Combination Vaccine within Sanofi Pasteur

Brief History and focus on Pentaxim experience

Calmet J. September 2011

The trio that made it possible Veyrier-du-Lac, 1978

Charles Mérieux

Hans Cohen Jonas Salk

The Sanofi Pasteur combination approach is enrooted in Polio, through Injectable Polio

The problem in 1975

1. Safety of OPV in question

2. Efficacy in routine immunization with 3 OPV sub-optimal in the tropics

The challenge for IPV

1. Industrialize IPV production

2. Standardize antigenicity (test in vitro)

3. Demonstrate immunogenicity and efficacy both in developed and developing countries

4. License new product in all countries

Clinical Studies were conducted in West Africa

1 – Studies of immunogenicity of IPV of different

potency, adsorbed and non-adsorbed

Poliovirus Vaccines Type 2 Type 3 Type 1

320 32 64

8 16

4 2

80

20

5 0,5 1

Adsorbed

&

Non-adsorbed

Control : TT

2 – Studies of immunogenicity of 40-4-16 followed by 40-

8-32 D-Ag units for type 1, 2 and 3 respectively

3 – Studies of immunogenicity, effectiveness and

efficacy in Kolda, Sénégal

Dr. AL. Van Wezel and Dr. A. Kaboré

in Burkina Faso on an AMP mission for

FAIR

Studies were conducted in humans to determine the best antigen dosage

Killed Poliovirus antigen titration in humans, J. Salk, H. Cohen, A.L.van Wezel, P. Stœckel & al. in 15th IABS Congress, Dev. Biol. Stan., vol 41, pp.119-132 (S. Karger, Basel, 1978) Antigen content of Inactivated Poliovirus Vaccine for use in One- or Two-dose Regimen J. Salk, P. Stœckel, AL van Wezel, K. Lapinleimu, G van Steenis In Annals of Clinical Research 14: 204-212, 1982

40, 8, 32 D-antigen unit/dose

for type 1, 2 and 3

respectively

Finland inactivated poliovirus

study

Geometric mean antibody titers

induced by a first dose of vaccines

of different D-Ag U content:

comparison of vaccines prepared

by RIVM and manufacturers B & C

Clinical efficacy of a new, enhanced-potency, inactivated poliovirus vaccine was demonstrated during an outbreak of paralytic poliomyelitis in Senegal in 1986-87

Enhanced-potency vaccine (eIPV): 40, 8, 32 D-antigen unit/dose for type 1, 2 and 3 respectively The outbreak provided an opportunity to conduct a vaccine efficacy study of e-IPV in the Kolda region where it had been used since 1980. 89 cases, confirmed to have Poliomyelitis, were enrolled in a case control study, 5 matched controls being obtained for each case

Estimates of efficacy of e-IPV* in Kolda (Sénégal)

1 dose vs 0 doses

2 doses vs 0 doses

36% (0% - 67%)

89% (62% - 97%)

The Lancet, April 23, 1988

*AMP began a pilot vaccine delivery program in the Kolda region of Senegal in 1980. AMP used the quadruple DTwP-

eIPV vaccine prepared by Institut Mérieux. The formulation for Polio type 1,2 and 3 was respectively 40-4-16 D-antigen

units per dose in 1980 & 1981, and 40-8-32 thereafter. The vaccine was delivered by mobile team using jet injectors.

56 countries have already introduced IPV in their routine pediatric public vaccination schedule

Countries that have introduced IPV as of January 2011

Sources: WHO data + sanofi pasteur internal analysis

Countries that plan to introduce IPV

[1] Adapted from Orenstein WA. In: Brown et al. Dev Biol Stand. Basel 1997

Advantages of acP Vaccines Led to Increased Use and Increased Compliance

The base of combination vaccines (DTP) is affected by a technological shift: From whole cell to Acellular Pertussis

Since nearly 30 years, sanofi pasteur has developed a wide range of IPV-containing vaccines

Vaccine Product name 1st license Volume distributed since 1st

licensure Countries were registered

IPV Imovax Polio France, 1982 Over 272 M doses Over 90 countries

DTacP-IPV

Tetraxim Sweden, 1998 Over 15M doses Over 80 countries

Quadracel* Canada, 1997 Over 6,5M doses Australia, Canada, Mexico,

New Zealand

DTacP-IPV//Hib Pentaxim Sweden, 1997 Over 100M doses Over 100 countries

Pentacel* Canada, 1997 Over 55M doses North America

DTacP-IPV-Hib Pediacel Canada, 2000 Over 30M doses Over 45 countries

TdacP-IPV Adacel Polio Germany, 2001 Over 18M doses 25 countries

Td-IPV Revaxis Germany, 1999 Over 65M doses 54 countries

*mrc5-IPV containing vaccines

Sanofi pasteur marketed IPV containing vaccines as of May 2011

• 1st licensed in Sweden in 1997

• Licensed in >100 countries

• >110 Million doses distributed to date

* Licensed under the trade name PENTAVAC® in the European Union

PENTAXIM® Experience

Countries where PENTAXIM®* is licensed

PENTAXIM® : Increasing use in National Immunization Programs

• Pentaxim® is used Private markets of 80 countries around the world.

• Past / current National Immunization Program (NIP) / Public market use includes: • Austria, Belgium, France, Germany Iceland, Italy, Ireland, Spain, Portugal, Nordic countries

• Estonia, Latvia, Lithuania, Romania, Slovenia, Ukraine

• Dutch Antilles, French Polynesia, French Guiana, Guadeloupe, Martinique, Mayotte, New Caledonia

• Recent Pentaxim® Public Markets introductions has enabled the switch from wcP/OPV to acP/IPV: • Mexico

• Turkey

• Malaysia

• South Africa

• Planned expanded use of Pentaxim® in NIP in various regions of the world

• PENTAXIM®: administered in primary series during the first year of life has been

investigated under numerous schedules: • 2-3-4 months in 5 studies in France, Turkey and China

• 2-4-6 months in 4 studies in France, Sweden, Chile and Thailand

• 3-4-5 months in the study in China

• 3-5 months in the study in Sweden

• EPI schedule (6-10-14 weeks) in India, the Philippines and S. Africa

• In addition, PENTAXIM®

• Assessed in comparison to administration of separate vaccines in 3 studies

• Co-administration of Pentaxim with Hep B vaccines was assessed in 6 studies

• Booster administered in the second year of life investigated in most studies

PENTAXIM® has been Extensively Studied in Numerous Immunogenicity and Safety Trials around the Globe

() Langue et al. ESPID, 1997 () Mallet et al. ESPID, 1997 () Reinert. ESPID, 1997 () Kanra et al. Vaccine, 2000 () Li et al. 13th APCP, 2009 () Carlsson et al.

PIDJ, 1998 () Lagos et al. PIDJ, 1998 () Thisyakorn et al. SA J TMPH, 2010 () Dutta et al. 3rd APCP, 2009

() Madhi et al. 13th ICID, 2008 () Capeding et al. Bull WHO, 2008;86(6) () SP. Study A181 IVBI/A3R08396 ()

Immunogenicity of PENTAXIM®

Primary vaccination

• All infants achieved seroprotection to diphtheria and tetanus antigens 0.01 IU/ml regardless of vaccination schedule

PENTAXIM® Provides High D & T Immune Responses Across Countries and with All Routine Vaccination Schedules

Response to Diphtheria and Tetanus antigens

post primary series (% ≥0,01 IU/ml)

100 100 100 100 100 99,4 100100

0

20

40

60

80

100

3-4-5 2-3-4 2-3-4 2-3-4 2-4-6 2-4-6 2-4-6 2-4-6

Sero

pro

tecti

on

rate

s (

%)

China Turkey France Chile Thailand Sweden

99.4 D

100 T

() Li et al. 13th Asian Pacific congress of Pediatrics, 2009 () Reinert. ESPID, 1997 () Mallet et al. ESPID, 1997

() Carlsson et al. PIDJ, 1998;17(11) () Lagos et al. PIDJ, 1998;17(4) () Thisyakorn et al. SA J Trop Med Public Health, 2010

• Seroconversion rates to PT & FHA antigens are similarly high (90.8% and 92.5% respectively) under all primary vaccination schedules

PENTAXIM® Provides High Immune Responses to PT and FHA across Countries and with All Routine Vaccination Schedules

Response to FHA antigen post primary series

(% ≥4-fold rise)

95.9 93.693.093.992.510095.999.6

0

20

40

60

80

100

3-4-5 2-3-4 2-3-4 2-3-4 2-4-6 2-4-6 2-4-6 2-4-6

Response to PT antigen post primary series

(% ≥4-fold rise)

100 98.9

100 90.8 92.4 94.1 91.393.9

0

20

40

60

80

100

3-4-5 2-3-4 2-3-4 2-3-4 2-4-6 2-4-6 2-4-6 2-4-6

Sero

co

nversio

n r

ate

s (

%)

Response to pertussis antigens post primary series

PT FHA (% 4-fold rise) (% 4-fold rise)

China Turkey France Chile Thailand Sweden China Turkey France Chile Thailand Sweden

() Li et al. 13th Asian Pacific congress of Pediatrics, 2009 () Reinert. ESPID, 1997 () Mallet et al. ESPID, 1997

() Carlsson et al. PIDJ, 1998;17(11) () Lagos et al. PIDJ, 1998;17(4) () Thisyakorn et al. SA J Trop Med Public Health, 2010

Response to Poliovirus antigens (PV1, PV2 and PV3)

post primary series (% 1/dil ≥8)

100100100100100100

0

20

40

60

80

100

3-4-5 2-3-4 2-3-4 2-3-4 2-4-6 2-4-6 2-4-6 2-4-6

Sero

pro

tecti

on

rate

s (

%)

• Seroprotection rates to all poliovirus antigens post primary vaccination are similarly high (>99%) under all vaccination schedules

China Turkey France Chile Thailand Sweden

Range 99.6-100

Range 99.3-100

PENTAXIM® Provides High Immune Responses to All Polio-viruses across Countries with All Routine Vaccination Schedules

() Li et al. 13th Asian Pacific congress of Pediatrics, 2009 () Reinert. ESPID, 1997 () Mallet et al. ESPID, 1997

() Carlsson et al. PIDJ, 1998;17(11) () Lagos et al. PIDJ, 1998;17(4) () Thisyakorn et al. SA J Trop Med Public Health, 2010

Response to PRP antigen post primary series

(% ≥0,15 µg/ml)

99.1 98 98 98 98.1 99.3 10092.2

0

20

40

60

80

100

3-4-5 2-3-4 2-3-4 2-3-4 2-4-6 2-4-6 2-4-6 2-4-6

• Seroprotection rates to PRP-T antigen are similarly high (>92.2%) under all vaccination schedules

PENTAXIM® Provides High Immune Response to PRP-T across Countries and with All Routine Vaccination Schedules

China Turkey France Chile Thailand Sweden

() Li et al. 13th Asian Pacific congress of Pediatrics, 2009 () Reinert. ESPID, 1997 () Mallet et al. ESPID, 1997

() Carlsson et al. PIDJ, 1998;17(11) () Lagos et al. PIDJ, 1998;17(4) () Thisyakorn et al. SA J Trop Med Public Health, 2010

Safety of PENTAXIM®

Sanofi Pasteur. Data in File

9.8

26.9

8.3

30.9

1.2

15.8

22.9

53.3

13.9 17.2

29.5

1.0

TETRAXIM™

DTwcP-IPV

% o

f s

ym

pto

ms

redness induration pain fever fever irritability abnormal vomiting drowsiness

[38-38.9°C] ≥39°C crying

0

10

20

30

40

50

60

70

80

11.6

4.7

21.3

34.4

9.7

23.5

DTaP-IPV vs DTwP-IPV TRIAL: France, 1989-1991 Reactogenicity Post-dose 3

% of Local and Systemic reactions following any dose of the primary series (3, 4 & 5 months of age)

DTacP-IPV Vaccine is less Reactogenic DTwP-IPV Vaccine

• The safety of Pentaxim vs Tetraxim + Hib was assessed in 2195 French infants primed at 2-3-4 and boosted at 16-24 months of age (Reinert; Clin rep) • Incidences of local reactions were similarly low in both vaccine groups

Local reactions following any dose of primary vaccination

(at 2-3-4 months) and booster (at 16-24 months)

(France 1995, 2195 infants)

0.6

11.114.4

1.1

9.512.4

3.4

23.120.4

2.9

21.418.2

0

20

40

60

80

100

Induration Redness other

Inc

ide

nc

e (

%)

() Reinert et al. ESPID, 1997; Ab. 75

Pentaxim® (n=3248 primary doses)

(n= 589 booster doses)

DTaP-IPV (n=3202 primary doses)

(n= 555 booster doses)

PENTAXIM®: As Well Tolerated As Separate Injections of DTaP-IPV and Hib

Primary Booster Primary Booster Primary Booster

Induration Redness Other

• Incidences of systemic reactions were similar in both vaccine groups

• Most fever episodes were below 39°C (fever 39°C <1.0% in both groups after primary series)

Incidence of fever increased after the booster (22.1 and 23.8% respectively)

• No HHE, seizure, nor SAE related to vaccination were detected reported after primary or booster vaccination in either group

PENTAXIM®: As Well Tolerated As Separate Injections of DTaP-IPV and Hib

() Reinert et al. ESPID, 1997; Ab. 75

Systemic reactions following any dose of primary vaccination

at 2-3-4 months of age

(France 1995, 2195 infants)

7.1

0.2

15.19.79.3 7.2

0.1

19.6

9.99.5

0

20

40

60

80

100

Fever ³38°C Drowsiness Irritability Inconsolable crying Other

Incid

en

ce (

%)

Pentaxim® (3254 doses)

DTaP-IPV (3211 doses)

Data from the 10-year Report

(1 Oct 1997 – 31 Dec 2007)

Swedish National Surveillance System

Swedish Institute for Infectious Disease

Control

Long-term impact of PENTAXIM® in the

reduction and control of pertussis in Sweden

(1997-2007)

• 1979 – withdrawal of wcP vaccine in Sweden due to safety concerns [1]

• 1996 – introduction of acP vaccines, switching from DT to DTacP at 3-5-12m; 3-dose coverage

reached 98-99% within a year. [1]

Without pertussis vaccination (1979-96), pertussis remained highly endemic in Sweden until introduction of acP vaccines

Cases of pertussis per year in Sweden [adapted from (1)]

[1] Gustafsson L, Carlsson RM. TEN YEAR REPORT – Pertussis surveillance in Sweden progress report October 1, 1997 – December 31, 2007.

Age-specific incidence of pertussis before and after introduction

of DTacP in 1996 (national cohort) [adapted from (1)]

Introduction of acellular pertussis vaccines reduced the incidence of pertussis in Sweden

• Birth cohorts after introduction of acP had a much lower age-specific incidence of pertussis than had the corresponding age-groups before introduction of acP

• The modest increase in pertussis incidence approximately 5 years after the acP doses were administered could suggest waning of protection.

[1] Gustafsson L, Carlsson RM. TEN YEAR REPORT – Pertussis surveillance in Sweden progress report October 1, 1997 – December 31, 2007.

Conclusions

• Acellular/IPV combination vaccines are well documented in terms of • Safety

• Effectiveness

• Programmatic suitability

• With more than 30 years of experience, Sanofi Pasteur can: • Provide a wide range of different combination vaccines, adapted to various scheme,

including for booster dose.

• Provide a documented effectiveness of its Pentavalent vaccine when used in national programs

• Considering the changes both in terms of epidemiology (disappearance of polio, shift in age of pertussis) and technology (switch to acellular pertussis), all parameters are in line with a safe introduction of a combination vaccine in most region of the globe as long as the region is non polio endemic and the program can be sustainably funded by the public sector.