Immunoprophylaxis and Immunotherapy

1. Immunoprophylaxis and Immunotherapy Wei Chen, Associate professor Institute of Immunology E-mail:chenwei566@zju.edu.cn

2. Objectives • 􀁺 To understand the concepts of artificial active immunization and artificial passive immunization • To know the concept and classification of vaccine. • 􀁺 To know the classification of immunotherapy and their biological materials.

3. Content • Immunoprophylaxis • Introduction • Vaccine • Immunotherapy • Molecular immunotherapy • Cellular immunotherapy • Biological response modifier and immunosuppressive agent

4. Content • Immunoprophylaxis • Introduction • Vaccine • Immunotherapy • Molecular immunotherapy • Cellular immunotherapy • Biological response modifier and immunosuppressive agent

5. Immunoprophylaxis • The goal of immunization in any one individual is the prevention of disease. The goal of immunization of populations is the eradication of disease. • Artificial active immunity Artificial passive immunity

6. （16~17世纪） 明朝 天花病人局部痂皮磨成粉 鼻吸入 预防儿童天花 中国古代“种人痘”

7. Edward Jenner (1749-1823)

8. The last known person in the world to have a natural case of smallpox. Variola minor in 23-year-old Ali Maow Maalin, Merka, Somalia CDC • In 1980, WHO announced that smallpox has been eradicated in the world.

9. Why Can we eradicate the smallpox? • No animal reservoir • Lifelong immunity • Subclinical cases rare • One serotype • Effective vaccine • Major commitment by governments

10. 自然免疫 人工免疫 被动 主动 被动 主动 Immune prophylaxis How to get immunity to the diseases ?

11. Artificial active immunization Features: 1. The production of the effect: slow ( induction phase:1-4weeks ) 2. The persistent time of immunity: long (months-years) 3. The application: specific prophylaxis 4. The agents: Ag--vaccine, toxoids

12. Artificial passive immunization Features: 1. The production of the effect: fast 2. The persistent time of immunity: short (2-3 weeks) 3. The application: treatment and urgent prophylaxis 4. The agents: Ab: antitoxin antiserum human gamma-globulin synthetic peptides anti-idiotype antibodies

13. Injecting agents: Ag (vaccines, toxids) Ab (antitoxin, antiserum) Producting time: slow (induction phase:1-4W) at once Persistenting time: long (months or years) slow (2weeks or months) The main application: specific prophylaxis urgent prophylaxis or (infectious diseases) treatment Artificial active Artificial passive immunization immunization

14. Essential requirements of vaccine

15. Agents used in active immunization • The agent used for artificial active immunization is called vaccine. • Most vaccines in use today work by inducing humoral immunity. • stimulate the development of long-lived plasma cells that produce high-affinity antibodies as well as memory B cells. • Requires help provided by protein antigen-specific CD4+ T cells.

16. The type of vaccines • inactivated vaccine (Dead vaccine ) • Live-attenuated vaccine • Toxoid • Subunit vaccine • Conjugate vaccine • Genetic engineering vaccine • Synthetic peptide vaccine • DNA vaccine • Transgenic plant vaccine

17. Agents used in active immunization • Inactivated (killed) vaccines 灭活疫苗 Standard strain of a microbe is killed and severved as an immunogen. For example: cholera vaccine (霍乱) Japanese encephalitis vaccine(乙脑) rabies vaccine (狂犬病) typhoid vaccine (伤寒)

18. Inactivated (killed) vaccines Advantages Greater stability Safety (no risk of infection) Limitations Low immunogenicity (only Ab induced, adjuvant required) Shorter immunity (multiple, booster administration required)

19. 2. Live-attenuated vaccine减毒活疫苗 Principle Imunization with attenuated (weakened) pathogen Advantages Induction of both humoral (Abs) and cellular response (CTLs) Long-lasting immunity (administered in one or two doses) Limitations Risk in immunocompromised persons Instability (termolabile)

20. Examples of live vaccines • Measles virus vaccine (麻疹病毒) • Oral Polio virus vaccine (脊髓灰质炎病毒) • bacillus Calmette-Guerin (BCG) vaccine • Typhoid vaccine (oral live attenuated bacteria) (伤寒杆菌)

21. Live attenuated vs inactivated Vaccines Jonas Salk Albert Sabin

22. Live attenuated vs inactivated Vaccines

23. 3. Toxoid类毒素 • Exotoxin can be converted into nontoxic but still immunogenic preparations called toxoid. • Examples: Diphtheria toxoid, Tetanus toxoid

24. 4. Subunit vaccine 亚单位疫苗 These vaccines are in use which make use of antigens either purified from microorganisms or produced by recombinant DNA technology. e.g. Vaccine against pertussis (acellular), tetanus and diphteria (toxoid),influenza (Hemagglutinin and Neuraminidase), hepatitis B (HBsAg) and human papilloma virus (L1 protein)

25. Subunit (antigenic) vaccines Principle Immunization with structural antigens (protein or polysaccharide) of pathogens or their products (e.g. toxoid) Advantages Same as for inactivated vaccines (greater safety) Limitations Same as for inactivated vaccines (lower immunogenecity)

26. 5. Conjugate vaccine 结合疫苗 • These vaccines are obtained by conjugating the purified polysaccharides (bacterial capsular polysaccharides) to carrier proteins such as diphtheria toxoid. • Vaccines against pneumococcus, menigococcus and H. influenzae type B (capsular polysaccharide bound to diptheria toxoid )

27. Conjugate vaccines Advantages Same as for subunit vaccines Good immune response to capsular antigens Efficient in children in the first two years of life and asplenic persons Limitations Same as for subunit vaccines Relatively high cost

28. 6. Genetic engineering vaccine 基因重组疫苗 • Recombinant antigen vaccine To clone the selected gene into a vector (yeast) →to culture→to purify the Ag from the culture supernatant→antigen • Recombinant vector vaccine To insert the desired gene into a vector (vaccinia) which can then be injected into the patient, allowed to replicate, express the gene and produce large amounts of the antigen.

29. Recombinant vector vaccine Principle Immunization with live viral vectors (e.g. vaccinia virus) with introduced genes for immunodominant peptides of different pathogens Examples Ongoing clinical trials for several vaccines (e.g. against HIV) Advantages Induction of both humoral (Abs) and cellularimmune response (CTLs) Possibility of polyvalent vaccine preparation Limitations Repeated administration not possible

31. 7. Synthetic peptide vaccine 合成肽疫苗 • Small antigens can be made synthetically. e.g. HBs vaccine.

32. 8. DNA vaccine • These are based on the discovery that when DNA encoding a chosen microbial protein is injected intramuscularly or intradermally, host cells can take up these artificial genes and express the foreign protein for several weeks. Depending on the protein expressed, this can induce specific humoral or cellular immunity, or both.

33. DNA vaccines Principle Injection of bacterial plasmid with DNA containing genes for various microbial antigenes Example Ongoing clinical trials for several pathogens Advantages Induction of both humoral (Abs) and cellularimmune response (CTLs) Simple handling, possibility of polyvalent vaccines preparation Limitations Mechanism of action and possible adverse effects not well understood

35. 9. Transgenic plant vaccine edible vaccine • Genes encoding the protective immunogens are transduced into plant cells. • Such as tomato, potato, and banana, etc.

36. New Vaccines • Mucosal vaccine • Transdermal Vaccine • Therapeutic vaccines Prime-boost strategy DNA疫苗+重组载体疫苗 DNA疫苗（重组载体疫苗）+蛋白类疫苗

37. Preventative Vaccine

38. Therapeutic Vaccine

39. Application of Vaccines • 1. Anti-infection and planned immunization • planned immunization • A rational program of immunization against infectious diseases has been committed in children worldwide when many of the most damaging and preventable infections normally appear. • The program of childhood immunization is called planned immunization.

40. Age Type of vaccine Primary Immunization Birth BCG vaccine, HBV vaccine (1st) 1 month HBV vaccine (2nd) 2 months Poliovirus vaccine (1st) 3 months Poliovirus vaccine (2nd), DTP (1st) 4 months Poliovirus vaccine (3rd), DTP (2nd) 5 months DTP (3rd) 6 months HBV (3rd), Meningococcal polysaccharide vaccine 8 months Measles virus vaccine 1 year Japanese encephalitis vaccine (1st and 2nd) Booster/ reimmunization 1.5 years DTP, Measles virus vaccine, Poliovirus vaccine, Meningococcal polysaccharide vaccine 2 years Japanese encephalitis vaccine 3 years Japanese encephalitis vaccine 4 years Poliovirus vaccine 5 years DTP, Measles virus vaccine, BCG vaccine, Meningococcal polysaccharide vaccine Planned immunization schedule in China

41. Application of vaccines 2. Anti-tumor 3. Birth control Vaccines based on the  chain of HCG, coupled to tetanus or diphtheria toxoid, have been extremely successful in preventing conception in humans. 4. Prevention of immunopathologic damage

42. Content • Immunoprophylaxis • Introduction • Vaccine • Immunotherapy • Molecular immunotherapy • Cellular immunotherapy • Biological response modifier and immunosuppressive agent

43. I. Conception and classification • Conception of immunotherapy • Immunotherapy is the approach to balance or intervene the immunologic function in order to fight against the disease by the principle of immunology. • 分子、细胞、整体水平

44. Classification of Immunotherapy

45. II. Molecular Immunotherapy 1. Molecular Vaccine • Synthetic peptide vaccine • Recombinant vector vaccine • DNA vaccine used as treatment of tumor and infection

46. II. Molecular Immunotherapy 2. Antibody-polyclonal Ab • antitoxic serum • placental gamma-globulin • antibacterial immune serum • antiviral immune serum • anti-lymphocyte gamma-globulin, ALG Von Behring (1854~1917)

47. II. Molecular Immunotherapy 3. Antibody-Monoclonal antibody, mAb • mAb against surface membrane molecules on lymphocytes：CD3 • mAb against cytokines: TNFα • mAb-directed therapy mAb coupled to isotopes, drugs, toxins

49. II. Molecular Immunotherapy 4. Antibody-Genetic engineering Ab • Chimeric Ab • Humanized Ab (CDR-grafted Ab) • Single chain Ab • Bispecific Ab