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

How and dwh Why Vaccines are Made Stanley A. Plotkin ADVAC 1 2010 5/10/2010 2:35 PM 1

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

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

Outline of the Development of Human Vaccines (1) Live Attenuated Killed Whole Purified Proteins Organisms or Polysaccharides Smallpox 1798 18 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 1927 6

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 1927 8 Rickettsia 1938

Daniel Elmer Salmon (1850-1914) 9

Theobald Smith (1899-1950) 10

Emil Adolf von Behring 1854-1917 Nobel Prize 1901 12

Kitasato Shibasaburo 1853-1931 13

Paul Ehrlich 14

Pierre Paul Émile Roux 1853-19331933 15

Gaston Ramon, 1940 16

Calmette administering oral BCG vaccination 18

Max Theiler, South African born physician. Nobel Prize 1951 20

John Enders, Frederick Robbins, Thomas Weller, 1954 22

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

Maurice Hilleman 1919-2005 24

Robert Austrian 25

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

Jane Pittman 27

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

John Robbins 29

Herbert Boyer 31

Stanley Cohen 32

Ilya Ilyich Mechnikov Nobel Prize 1908 1845-1916 34

Dr. Jacques Miller 35

Dr. Robert Good 36

20th Century Impact of Vaccines Vaccine- Preventable Peak Cases % Disease Cases 2006 Reduction Diphtheria i 30,508 0 Measles 763,094 55 Mumps 212,932 6,584 Pertussis 265,269 15,632 Polio (acute) 42,033 0 Polio (paralytic) 21,269 0 Rubella 488,796 11 Congenital rubella 20,000 1 Smallpox 110,672 0 Tetanus 601 41 100.00 99.9 95.99 92.2 100.00 100.0 99.99 99.3 100.00 37 92.9

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

Global Immunization 1980-2008, DTP3 coverage global coverage at 82% in 2008 100 80 60 8181 82 75 71 64 68 7070 7373 7272 7272 737474 75 77 78 52 55 49 44 38 20 2325 rage g 40 20 % Cove 0 1980 2001 2002 2 2003 2004 2005 2006 2007 2008 1981 1982 1983 1984 1985 1986 1987 1988 8 1989 9 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 9 2000 0 Global African American Eastern Mediterranean European South East Asian Western Pacific 39

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

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

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

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

Trend in Number of Vaccine Originators Worldwide, 1995-2008 Davis, MM, et al. Vaccine in press, 2009 44

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

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

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

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

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

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

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

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

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

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

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

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

Phases of Vaccine Development Preclinical - Yield, Animal safety and Immunogenicity Phase 1 - Safety and Immunogenicity (10-100) Phase 2 - Dose, Schedule, Safety, Immunogenicity (100-1000) Phase 3 - Efficacy, Safety (10,000 70,000) Consistency Phase 4 - Safety (100,000 -, 1,000,000) 57

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

Estimates of Transitional and Cumulative Success Probabilities for Vaccines Transition Probability Preclinical to Phase 1 0.57 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 068 0.68 Registration to Launch 0.96 59

Trend in Number of Vaccines in Development Worldwide, 1995-2008 Davis, MM, et al. Vaccine in press, 2009 60

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

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

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

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

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

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: $500-800 million 66

Changes in Vaccine Costs for Childhood and Adolescent Immunization, 1987-2007 1987 2007 CDC Catalog CDC Catalog TOTAL $33.70 $115.99 $1,158.42 - $1,704.13- $1,164.02 $1,715.58 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

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

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

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

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

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, 1988 73