Vaccination& Mucosal Immune system

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

1. What is a vaccine?2. How do vaccines prevent serious infection?3. Adjuvants

Vaccines

The most cost-effective drugs.

Eradicated smallpox and polio.

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

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

3 doses

3 doses5 doses

4 doses

4 doses4 doses

1-2 doses2 doses2 doses2 doses

Recent changes

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

Only for the immunocompetent

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

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.

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

Vaccine = antigen + adjuvant (immune booster)

Microbial productsAlumOil emulsionB cells

Hum. Imm (Ab)

APC

CTLCD4-Th

CMI

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.

Adjuvants in vaccines enhance immune response to vaccine components by creating a state of inflammation

Adjuvants approvedby FDA

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

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

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

BCG in other countries

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

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

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

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.

Figure 8-38 part 1 of 2Intestine has built-in secondary lymphoid tissues=Peyer's Patches

Figure 8-38 part 2 of 2M cells sample and transport antigens to DCs

Figure 8-42Lymphocyte migration in the gut and other mucosal tissue sites

Skin

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.

A typical immune response in the skin:Skin delayed type hypersensitivity reaction

naive Th1

Lymph nodes

Migration

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

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