Vaccines - the immunology behind the protection

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the immunology behind the protection

History of Vaccines
Edward Jenner, M.D. (1749-1823)

John Raphael Smith’s Royal Academy Exhibit (1800)

• Jenner's Inquiry • First published in 1798

• • • •

Summary of Jenner’s Inquiry: Over a period of years, Jenner had noticed the immunity toward smallpox provided by cow-pox He decided deliberately to introduce the disease into a patient to see if the effect could be artificially produced. Soon afterwards, he would again inoculate his patients, this time with live smallpox virus ("variolation"), to see if the cow-pox had worked. The "healthy boy" whom Jenner, on May 14 1796, first vaccinated with virus from the dairymaid Sarah Nelmes was James Phipps, who proved Jenner's point by surviving repeated unsuccessful attempts to infect him with smallpox.

Outline for the Immunology Behind the Protection
• Stimulating Desired Immune Response
• Perception/Evidence of Vaccine Efficacy and Safety • Types of Vaccines

Immune Response Innate vs. Adaptive

The Adaptive Immune System
• Two Significant Characteristics
– Specificity – Memory

• Two Types of Cells:
– B lymphocytes (B cells) – T lymphocytes (T cells)

Players in the Adaptive Immune System
• B cells
• Produce Immunoglobulins (Antibodies)

• T cells (2 types)
– Cytotoxic T cells – Helper T cells • Activate/attract phagocytic macrophages come and kill (delayed-type hypersensitivity response; Th1) • Regulate Antibody responses (Th2)

Features of Effective Vaccines
• Immunogenic
– strong immune response – necessary type of immune response(s)

• Stable/retains potency • Safe
– protective immunity with minimal side effects – perception

Two Intracellular Compartments
• Cytosol
– contiguous with nucleus

• Vesicular System
– contiguous with extra-cellular fluid

Pathogen Replication Sites
Cytosolic all viruses
obligate cytosolic bacteria

Vesicular most pathogenic bacteria
some parasites

Extracellular (Vesicular) some bacteria

Processing in the Cytosol
Cytotoxic T cells  Cell Death

Processing of Extracellular Derived Products
TH2 cells 
Activate B cells to make Antibodies

Fig. 4.2

• Antibodies may bind directly to structures on the surfaces of bacteria or viruses which are used to attach to and enter cells. • Antibodies may bind and inactivate harmful soluble products (e.g., toxins).

Neutralization (viruses)

•Blockage of viral ability to bind to specific cellular receptors. •This is one of the primary means by which antibody protects against secondary, tertiary, etc Fig. 9.25 . infections.

Neutralization (bacteria)
•Blockage of binding structures on intracellular bacteria also inhibits their adhesion and entry into cells

•Antibodies can also neutralize bacterial binding structures used to colonize non-cellular surfaces.

Fig. 9.26

Neutralization (soluble molecules)

Antibodies can bind and inactivate microbial products such as toxins and those which would not be normally thought of as toxins (e.g., enzymes secreted by Streptococcus mutans which are involved in tooth decay).
Fig. 9.24

Features of Effective Vaccines
• Immunogenic
– strong immune response – necessary type of immune response(s)

• Stable/retains potency • Safe
– protective immunity with minimal side effects – perception

Concerns Related to Vaccines
Genuine Parenting Concerns
Coinciding Occurrences

Groups opposed to Medical Research
Some Homeopathic & related Groups

“Associations” between Vaccines & Disease Onset
• Influenza (specifically Swine Flu) Vaccine and Guillain Barre Syndrome – Camplobacter infections • Hepatitis B (HBV) Vaccine and Multiple Sclerosis, Chronic Fatigue Syndrome, or Rheumatoid Arthritis, etc. – Cause or Effect? Immune Stimulation? Associations still under study • Measles, Mumps, and Rubella (MMR) Vaccine and Autism – Statistical Coincidence

Macrophagic Myofaciitis (MMF) & IM injection of Aluminum-containing Vaccines • Brain (2001) 124: 974-983
– Study of 92 MMF patients: • 7 had demyelinating CNS disorders (MSlike) • All 7 had received an aluminumcontaining vaccine 3-78 months prior (mean = 33 months) • Of the remaining 85
– Vaccine history?

• Coinciding or Causative?

“As infectious disease epidemics have waned and fear of death or disability due to infection has lessened, increasing concerns over possible vaccine side effects and safety have arisen.”
Poland & Jacobson Vaccine 19: 2440-2445

Table 2. Comparison of the number of maximum and provisional cases of selected vaccine-preventable diseases that occurred in 1999.
Disease Measles Mumps Polio (paralytic)† Rubella Diphtheria Tetanus Pertussis Haemophilus influenzae§ invasive disease Hepatitis B Maximum cases 894,134 152,209 21,269 57,686 206,939 1,560‡ 265,269 1,563 26,654 1999* 309 840 0 146 0 34 4,315 276 10,079 Percentage reduction 99.9 99.4 100.0 99.7 100.0 97.8 98.4 82.3 62.2

*Subject to change because of late reporting.
† ‡

Caused by wild virus Number who died. § Reporting began in 1991; estimates in prevaccine era,  20,000

CDC Report

Type of Vaccines
• 1st Generation
– Live - Attenuated – Dead or Inactivated

• 2nd Generation
– Extracts (proteins/peptides) – Conjugated – Recombinant

• 3rd Generation

Attenuated/Recombinant Vaccines
Attenuated: Recombinant:
• less virulent than • deliberately modified naïve pathogen via to delete/alter mutation virulence or replication genes • effective protection • effective protection • risks: – that necessary epitopes are not present – wild-type reversion

Dead or Inactivated Vaccines
• Less effective protection • Lack replication-associated epitopes • Lack reversion risk

Extract Vaccines
• Proteins or Peptides derived from pathogen or synthetically manufactured • Peptide vaccines are very effective if…
• correct epitope(s) are known • presented so as to generate desired immune response • e.g. diphtheria and tetanus - toxins immunized

Conjugated Vaccines
• Unite desired pathogenic epitope + immune stimulatory molecule • usually either peptide/protein or DNA constructs
– e.g. Hib vaccine = Haemophilus protein (pathogenic immune response) + LPS protein (direct T-dependent Ab response)

DNA Vaccines
• Introduce the DNA of desired epitopes usually intramuscularly
– prolonged expression of the peptides – must know the pertinent epitopes – limited presentation

• Currently experimental for:
– pathogens, allergies, cancers, and autoimmunity


Methods Useful in Enhancing Efficacy of a Vaccine

• “substance enhancing the immunogenecity of vaccine” – act at site of presentation • Many vaccines are inherently weak immunologically – limits need for boosting with multiple immunizations – helps immunocompromised, e.g. the young and the aged • Risks: – induction of inflammatory diseases • e.g.: pertussis toxin (DPT); emulsification in oil; and aluminum salts

Methods Useful in Enhancing Efficacy of a Vaccine
ISCOM = immune stimulatory complex

• Particularly effective with peptide vaccine • Enhance cytosoloic presentation

lipid micelles

Additional Considerations in Developing a Vaccine
• Targeting Vaccine
– Necessary to prevent proteolysis – Necessary that the vaccine is taken up – Necessary to get into the appropriate presenting pathway

• Rapid mutations in pathogen
– e.g. HIV, Influenza, Nisseria

• Pathogen sequestration
– e.g. Plasmodium (malaria)

See also Fig 14.21

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