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IMMUNIZATION 

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IMMUNIZATION 

• Immunization is a means of providing specific protection against many common and damaging pathogens by stimulating an organism's immune system.

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Milestones in immunizationMilestones in immunization

1500BC Turks introduce

variolation

3000BC Evidence of sniffing

powdered small pox crust in Egypt

2000BC Sniffing of small

pox crust in China

1700AD Introduction of

variolation in England and later in the US

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1920sDiphtheria and Tetanus

1934Pertussis

1955Salk polio

Modern era of the vaccineModern era of the vaccine

1885Rabies vaccine (Pasteur)

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1960sMumps measles and rubella virus

Sabin polio

1990s

Hepatitis and varicella

1985

Haemophilus

Modern era of the vaccineModern era of the vaccine

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Pre- & post-vaccine incidence of common preventable diseases

Pre- & post-vaccine incidence of common preventable diseases

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Different modes of acquiring immunity

Different modes of acquiring immunity

Natural

PassiveIgG

ActiveInfection

Immunity

Acquired

PassiveIgs

ActiveVaccination

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Natural Artificial

Colostral transfer of IgA

Placental transfer of IgG

Antibodies or immunoglobulins

Immune cells

Passive ImmunityPassive Immunity

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 disease  indicationantibody source

Passive ImmunizationPassive Immunization

human, horsediphtheria, tetanus prophylaxis, therapy

vericella zoster human immunodeficiencies

gas gangrene, botulism, snake bite, scorpion sting

horse post-exposure

rabies, human post-exposure

hypogamma-globulinemia

human prophylaxis

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Advantages Disadvantages

serum sicknessimmediate protection

no long term protection

graft vs. host disease (cell graft only)

risk of hepatitis and Aids

Advantages and Disadvantages of Passive Immunization

Advantages and Disadvantages of Passive Immunization

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Active ImmunizationActive Immunization

Natural Artificial

exposure to sub-clinical infections

Attenuated organisms

killed organisms

sub-cellular fragments

toxins

others

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Types of vaccines• Killed vaccines: These are preparations of the normal (wild

type) infectious, pathogenic MO that has been rendered non-pathogenic, usually by chemical treatment such as with formalin that cross-links viral proteins.

• Attenuated vaccines: These are live MO particles that grow in the vaccine recipient but do not cause disease because the vaccine virus has been altered (mutated) to a non-pathogenic form; for example, its tropism has been altered so that it no longer grows at a site that can cause disease.

• Sub-unit vaccines: These are purified components of the MO, such as a surface antigen.

• DNA vaccines: These are usually harmless MO into which a gene for a (supposedly) protective antigen has been spliced. The protective antigen is then made in the vaccine recipient to elicit an immune response

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Advantages of attenuated vaccines 1. They activate all phases of immune system. They elicit

humoral IgG and local IgA (figure 8)2. They raise an immune response to all protective antigens.

Inactivation, such as by formaldehyde in the case of the Salk vaccine, may alter antigenicity

3. They offer more durable immunity and are more cross-reactive. Thus, they stimulate antibodies against multiple epitopes which are similar to those elicited by the wild type virus

4. They cost less to produce5. They give quick immunity in majority of vaccinees6. In the cases of polio and adenovirus vaccines, administration

is easy 7. These vaccines are easily transported in the field8. They can lead to elimination of wild type virus from the

community

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Disadvantages of Attenuated vaccine

1. Mutation. This may lead to reversion to virulence (this is a major disadvantage)

2. Spread to contacts of the vaccinee who have not consented to be vaccinated (This could also be an advantage in communities where vaccination is not 100%)

3. Spread of the vaccine virus that is not standardized and may be mutated

4. Sometimes there is poor "take" in tropics5. Live viruses are a problem in immunodeficiency

disease patients

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Advantages of inactivated (Killed) vaccine

1. They give sufficient humoral immunity if boosters given

2. There is no mutation or reversion (This is a big advantage)

3. They can be used with immuno-deficient patients

4. Sometimes they perform better in tropical areas

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Disadvantages of inactivated (Killed) vaccines

1. Some vaccinees do not raise immunity2. Boosters tend to be needed3. There us little mucosal / local immunity (IgA).

This is important (figure 8)4. Higher cost5. In the case of polio, there is a shortage of

monkeys6. In the case of smallpox, there have been

failures in inactivation leading to immunization with virulent virus.

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tuberculosis

Polio (Oral) Sabinnot used in std. schedulemeasles, mumps & rubella

yellow feverMilitary and travelers

Varicella zosterchildren with no history of chicken pox

hepatitis Anot required in SC

Live Attenuated VaccinesLive Attenuated Vaccines

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Polio Salk IM

influenzaelderly and at risk

typhoid, cholera, plagueepidemics and travelers

rabiespost exposure

pertussis replaced by the acellular vaccine

Killed Whole-Organism VaccinesKilled Whole-Organism Vaccines

Q feverpopulation at risk

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Microbial Fragment VaccinesMicrobial Fragment Vaccines

Bordetella. Pertussisvirulence factor protein

Haemophilus influenzae Bprotein conjugated polysaccharide

Streptococcus pneumoniaePolysaccharide mixture

Neisseria meningitidispolysaccharide

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Microbial Fragment VaccinesMicrobial Fragment Vaccines

Clostridium tetani (tetanus)inactivated toxin (toxoid)

Corynebacterium diphtheriaeinactivated toxin (toxoid)

Vibrio choleraetoxin subunits

Hepatitis B viruscloned in yeast

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Modification of Toxin to ToxoidModification of Toxin to Toxoid

toxin moiety antigenic determinants

chemical

modification

Toxin Toxoid

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Future VaccinesFuture Vaccines

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NEW METHODS OF VACCINE PRODUCTION

1. Selection for mis-sense

2. Synthetic peptides

3. Anti-idiotype vaccines

4. Recombinant DNA techniques

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Selection for mis-senseConditional lethal mutants. Temperature-sensitive

mutants in influenza A and RSV have been made by mutation with 5-fluorouracil and then selected for temperature sensitivity. In the case of influenza, the temperature-sensitive gene can be reassorted in the laboratory to yield a virus strain with the coat of the strains circulating in the population and the inner proteins of the attenuated strain.  Cold adapted mutants can also be produced in this way. It has been possible to obtain mis-sense mutations in all six genes for non-surface proteins.

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Synthetic peptides

Injected peptides which are much smaller than the original virus protein raise an IgG response but there is a problem with poor antigenicity.  This is because the epitope may depend on the conformation of the virus as a whole. A non-viral example that has achieved some limited success is a prototype anti-malarial vaccine. 

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Anti-idiotype vaccines

An antigen binding site in an antibody is a reflection of the three-dimensional structure of part of the antigen, that is of a particular epitope. This unique amino acid structure in the antibody is known as the idiotype which can be thought of as a mirror of the epitope in the antigen. Antibodies (anti-ids) can be raised against the idiotype by injecting the antibody into another animal. This gives us an anti-idiotype antibody and this, therefore, mimics part of the three dimensional structure of the antigen, that is, the epitope. This can be used as a vaccine. When the anti-idiotype antibody is injected into a vaccinee, antibodies (anti-anti-idiotype antiobodies) are formed that recognize a structure similar to part of the virus and might potentially neutralize the virus. This happens: Anti-ids raised against antibodies to hepatitis B S antigen elicit anti-viral antibodies.

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Recombinant DNA techniques

1. Attenuation of virus

2. Single gene approach (Yeast)

3. Cloning of a gene into another virus

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DNA VACCINES

• These vaccines are based on the deliberate introduction of a DNA plasmid into the vaccinee. The plasmid carries a protein-coding gene that transfects cells in vivo at very low efficiency and expresses an antigen that causes an immune response.

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Advantages of DNA vaccines 1. Plasmids are easily manufactured in large amounts2. DNA is very stable3. DNA resists temperature extremes and so storage and transport are straight

forward4. A DNA sequence can be changed easily in the laboratory. This means that we

can respond to changes in the infectious agent5. By using the plasmid in the vaccinee to code for antigen synthesis, the antigenic

protein(s) that are produced are processed (post-translationally modified) in the same way as the proteins of the virus against which protection is to be produced. This makes a far better antigen than, for example, using a recombinant plasmid to produce an antigen in yeast (e.g. the HBV vaccine), purifying that protein and using it as an immunogen.

6. Mixtures of plasmids could be used that encode many protein fragments from a virus or viruses so that a broad spectrum vaccine could be produced

7. The plasmid does not replicate and encodes only the proteins of interest8. There is no protein component and so there will be no immune response against

the vector itself9. Because of the way the antigen is presented, there is a cell-mediated response

that may be directed against any antigen in the pathogen. This also offers protection against diseases caused by certain obligate intracellular pathogens (e.g. Mycobacterium tuberculosis)

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Possible Problems of DNA vaccines

1. Potential integration of plasmid into host genome leading to insertional mutagenesis

2. Induction of autoimmune responses (e.g. pathogenic anti-DNA antibodies)

3. Induction of immunologic tolerance (e.g. where the expression of the antigen in the host may lead to specific non-responsiveness to that antigen)

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Problems in vaccine development• Different types of virus may cause similar diseases -- e.g.

the common cold. As a result, a single vaccine will not be possible against such a disease

• Antigenic drift and shift -- This is especially true of RNA viruses and those with segmented genomes

• Large animal reservoirs. If these occur, re-infection after elimination from the human population may occur

• Integration of viral DNA. Vaccines will not work on latent virions unless they express antigens on cell surface. In addition, if the vaccine virus integrates into host cell chromosomes, it may cause problems (This is, for example, a problem with the possible use of anti-HIV vaccines based on attenuated virus strains)

• Transmission from cell to cell via syncytia - This is a problem for potential AIDS vaccines since the virus may spread from cell to cell without the virus entering the circulation.

• Recombination and mutation of the vaccine virus in an attenuated vaccine.

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The eradication of smallpox • There is no animal reservoir for variola, only humans

are infected by this virus• Once a person has been infected by the virus, there

is lifelong immunity, although this may not be the case with people immunized using the vaccine strain

• Subclinical cases rare and so an infected person can be identified and isolated

• Infectivity does not precede overt symptoms, that is there is no prodromal phase

• There is only one Variola serotype and so the vaccine is effective against all virus strains

• The vaccine is very effective• There has been a major commitment by the World

Health Organization and governments

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Vaccination checklist

Here's a checklist of the vaccines that are routinely offered to everyone in the UK for free on the NHS, and the age at which you should ideally have them.2 months:Diphtheria, tetanus, pertussis (whooping cough), polio and Haemophilus influenzae type b (Hib, a bacterial infection that can cause severe pneumonia or meningitis in young children) given as a 5-in-1 single jab known as DTaP/IPV/Hib Pneumococcal infection 

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Vaccination checklist

Basic Vaccination Schedule األساسية التطعيمات جدول

Visit Vaccine اللقاح الزيارة

At Birth BCG الدرن

الوالدةHepB ) ب ) الكبدي اإللتهاب

2 months IPV المعطل األطفال شلل

شهرين( DTP , HepB )

( ) ؛ ) ب الكبدي اإللتهاب ؛ البكتيري الثالثيالنزلية (المستدمية

4 months OPV الفموي األطفال شلل

شهور 4(DRP , HepB , Hib)

( ) ؛ ) ب الكبدي اإللتهاب ؛ البكتيري الثالثيالنزلية (المستدمية

6 months OPV الفموي األطفال شلل

شهور 6(DRP , HepB , Hib)

( ) ؛ ) ب الكبدي اإللتهاب ؛ البكتيري الثالثيالنزلية (المستدمية

9 months Measles (mono) المفرد شهور 9 الحصبة

12 months

OPV الفموي األطفال شلل

الفيروسي MMR شهر 12 الثالثي

Varicella المائي الجديري

18 months

OPV الفموي األطفال شلل

) ( DTP m HibH influenzae type B ) شهر 18 النزلية المستدمية ؛ البكتيري (الثالثي

Hepatitis ( A ) ) أ ) الكبدي اإللتهاب

24 months Hepatitis ( A ) ) أ ) الكبدي شهر 24 اإللتهاب

4-6 years

OPV الفموي األطفال شلل

البكتيري DTP سنوات 4-6 الثالثي

MMR, Varicella + المائي الجديري الفيروسي الثالثي

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Adverse Events OccurringWithin 48 Hours DTP of Vaccination

Adverse Events OccurringWithin 48 Hours DTP of Vaccination

 Eventlocalredness, swelling, pain

systemic: Mild/moderatefever, drowsiness, fretfulness vomiting anorexia

systemic: more serious persistent crying, fevercollapse, convulsionsacute encephalopathypermanent neurological deficit