Control of Viruses

8/3/2019 Control of Viruses

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Control of Viral diseases


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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.


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CMI activates antigen-specific Tc Cells whichinduce 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 cellsinvolved in adaptive immune responses andinnate immune responses.


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CMI is most effective in removing virus-

infected 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).


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Long before the cause of diseases was even known, Anobservation 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.

A brief History


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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 hopesof 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.


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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 ofLondon, 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.


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Louis Pasteur generalized Jenner's idea by developing what

he called a rabies vaccine now called antitoxin

Pasteur also worked with chicken cholera bacillus andanthrax 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


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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 laterencounters.


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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)


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Types of Vaccines: Attenuated

Killed

Toxoid

Subunit

Conjugate Multivalent subunit

DNA

T-cell receptor peptide Recombinant Vector

Anti idiotypic Vaccines

Dendritic cell vaccines


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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 ofmutants better suited to abnormal culture

than original host

Pasteur first achieved the production of live but non-

virulent forms of chicken cholera bacillus and anthraxby culturing at higher temperatures and under

anaerobic conditions


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Sabin polio vaccine by attenuation of 3 polio

virus -monkey kidney epithelial cells

Measles vaccine by growing Rubella virus in duckembryo cells and later in human cell lines

Provide increased immunogenicity by prolonged

exposure of immune system to individualepitopes 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


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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 vaccinemediated immunosuppresion (Edmonston

Zagreb strain for measles vaccine)


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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 geneof virus

Possible strategy for developing AIDS vaccine

other examples include the viral diseasesyellow fever, mumps and the bacterial disease

typhoid


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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


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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


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Other examples are the influenza vaccine,

cholera vaccine, bubonic plague vaccine,

hepatitis A vaccine, and rabies vaccine.


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Toxoid Vaccine Are made from inactivated toxic compounds

that cause illness rather than the micro-

organism

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 exotoxinsthat produce many of the disease symptoms of

the infection


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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 havebeen produced by cloning the exotoxin genes and

expressing them in easily grown host cells


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Subunit Vaccines

Protein subunit rather than introducing aninactivated 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)


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The virus-like particle (VLP) vaccine against

human papillomavirus (HPV) that is composedof 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)


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Conjugate Vaccines

certain bacteria have polysaccharide outer coatsthat are poorly immunogenic.

linking these outer coats to proteins (e.g. toxins),

the immune system can be led to recognize thepolysaccharide as if it were a protein antigen.

e.g. Vaccine for H. influenzae type b (Hib)

(bacterialmeningitis) consists of type b capsular

polysaccharide covalently linked to a protein

carrier, tetanus toxoid

The polysaccharide-protein conjugate is more

immunogenic


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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 B-

cell epitopes.

Micelles and liposomes - the hydrophilic residues of

the antigen molecules are oriented outward

ISCOMs (immune stimulating complexes)- longfatty-acid tails of external detergent layer are

adjacent to the hydrophobic residues of the

centrally located antigen molecules


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ISCOMs and liposomes deliver antigens inside

cells -mimic endogenous antigens

Influenza, measles, rabies, gp340 from EB-

virus, 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


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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 theseproteins and cells expressing them.

if the pathogen expressing these proteins is

encountered at a later time, attacked instantly bythe immune system.

DNA vaccination is still experimental i.e in the

early stages.


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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


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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 syringesand needles

Being tested for diseases like malaria, AIDS,influenza, and herpes virus infections


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Drawbacks:

Insertional mutagenesis

Autoimmune responses

Immunologic tolerance Transformation


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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 cellmediated immunity.


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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 ofSalmonella, BCG

strain ofMycobacterium bovis, and certain strains of

streptococcus that normally exist in the oral cavity are

used as vectors


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Development of CMI and HI response

Introduction of genes encoding antigens from

pathogenic organisms into normal flora elicitsimmunity at the mucosal surface


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Anti idiotypic vaccines Anti-idiotypic antibodies bind to the antigen-

combining sites of antibodies Effectively mimics the three-dimensional

structures and functions of the external antigens

Can be used as surrogate antigens for activespecific immunotherapy

Several monoclonal anti-Id antibodies that mimicdistinct 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


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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.


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Vaccine Time

BCG At birth

OPV(1) + HEPATITIS B(1) At birth

HEP B (2) 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

Babies are born

with some natural

immunity fromtheir mother and

through breast-

feeding.

This graduallywears off as the

baby's own

immune system

starts to develop.

Having your child

immunized gives

extra protection

against illnesses

which can kill.

Vaccine program


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HIB(booster) 15-18 months

DTP+OPV(1st Booster) 18-24 months

Hep A vaccine 2 years

Typhoid injection 3 years

DTP+OPV(2ndBooster) 5 years

Typhoid oral 6 years

Typhoid oral 9 years

Tetanus 10 years

Typhoid oral 12 yearsTetanus toxoid 16 years

Many childhood

immunizations do not

last a lifetimeAdults 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


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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

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Control of Viruses

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