Control of Viral diseases

Immunity- State of protection from infectious disease. 2 Types:- Humoral and Cell Mediated Immunity. (HI) & (CMI) HI (Ab mediated)
Complement mediated Antibody cell cytotoxicity

CMI
does not involve antibodies or complement but rather involves the activation of other immune cells, and the release of various cytokines in response to an antigen.

 CMI activates antigen-specific Tc Cells which induce apoptosis in body cells displaying epitopes of foreign antigen on their surface, such as
virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens

Activate macrophages and NK cells, which destroy intracellular pathogens Stimulate cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.

 CMI is most effective in removing virusinfected cells All cells express class I MHC at their surface that can display antigenic fragments of viral components. Tc cells that can bind to these epitopes can then destroy the cell (often before it can release a fresh crop of viruses to spread the infection).

A brief History
Long before the cause of diseases was even known, An observation was made that if people recovered from a disease, they appeared to be immune from a second bout with the same illness. Led the Chinese to try Variolation against small pox. Lady Mary Wortley Montagu, wife of the British Ambassador to Turkey, observed variolation in the early 1700s and took it back to England. Caused a mild illness in most individuals, death in a few, But the mortality and morbidity rates due to smallpox were certainly lower in populations that used variolation than in those that did not.

 In the late 1700s Edward Jenner, a young boy who survived the variolation period, grew up to become a country doctor in England whence he noticed that farmers who treated horses with grease lesions often saw the development of cow pox in their cows, with blisters similar to those seen in smallpox infection. Unlike lethal smallpox, however, the cowpox blisters eventually disappeared, leaving only a small scar. At the same time, a milkmaid told him that she could not catch smallpox because she had had cowpox. Jenner noted many people like the milkmaid. In 1796 Jenner infected a young boy with cowpox in hopes of preventing subsequent smallpox infection. Allowed the boy to recover fully from cowpox, then infected the boy with smallpox by injecting pus from a smallpox lesion directly under his skin.

 As Jenner had predicted, the boy did not contract smallpox. Jenner wanted to report his first case study in the Transactions of the Royal Society of London, his study was rejected. Jenner went on to collect 23 case histories over the next months and published his own book detailing his observations. The book was called "An inquiry into the causes and effects of the variolae vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire, and known by the name of The Cow Pox. Jenner's process came to be called "vaccination," after "vacca," the Latin word for cow, and the substance used to vaccinate was called a "vaccine.

 Louis Pasteur generalized Jenner's idea by developing what he called a rabies vaccine now called antitoxin Pasteur also worked with chicken cholera bacillus and anthrax employing the same principles Major achievements include the development of the polio vaccine in the 1950s and the eradication of smallpox during the 1960s and 1970s

However, vaccines remain elusive for many devastaing diseases, including malaria and HIV

So , what is a Vaccine??
A biological preparation that improves immunity to a particular disease. Typically made from weakened or killed forms of the microorganism or its toxins. Stimulates the body's immune system to recognize an agent as foreign, destroy it, and memorize it, so that the immune system can more easily recognize and destroy later encounters.

 Vaccines can be
Prophylactic (e.g. to prevent or ameliorate the effects of a future infection by any natural or "wild" pathogen), or Therapeutic (e.g. vaccines against cancer; being investigated)

Types of Vaccines:
Attenuated Killed Toxoid Subunit Conjugate Multivalent subunit DNA T-cell receptor peptide Recombinant Vector Anti idiotypic Vaccines Dendritic cell vaccines

Attenuated vaccines
A preparation of viruses or bacteria that have lost their pathogenicity but retain their capacity for transient growth in an inoculated host By growing the organism for prolonged periods under abnormal culture conditions Selection of mutants better suited to abnormal culture than original host Pasteur first achieved the production of live but nonvirulent forms of chicken cholera bacillus and anthrax by culturing at higher temperatures and under anaerobic conditions

 Sabin polio vaccine by attenuation of 3 polio virus -monkey kidney epithelial cells Measles vaccine by growing Rubella virus in duck embryo cells and later in human cell lines Provide increased immunogenicity by prolonged exposure of immune system to individual epitopes due to their capacity for transient growth Memory cell production ; require only single immunization Induce humoral and cell mediated responses The immune response takes place largely at the site of the natural infection

 Sabin polio vaccine however requires 2 booster doses as the 3 strains of attenuated polio viruses interfere with each others replication Major disadvantage - possibility of reversion to virulent form (although rare) Presence of viral contaminants (SV 40 in monkey kidney cells for Sabin polio vaccine) Post vaccine complications and vaccine mediated immunosuppresion (Edmonston Zagreb strain for measles vaccine)

 Risk to immunocompromised patients where may behave as opportunistic pathogens Irreversible attenuation possible by genetic engineering Development of Herpes virus vaccine for pigs by selective removal of Thymidine kinase gene of virus Possible strategy for developing AIDS vaccine other examples include the viral diseases yellow fever, mumps and the bacterial disease typhoid

Killed Vaccines
a.k.a inactivated vaccines The pathogen is inactivated by heat or chemicals so that it is no longer capable of replication in the host Important to maintain the structure of epitopes on surface antigens Chemical inactivation is preferred as heat treatment causes extensive protein denaturation Formaldehyde, alkylating agents

 Salk polio vaccine and Pertussis vaccine developed by inactivation with formaldehyde Parasitic worms and protozoa are extremely difficult to grow up in bulk to manufacture killed vaccines Necessitate repeated booster doses to maintain immune status of host Immune response is predominantly humoral; less effective Inadequate killing may lead to complications

 Other examples are the influenza vaccine, cholera vaccine, bubonic plague vaccine, hepatitis A vaccine, and rabies vaccine.

Toxoid Vaccine
Are made from inactivated toxic compounds that cause illness rather than the microorganism Vaccination with the toxoid induces anti-toxoid antibodies that bind to the toxin, neutralizing it Detoxification should be achieved without excessive modification of the epitope structure Some bacterial pathogens produce exotoxins that produce many of the disease symptoms of the infection

 Diphtheria and tetanus vaccines can be made by purifying the bacterial exotoxin and then inactivating it with formaldehyde to form a toxoid Large quantities of the exotoxin can be produced, purified and inactivated. Sufficient quantities of the purified toxins have been produced by cloning the exotoxin genes and expressing them in easily grown host cells

Subunit Vaccines
Protein subunit rather than introducing an inactivated or attenuated micro-organism to an immune system ("whole-agent" vaccine), a fragment of it can create an immune response. Examples subunit vaccine against Hepatitis B virus composed of only the surface proteins of the virus (previously extracted from the blood serum of chronically infected patients, but now produced by recombination of the viral genes into yeast)

 The virus-like particle (VLP) vaccine against human papillomavirus (HPV) that is composed of the viral major capsid protein, And the hemagglutinin and neuraminidase subunits of the influenza virus Polysaccharide Capsules - hydrophilic polysaccharide capsule is antiphagocytic Coating of the capsule with antibodies and/or complement proteins increases the ability of macrophages and neutrophils to phagocytose them.(mainly in Bacteria)

Conjugate Vaccines
certain bacteria have polysaccharide outer coats that are poorly immunogenic. linking these outer coats to proteins (e.g. toxins), the immune system can be led to recognize the polysaccharide as if it were a protein antigen. e.g. Vaccine for H. influenzae type b (Hib) (bacterial meningitis) consists of type b capsular polysaccharide covalently linked to a protein carrier, tetanus toxoid The polysaccharide-protein conjugate is more immunogenic

Multivalent subunit vaccines

Present multiple copies of a given peptide or a mixture of peptides to the immune system Solid matrix antibody-antigen complexes (SMAA) contain synthetic peptides - T-cell epitopes and Bcell epitopes. Micelles and liposomes - the hydrophilic residues of the antigen molecules are oriented outward ISCOMs (immune stimulating complexes)- long fatty-acid tails of external detergent layer are adjacent to the hydrophobic residues of the centrally located antigen molecules

 ISCOMs and liposomes deliver antigens inside cells -mimic endogenous antigens Influenza, measles, rabies, gp340 from EBvirus, gp120 from HIV, Plasmodium falciparum and Trypanosoma cruzi Only been used for veterinary vaccines Cytosolic pathway and presentation with class I MHC molecules - cell-mediated response

DNA Vaccines
insertion (and expression, triggering immune system recognition) of viral or bacterial DNA into human or animal cells. immune system recognizes the proteins expressed & mounts an attack against these proteins and cells expressing them. if the pathogen expressing these proteins is encountered at a later time, attacked instantly by the immune system. DNA vaccination is still experimental i.e in the early stages.

 Plasmid DNA encoding antigenic proteins is injected directly into the muscle of the recipient or Microscopic gold beads coated with plasmid DNA for delivering through the skin into the underlying muscle with an air gun (called a gene gun) The encoded protein is expressed in its natural form Induce both humoral and cell-mediated immunity Prolonged expression of the antigen generates significant immunological memory

 Refrigeration not required for handling and storage of plasmid DNA The same plasmid vector can be used to make many proteins; same manufacturing techniques can be used for different DNA vaccines Rapid delivery; eliminates the need for syringes and needles Being tested for diseases like malaria, AIDS, influenza, and herpes virus infections

Drawbacks:
Insertional mutagenesis Autoimmune responses Immunologic tolerance Transformation

T-cell receptor peptide Vaccines

under development for several diseases using models of Valley Fever, stomatitis, and atopic dermatitis. These peptides have been shown to modulate cytokine production and improve cell mediated immunity.

Recombinant vector Vaccines

Genes encoding antigens of virulent pathogens can be introduced into attenuated viruses or bacteria The attenuated organism serves as a vector, replicating within the host and expressing the gene product of the pathogen. Vaccinia virus, canarypox virus, attenuated poliovirus, adenoviruses, attenuated strains of Salmonella, BCG strain of Mycobacterium bovis, and certain strains of streptococcus that normally exist in the oral cavity are used as vectors

 Development of CMI and HI response Introduction of genes encoding antigens from pathogenic organisms into normal flora elicits immunity at the mucosal surface

Anti idiotypic vaccines

Anti-idiotypic antibodies bind to the antigencombining sites of antibodies Effectively mimics the three-dimensional structures and functions of the external antigens Can be used as surrogate antigens for active specific immunotherapy Several monoclonal anti-Id antibodies that mimic distinct human tumor-associated antigens have been developed and characterized They have been used to induce immunity against HBV, rabies, Newcastle disease virus, FeLV, reoviruses and polioviruses

Dendritic Cell Vaccine

combine dendritic cells with antigens in order to present the antigens to the body's white blood cells, thus stimulating an immune reaction. These vaccines have shown some positive preliminary results for treating brain tumors.

Vaccine program
Babies are born with some natural immunity from their mother and through breastfeeding. This gradually wears off as the baby's own immune system starts to develop. Having your child immunized gives extra protection against illnesses which can kill.
Vaccine Time

BCG OPV(1) + HEPATITIS B(1) HEP B (2)

At birth At birth 4 weeks

DPT (1)+OPV(2)+HIB(1) 8 weeks DPT (2)+OPV(3)+HIB(2) 12-14 weeks DPT (3)+OPV(4)+HIB(3) 18-20 weeks MEASLES+OPV+HEPB(3) 8-9 months MMR 15-18 months

Many childhood immunizations do not last a lifetime Adults need to be reimmunized against tetanus, diptheria and other illnesses Adults over the age of 50 years should be immunized annually against current influenza strains, individuals aged 65 years and older should receive the pneumococcal vaccine

HIB(booster) DTP+OPV(1st Booster) Hep A vaccine Typhoid injection DTP+OPV(2ndBooster) Typhoid oral Typhoid oral Tetanus Typhoid oral Tetanus toxoid

15-18 months 18-24 months 2 years 3 years 5 years 6 years 9 years 10 years 12 years 16 years

List of references:
1. Biopharmaceuticals-Biochemistry and Biotechnology; Gary Walsh; John Wiley and Sons Ltd,2004 2. http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CMI.html 3. http://en.wikipedia.org/wiki/Cell-mediated_immunity 4. Immunology; Janis Kuby; W H Freeman & Co, 1998 5. http://en.wikipedia.org/wiki/Vaccine 6. http://www.accessexcellence.org/AE/AEC/CC/vaccines_how_why.php