VACCINES

1. VACCINES

2. Outline • Why do we need vaccines? • Concept of vaccination - how vaccines work • Types of vaccines • Success and failure of vaccines • Vaccine development

3. Why do we need vaccines? Infectious Disease • 1969 U.S. Surgeon General “time to close the book on infectious disease” • 1996 Director General WHO “We stand on the brink of a global health crisis in infectious diseases”

4. Challenges • Increase in nosocomial infections • Drug resistance pathogens • Immunosuppressed patients • Aging population • New emerging diseases • Globalization (increased movement and trade) • Bioterrorism

5. Control of Infectious Disease • Antimicrobials • Vaccines • Immune modulators

6. History of vaccination • Jenner observation that milkmaids did not develop smallpox disease • Introduced the concept of vaccination using live vaccinia virus • 100 years later Pasteur introduced a new approach in vaccination by killing the organism and introducing the agent as a non-replicating vaccine • Today genetic engineering and biotechnology generated recombinant subunit vaccines HBsAg, HPV

7. Concept of vaccination - how vaccines work • Individual - Stimulation of immune responses (humoral and cellular) - Induction of neutralizing antibody - Training the adaptive immune response to generate immune memory • Community - Herd immunity reducing transmission of the pathogen

8. Ideal situation • Epidemiologist would suggest that the ideal situation would be that everyone in the world is vaccinated except you. In this situation you derive most of the benefit and none of the risk. • This situation breaks down if you know that you will be exposed to the pathogen

9. Infection and disease • The selection of immune memory cells by vaccination allows the animal to control the infection before it gets out of control

10. Correlates of disease protection • It is likely impossible to develop an effective vaccine to a disease where there is no correlate of disease protection (If an infection is always fatal)

11. Importance of the proper immune response • It is critical for a vaccine to generate the appropriate immune response necessary for protection • A vaccine must stimulate the appropriate immune response

12. Vaccine Classes • Prophylactic/acute disease • Therapeutic/chronic • Physiological alteration - Contraceptive - Production alteration • Food safety vaccines

13. Types of Vaccines • 1 Conventional • Live • Inactivated • 2 Genetically Engineered • Live • Replication defective • Subunit • DNA vaccines

14. Live vaccines • Pros - Induce broad immunity (both cellular and humoral) - Induce stronger immune memory then killed vaccines - Can induce mucosal immunity if administered at mucosal surfaces - Can shed from vaccinated individuals to vaccinate unvaccinatated individuals - Do not require adjuvants • Cons • Safety issues • Can cause disease • Reversion to virulence • Can be shed from vaccinated population

15. Inactivated killed vaccines • Pros - Safe since they are killed - Multiple antigens for more broad immunity • Cons - Require adjuvants - Difficult to generate cell mediated immunity - Difficult to generate mucosal immunity

16. Genetically engineered vaccines live replication defective • Pros - Generation of both cellular and humoral immunity - Natural antigen expression - Good induction of immune responses • Cons - Immunity generated to the vector - Regulatory hurdles

17. Subunit vaccines • Pros - Safety - More expensive • Cons - Require adjuvants - Antigen is not processed effectively on class I MHC therefore CTLs are not effectively generated - Only a few vaccines are recombinant (HBsAg) - Usually only a single antigen

18. Conjugated vaccines • Conjugation to add help Haemophilus influenzae type B vaccine • Bacterial polysaccacharides T cell independent antigens

19. 7 Antigenic peptides 6 8 MHC I 4 5 Antigen Nucleus 3 2 Plasmid 1 mRNA DNA Vaccines Work by Transfection of Host Cells

20. Production of DNA vaccines • Pros - Single simple platform - Ease of manipulating DNA to create vaccine - Ease of mixing different antigen-encoding plasmids together - Ease in manufacturing - Low cost - Rapid production • Cons - Current capacity to produce Kg quantities of plasmid is very limited - Current production processes need to be streamlined and become more efficient

21. Distribution of DNA vaccines • Pros - Do not require refrigeration • Cons - Currently there are no commercial DNA vaccines for any human disease

22. Safety of DNA vaccines • Pros - Non-infectious (no reversion to virulence) - Low toxicity - Low immunogenicity compared to conventional vectors - No harsh adjuvants (plasmid backbone has adjuvant properties) • Cons - Regulatory issues - Very small risks of integration - Risk adverse society that may not accept the extremely rare theoretical risks with DNA vaccines.

23. Immunity generated by DNA vaccines • Pros - Antigen is produced in natural form - No specific immunity is generated to plasmid vector - Antigen presentation on both MHC I and MHC II - Generate both humoral and cellular immunity - Protective immunity demonstrated for several infectious agents - Potential for improved memory responses • Cons - Poor translation of results from mice to host species - Some pathogens may require many antigens to induce protective immunity - Require some molecular knowledge of pathogen - Limited studies evaluating immune memory

24. Adjuvants • An agent that without antigen does not stimulate the adaptive immune response but when combined with antigen enhances the adaptive immune response. • How do adjuvants work? - Stimulation of innate immune responses such as inflammation - Improved antigen uptake and processing

25. Adjuvants • Licensed adjuvants - Alum - QS21 MF59 • Safety issues with adjuvants - Alum can cause sarcomas at the injection site in cats following vaccination

26. Immunization with cocktail of HIV-derived peptides in montanide ISA-51 is immunogenic, but causes sterile abscesses and unacceptable reactogenicity. Graham BS, et al. PLoS One. 2010 5:e11995.

27. Success and failure of vaccines • Vaccination is one of the most cost-effective approaches for the management of infectious disease

28. Vaccines/Disease Eradication • Small pox -1980 • Polio –WHO target 2005 • Measles –WHO target 2010

29. Failure of vaccines • There are still many infectious diseases where there is no effective vaccine • Diseases which cell mediated immunity is essential are very difficult to generate vaccines to • Viruses that are latent are difficult to generate vaccines for • Viruses that mutate frequently require new vaccines each year

30. RSV vaccine failure • Vaccine increased pathogenesis of RSV in infants following exposure to RSV • Mechanism hypothesised - formalin inactivated RSV induced biased Th2 responses that lead to increased disease caused by RSV

31. Influenza A vaccines • Require a new vaccine to be generated every year • There is no universal vaccine available for influenza

32. Common cold virus vaccine • Failure to generate a vaccine for the common cold • Reason - there are several different viruses and serotypes that cause colds • To generate a vaccine for the common cold it would require antigens from all of the different cold viruses

33. Herpes simplex virus vaccines • No licensed vaccine • Reason - Latent nature of HSV means the vaccine must provide sterile immunity since once infected the virus will go latent

34. HIV vaccine failure • Neutralizing antibodies can be evaded by mutation of HIV envelop glycoproteins • Latent HIV can hide from the immune system • Resistance of exposed individuals to HIV is questionable • Mechanism of protection is not well understood or may not exist

35. Vaccines for parasites • Complicated lifecycle • Many different antigens in the parasite make antigen selection difficult

36. Summary of success and failure of vaccines • Clearly there have been successful application of vaccines against infectious disease • However there is still challenges in developing vaccines to many different pathogens

37. Immune memory • 500 B.C. Thucydides noted that those whose survived the plague were protected from the plague “the same man was never attacked twice” • Definition: An immune response that is more rapid and vigorous in amplitude • Greater number of antigen specific cells and cells that can respond to antigen faster than naïve cells.

38. How is immune memory measured • Antigen recall responses • Antibody responses in serum • Cellular immune responses ELISPOT, CTL, and FACs analysis • Challenge experiments

39. Immune memory

40. Memory cells • There is a time lag for memory cells to become effector cells • This is illustrated best with Montezuma’s Revenge - locals have immunity, however when the leave for a period of time and come back they get sick • Reason - their effector cells have waned and there is a lag time for memory cells to become effector cells

41. Rabies Vaccine • Can give the vaccine following exposure • Reason: - Virus is slow growing and effector cells can be generated by vaccination in time to protect from disease

42. Can immune memory last a lifetime • It has been illustrated that B cell memory can last at least 50 years after Smallpox vaccination • However, memory wanes with time • Other vaccines do not induce long lasting immune memory • Require repeated administration of vaccines

43. Ideal vaccine • Safe • Single administration (ideally needle-free) • Long lasting immunity • Protect against many diseases (combination vaccine) • Induce sterile immunity • No current vaccine has all the traits of an ideal vaccine

44. Future Directions • Improved delivery of vaccines • Mucosal protection • Improved vaccine production (influenza vaccine) • Combination vaccines • Universal vaccines • Single dose vaccines • Improved adjuvants • Improved efficacy of DNA vaccines

45. Improved delivery of vaccines • Why? - Improved compliance - Ease of delivery (No need for trained medical personnel) - Prevent disease caused by needle-sticks - Prevent disease caused by the reuse of needles • How - Needle-free delivery - Oral - Nasal - Topical

46. Mucosal immunity • Why - The vast majority of pathogens enter via mucosal surfaces - Especially important for respiratory infections - Can reduce shedding at mucosal surface • Challenge - Development of vaccines the stimulate mucosal immunity - Oral and nasal delivery of vaccines

47. Topical delivery of vaccines • Principle - Topical application of vaccines has been demonstrated to induce immunity • Challenges - Inefficient antigen penetration through the skin • Possible solutions - Delivery using liposomes - Delivery using physical methods to penetrate the skin

48. Improved vaccine production • Why - Lack of vaccine production capacity - Illustrated by influenza virus vaccines - If there was an influenza virus pandemic there would not be enough vaccine to vaccinate the entire population • Challenges - Develop improved vaccine production methods using cell culture in addition to current egg production methods

49. Combination vaccines • Why - Improve compliance - Reduce the number of vaccine administrations • Challenges - Regulatory issues - Need to demonstrate safety and efficacy with the new vaccine combination

50. Single dose vaccines • Why - Generate rapid immunity - Reduce the number of vaccine administrations • Challenge - It is difficult to generate strong primary immune responses to vaccines other then live vaccines