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Current status, Challenges, and Opportunities

Rodney Carbis

Head Vaccine Development

International Vaccine Institute

The Vaccine Business

BioMalaysia, 2011 Conference

Kuala Lumpur, MalaysiaNovember 21 – 23, 2011



International Vaccine InstituteMission

To promote the health of people in developing countries by thedevelopment, introduction and use of new and improved vaccines”

- From: Const i tu t ion o f IVI (1996)

Disease surveillance

Vaccine introduction

and Advocacy

Vaccinedemonstration

projects

Clinical trials

Vaccine developmentTechnology Transfer

Oral inactivatedCholera vaccine

Typhoid andparatyphoid

conjugate vaccines



The Value of Vaccines

Ali Maouw Maalin,last case of smallpox

(Somalia,1977)

3

Luis Fermín Tenorio,the last polio case in the

Americas(Peru, 1991)

Vaccines are the most cost-effective toolsfor preventing death and disability frominfectious disease.



Contrast between Vaccines and other Pharmaceuticals

Vaccines Pharmaceuticals

Focus on prevention

– not patients, but healthy people

Key role for the government agencies

Very low acceptance of side effects

Large clinical trials

5,000 to 10,000 subjects before registration

(67,000 for Wyeth’s Rotavirus vaccine)

Focus on treatment

– patient is generally sick

Key role for the doctors and pharmacists

Acceptance of side effects varies with

severity of disease

Less demanding clinical trials

2000 to 3000 subjects before registration



Contrast between Vaccines and other Pharmaceuticals

Vaccines Pharmaceuticals

High manufacturing complexity

Biological processes are difficult to

control

Supply chain complexity generally require

storage at or below 4oC

Medium manufacturing complexity

Easier to manage chemical synthesis in

most cases

Supply chain less complex, many drugs

stored at room temperature

Very few generic products

(Due to manufacturing complexity)

Increasing generic threat



World Vaccine Market

Therapeutic vaccines segment:Cancer vaccines market>US$8 billion by 2012.

No growth for EPI vaccinescontinue to since year 2003.

World Vaccines Market 2008-2013 Future Forecast,Critical Trends and Developments.

US$ 21.05 Billion in 2010 at rate of 8-9 %.Emerging markets growing at 16-17 %.Rise in adult vaccines.Increased uptake of hepatitis and influenza vaccines.



Three market segments

Market Type Clients Geographical areas Market organization

Commercial MarketBiggest markets invalue by far

Public or private Mainly for developedcountries

Strongly regulatedmarket wherecompetition exists.

Donor MarketBiggest markets indoses but low invalue

Managed byInternationalorganizations suchas WHO, UNICEF,PAHO and GAVI**

Poor or developingcountries

Mostly EPI vaccines forroutine or massimmunization

Closed market Local clients e.g. India, Indonesia,

China, Brazil, Cuba

Local producers supply

the local needs withEPI* vaccines

*Expanded program on immunization (EPI)**World Health Organization (WHO), United Nations Children’s Fund (UNICEF), Pan American Health Organization (PAHO),

Global Alliance for Vaccines and Immunization (GAVI).

Source: Bionest Partners, Exane BNP Paribas



Value and volume of vaccines2003-2004

0.71.6

11.4

13.7

0

2

4

6

8

10

12

14

16

Poor Middle Rich Total

b i l

l i o n

U S $

Countries

Value of vaccines US$

3.1

1.7

0.8

5.6

0

1

2

3

4

5

6

Poor Middle Rich Total

b i l l i o n

d o s e s

Countries

Number of doses

Most money is made in the rich countries(high profit relatively low number of doses)

Most vaccines are delivered to poor and middle income countries(low profit high number of doses)



Supply to UNICEFWHO prequalification

Most vaccines for national immunization programs in developing countries are acquired through procurement by UNICEF.

Vaccines must be prequalified by the WHO to be considered in these tenders.

Prequalification involves the National Regulatory Authority as well as the manufacturing company. Prequalification isspecific to a certain vaccine produced by a certain company. It does not mean that the company can apply for tender for allits products only those that are prequalified.

How important is prequalification:

Manufacturers ofPentavalent vaccine

CountryPrequalified

productVolume/value on theInternational market

Bharat Biotech India No

Panacea Biotech India YesUS$34.2M to UNICEF: >15Mdoses

Shantha Biotechnics India Yes US$340M contract with UNICEFfor 2010-2012

Berna Biotech/CrucellRepublic of

KoreaYes

In 2008, supplied >29M dosesthrough UNICEF/GAVI

Serum Institute India No

Biological E India No



Increasing contribution from emergingmarkets

Source: UNICEF Supply Division, 2011



Continuing contraction of the vaccineindustry

Big Pharma showing more interest in vaccines and taking positions indeveloping country manufacturers:

$68 billion acquisition of Wyeth, Pfizer is now in the vaccine business

Abbott Laboratories spent $6.6 billion to purchase flu vaccine maker Solvay

Johnson & Johnson bought 18 percent of Dutch vaccine manufacturer Crucell

GSK signed a $78 million joint venture with China's Shenzhen NeptunusInterlong Bio-Technique

Sanofi acquired a majority stake in Indian vaccine maker Shantha Biotechnics,

Novartis spent $125 million for an 85 percent stake in privately ownedChinese vaccines company Zhejiang Tianyuan

Source: Spiegel Online –Germany-

Author: By Kerry Capell Titel: The Vaccine Renaissanc e ; Published:November 25th 2009



Blockbusters in 2008Sales greater than 1 billion US$

Vaccines approved in last five years have created new markets. Theseleading products in 2008 totaled to US$10 billion

Worldwide markets more than doubled in last three years. It is forecasted thatsales will double again to US$50.7 billion by 2013.

Product Company Sales US$

Prevnar Wyeth 2.7 billion

Gardasil Merck 1.4 billion

Proquad/Varivax Merck 1.3 billion

Infantrix GSK 1.3 billionPolio/whoopingcough/Hib vaccines

Sanofi Pasteur 1.1 billion

Influenza Sanofi Pasteur 1.1 billion

Hepatitis Vaccines GSK 1.2 billion

www. pipeline review. com . LaMerie Biologic Report Recommendation: The new vaccines



Vaccine Development1910-2010



List of vaccine preventable diseases



TrendsCombination vaccines

3 valent DTwP

4 valent DTwP-Hep B5 valent DTwP-Hep B-Hib6 valent DTaP-Hep B-Hib-IPV

Measles combination vaccine1 valent Measles3 valent Measles/Mumps/Rubella

To reduce the number of vaccinations children receivevaccines are increasingly becoming multivalent.



TrendsMultivalent vaccines

Protect against more strains.Differentiation of one companies product from another to gainmarket advantage.

Rotavirus

Rotarix (GSK) 1 strain G1[P8]Rota Teq (Merck) 5 strains G1,G2, G3, G4, [P7, P1A]

HPVGardasil (Merck) types 16, 18, 6 and 11Cervarix (GSK) types 16 and 18

Pnuemococcal conjugatePrevnar (Wyeth now Pfizer) - (originally 7 valent)Prevnar 13 (Wyeth now Pfizer) - (now 13 valent)

Synflorix (GSK) contains 10 strains



TrendsSafety

Oral Live attenuated polio vaccine (OPV) has been replaced by the inactivatedpolio (IPV) in industrialized countries. Issues with reversion to virulence withone of the three strains in the OPV

Whole cell pertussis (wP) which is reactogenic has been replaced with acellular pertussis (aP) in industrialized countries. Currently aP is too expensive forroutine use in developing countries.

Single use auto-disable syringes so that syringes cannot be reused.

Preservatives such as thiomersal being excluded from formulations (particularlysingle dose presentations)

Increased emphasis on safety



TrendsManufacturing

Stronger emphasis on Validation

Use of single use technologies hassimplified validation.

Single use technologies are easier toinstall and facilitate earlier time tomarket than conventional equipment



ChallengescGMP compliance

Vaccine manufacturers must comply with current Good Manufacturing Practice(GMP), keeping track of the latest guidelines is time consuming and difficult.

cGMP is a part of the quality system used in the manufacturing, testing anddevelopment of vaccines

Companies who fail inspections can expect to facepenalties. Fines and product bans are common butoften most damaging is the loss of consumerconfidence in the product.



ChallengesLimited manufacturing capacity

Very little surge capacity as redundant capacity is costly, long timelines torespond to increased demand.

For many vaccines there are only one or two producers.

Demand for pediatric vaccines is predictable and is related to the birth cohort.

Lack of capacity creates vulnerabilities should demand suddenly increase suchas occurred during the 2009-10 H1N1 outbreak.



Challenges

As disease is controlled by vaccination the need for vaccination is less obvious.

Pressure from anti vaccine groups can also reduce vaccine acceptance andcoverage.

Complacency can lead to re-emergence of disease as occurred in Russia in the1990s



Adjuvants

Aluminum salts were first used in the 1920s.New adjuvants introduced in the last decade.

An immunologic adjuvant acts to accelerate, prolong,or enhance antigen-specific immune responses whenused in combination with specific vaccine antigens

AdjuvantName

Class Company Indications Status

Alum Mineral salts Various Various Marketed (EU, USA)

MF59® Oil-in-water emulsion Novartis Influenza Marketed (EU)

AS03 Oil-in-water emulsion GSK Influenza Marketed (EU)

AS04 Alum + TLR4 antagonist GSKHepatitis B, human

papillomavirusMarketed (EU, USA)

AS01 Liposome, MPL, QS-21 GSK Malaria Phase 3



Stabilization

Storage of vaccines is costly, generally require refrigeration

Experience with monovalent H1N1 vaccine for the 2009/2010 season.

Significant losses due to expiry of product.- US: 71 out of 162 million doses.

- Australia: 9.7 out of 19 million doses.

Vaccine recall due to inadequate stability.- 13 lots of live attenuated H1N1 influenza.

- One lot split H1N1 pediatric vaccine (800,000 doses).

Substantial amount of work being doneon developing more stable formulationsto reduce product loss and reduce thedependence on the cold chain



FuturePhase III vaccines in development

Disease Company Drug NameSmoking addiction Nabi Biopharmaceuticals NicVAX

Grass Allery ALB Abello GRAZAX

Grass Allery Allergy Therapeutics Pollinex Quattro Grasses

Ragweed Allergy Allergy Therapeutics Pollinex Quattro Ragweed

Grass Allery Fornix Biosciences Oralgen Grass Pollen

Grass Allery Greer Labs Sublingual-oral immuno-therapy

Grass Allery Paladin Labs Oralair Grasses

Pollen Allergy Schering-Plough/Merck Allergy Immunotherapy Tablet

Dengue Sanofi Pasteur ChimeriVax

Diabetes Diamyd Medical DiamydETEC infection Intercell Traveler's Diarrhea vaccine patch

Herpes virus GlaxoSmithKline Simplirix

Leishmaniasis Tehran University of Medical Sciences Alum-ALM

Malaria GlaxoSmithKline Mosqurix

Shigellosis NICHHD, NIH N/A



Other interesting disease targetsVaccines currently in phase II trials

Disease Clinical development phase

Alzheimer's Phase II

Ebola Phase II

Hepatitis C Phase II

Hypertension Phase II

HIV/AIDS Various phases

MRSA(Methicillin-resistant Staphylococcus aureus)

Phase II

Multiple Sclerosis Phase II

Obesity Preclinical

Cancer Many in various stages of development

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Thank you

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