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Synthesis of Structure Based Vaccine Against Hepatitis C

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C1.RESEARCH AREA

Molecular Biology, Bioinformatics and Biochemistry

D.PROJECT DIGEST

HCV is very common infectious disease all around the world (180 million people effected per year) and in Pakistan too and is a cause of chronic liver hepatitis C. It’s a small virus containing RNA as a genetic material. Over the course of evolution this virus has developed themselves and now we come across different viral genotypes all over the world. These viruses modify themselves structurally and functionally in an effort to evade from host immune response. Eleven different HCV genotypes are available. Drugs and vaccines are being developed all over the world but a major drawback is that these drugs and vaccines show genotype specific responses so drugs developed in other areas of world are not showing disease recovery in Pakistani hepatitis C patients. Currently IFN and ribavirin therapy is going on to cure HCV but it’s showing neutralization of virus in some patients but not in the other. So there is a need to develop such drugs here against specific Pakistani genotype i.e. 3a . HCV genotype found in Pakistan is type 3a so we are trying to explore the structure and then synthesis of structure based vaccine against HCV which show effective immunological responses against all viral strains. Our purpose is to do a genome wide study of all viral genotypes and then find out conserved regions present in all viral genotypes which would then be a target for vaccine development.

Project Details

1. PROJECT SUMMARY

Virus of all different genotypes is collected from all over the world then a genome wide study will be performed to screen out conserved regions of genome and hence protein by using molecular biology techniques, bioinformatics tools and sequencing. These regions will then be targeted for vaccine development because these are important characteristic components of all viral genotypes. Antigenic potential of these conserved proteins will be determined by looking for antibodies present in blood of virally infected patients. We are thinking to target some of the viral polymerases which are required for viral RNA replication as well as structural glycoprotein present on viral surface.

2. PROPOSED GOALS/OBJECTIVES

HYPOTHESIS/BASIS OF RESEARCH

Hypothesis is to develop vaccine against structural and functional region of HCV which show affectivity against all viral genotypes present all over the world.

RESEARCH OBJECTIVES

  1. Sequencing of viral genomes of all genotypes
  1. To find out conserved regions present in all genotypes
  1. To root out viral infection

3. INTRODUCTION

As HCV is to be reported as a chronic disease of liver effecting with its different genotypes existing all over the world. According to WHO report 2015 genotype 3 is most prevalent effecting 83.4 million people worldwide [1]. Genotype 3a is most prevalent in Pakistan[2]. These genotypes don’t differ dramatically in their structure but show different responsive behavior to drugs and vaccines. Such heterogeneity in their responsiveness is a major obstacle to develop a vaccine which is able to neutralize all types of these viral genotypes. But science is still far away. For global protection of Hepatitis C Virus a vaccine is needed able to neutralize all genotypes. One of the vaccines developed against Hepatitis C is reported but it is specific for genotype1a and 1b. We are therefore in a need to synthesize vaccine against genotype 3a, most prevent in Pakistan.

For this purpose we are trying to conduct a genome wide study of all viral strains and trace their conserved regions in their genome. Then antigenic potential of these conserved regions’ll be determined by looking for antibodies present in the blood of chronically infected HCV patients. These antigenic regions’ll then be studied and characterized by using different molecular biology techniques. These antigenic regions used as vaccine to mount antibody response in healthy individuals so whenever they come across with virus in their future life they would be able to produce a stronger response against that virus and don’t let them to grow.

This vaccine will be able to neutralize the disease burden not only against 3a genotype but all other genotypes too because we’ll target those regions which are conserved in al viral genotypes. Although drug against this hepatitis C virus is now available which is effective against all strains of viruses but due to its high economic cost it isn’t in the range of poor community in our country. So it’s good to make an effort to root out this devastating disease. Our struggle to develop vaccine is in line with this effort.

4 A. BACKGROUND OF THE RESEARCH PROBLEMS TO BE ADDRESSED

A comprehensive and up-to-date literature survey clearly highlighting the existing gaps and what new information will be added to the existing pool of knowledge.

As HCV is to be reported as a chronic disease of liver effecting with its different genotypes existing all over the world. Genotype 3a is most prevalent in Pakistan [2]. Different drugs are available against different viral strains. Sofobuvir is reported to be effective against HCV type 2 & 3 genotype. Type 3a genotype is hardest to treat so higher dose of sofobuvir along with ribavirin and pegylaed interferons is being administered but duration of this treatment is very slow and its 24 weeks to recover as well as its due to its high cost it is impossible for patients in developing countries like Pakistan to purchase it [3]. It’s a polymerase inhibitor of HCV virus so virus can’t replicate without this polymerase and as a result inhibited. Although it’s an effective drug but it seems to be costly cure for HCV in developing countries like Pakistan [3].

Most of the vaccines designed against viruses are strain specific e.g. Vaccine designed and in Phase I clinical trial in Korea. It is designed specially against HCV 1a and 1b genotypes. Neither of other HCV vaccine is being available now. This vaccine targets NS3A/4A antigen of HCV. These are nonstructural proteins of HCV and are being administered in a form of four monthly vaccines i.e. 1mg, 3mg and 6mg [5]. Trials are going on but still no successful story comes in front of the scientific community. A vaccine has been synthesized against HIV virus in which conserve regions present on viral surface protein are targeted for vaccine development. All HIV viruses use a conserved region present on gp120 protein (viral envelop protein) to bind to host cell surface CD4 receptors. This site is well conserved in all viral genotypes because all genotypes have to bind to host cell surface receptor in order to invade to the cell. This region was target so as to develop antibodies against this disease in humans. This proved to be a promising candidate for vaccine development [4].

4 B. RESEARCH PLAN/ METHODOLOGY: SCHEDULE/PHASING

Experiment

Duration

  1. Collection of all viral genotypes
  2. DNA isolation from all
  3. Genome wide sequencing so as to find out conserved regions as targets for vaccine development
  4. Using computational biology to find out corresponding proteins of conserved regions

3 Months

  1. Designing probes of these conserved regions
  2. To find out antigenic potential of these conserved regions by FACS anaysis

2 Months

  1. Isolation and characterization of antibodies directed against these conserved regions
  2. To find out kinetics of Interaction of these antibodies with our probes by using ITC Isothermal Calorimetric) Assay
  3. Binding affinity of these antibodies with our probes as well as with viral E2 proteins will be determined by SPR (Surface Plasmon resonance)

4 Months

 

4 C. REFERENCES

  1. Messina, J.P., et al., Global distribution and prevalence of hepatitis C virus genotypes. Hepatology, 2015. 61(1): p. 77-87.
  2. Attaullah, S., S. Khan, and I. Ali, Hepatitis C virus genotypes in Pakistan: a systemic review. Virol J, 2011. 8(1): p. 433.
  3. Linas, B.P., et al., The cost-effectiveness of sofosbuvir-based regimens for treatment of hepatitis C virus genotype 2 or 3 infection. Annals of internal medicine, 2015. 30.
  4. Georgiev, I.S., et al., Elicitation of HIV-1-neutralizing antibodies against the CD4-binding site. Current opinion in HIV and AIDS, 2013. 8(5): p. 382.
  5. (http://www.inovio.com/products/infectious-disease- vaccines/ hepatitis/ ino8000HCV/).

5. IMPACT

As a result of development of this vaccine this’ll be a good step in the field of HCV vaccine development because it’ll be able to neutralize all types of viral genotypes.


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