Stanley A. Plotkin ADVAC /10/2010 2:35 PM

Transcription

1 How and dwh Why Vaccines are Made Stanley A. Plotkin ADVAC /10/2010 2:35 PM 1

2 Vaccines 1. History of vaccination 2. The vaccine industry 3. Why vaccines are developed 4. The current problems of vaccinology 2

3 What is a vaccine? An inactivated or attenuated pathogen or a component of a pathogen (nucleic acid, protein) that when administered to the host, stimulates a protective response of the cells in the immune system 3

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6 Outline of the Development of Human Vaccines (1) Live Attenuated Killed Whole Purified Proteins Organisms or Polysaccharides Smallpox th Century 19 th Century Rabies 1885 Typhoid 1896 Cholera 1896 Plague 1897 BCG 1927 (Tuberculosis) Yellow Fever 1935 Early 20 th Century Pertussis 1926 (Whole Cell) Influenza 1936 Rickettsia 1938 Diphtheria 1923 Tetanus

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8 Outline of the Development of Human Vaccines (1) Live Attenuated Smallpox 1798 Rabies 1885 Killed Whole Organisms 18 th Century 19 th Century Typhoid 1896 Cholera 1896 Plague 1897 Early 20 th Century Purified Proteins or Polysaccharides BCG 1927 (Tuberculosis) Yellow Fever 1935 Pertussis 1926 (Whole Cell) Diphtheria i 1923 Influenza 1936 Tetanus Rickettsia 1938

9 Daniel Elmer Salmon ( ) 9

10 Theobald Smith ( ) 10

11 Outline of the Development of Human Vaccines (1) Live Attenuated Smallpox 1798 Rabies 1885 Killed Whole Organisms 18 th Century 19 th Century Typhoid 1896 Cholera 1896 Plague 1897 Early 20 th Century Purified Proteins or Polysaccharides BCG 1927 (Tuberculosis) Yellow Fever 1935 Pertussis 1926 (Whole Cell) Diphtheria i 1923 Influenza 1936 Tetanus Rickettsia 1938

12 Emil Adolf von Behring Nobel Prize

13 Kitasato Shibasaburo

14 Paul Ehrlich 14

15 Pierre Paul Émile Roux

16 Gaston Ramon,

17 Outline of the Development of Human Vaccines (1) Live Attenuated Smallpox 1798 Rabies 1885 Killed Whole Organisms 18 th Century 19 th Century Typhoid 1896 Cholera 1896 Plague 1897 Early 20 th Century Purified Proteins or Polysaccharides BCG 1927 (Tuberculosis) Yellow Fever 1935 Pertussis 1926 (Whole Cell) Diphtheria i 1923 Influenza 1936 Tetanus Rickettsia 1938

18 Calmette administering oral BCG vaccination 18

19 Outline of the Development of Human Vaccines (1) Live Attenuated Smallpox 1798 Rabies 1885 Killed Whole Organisms 18 th Century 19 th Century Typhoid 1896 Cholera 1896 Plague 1897 Early 20 th Century Purified Proteins or Polysaccharides BCG 1927 (Tuberculosis) Yellow Fever 1935 Pertussis 1926 (Whole Cell) Diphtheria i 1923 Influenza 1936 Tetanus Rickettsia 1938

20 Max Theiler, South African born physician. Nobel Prize

21 Outline of the Development of Human Vaccines (1) Live Attenuated Smallpox 1798 Rabies 1885 Killed Whole Organisms 18 th Century 19 th Century Typhoid 1896 Cholera 1896 Plague 1897 Early 20 th Century Purified Proteins or Polysaccharides BCG 1927 (Tuberculosis) Yellow Fever 1935 Pertussis 1926 (Whole Cell) Diphtheria i 1923 Influenza 1936 Tetanus Rickettsia 1938

22 John Enders, Frederick Robbins, Thomas Weller,

23 Outline of the Development of Live Attenuated Polio (OPV) Measles Mumps Rubella (ca) Adenovirus Typhoid Ty21a Varicella Cholera CVD103 Zoster Human Vaccines (2) Killed Whole Organisms or Subunit Post World War II Influenza Polio (IPV) Rabies (new) Anthrax Japanese encephalitis Hepatitis A Tick-borne encephalitis E. coli (+ CTB) 23

24 Maurice Hilleman

25 Robert Austrian 25

26 Outline of the Development of Human Vaccines (3) Purified Proteins or Polysaccharide Reassortants Post World War II Genetically Engineered Pneumococcus Influenza Hepatitis B recombinant Meningococcus (killed + live) Cholera toxin Hepatitis B Rotavirus (plasma derived) Pertussis toxin Hifl H. influenzae Papillomavirus i Typhoid (Vi) Pertussis (acellular) H. influenzae, pneumo, mening, (protein conjugated) 26

27 Jane Pittman 27

28 Outline of the Development of Human Vaccines (3) Purified Proteins or Polysaccharide Reassortants Post World War II Genetically Engineered Pneumococcus Meningococcus Hepatitis B (plasma derived) Hifl H. influenzae Typhoid (Vi) Influenza (killed + live) Rotavirus Hepatitis B recombinant Cholera toxin Pertussis toxin Papillomavirus i Pertussis (acellular) H. influenzae, pneumo, mening, (protein conjugated) 28

29 John Robbins 29

30 Outline of the Development of Human Vaccines (3) Purified Proteins or Polysaccharide Reassortants Post World War II Genetically Engineered Pneumococcus Meningococcus Hepatitis B (plasma derived) Hifl H. influenzae Typhoid (Vi) Influenza (killed + live) Rotavirus Hepatitis B recombinant Cholera toxin Pertussis toxin Papillomavirus i Pertussis (acellular) H. influenzae, pneumo, mening, (protein conjugated) 30

31 Herbert Boyer 31

32 Stanley Cohen 32

33 Outline of the Development of Human Vaccines (3) Purified Proteins or Polysaccharide Reassortants Post World War II Genetically Engineered Pneumococcus Meningococcus Hepatitis B (plasma derived) Hifl H. influenzae Typhoid (Vi) Influenza (killed + live) Rotavirus Hepatitis B recombinant Cholera toxin Pertussis toxin Papillomavirus i Pertussis (acellular) H. influenzae, pneumo, mening, (protein conjugated) 33

34 Ilya Ilyich Mechnikov Nobel Prize

35 Dr. Jacques Miller 35

36 Dr. Robert Good 36

37 20th Century Impact of Vaccines Vaccine- Preventable Peak Cases % Disease Cases 2006 Reduction Diphtheria i 30,508 0 Measles 763, Mumps 212,932 6,584 Pertussis 265,269 15,632 Polio (acute) 42,033 0 Polio (paralytic) 21,269 0 Rubella 488, Congenital rubella 20,000 1 Smallpox 110,672 0 Tetanus

38 Infectious Diseases in Children, August 2003, p.19, 38

39 Global Immunization , DTP3 coverage global coverage at 82% in rage g % Cove Global African American Eastern Mediterranean European South East Asian Western Pacific 39

40 Why Vaccines are Different than Drugs 1) Given to healthy people, high safety required 2) Larger governmental role 3) Low efficacy unacceptable 4) Often used in infants 5) Given once or a few times 6) Manufacturing larger part of cost 7) High regulatory and quality control burden 8) Supposed to be cheap 40

41 The BIG 5 Vaccine Manufacturers GlaxoSmithKline Merck Novartis Pfizer-Wyeth Sanofi Pasteur 41

42 Smaller Market Share or Limited Range: Baxter Crucell-Berna CSL MedImmune-AstraZeneca Serum Institute of India Avant Bioport ID Biomedical Intercell North American Biologicals RIVM Solvay Statens Serum Inst. 42

43 Producers Outside North America and Europe Japanese Local Producers: Biken, Takeda, Kitasato, Katesuken, Japan BCG Chinese Local Producers : Sinovac, Chengdu, Liao Ning, Wuhan, Dalian, Xiamen Indian Local Producers: Panacea, Bharat, Shanta, Biological E., Indian Immunologicals, Zydus Korean Local lproducers: Green Cross, LG Latin American Local Producers: Butantan, Fiocruz, Birmex, Bio-Manguinhos, Finlay Inst. Biofarma [Indonesia] Saovabha [Thailand] Razi [Iran] IVAC, Vabiotech [Viet Nam] Microgen [Russia] 43

44 Trend in Number of Vaccine Originators Worldwide, Davis, MM, et al. Vaccine in press,

45 Vaccines 6,9 B$ = 1,8 % Pharma Vaccines TOTAL Pharma : 380 B$ 45

46 Size of Vaccine Market 1992 $2.2 billion 1995 $5.4 billion 2000 $6.0 billion 2004 $7.9 billion 2006 $10.2 billion 2009 $18.0 billion 2015 $30 billion 46

47 Why is There an Increase in the Vaccine Market? New vaccines give higher profits Hib, Hepatitis B and Pneumococcal vaccines changed the paradigm of a cheap vaccine 47

48 Worldwide Vaccine Market Share (2008) Vaccines Market Share (%) (1) Others 15.0% SA 21.8% (2) Novartis 8.0% Wyeth 12.3% Merck 21.6% (2) GSK 21.2% (1) 15 B Global Market (1) Based on reported FY2008 results and sanofi-aventis internal estimates for Others (2) Includes 50% of Sanofi Pasteur MSD joint venture sales 48

49 Worldwide Vaccine Market Share (Doses) 6.3 Billion Dose Global Market 36B 3.6 sanofi pasteur 14%.9 B 1.2 B.4 B GSK 20% Others 57% Chiron 7% Merck 1% Wyeth 1% Source: WMA 2004, SP Internal Note: SP MSD sales split by origin 49

50 Reasons Why Vaccine Manufacturers Launch a Development Program 1) Market 2) Market 3) Market 50

51 How Market is Determined 1. Epidemiologic data e.g. Pneumococcal conjugate 2. Demand from consumers in developed countries e.g. Lyme Disease, Acellular Pertussis 3. Demand from authorities in developed countries e.g. Mening C 4. Expert opinion e.g. Mumps 5. Guesses, buttressed by precise but inaccurate 51 data. e.g. Hepatitis B

52 Public Health Interest t Development programs for HIV vaccines based more on this than on expectation of profit 52

53 Technical Feasibility Breakthroughs come from academia and government, and now biotech Importance of f proof of concept. An approach is useless unless it can be scaled up. e.g. vectors Mice lie, or at least exaggerate. e.g. DNA 53

54 Intellectual Property A quagmire May block development or sale e.g. Hepatitis B Lyme 54

55 Fit with Other Vaccines Combinations Travel Vaccines Syndrome Coverage e.g. Meningitis 55

56 The Road to Vaccine Development Academic and Biotech 1. Identify the mechanism of natural protection 2. Isolate the antigen(s) responsible for the protection 3. Show in animals that the vaccine protects 4. Find the best formulation of the antigen Industry 5. Increase yield and purity of vaccine 6. Show the safety of the vaccine in animals 7. Produce a lot under GMP 8. Perform Phase 1, 2, 3, 4 clinical trials 56

57 Phases of Vaccine Development Preclinical - Yield, Animal safety and Immunogenicity Phase 1 - Safety and Immunogenicity (10-100) Phase 2 - Dose, Schedule, Safety, Immunogenicity ( ) Phase 3 - Efficacy, Safety (10,000 70,000) Consistency Phase 4 - Safety (100,000 -, 1,000,000) 57

58 Estimates of Clinical Development and Approval Times Mean Time Duration in Months Study Phase Time (mo.) Preclinical NA Phase I 19.5 Phase II 29.3 Phase III 32.9 Registration, Review and Launch 16.0 Total Excluding Preclinical 97.7 (8+ Yrs.) 58

59 Estimates of Transitional and Cumulative Success Probabilities for Vaccines Transition Probability Preclinical to Phase Phase 1 to Phase II 0.72 Phase II to Phase III 0.79 Phase III to Registration 0.71 Registration to Launch 0.96 Cumulative Launch Probability Preclinical to Launch 0.22 Phase I to Launch 0.39 Phase II to Launch 0.64 Phase III to Launch Registration to Launch

60 Trend in Number of Vaccines in Development Worldwide, Davis, MM, et al. Vaccine in press,

61 The Scientific Problems of Vaccinology at the Beginning of the 21 st Century 1. Induction of long-term B cell memory both effector and central 2. Induction of cellular responses equivalent to natural immunity 3. Overcoming poor neonatal antigen processing 4. Overcoming T cell exhaustion in the elderly 5. Better induction of mucosal immunity 6. Specific adjuvants for selective stimulation of Dendritic B, CD4+, CD8+, Tregs, Th1, Th2, Th 61 17

62 Social Problems for the 21 st Century Safety and Acceptance Cost and Availability Sufficient Production 62

63 Safety Issues Less and less tolerance of reactions Higher and higher levels of regulation Fl False issues may be as costly as true issues 63

64 Critical Needs for Vaccinovigilance More epidemiologic studies of background incidence of serious events e.g. Guillain-Barré, myocarditis Phase IV studies including 1 million vaccinees 64

65 Design of Vaccines Technology is useless unless vaccines are accepted: by authorities e.g. Lyme by public HIV? by vaccinee Flumist Antivaccinationism i i Threatens vaccine coverage 65

66 For New Vaccines, Prices Can Only be Higher R&D Costs/ Risks/ Length of Development Cost of Patents Regulatory Requirements / Quality impacts Current estimate t per vaccine: $ million 66

67 Changes in Vaccine Costs for Childhood and Adolescent Immunization, CDC Catalog CDC Catalog TOTAL $33.70 $ $1, $1, $1, $1, Prices as of 10/31/06 Representative series; other choices are possible. Excise tax of $0.75 per dose per disease prevented (e.g., IPV=$0.75, DTaP=$2.25) is included. CDC and catalog includes 3 doses of HPV recommended for females, $288 and $360, respectively. 67

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69 Vaccines for Poor Countries 1. Tiered pricing 2. Local manufacture 3. Donations by rich countries or philanthropists 4. More investment by governments 69

70 Vaccine Supply Limited production facilities Large capital investment needed Need for new factories/producers in developing countries or pharmaceutical alliances 70

71 Conclusions The Vaccine industry is thriving: i interest in vaccines is high and technology is exploding. However, there are insufficient manufacturers doing research; successful development is complicated and expensive; and without the Gates Foundation, the hopes of extending vaccination to all would be limited. 71

72 Vaccinology A combination of: Microbiology Immunology Epidemiology Public Health and Pharmacy 72

73 The impact of vaccination on the health of the world s peoples is hard to exaggerate. With the exception of safe water, no other modality has had such a major effect on mortality reduction and population growth. Susan and Stanley Plotkin, A Short History of Vaccination, in Vaccines 1 st Edition,