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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