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Genetic Vaccines. Dr. Ziad Jaradat. INTRODUCTION.

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Genetic vaccines

Genetic Vaccines

Dr. Ziad Jaradat


Introduction
INTRODUCTION

  • Despite the marked advances in public health measures and antimicrobial medications over the last half century, infectious diseases remain one of the leading causes of morbidity and mortality worldwide. The most powerful and cost effective way to control such infectious diseases remains the prophylactic vaccines.



  • The World Health Organization estimates that vaccination against diptheria, tetanus, whooping cough, measles, polio and tuberculosis prevents approximately 3 million deaths a year making vaccination the most effective public health measure in decreasing morbidity and mortality in humans.



  • The traditional vaccines may not be appropriate either due to safety issues in which some attenuated pathogens revert back to their active stage or due to a lack in immune potency. Therefore, genetic immunization also known as DNA vaccines might be the alternative strategy for solving such problems.


Types of traditional vaccines
Types of Traditional Vaccines to safety issues in which some attenuated pathogens revert back to their active stage or due to a lack in immune potency. Therefore, genetic immunization also known as DNA vaccines might be the alternative strategy for solving such problems.

Killed vaccines: Vaccination with killed pathogen such as hepatitis A or antigens isolated from a pathogen such as parts of hepatitis B can not make their way into cells, they therefore give rise to primarily humoral responses and do not activate killer T cells.



Attenuated live vaccines: infiltrate cells. Even when non-living vaccines do prevent a disease, the protection often wears off after a time, consequently, recipients may need periodic booster shots.

  • usually viruses, do inter cells and make antigens that are displayed by the inoculated cells. They thus spur attack by killer T lymphocytes as well as by antibodies.



Genetic vaccines1
Genetic Vaccines many viruses. Due to this dual activation of both humoral and cellular immunity, live vaccines such as measles, mumps, rubella and polio provide long life immunity.

History:

1- Stansey and Parchkis (1955) and Ito et al (1957) performed DNA transfer experiments and were able to induce tumor and antibody formation.





Definition of dna vaccines and basic concept
Definition of DNA Vaccines and Basic Concept: coated onto gold beads and delivered into mice to derive the expression of a foreign protein and stimulate an antibody response to influenza virus. (These authors coined the term

  • Genes encoding antigen(s) specific to a particular pathogen are cloned into a plasmid with an appropriate promoter, and the plasmid DNA is administered to the vaccine recipient.



How does dna vaccines work
How Does DNA Vaccines Work expressed. The resultant foreign protein antigens is produced in the cell and then processed and presented appropriately to the immune system.:

  • DNA vaccines elicit protective immunity against an infectious agent or pathogen primarily by activating two branches of the immune sysem: the humoral arm, which attacks pathogens outside of cells, and the cellular arm which eliminates cells that are colonized by an invader. Immunity is achieved when such activity generates long lasting memory cells.



  • In the humoral response DNA vaccine into a targeted cell, such as muscle and the subsequent production of the antigens normally found on the pathogen of interest. , B cells bind to released copies of antigenic proteins and then multiply.

  • Many of the progeny secrete antibody molecules that during an infection would glom (jump and confiscate) onot the pathogen and mark it for destruction. Other offspring become the memory cells that will quell the pathogen if it circulates outside cells.


  • Meanwhile DNA vaccine into a targeted cell, such as muscle and the subsequent production of the antigens normally found on the pathogen of interest. display of antigenic protein fragments or peptides on inoculated cells (within grooves on MHC class I molecules) can trigger a cellular response .

  • Binding to the antigenic complexes induces cytotoxic (killer cells) to multiply and kill the bound cells and others displaying those same peptides in the same way. Some activated cells will also become memory cells ready to eliminate cells invaded by the pathogen in the future.


  • In actuality, DNA vaccine into a targeted cell, such as muscle and the subsequent production of the antigens normally found on the pathogen of interest. several preliminary steps must occur before such response can occur.

  • To set the stage for B cell activation the following steps occur:




To activate the cytotoxic T cells the following steps occur: complexes and “ a co-stimulatory molecule” found only on APCs.

  • APCs have to take up the vaccine plasmid, synthesize the encoding antigens and exhibit fragments of the antigens on MHC class I molecules along with co-stimulatory molecules.




Methods and location of immunization
Methods and Location of Immunization needed to support the defense activities of other memory cells.

  • One feature of genetic immunization that has become apparent over the past few years is that the way a DNA vaccine is delivered may have an effect on the type of immune response generated.



Successful DNA vaccination has been demonstrated via a number of different routes including:

  • - intravenous

  • - intramuscular

  • - intra epidermal

  • - intra spleenic

  • - intra hepatic

    with the majority of DNA vaccines so far being administered through skin or muscle.



  • Tissues are also differ in the efficiency with which they present antigens to the immune system.

  • Tissues such as skin and the mucosal linings of the respiratory tract and the gut that serve as barriers against the entry of pathogens have associated lymphoid tissues that provide high levels of local immune surveillance.




Methods of administration
Methods of Administration of administration, however they do not support efficient transfection.

  • Plasmid delivery at these sites is usually accomplished by one of two methods:

    • 1- needle injection of DNA suspended in saline

    • 2- Gene gun, this method has more commonly used for epidermal rather than intramascular administration.


  • Several researchers have reported that the gene gun mediated immunization is far more efficient than needle injection, eliciting similar levels of antibody and cellular responses with 100-5000 fold less DNA.

  • It was reported that as little as 16 ng of plasmid DNA delivered epidermally via gene gun could induce antibody and CTL responses in mice, wherase intradermal injection of the same plasmid requires 10-1000 µg of DNA to elicit comparable responses.



Enhancement of dna vaccines action
Enhancement of DNA vaccines action any regimen that is shown to be superior to others, it seems that each disease and each vaccine construct differs from the other, therefore, the best regimen of DNA vaccine administration yet to be determined.

  • The most promising method of vaccine enhancement is the co-administration of plasmid encoding cytokines along with a plasmid encoding an antigen.




IL-2 : with the gene to enhance the immune response to genetic immunization. a potent stimulator of cellular immunity that induces proliferation and differentiation of T cells as well as B cell and NK cell growth.

 Watanable et al...... reported a five fold increase in antibody response when IL-2 plasmid was co- injected with the plasmid encoding the antigen.


  • Chow et al...... Demonstrated that injection of a vector that encoded HbsAg and IL-2 on the same plasmid induced marked increase of Ab responses and T-cell proliferation compared to a plasmid encoding HbsAg alone.

  • Taken these results and results from other studies, it is suggested that IL-2 gene co-injection can increase both humoral and cellular immunity .


IL-4: that encoded HbsAg and IL-2 on the same plasmid induced marked increase of Ab responses and T-cell proliferation compared to a plasmid encoding HbsAg alone.

induces differentiation of T-helper cells into Th2 subtype, enhances B cell growth, and mediates Ig class switching. It was reported that injection of a plasmid encoding IL-4 3 days before immunization with a protein antigen increased Ag specific antibody levels compared to protein immunization alone.


However, studies showed that IL-4 inhibits Th1 mediated responses, thus put limitation on using it as adjuvant in viral or tumor vaccines or immunotherapy.


Granulocyte monocyte colony stimulating factor gm csf
Granulocyte-monocyte colony-stimulating factor (GM-CSF): responses, thus put limitation on using it as adjuvant in viral or tumor vaccines or immunotherapy.

This cytokine increases production of granulocytes and macrophages and induces maturation and activation of APCs such as dendritic cells.

  • Xiang and Ertl tested this theory in vivo by co-inoculating mice with plasmids encoding GM-CSF and rabies glycoprotein.


  • Co expression of GM-CSF and rabies glycoproeins increased Ab response in a dose dependant manner and enhanced T-helper cell responses compared to injection with plasmid encoding rabies protein alone.

  • Same results were obtained with DNA vaccines against HIV-I, influenza, encephalomyocarditis virus and HCV.


Advantages and properties of dna vaccines
Advantages and properties of DNA vaccines response in a dose dependant manner and enhanced T-helper cell responses compared to injection with plasmid encoding rabies protein alone.

  • Plasmid vectors can be constructed and tested rapidly.

  • Rapid and large-scale manufacturing procedures are available.

  • DNA is more temperature stable than live preparations.

  • Microgram quantities of expression vector can induce immune response.


  • Unlike killed vaccines, DNA vaccines can produce diverse and persistent immune response (both humoral and cellular arms of the immune response)

  • Protection can be achieved in large primate models of human infections

  • Multiple vectors encoding several antigens can be delivered in a single administration


  • Unlike the live attenuated vaccines, who posses the risk of reversion to pathogenic state while replicating inside the host, DNA vaccines are safe and do not encode for genes that cause diseases

  • Unlike the killed vaccines, who induce short immunity and need frequent boosting, DNA vaccines cause long lasting immunity with minimum boosts


Thank you reversion to pathogenic state while replicating inside the host, DNA vaccines are safe and do not encode for genes that cause diseases


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