vaccination
TRANSCRIPT
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Vaccination& Mucosal Immune system
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15. Immunomodulation
a. Vaccines(1) active immunization (principles, complications, and
examples; childhood immunizations; antigens [live, dead, toxoids]; adjuvants)
(2) passive immunization (principles, complications, and examples)
(3) DNA vaccines and recombinant vaccines
CORE
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1. What is a vaccine?2. How do vaccines prevent serious infection?3. Adjuvants
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Vaccines
The most cost-effective drugs.
Eradicated smallpox and polio.
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1. Small amount of live viruses obtained from patients used as vaccine (variolation, 18th century vaccination; side effect 1/100)
2. Non-disease causing bovine viruses used as vaccine against human viruses (Jenner’s vaccine)
3. Inactivated or killed virus vaccines (Influenza; Rabies)4. Live-attenuated mutant virus used as vaccine (oral polio virus)5. Subunit vaccines (Hep B surface Ag as HBV vaccine)
History of vaccines
Attenuated viruses are selected by growing human viruses in non-human cells
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Active vs. Passive Immunization
• Active immunity is the development of antibodies in response to stimulation by an antigen.
(= Vaccination)
• Passive immunity. Once formed, antibodies can be removed from the host and transferred into another recipient where they provide immediate passive immunity.
(e.g. 1. Ig transfer from healthy persons into patients with X-linked
agammaglobulinemia, who are unable to manufacture antibodies)2. Injection of anti-HBV Ig into infants born to HBV SAg(+) mothers
within 12 hours after birth
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3 doses
3 doses5 doses
4 doses
4 doses4 doses
1-2 doses2 doses2 doses2 doses
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Recent changes
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Rotavirus: 3-dose schedule at ages 2, 4, and 6 months
Varicella: The first dose should be administered at age 12-15 months, and a second dose should be administered at age 4-6 years
Papillomavirus vaccine (HPV) is recommended in a 3-dose schedule with the second and third doses administered 2 and 6 months after the first dose
Oral Polio Virus is no longer recommended for routine immunization in the United States. All infants and children should receive four doses of IPV at 2, 4, and 6 through 18 months of age, and 4 through 6 years of age;
For more info: http://www.cdc.gov/nip/recs/child-schedule.PDF
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Only for the immunocompetent
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Bacterial vaccines
BCG vaccine against Mycobacterium tuberculosis: derived from bovine strain; not used in USA
Live-attenuated vaccine against Salmonella typhi; made by mutagenesis and selection for loss of LPS necessary for pathogenesis
Inactivated toxins (toxoids) used as vaccines: diphtheria toxin or tetanus toxin
Combination vaccine: multiple vaccines combined in a single vaccine: DTP (Diphtheria Tetanus Pertussis)
Conjugate vaccine: capsule polysaccharides from encapsulated bacteria (e.g. H. Influenza) are cross-linked to carrier protein (e.g. tetanus toxin protein); carrier proteins induce CD4 T cell response against the T-independent antigens. e.g. Haemophilus influenzae type b, meningococcal C and pneumococcal infections
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Conjugate vaccine: HIB polysaccharide-conjugated to a protein
Bacterial (e.g. HIB) polysaccharides can not activate T cells because MHC molecules can not present them.Without T cell activation B cell cannot make high affinity antibodies.This is to induce T-dependent B cell response to polysaccharide antigens.
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Viral vaccines
Killed inactivated vaccine: e.g. inactivated poliovirus vaccine
Live attenuated vaccine: e.g. chickenpox virus vaccine
Subunit vaccine: e.g. Surface antigen in HBV vaccine
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Vaccine = antigen + adjuvant (immune booster)
Microbial productsAlumOil emulsionB cells
Hum. Imm (Ab)
APC
CTLCD4-Th
CMI
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Functions of “Adjuvants”Adjuvants =Alum, oil and microbial components
1. Activate cells (APC, B cells, T cells and tissue cells)
through TLRs (microbial components):-Activate (or maturate) antigen presenting cells
-Increase expression of co-stimulatory molecules and MHC molecules
-Induce chemokines to recruit phagocytes
2 Sustained release of antigens (alum or oil); Enhance antigen-
uptake by APC (alum or oil). *Slow release is beneficial.
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Adjuvants in vaccines enhance immune response to vaccine components by creating a state of inflammation
Adjuvants approvedby FDA
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Routes of vaccine introduction
Injection (s.c. or i.m.) : used for most vaccines; not a natural route; painful (?)
Oral or nasal administration: physiologically relevant, easy to administer; no pain; used for some virus vaccines
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A risk of vaccination
Vaccination can cause real disease:
e.g. Live-attenuated viruses can revert to become pathogenic. This can cause polio symptoms in 3 persons per million vaccinated for Sabin polio virus (trivalent oral polio vaccine, TVOP).TVOP contains three attenuated virus strains. Strain 3 with 10 nucleotide substitutions can revert to the wild type.
Live polio vaccine was banned in the USA.
Immunodeficient humans should not get this type of vaccines
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New technologies in vaccine design
1. Gene cloning and expression for subunit vaccine e.g. HBV vaccine
2. Genetic engineering to make attenuated mutant strains
3. Vaccine containing peptide epitopes (rather than whole proteins) for efficient presentation on MHC
4. DNA vaccine: DNA (coding pathogen’s antigen) as vaccine
5. Vaccine containing cytokines (e.g. IL-12) to boost (Th1) immune response
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BCG in other countries
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14. Cutaneous and Mucosal Immune systems
• a. Cutaneous (cells, DTH)
• b. Mucosal (cells, tissue, IgA)
• (1) M cells
• (2) Polymeric Ig receptor and transepithelial IgA transport
CORE
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Two special features of the intestinal Two special features of the intestinal immune systemimmune system
Predominance of secretory IgA in intestinal secretions
Selective non-responsiveness ("oral tolerance") towards numerous ingested antigens
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IgA transport into the intestinal lumen:IgA transport into the intestinal lumen:TranscytosisTranscytosis
IgA plasma celldimeric IgA
pIgR
intestinal epithelial cells
intestinal lumenantigen
secretory IgA
pIgR
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2. Intraepithelial lymphocytes (IEL)
3. Lamina propria lymphocytes (LPL)
Lamina propria
Lumen
Three major lymphoid populations Three major lymphoid populations in the intestinal tractin the intestinal tract
1. Peyer's Patch
M cells are here.
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Figure 8-38 part 1 of 2Intestine has built-in secondary lymphoid tissues=Peyer's Patches
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Figure 8-38 part 2 of 2M cells sample and transport antigens to DCs
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Figure 8-42Lymphocyte migration in the gut and other mucosal tissue sites
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Skin
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Cutaneous immune system
1. Skin is the largest organ of our body and is composed of epidermis and dermis layers.
2. Keratinocytes and Langerhans cells reside in epidermis.
3. Langerhans cells are immature dendritic cells. In infection by pathogens, Langerhans cells maturate and migrate to skin-draining lymph nodes through afferent lymphatic vessels. In lymph nodes, they present antigen to T cells that are specific to the pathogens.Lymphocytes, activated in the skin-draining lymph nodes, migrate back to skin for surveillance.
4. Lymphocytes found in skin express a specialized adhesion molecule called CLA (cutaneous lymphocyte antigen), P-/E-selectin ligands, and chemokine receptors (e.g. CCR4, CCR8 and CCR10). These lymphocyte surface molecules guide the migration of skin-homing lymphocytes to the inflamed skin.
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A typical immune response in the skin:Skin delayed type hypersensitivity reaction
naive Th1
Lymph nodes
Migration
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b. Immunosuppressive drugs (mechanisms of action and examples of their uses)
(1) Cycle-nonspecific (radiation, corticosteroids, nonsteroidal anti-inflammatory agents, cyclosporin)
(2) Cycle-specific (cyclophosphamide, chlorambucil, azathioprine, methotrexate): nucleotide analogs
See the ‘Transplantation Immunology Lecture’
CORE
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c. Pathologically induced immunosuppression
• Immunodeficient diseasese.g. AIDS
• Disease-induced anergyInability to activate T cells in response to pathogens.
Susceptible to super-infection by different pathogens.
Evasion of immune responses by pathogens
e.g. some pathogens induce regulatory T cells to suppress the responses.
See the ‘Immunodeficiency Lecture’
CORE