- 1 HEPATITIS
- 2 TYPES
- 3 Symptoms
- 4 No Vaccines for Hepatitis C
- 5 Genetic variability – a major challenge for vaccine development
- 6 Clinical trials
- 7 DRAWBACKS
- 8 DNA VACCINES
- 9 Vector vaccines
- 10 Future vaccine approaches
The word “Hepatitis” means “inflammation of the liver”. Hepatitis is mostly caused by viral infections and can result into following conditions:
- Hepatitis A
- Hepatitis B
- Hepatitis C
Hepatitis C is a viral infectivity which occurs due to liver inflammation, and hence leads to stern liver damage. Hepatitis C virus is the major causative agent of this ailment. It spreads mainly by the contaminated blood. The virus can cause both acute and chronic hepatitis
It has basically two types:
- Acute hepatitis;
- Chronic hepatitis.
Acute hepatitisOrder now
This type of hepatitis referred as a temporary ailment that occurs when an individual is first time infected with the hepatitis C virus (HCV).Symptoms appear in about 70% of patients ( 12 weeks after exposure). Our immune system usually suppresses the virus and in this case virus can be eliminated from body within very short period of time. It involves symptoms like:
- Abdominal discomfort
- Joint pain
- Jaundice rarely.
It is a permanent disease which occurs when immune system fails to remove virus from body. It may be a-symptomatic or vague symptoms appear. Patients know about it when it becomes very severe and in last stages. Chronic hepatitis includes cirrhosis, liver cancer, and then eventually leads to death. Vague symptoms in case of chronic infection is as follow:
- hemorrhage effortlessly
- sudden yellowing or paleness of patient
- Dark-colored urine
- Itchy skin
- Weight loss
- hepatic encephalopathy
- spider angiomas.
Many cases in the world are reported which are due to hepatitis C virus and causes death of many individuals.The rate of infection due to it I different localities of the world is given below:
- Northern Europe 0.02%
- Southern Europe 1-3%
- Africa 6%
- United States 0.02%
- Flu like illness
- Loss of appetite
- Joint pain
- Muscle pain
- Unsterilized needles
- Sharing razors and toothbrushes
- Blood transfusion
- From mother to new born
- Organ transplant
No Vaccines for Hepatitis C
Despite of large number of efforts there is no effective vaccine against this ailment. The reasons for the no successful development of vaccine against it are:
- Genetic Variability
- Rapidly Mutating
- Lack of efficient in vitro replication and infection model system
- Challenge for the development of a B cell vaccine
- T cell response failure in patients
Genetic variability – a major challenge for vaccine development
The hepatitis C has about 6 genotypes (100 subtypes). Hepatitis C virus has a positive sense single-stranded RNA genome. The hepatitis C virus particle consists of a core of genetic material (RNA), surrounded by an icosahedral protective shell of protein, and further encased in a lipid (fatty) envelope of cellular origin. Polypeptides encode 10 proteims.it has 2 glycoproteins, E1 and E2. on–structural proteins like p7 ion channel, the NS2-3 protease, the NS3 serine protease and RNA helicase, the NS4A polypeptide, the NS4B and NS5A proteins and the NS5B RNA-dependent RNA polymerase . The half-life of this virus is only a few hours. They have high replicative activity and HCV mutates at nearly one nucleotide per replication cycle and have poor fidelity of the NS5B viral polymerase. So this virus has short viral half-life and rapid turnover.
The lack of an efficient in vitro replication and infection
In this virus there is lack of an efficient in vitro replication and infection model system which act as more difficulty in the characterization of neutralizing antibodies and functional studies of viral variants escaping B and T cell responses. About in 2003, the development of retroviral particles pseudo typed with HCV envelope glycoprotein’s (HCVpps) and study of viral entry and antibody-mediated neutralization. At the present time novel HCV entry factors such as claudin-1 are identified. It is also investigated in HCV-infected chimpanzees and human cells.
Challenge for the development of a B cell vaccine
It is due to its break away from neutralizing the antibody response as follows:
- The production of antibodies that interfere with neutralizing antibodies
- HCV and serum factors such as LDL and VLDL association
- The interchange of HCV glycoprotein and SR-BI with HDL
- Viruses are transferred directly from one cell to other cell.
Epitopes are difficult to be recognized that are largely conserved in different genotypes, thus the isolates that can produce antibodies have ability to neutralize powerfully.
T cell response failure in patients
Viruses are escaped from CD8+T cell and give very mild response to targeted T-cell. So humans having strong CD8+ T cell responses in acute infections not strong enough to avoid development to chronicity. As a result CD8 responses are self-limited and chronically evolving infections.
Viral escape from T-cell recognition
T cells recognize short viral peptides (T-cell epitopes) attached with MHC molecules. During viral replication, Tcell epitopes of viruses are evolved to prevent binding. T-cell exhaustion: Antigen-specific T-cell frequency and functions are slow down due to chronic Ag stimulation.
Ideal vaccine for HCV
As vaccines against HCV are very difficult it must meet to some extent with these properties to become good vaccine for use. Vaccines should be active for viral genetic diversity (between and within hosts) vaccines. Vaccines are of such type that they induce adaptive immunity with high T cell production and also induce hummoral response. Safety is major requirement for vaccine production.
Following are two clinical trials that are taken in terms of safety and effectiveness.
- Therapeutic vaccine trial
- Prophylactic (preventive) vaccine trial
Therapeutic vaccine trial
This vaccine is for people having incidence of getting chronic hepatitis C and also decide that each vaccine should be safe and successful and reduce evidence of developing hepatitis C.It has significant side effects & SVR and have 40–50% genotype 1 infection, 65–70% with genotype 3, 80% of those with genotype 2. This vaccine is costly. The first therapeutic vaccine for HCV was administered to humans in 2003. This vaccine based on the hepatitis C E1 protein. It was administered over 6 to 3 years. By this vaccine both humoral and cellular immune responses to the E1 protein were activated and both antibody and Tcell response is activated.
It does not inhibit the progression of liver disease especially liver fibrosis.
Prophylactic (preventive) vaccine trial
It is against those people who are at high risk of developing hepatitis C and it finds out the safety of the two vaccines. Placebo (inactive) vaccine, also given in which there are chances of developing infection with this vaccine. It may change in social or cultural practices and involve in elimination of new HCV infections. The first clinical trial candidate of a prophylactic vaccine utilized a recombinant E1/E2 protein adjuvant with MF59C (adjutant). It is given to healthy individual and is safe. It was administered in 60 healthy subjects and all developed neutralizing antibodies and T-cell lymphocyte proliferation responses to E1/E2 and antagonist response to increasing Ag.
Challenges for development of prophylactic and therapeutic vaccine
The basic challenge for production of vaccines for HCV genotypes and the multiple circulating viral quasispecies is to design a vaccine targeted at eliciting broad T cell responses, not the quality of a successful T cell response is understood .A successful HCV vaccine should have long term maintenance of CD4+ and CD8+ T cells memory responses generated by a successful HCV vaccine. It is also challenge by secondary T cell failure associated with persistent HCV infection.
HCV vaccine strategies
Four main vaccine strategies have been investigated in human clinical studies:
- Recombinant protein vaccines
- Peptide vaccines
- DNA vaccines
- Vector vaccines
Recombinant protein vaccines
These vaccines are effective for minimum number of viral epitopes and have efficient immunity. In this first genes are isolated that encodes for protein and inserted into bacteria or other eukaryotic cells. These produce antibody and CD4+ T-cell responses.
These are well tolerated with low toxicity; induces cross-neutralizing antibodies; proof-of-concept (HBV vaccine).
These produce only weak T-cell responses elicited.
Peptide HCV vaccines
This vaccine produces HCV-specific T-cell immunity by the direct presentation of vaccine peptide instead of using RNA or whole virus.
e.g. IC41 is in clinical development. It has five synthetic peptides from core. Three CD4+ T-cell and five HLA A2-restricted CD8+ T-cell HCV epitopes are used.
The response is weak and produces mild effective HCV-specific T-cell response and minimize viral load.
It is well tolerated with low toxicity; induces both cellular and humoral responses.
It has limited immunogenicity (few epitopes only)
This vaccine was used for chronic hepatitis C virus (HCV) infection in 2009. In 2014, South Australian researchers successfully treated the patients. They directly injected the vaccine in skin, because skin has more WBCs as compared to muscle tissue hence induces inflammation at the site of injection and attracts more WBCs. It is a preventive vaccine.
As mouse has different conserve regions than human therefore does not give similar results to human. So efficacy of this vaccine is reduced.
This vaccine presents a broad range of epitopes.
In this vaccine electroporation is used which is painful.
In this vaccine viral RNA is injected into individuals in form of vectors and adenoviral vectors induce HCV-specific T-cell responses in the chimpanzee model and minimize HCV viremia during primary infection. This vector is employed in a Phase I vaccine trial and deliver NS HCV proteins (NS3–5B) to 36 healthy volunteers. This vaccine produces viral epitopes than a peptide-based.
These vaccine vectors cannot replicate and reduces the polymerase activity of the NS proteins and safety is not meet. It is because these vectors are modified by genetic engineering. They may also have vectors in which efficacy is reduced.
These vaccines induce cellular immune responses, which presents broader range of viral epitopes.
Pre-existing immunity to viral vector (adenovirus; may be overcome by the use of rare serotypes); limited experience in humans
Future vaccine approaches
Virus-like particle (VLP)-based vaccines are used against acute as well as chronic infections like hepatitis B which is employed successfully. These vaccines assist the transfer of neutralizing antibody- and core-specific T-cell epitopes (HCV virions). These vaccines can also produce the innate immune responses (secondary effects on adaptive responses i.e.TLR-9 ligands). These can also act as viral protease inhibitors in near future.