1. Immunity Specific defenses Immunity Active immunity Passive immunity Following clinical infection natural Transfer of maternal Antibodies Through placenta Following subclinical infection Transfer of maternal Antibodies Through milk acquired Following vaccination Following administration of Immunoglobulin or antiserum

2. Viral Vaccines

3. Immunizing agents vaccines immunuglobulins antisera Immunizing agents

4. Vaccination • Vaccination is a method of giving antigen to stimulate the immune response through active immunization. • A vaccine is an immuno-biological substance designed to produce specific protection against a given disease. • A vaccine is “antigenic” but not “pathogenic”.

5. Let’s go back in time to seehow this strategy works The time: 500 B.C. The place: Greece

6. Even 2,500 Years Ago, People Knew Immunity Worked. • Greek physicians noticed that people who survived smallpox never got it again. • The insight: Becoming infected by certain diseases gives immunity.

7. Fast forward 2300 years I had a brilliant idea pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

8. Vaccination • Charles Jenner 1796 : Cowpox/Swinepox • 1800’s Compulsory childhood vaccination

9. 1% v. 25% mortality • Life-long immunity • UK: 1700’s • China 1950 • Pakistan/Afghanistan/ Ethiopia 1970 Smallpox pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

10. No animal reservoir • Lifelong immunity • Subclinical cases rare • Infectivity does not precede overt symptoms • One serotype Smallpox presented many advantages that made this possible pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

11. As a result, after a world-wide effort Smallpox was eliminated as a human disease in 1978 pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

12. Types of vaccines • Live vaccines • Attenuated live vaccines • Inactivated (killed vaccines) • Toxoids • Polysaccharide and polypeptide (cellular fraction) vaccines • Surface antigen (recombinant) vaccines.

13. Live vaccines • Live vaccines are made from live infectious agents without any amendment. • The only live vaccine is “Variola” small pox vaccine, made of live vaccinia cow-pox virus (not variola virus) which is not pathogenic but antigenic, giving cross immunity for variola.

14. Live attenuated (avirulent) vaccines • Virulent pathogenic organisms are treated to become attenuated and avirulent but antigenic. They have lost their capacity to induce full-blown disease but retain their immunogenicity. • Live attenuated vaccines should not be administered to persons with suppressed immune response due to: • Leukemia and lymphoma • Other malignancies • Receiving corticosteroids and anti-metabolic agents • Radiation • pregnancy

15. Live Attenuated Vaccineshave several advantages • Attenuated (weakened) form of the "wild" virus or bacterium • Can replicate themselves so the immune response is more similar to natural infection • Usually effective with one dose

16. Live Attenuated Vaccinesalso have several disadvantages • Severe reactions possible especially in immune compromised patients • Worry about recreating a wild-type pathogen that can cause disease • Fragile – must be stored carefully MMWR, CDC

17. A number of the vaccines you receivedwere live Attenuated Vaccines • Viral measles, mumps,rubella, vaccinia, varicella/zoster, yellow fever, rotavirus, intranasal influenza, oral polio • Bacterial BCG (TB), oral typhoid

18. Inactivated (killed) vaccines • Organisms are killed or inactivated by heat or chemicals but remain antigenic. • They are usually safe but less effective than live attenuated vaccines. • The only absolute contraindication to their administration is a severe local or general reaction to a previous dose.

19. Inactivated Vaccines Minuses • Cannot replicate and thus generally not as effective as live vaccines • Usually require 3-5 doses • Immune response mostly antibody based

20. Inactivated Vaccines Pluses • No chance of recreating live pathogen • Less interference from circulating antibody than live vaccines

21. Inactivated Vaccines are alsoa common approach today Whole-cell vaccines • Viral polio, hepatitis A, rabies, influenza* • Bacterial pertussis*, typhoid* cholera*, plague* *not used in the United States

22. Other Inactivated Vaccinesnow contain purified proteinsrather than whole bacteria/viruses • Proteins hepatitis B, influenza, acellularpertussis,human papillomavirus, anthrax, Lyme • Toxins diphtheria, tetanus

23. Sabin Polio Vaccine Attenuated by passage in foreign host (monkey kidney cells) Selection to grow in new host makes virus less suited to original host

24. Sabin Polio Vaccine • Attenuated by passage in foreign host (monkey kidney cells) • Selection to grow in new host makes virus • less suited to original host • Grows in epithelial cells • Does not grow in nerves • No paralysis • Local gut immunity (IgA)

25. Salk Polio Vaccine • Formaldehyde-fixed • No reversion

26. Polio Vaccine illustrates the pluses and minuses of live vaccines • US: Sabin attenuated vaccine • ~ 10 cases vaccine-associated polio per year = • 1 in 4,000,000 vaccine infections • Scandinavia: Salk dead vaccine • No gut immunity • Cannot wipe out wt virus pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

27. Live virus generates a more complete immune response Killed (Salk) Vaccine Live (Sabin) Vaccine Serum IgG 512 Serum IgG 128 32 Serum IgM Serum IgM Reciprocal virus antibody titer Nasal IgA Serum IgA 8 Serum IgA 2 Duodenal IgA Nasal and duodenal IgA 1 48 96 96 48 Vaccination Days Vaccination

28. Modern molecular biologyhas offered new approaches to make vaccines • Clone gene from virus or bacteria • and express this protein antigen • in yeast, bacteria or • mammalian cells in culture

29. Modern molecular biologyhas offered new approaches to make vaccines 2. Clone gene from virus or bacteria Into genome of another virus (adenovirus, canary pox, vaccinia) And use this live virus as vaccine

30. Cloned protein antigenshave pluses and minuses • Pluses • Easily manufactured and often relatively stable • Cannot “revert” to recreate pathogen • Minuses • Poorly immunogenic • Post-translational modifications • Poor CTL response

31. Viral vectors have pluses and minuses • Pluses • Infects human cells but some do not replicate • Better presentation of antigen • Generate T cell response • Minuses • Can cause bad reactions • Can be problems with pre-exisiting immunity to virus • Often can only accommodate one or two antigens

32. Toxoids • They are prepared by detoxifying the exotoxins of some bacteria rendering them antigenic but not pathogenic. Adjuvant (e.g. alum precipitation) is used to increase the potency of vaccine. • The antibodies produces in the body as a consequence of toxoid administration neutralize the toxic moiety produced during infection rather than act upon the organism itself. In general toxoids are highly efficacious and safe immunizing agents.

33. Polysaccharide and polypeptide (cellular fraction) vaccines • They are prepared from extracted cellular fractions e.g. meningococcal vaccine from the polysaccharide antigen of the cell wall, the pneumococcal vaccine from the polysaccharide contained in the capsule of the organism, and hepatitis B polypeptide vaccine. • Their efficacy and safety appear to be high.

34. Surface antigen (recombinant) vaccines. • It is prepared by cloning HBsAg gene in yeast cells where it is expressed. HBsAg produced is then used for vaccine preparations. • Their efficacy and safety also appear to be high.

35. Types of vaccines

36. Routes of administration • Deep subcutaneous or intramuscular route (most vaccines) • Oral route (sabine vaccine, oral BCG vaccine) • Intradermal route (BCG vaccine) • Scarification (small pox vaccine) • Intranasal route (live attenuated influenza vaccine)

37. Scheme of immunization • Primary vaccination • One dose vaccines (BCG, variola, measles, mumps, rubella, yellow fever) • Multiple dose vaccines (polio, DPT, hepatitis B) • Booster vaccination To maintain immunity level after it declines after some time has elapsed (DT, MMR).

38. Periods of maintained immunity due to vaccines • Short period (months): cholera vaccine • Two years: TAB vaccine • Three to five years: DPT vaccine • Five or more years: BCG vaccine • Ten years: yellow fever vaccine • Solid immunity: measles, mumps, and rubella vaccines.

39. Levels of effectiveness • Absolutely protective(100%): yellow fever vaccine • Almost absolutely protective (99%): Variola, measles, mumps, rubella vaccines, and diphtheria and tetanus toxoids. • Highly protective (80-95%): polio, BCG, Hepatitis B, and pertussis vaccines. • Moderately protective (40-60%) TAB, cholera vaccine, and influenza killed vaccine.

40. HIV Vaccine

41. Given that introduction, should we search for a vaccine against HIV and how would we do so?

42. This formidable array of defense mechanisms Allows HIV to avoid being suppressed by our immune system Integration and latency Destruction of CD4+ T cells Inaccessible epitopes Antigenic escape Downregulating MHC

43. An effective vaccine could have a MAJOR Impact on the future prognosis iavi.org

44. An effective vaccine must get around the strategies HIV uses to evade the immune system

45. The vaccine must be able to target conserved and essential parts of the viruses machinery Inaccessible epitopes Antigenic escape + existence of many viral strains

46. The vaccine must act early in the process Before the virus becomes firmly established And destroys the immune system Integration and latency Destruction of CD4+ T cells Molecular Biology of the Cell Alberts et al

47. Protein subunit Synthetic peptide Naked DNA Inactivated Virus Live-attenuated Virus Live-vectored Vaccine There are many possible HIV Vaccine Approaches RamilSapinoro, University of Rochester Medical Center

48. To begin we need to ask some key questions What should vaccine elicit?

49. To begin we need to ask some key questions Whatshould vaccine elicit? Neutralizing antibodies to kill free virus

50. To begin we need to ask some key questions Whatshould vaccine elicit? Neutralizing antibodies to kill free virus T cell response to kill infected cells OR