1

How and Why Vaccines

Are Developed by Industry

Stanley A. Plotkin

Merieux 2012

2

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) Generic vaccines more difficult

3 3

Types of Vaccines

Live

Attenuated – e.g. measles, BCG

Reassortants – e.g. rotavirus, LAIV

Vectored- e.g. dengue

Inactivated

Whole microbe – e.g. rabies, IPV

Subunit – e.g. Influenza

Polysaccharide – e.g. typhoid Vi

Conjugate - e.g. pneumococcal

Toxoid – e.g. tetanus

VLP- e.g. HPV, Hep B

Proteins- e.g. pertussis

4

The BIG 5 Vaccine Manufacturers

GlaxoSmithKline

Merck

Novartis

Pfizer-Wyeth

Sanofi Pasteur

5

Smaller Market Share or Limited Range:

Astellas

Baxter Avant

Crucell-Berna Bioport

CSL ID Biomedical

MedImmune-AstraZeneca Intercell

Serum Institute of India North American Biologicals

RIVM

Solvay

Statens Serum Inst.

6

• Japanese Local Producers: Biken, Takeda, Kitasato,

Kaketsuken, Japan BCG

• Indian Local Producers: Panacea, Bharat, Shanta, Biological

E., Indian Immunologicals, Zydus

• Korean Local Producers: 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]

Producers Outside North America and Europe

7

The Growing Chinese Vaccine Industry

• 46 different companies producing 24 vaccines

• Many recently consolidated as “Sinopharm”

• Most important producers are LanZhou,

Chengdu, Wuhan, Changchun, Hualan

• Joint ventures with GSK, Novartis, Sanofi

• Already world’s largest producers

8

TOTAL Pharma : $880B in 2011*

Vaccines $18B = 2.1 %

* Source: Thompson Reuters

Pharma Fact book, 2012

WMA 2011, SP Internal

9

Projected Growth of the Vaccine Market by Adult

And Pediatric Segments

Vaccine Fact Book, 2012

Pharma, page 53

10

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

11 Vaccine Fact Book, 2012

Pharma, page 53

12

Sanofi

Pasteur

25%

Merck

32%

Pfizer

22%

Others

3%

Novartis

3%

GSK

12%

2011 Market Share

US Market €7B

Source: Internal Sanofi Pasteur World Market Analysis, derived from publicly available data

Worldwide Vaccine Market Share

(Doses)

Sanofi

Pasteur

18%

Others

24%

Pfizer

16%

GSK

22%

Merck

16%

Novartis

4%

2011 Market Share Global Market €17B

3.8 B

2.8 B

719K 3.0 B

2.7 B

4.1 B

Source: Internal Sanofi Pasteur World Market Analysis, derived from publicly available data

14

The Free market has allowed rapid growth in

Emerging Economy producers (DCVMs).

15

Why is a Vaccine

Developed by Industry ???

16

The Road to Vaccine Development

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

Academia and Biotech

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

17

What Does “Preclinical Development” Mean?

How to formulate antigen?

Is adjuvant needed?

Compatibility of antigen and adjuvant?

How to measure antigen?

How long is antigen stable?

Can yield be increased?

Toxicology and safety in animals

Standardization of immunological assays

What animal species is surrogate

for immunogenicity?

Consistency of manufacture?

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Reasons Why Vaccine Manufacturers

Launch a Development Program

1) Market

2) Market

3) Market

19

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

data. e.g. Hepatitis B

20

Public Health Interest

Development programs for HIV

vaccines based more on this

than on expectation of profit

21

Technical Feasibility

Breakthroughs come from academia and

government, and now biotech

Importance of “proof of concept.”

An approach is useless unless it can be scaled up.

e.g. vectors

Mice lie, or at least exaggerate.

22

Intellectual Property

A quagmire

May block development or sale

e.g. Hepatitis B

Lyme

23

Fit with Other Vaccines

Combinations

Travel Vaccines

Syndrome Coverage

e.g. Meningitis

24

Phases of Clinical Development

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)

25

Estimates of Clinical Development and Approval

Times Mean Time Duration in Months

Study

Phase Time (mo.)

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.)

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Cumulative Launch Probability

Preclinical to Launch 0.22

Phase I to Launch 0.39

Phase II to Launch 0.64

Phase III to Launch 0.68

Registration to Launch 0.96

Estimates of Transitional and Cumulative

Success Probabilities for Vaccines

27

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 -

$1,164.02

$1,704.13-

$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.

28

Madsen LB, et al. Perspectives 2012

Prices of Childhood Vaccines

29

For New Vaccines,

Prices Can Only be Higher

R&D Costs/ Risks/ Length of Development

Cost of Patents

Regulatory Requirements / Quality impacts

Current estimate per vaccine: $500-800 million

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Vaccines for Poor Countries

1. Tiered pricing

2. Local manufacture

3. Donations by rich countries

or philanthropists

4. More investment by governments

32

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The free market has given rise to tiered pricing

Some Examples of Technology Transfer

(RIVM)

33

Micro-carrier technology

Measles vaccine to China

Serum-free medium

Hib conjugation

Influenza vaccine in eggs

Sabin - IPV

34

Safety Issues

• Less and less tolerance of reactions

• Higher and higher levels of regulation

• False issues may be as costly as true issues

35

Critical Needs for

Vaccinovigilance

More epidemiologic studies of

background incidence of serious events

e.g. Guillain-Barré, myocarditis

Better vaccinovigilance in low income

countries

Phase IV studies including

1 million vaccinees

36

Vaccine Supply

• Limited production facilities

• Large capital investment needed

• Need for new factories/producers

in developing countries or

pharmaceutical alliances

37

Conclusions

The Vaccine industry is thriving:

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.