEV vaccine

Knowledge of the structure of the HEV genome has been essential for vaccine development. The Open Reading Frame (ORF) 2 encodes the capsid protein against which all neutralizing antibodies are targeted (Figure 3) ^[11]. Therefore all of the efforts to develop a safe and effective vaccine have focused on ORF2. Vaccine antigens have been cloned in insects, yeast, baculovirus, etc. In 2011, the recombinant hepatitis E vaccine was licensed in China for use in people aged 16-65. The vaccine is recommended for persons at high risk of hepatitis E infection ^[3].

Figure 3 Hepatitis E viral genome.