Vaccination & Mucosal Immune system

1. Vaccination & Mucosal Immune system

2. CORE 15. Immunomodulation a. Vaccines • active immunization (principles, complications, and examples; childhood immunizations; antigens [live, dead, toxoids]; adjuvants) • passive immunization (principles, complications, and examples) (3) DNA vaccines and recombinant vaccines

3. What are vaccines? • How do vaccines prevent serious infection? • Adjuvants

4. Vaccines The most cost-effective drugs. Eradicated smallpox and polio.

5. History of vaccines • Small amount of live viruses obtained from patients used as vaccine (variolation, 18th century vaccination; side effect 1/100) • Non-disease causing bovine viruses used as vaccine against human viruses (Jenner’s vaccine) • Inactivated or killed virus vaccines (Influenza; Rabies) • Live-attenuated mutant virus used as vaccine (oral polio virus) • Subunit vaccines (Hep B surface Ag as HBV vaccine) Attenuated viruses are selected by growing human viruses in non-human cells

6. 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

7. 3 doses 3 doses 5 doses 4 doses 4 doses 4 doses 1-2 doses 2 doses 2 doses 2 doses

10. Recent changes

11. 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

12. Only for the immunocompetent

13. 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

14. 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.

15. Viral vaccines Killed inactivated vaccine: e.g. inactivated poliovirus vaccine Live attenuated vaccine: e.g. chickenpox virus vaccine Subunit vaccine: e.g. Surface antigen inHBV vaccine

16. Vaccine = antigen + adjuvant (immune booster) APC Microbial products Alum Oil emulsion B cells CD4-Th CTL HI (Ab) CMI

17. Functions of “Adjuvants” • Adjuvants =Alum, oil and microbial components • 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.

18. Adjuvants in vaccines enhance immune response to vaccine components by creating a state of inflammation Adjuvants approved by FDA

21. 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

22. 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

25. New technologies in vaccine design • Gene cloning and expression for subunit vaccine e.g. HBV vaccine • Genetic engineering to make attenuated mutant strains • Vaccine containing peptide epitopes (rather than whole proteins) for efficient presentation on MHC • DNA vaccine: DNA (coding pathogen’s antigen) as vaccine • Vaccine containing cytokines (e.g. IL-12) to boost (Th1) immune response

26. BCG in other countries

27. CORE 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

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

35. IgA

36. IgA transport into the intestinal lumen: Transcytosis secretory IgA intestinal lumen antigen intestinal epithelial cells pIgR pIgR IgA plasma cell dimeric IgA

37. Skin

38. Cutaneous immune system1. 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.

39. A typical immune response in the skin: Skin delayed type hypersensitivity reaction Migration naive Th1 Lymph nodes