Introduction to Immunization/ Vaccination

Hafez Sumairi

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Learning Objectives

At the end of this lecture, the student should:

Define the terms used in basic immunology and vaccination

Describe the various forms of immunity

Know the distinction between passive and active immunization and their examples

Describe the various types of vaccines

Distinguish between artificial and natural means of immunization

Outline the properties of ideal vaccines

Know the applications and problems of artificial passive immunization

Know the applications and problems of artificial active immunization

Describe new technology and ideas contributing to future vaccines development and delivery

Know the modern approaches to immunization

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Definitions

Immunization (Vaccination) is the process whereby a person is made immune or resistant to an infectious disease, typically by the administration of a vaccine.(WHO)

Immunogenicity: The inherent ability of an antigen to induce an immune response.

A vaccine is a biological preparation that improves immunity to a particular disease. (WHO)

Vaccine adjuvant: substance that is added to a vaccine to its immunogenicity without having any specific antigenic effect in itself.

Herd immunity: This develops when a high proportion of the target population in the community has been immunized with live vaccines, usually 80% and more in order to prevent the spread of infectious diseases

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Milestones in immunization

3000BC Evidence of sniffing powdered small pox crust in Egypt

2000BC Sniffing of small pox crust in China

1500BC Turks introduce variolation

1700AD Introduction of variolation in England and later in the US

1780AD

Edward Jenner discovers small pox vaccine

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Introduction of variolation

The wife of the British Ambassador in Turkey, in March 1717 wrote, following the variolation of her son, to a friend in England: “The small pox, so fatal, so general amongst us, is entirely harmless here by the invention of ingrafting….I am patriot enough to bring this invention into fashion in England.

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Edward Jenner

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Discovery of small pox vaccine

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Edward JennerAmong patients awaiting small pox vaccination

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Modern era of the vaccine

1885 Rabies vaccine (Pasteur)

1909 Bacillus calmette-Guerin (BCG)

1920s Diphtheria and Tetanus

1934 Pertussis & Yellow fever

1940s Diphtheria-tetanus-pertussis

(DTP) combination introduced

1955 Salk polio

1960s Mumps, measles and rubella virus

Sabin polio

1985 Haemophilus

First recombinant vaccine (hepatitis B)

1990s Hepatitis and varicella

First polysaccharide conjugate vaccine

Today-

Glycoconjugate vaccines, rotavirus vaccine, human papilloma virus vaccine and herpes zoster vaccine

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Aims of Immunisation Programmes

To protect those at highest risk (selective immunisation strategy) or

To eradicate, eliminate or control disease (mass immunisation strategy)

Currently, it is estimated that vaccination saves the lives of 3 million children a year

Eradication

Infection (pathogen) has been removed worldwide e.g. smallpox

Elimination

Disease has disappeared from one area but remains elsewhere e.g. polio, measles

Control

Disease no longer constitutes a significant public health problem e.g. neo-natal tetanus

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Pre- & post-vaccine incidence of common preventable diseases

Different modes of acquiring immunity

Immunity

Natural resistance

Acquired

Passive

Artificial

Natural

Active

Natural

Artificial

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Passive Immunity

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Passive Immunity

Natural resistance

Colostral transfer of IgA

Placental transfer of IgG

Artificial

Antibodies or immunoglobulins

Immune cells

Passive Immunization

Disease Antibody

source

Indication

Diphtheria, tetanus Human, horse Prophylaxis, therapy

Vericella zoster Human Immunodeficiencies

Gas gangrene, botulism,

snake bite, scorpion sting

Horse Post-exposure

Rabies, Human Post-exposure

Hypogamma-globulinemia Human Post-exposure

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Advantages and Disadvantages of Passive Immunization

Advantages

• Immediate protection

Disadvantages

• No long term protection

• Serum sickness

• Risk of hepatitis and Aids

• Graft vs. host disease (cell graft only)

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Active Immunity

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Active Immunity

NaturalExposure to sub-

clinical infections

Artificial

Attenuated organisms

Killed organisms

Sub-cellular fragments

Toxins

Others

Live Attenuated Vaccines

Polio

Measles, mumps & rubella

Varicella zoster children with no history of chicken pox

Hepatitis A

not required in SC

Yellow fever

Military and travelers

Tuberculosis

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Live Attenuated Vaccines

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Derivation of Sabin type 3 poliovirus vaccine

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Live Attenuated Vaccines

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New vaccine strategies: genetic reassortmentapproaches

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Advantages of attenuated vaccines

1. They activate all phases of immune system.

2. They raise an immune response to all protective antigens.

3. They offer more durable immunity and are more cross-reactive.

4. They cost less to produce

5. They give quick immunity in majority of vaccinees

6. In many cases (e.g. polio and adenovirus vaccines), administration is easy

7. These vaccines are easily transported in the field

8. They can lead to elimination of wild type virus from the community

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Disadvantages of Attenuated vaccine

1. Mutation.

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 tropics

5. Live viruses are a problem in immunodeficiency disease patients

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Inactivated vaccines

•Virions inactivated by chemical procedures (e.g. formalin, β-propriolactone, nonionic detergents)

•Infectivity is eliminated but antigenicityis not compromised

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Killed Whole-Organism Vaccines

Polio

Influenza Elderly and at risk

Rabiespost exposure

Q feverPopulation at risk

Typhoid, cholera, plagueepidemics and travelers

PertussisReplaced by the acellular vaccine

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Microbial Fragment Vaccines

Bordetella pertussis

virulence factor protein

Haemophilus influenzae B

Protein conjugated polysaccharide

Streptococcus pneumoniae

Polysaccharide mixture

Neisseria meningitidis

Polysaccharide

Clostridium tetani (tetanus)

inactivated toxin (toxoid)

Corynebacterium diphtheriae

inactivated toxin (toxoid)

Vibrio cholerae

toxin subunits

Hepatitis B virus

Cloned in yeast

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Modification of Toxin to ToxoidModification of Toxin to Toxoid

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toxin moiety antigenic determinants

chemical

modification

Toxin Toxoid

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Inactivated vaccine

Advantages of inactivated 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

Disadvantages of inactivated vaccines

1. Some vaccinees do not raise immunity

2. Boosters tend to be needed

3. There us little mucosal / local immunity (IgA)

4. Higher cost

5. In the case of polio, there is a shortage of monkeys

6. Failures of smallpox virus in inactivation

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Recommended Childhood Immunization Schedule

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Future Vaccines (New Methods Of Vaccine Production)

1. Anti-Idiotype Vaccine

2. Immuno-dominant peptide (Synthetic peptides)

3. Recombinant vector vaccines

4. DNA

5. Others

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Anti-Idiotype Vaccine

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Recombinant vector vaccines

• Cloning of a gene into another virus

• Vaccinia (the smallpox vaccine virus) is a good candidate since it has been widely used in the human population with no ill effects.

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Conjugate or Multivalent Vaccines Can Improve Immunogenicity and Outcome

A conjugate vaccine protects against Haemophilus influenzaetype b (Hib)

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Multivalent subunit vaccines

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DNA vaccines The Third Vaccine Revolution

These vaccines are based on the deliberate introduction of a DNA plasmid into the vaccinee.

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Advantages of DNA vaccines

1. Production : Simpler and cheap –Plasmids-2. Stability : Does not require cold chain

3. Infectivity : No risk of infection

4. Flexibility : Fusion of multiple epitopes5. Versatility : Activates both cellular and humoral

immunity, long lasting immunity

6. DNA vaccines potentially have more widespreadapplications

7. Instead of injecting plasmid DNA into skeletal muscle, immune response can also induced by coating plasmid DNA onto gold beads and propel the beads into the skin by using a gene gun

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The Helios GENE GUN from BIORAD, USA

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Disadvantages (Possible Problems)

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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Disease targets for which DNA vaccines have been tested in animals

Viruses• Avian influenza, bovine herpes, bovine viral diarrhea virus, dengue fever,

encephalitis, feline immunodeficiency virus, hepatitis B, hepatitis C, human cytomegalovirus, herpes simplex virus, human immunodeficiency virus I, influenza, lymphocytic choriomeningitis virus, measles, papilloma, rabies, respiratory syncitial virus, simian immunodeficiency virus, simian virus 40.

Bacteria• Borrelia burgdorferi (Lyme disease), Moraxella bovis, Mycobacterium

tuberculosis, Mycoplasma, Ricketsia, Salmonella, tetanus toxin.

Parasites• Cryptosporidium parvum, Leishmania, Plasmodium falciparum (malaria),

Schistosoma.

Cancer-associated antigens • Carcinoembryonic antigen (CEA), melanoma-associated antigen, the MHC

molecule HLA-B7.

• There have been more than 42 Phase I/II clinical trials involving DNA Vaccines.

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New vaccine strategies: reverse genetic approaches

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Adverse Events Occurring Within 48 Hours DTP of Vaccination

Event Local

redness, swelling, pain

Systemic: Mild/moderate fever, drowsiness, fretfulness

vomiting anorexia

Systemic: more serious persistent crying, fever collapse, convulsions acute encephalopathy permanent neurological deficit

Frequency

• 1 in 2-3 doses

• 1 in 2-3 doses

• 1 in 5-15 doses

• 1 in 100-300 doses

• 1 in 1750 doses

• 1 in 100,000 doses

• 1 in 300,000 doses

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Vaccine constituents

Active material(s): Antigens or molecules that react with specific receptors on T and B cells and activate these cells to induce antigen-specific T and B immune responses.

Inactive materials

Adjuvants (aluminium salts, mono-phosphoryl lipid A or MPL, etc) enhance immune responses of vaccine antigens

Preservatives (phenoxyethanol, formaldehyde, thiomersal / thimerosal, or antibiotics) prevent bacterial growth especially in multi-dose vaccines

Stabilizers (proteins or other organic compounds) extend the shelf-life of the vaccine

Salts and acidic solutions (sodium hydroxide, sodium chloride, sodium borate and acetic acid) maintain pH

Solvents such as calcium carbonate, xanthan gum and sterile water

Diluents for reconstituting lyophilised or freeze-dried vaccines

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Vaccine adjuvant

Adjuvant type Human use Experimental only

Salts:

Aluminum hydroxide,

aluminum phosphate-calcium

phosphate

Yes

Yes Slow release of antigen, TLR

interaction and cytokine induction

Beryllium hydroxide No

Synthetic particles:Liposomes, ISCOMs,

polylactates

No

NoSlow release of antigen

Polynucleotides:CpG and others No*

TLR interaction and cytokine

induction

Bacterial products:B. pertussis

YesTLR interaction and cytokine

inductionM. bovis (BCG and others) No

Mineral oils No Antigen depot

Cytokines:IL-1, IL-2, IL12, IFN-γ, etc.

No*Activation and differentiation of T-

and B cells and APC49

Characteristics of an ideal vaccine

1. Immunogenic, provoking a good immune response; but not pathogenic

2. Providing long-lasting immunity

3. Safe, with no or very rare adverse event following immunization (AEFIs)

4. Stable in field conditions and can be stored reasonably long without or with minimum cold chain requirements (heat stable)

5. Combined with several antigens producing immunity against a number of diseases

6. Effective after a single dose hence requires few immunizations to induce protection

7. Administered preferably by non-injectable routes (oral or through inhalation)

8. With affordable cost and accessible to all

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Characteristics of an ideal vaccine

9. Suitable for administration early and late in life (Effective in the old & very young)

10. Give life-long immunity

11. Broadly protective against all variants of organism

12. Prevent disease transmission

13. Rapidly induce immunity

14. Transmit maternal protection to the baby

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Challenges in vaccine development

1. Adaptation of microbial agents to host immunityDevelopment of escape strategies by microbes:i. Emergence of new antigenic variants (e.g. Pneumo, flu,

Menb, malaria, HIV, tb…)ii. Complex interaction with host immune system (e.g.

immunomodulation)

2. Different types of virus may cause similar diseases

3. Antigenic drift and shift

4. Large animal reservoirs

5. Integration of viral DNA

6. Transmission from cell to cell via syncytia

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

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Future vaccine development

•Improved vaccines for optimizing immunogenicity & safety1. New adjuvants used to optimize b cell

responses (level, quality, duration, memory) and generate appropriate t cell responses (help, effector, memory)

2. Immune system targeting formulations

3. New live vaccine vectors (non-replicating)

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Viral Vaccines

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Bacterial Vaccines

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Target Fungal Vaccines

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Target Parasitic Disease

• Malaria

• Trypanosomiasis

• Leishmaniasis

• Toxoplasmosis

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Selective Vaccination

Vaccine given specifically to those at increased risk of disease:

• High risk groups

e.g. Pneumococcal vaccine

• Occupational risk

e.g. Hepatitis B, influenza

• Travellers

e.g. Yellow fever, rabies, meningitis

• Outbreak control

e.g. Hepatitis A. vaccine, measles

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More Possibilities

Therapeutic vaccines: Identification of specific tumor

antigens provide immune targets for which immunogenic

vaccines may conceivably be designed. Examples:

Leukemia

Breast cancer

Melanoma

Prostate cancer

Colon cancer

•Vaccines against autoimmune diseases

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Similarities between Vaccines and other Drug

Vaccines are also medicines

Potential for adverse effects

Multiple ingredients

Potential for interaction with disease and other medicines

Also need to comply with standards of safety, efficacy and quality

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Mass Vaccination (Herd immunity)

Objective: Make hosts resistant to infection without

having to experience disease

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Impact of Mass Vaccination Programmes

Reduce size of susceptible population

Reduce number of cases

•Reduce risk of infection in population

•Reduce contact of susceptible to cases

•Lengthening of epidemic cycle ->

honeymoon phase

• Increase in mean age of infection

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No Mass Vaccination

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Each host in contact with infected host becomes infected

(with a certain probability)

Mass Vaccination

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Outbreak attenuated (or averted) by lack of susceptible hosts

Steps on Vaccine Development1

• Recognize the disease as a distinct entity

• Identify etiologic agent

• Grow agent in laboratory

• Establish in animal model for disease

• Identify an immunologic correlate for immunity to the disease- usually serum

antibody

• Inactivate or attenuate the agent in the laboratory- or choose antigens

• Prepare candidate vaccine following GOOD manufacturing Procedures

• Evaluate candidate vaccine(s) for ability to protect animals

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Steps on Vaccine Development2

• Prepare protocol(s) for human studies

• Apply to MCC for investigational New drug (IND) approval

• Phase I human trials- Safety and immugenicity, dose response

• Phase II trials- Safety and immugenicity

• Phase III trials- Efficacy

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Steps on Vaccine Development3

• Submit Product Licensure Application MCC approval

• Advisory Committees review and make recommendations

• Marketing Post- Licensure Surveillance for safety and effectiveness

(Phase IV)

• Long and Complicated process

Usually takes 10-15 years

Many vaccine candidates fail for every success

Costs: $ 100- $ 700 million per successful vaccine

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Vaccine Evaluation

Pre-licensingRandomised, Blinded,

Controlled Clinical Trials

Vaccine efficacy:Protective Effect under Idealised

Conditions

RCT: controlled experiments, simple interpretation

Post-licensingObservational Studies

Vaccine effectiveness:Protective Effect under

Ordinary Conditions of a public health programme

Prone to bias, more complex interpretation

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The eradication of smallpox due to several reasons

1. There is no animal reservoir for variola

2. Lifelong immunity, although this may not be the case with people immunized using the vaccine strain

3. Subclinical cases are rare

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

5. There is only one Variola serotype

6. The vaccine is very effective

7. There has been a major commitment by the World Health Organization and governments to smallpox eradication.

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Thank you

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