1

Poliovirus vaccines: Their development and use, now

and in the future

Jeffrey Almond

Vice President Discovery Researchand External R&D

sanofi pasteur

Karl Landsteiner

2

Outline

Briefly revisit OPV and IPV history

Summarize the OPV experience and progress on global eradication

Summarize IPV experience and recent developments

Conclude on future requirements and options available

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3

Polio Eradication Progress, 1988-2008

1988 / 350,000 cases estimated 2008 / 1,655 cases

Endemic with wild polio virus (4 Countries)

Certified Polio-free regions (114 countries)

Not Certified but non-endemic (73 countries)

Significant progress to control polio made over the past 20 years thanks to the Global Polio Eradication Initiative

Thanks to GPEI, >5 million people healthy today, who would have been paralyzed, had they not received polio vaccines

Thanks to GPEI, >5 million people healthy today, who would have been paralyzed, had they not received polio vaccines

Adapted from WHO GPEI communication

4

Despite sustained investment, Global Polio Eradication Initiative is facing significant challenges

>1,500 cases/year reported since 2005 leading to iterative GPEI timelines shift>1,500 cases/year reported since 2005 leading to iterative GPEI timelines shift

2971

498

1922

784

1258

1951 1996

1308

1655

1198*

0

500

1000

1500

2000

2500

3000

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Global Polio case count [2000-2009*]*As of October 20th

GPEI Annual Expenditure [1988-2008]Financial Resource Requirements, Contributions

and Funding Gap 2009 - 2013

Adapted from WHO GPEI communication

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5

Polio is still endemic in 4 countries, reflecting both “vaccination failure” and “failure to vaccinate”

While awareness/program aspects and political buy-in are at stake in AFG, PAK and

NIG, immunization strategies could be revisited in India

While awareness/program aspects and political buy-in are at stake in AFG, PAK and

NIG, immunization strategies could be revisited in India

Polio Endemic countries in 2009

INDIA

0%

20%

40%

60%

80%

100%

2003

2004

2005

2006

2007

2008

2003

2004

2005

2006

2007

2008

2003

2004

2005

2006

2007

2008

0 dose 1-3 doses 4-6 doses 7+ doses

West UP Rest of countryBihar

Polio cases despite high vaccination coverage Vaccine Failure (Poor OPV efficacy)

NIGERIA

0%

20%

40%

60%

80%

100%

2003

2004

2005

2006

2007

2008

2003

2004

2005

2006

2007

2008

2003

2004

2005

2006

2007

2008

0 dose 1-3 doses 4-6 doses 7+ doses

Rest of countryHigh risk Medium risk

Failure to vaccinate

Adapted from WHO GPEI communication

The Early daysOf Polio Vaccines

Egyptian stele (stone carving) dating bet. 1580 and 1350 B.C

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7

Poliovirus was discovered by Karl Landsteiner in 1909

In collaboration with C. Levaditi of Institut Pasteur Paris, the infectious agent was shown to be a filterable virus that could spread along nerves and be transferred between monkeys

John F. Enders and his coworkers (Weller and Robbins) discovered in 1949 a method of growing the viruses on tissue in the laboratory

.

Poliovirus

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Jonas Salk

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1st Salk Polio Vaccine

1/ Salk, Jonas & al., Federation Proc. 11:480, 1952 Immunization of Monkeys with Polioviruses grown in Cultures of Monkey Tissue

2/ Salk, Jonas & al., J.A.M.A., March 28, 1953 Studies in Human Subjects on Active Immunization Against Poliomyelitis

Type 1 : MahoneyType 2 : MEF-1Type 3 : Saukett

Inactivation : 0.4% of a 37% solution of formaldehyde USP. Test of inactivation in cynomologus monkeys by intracerebral inoculation of 0.5ml of fluid in 6 to 10 animal.

National Foundation places a $9 million order to six drug companies to start stockpiling.

10

The Francis Field Trial

On April 12, 1955, Jonas Salk, along with his mentor, Dr. Thomas Francis, and the March of Dimes announced : The Salk polio vaccine works.

On the basis of the results of the trial and the data presented by 6 manufacturers, the Salk Vaccine was licensed within a few days after these results were announced.

"Safe, effective, and potent." The Salk polio vaccine was 60-90% effective in preventing paralytic polio.

A total of 1,829,916 children in communities from all parts of the US, Canada and Finland participated. The experiment involved vaccinees, observed controls and placebo controls.

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AlbertSabin

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Hilary Koprowski had started work on an attenuated oral vaccine in 1948 at Lederle. First clinical trials were in 1950. A mass immunization campaign was organized in the Congo in 1957 with a type 1 vaccine, and soon a type 3. By 1959 over 46,000 children had been immunized with the type 1. Efficacy in that tropical setting was 60%.

Sabin started working on attenuated strains in 1953. Merck Laboratories prepared industrial lots of genetically segregated strains in 1956. Sabin convinced the Russians to try the vaccine in the Soviet Union.

In 1957 the World Health Organization (WHO) decided Dr. Sabin's vaccine deserved world-wide testing. He was invited to administer the vaccine to large groups of children in parts of Russia, Holland, Mexico, Chile, Sweden, and Japan.

1961/2 monovalent oral poliovirus vaccines (MOPV) licensed; 1962. 1963, trivalent oral poliovirus vaccine (OPV) licensed.

Sabin live attenuated Oral Poliovirus Vaccine (OPV)

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13

14

Effects of vaccination against Poliomyelitis

USA

Poliomyelitis in the USA. 1951-1978 [reproduced fromSalk, D. Rev. Infect. Dis. 1980 2, 228 by permission of the UniversityOf Chicago Press]

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15

Polio Eradication Progress, 1988-2008

1988 / 350,000 cases estimated 2008 / 1,655 cases

Endemic with wild polio virus (4 Countries)

Certified Polio-free regions (114 countries)

Not Certified but non-endemic (73 countries)

Significant progress to control polio made over the past 20 years thanks to the Global Polio Eradication Initiative

Thanks to GPEI, >5 million people healthy today, who would have been paralyzed, had they not received polio vaccines

Thanks to GPEI, >5 million people healthy today, who would have been paralyzed, had they not received polio vaccines

Adapted from WHO GPEI communication

VAPP (Vaccine associated paralytic poliomyelitis)

VDPV (Vaccine-derived Polio viruses)andLong term excretors

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17

18

10

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Table 1 Base at position 472, time of isolation, neurovirulence and temperatureSensitivity of Sabin type 3 vaccine-derived strains of poliovirus

Virus Base atposition 472

Time of isolation aftervaccination

Meanhistologicallesion score

Rctmarker

testSabin vaccine U 0.36 > 5.5 (rct

-)

DM1 U 24 H ND ND

DM2 U 31 H 1.58 6.13 (rct-)

DM3 U / C 35 H ND ND

DM4 C 47 H 2.48 5.71 (rct-)

DM38 C 18 days ND ND

DM119 C 3-4 weeks 3.34 0.25 (rct-)

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Elizabeth Minor : Recombinant Type 3 viruses

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Areas with confirmed polio cases- Haiti & Dominican Republic, 2000 - 2001

Weekly Epidemiological Record WHO 2002 ; 13, 77 : 98-108.

163 AFP cases, 21 proven to be due to cVDPV Type 1

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23 0.1

COLOMBIA 91

SOMALIA 00

SIERRA LEONE 99

ANGOLA 99

NIGER 99

NIGERIA 99GUINEA 99

CAMEROON 99LIBERIA 99

CENTRAL AFRICAN REPUBLIC 99

BANGLADESH 99

CHINA 99

AFGHANISTAN 99

PAKISTAN 00

PAKISTAN 00

LIBERIA 99

CHAD 99SUDAN 99

GUATEMALA 87

BRAZIL 88 HAITI 85

SABIN 1DOMINICAN REPUBLIC 00

HAITI 00

BANGLADESH 99

DOMINICAN REPUBLIC 80

DOMINICAN REPUBLIC 82

Relationship Between Sabin 1-Derived Isolates from Haiti and the Dominican Republic to Type 1 Wild Polioviruses

VP1 (906 nt)

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AAA

nVP2 2BVP3 VP1 3D2A 2C 3A 3C

Sabin 1-Derived Poliovirus Isolates from Hispaniola OutbreakRecombination Patterns in Non-Capsid Sequences

AAAnVP2 2BVP3 VP1 3D2A 2C 3A 3C

Sabin 1

Haiti (Port-de-Paix) Isolate (n = 1)

VP2 2BVP3 VP1 3D2A 2C 3A 3C AAAn

Dominican Republic Isolates (n = 3)

VP2 2BVP3 VP1 3D2A 2C 3A 3C AAAn

Dominican Republic/Haiti Isolates (n = 21)

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The Case of “Birmingham man”

Hypogammaglobulineamic - requires IV serum globulins for healthy life

Detected in 1996 as part of a monitoring programme (he was a control)

Poliovirus type 2 in stool appeared “vaccine-like” but substantially evolved and neurovirulent

Monitored up to present day and still infected/shedding (~150 sequential isolates). And having children.

Last vaccinated (from memory) with OPV around 1987

Long Term Excretors:

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0864geo87

0301cae80

7079ind86

3845egy911526egy89

1534ind82

6876col860176per89

0295isr78

100747-95 1

3874ind923825pak95896vtn895882vtn87

1-11-99 12

6683yug782996wse77

102050-98 4

19-1-00 13

21-3-99 728-1-99 5

Sabin 20636els91

101850-95 2107359-95 3

24-3-99 83-4-99 103-2-99 6

6-4-99 112-4-99 9

25 0% difference between sequences

Order of isolation of patient samples

Comparison of type 2 poliovirus sequences through VP1/2A junction

Patient isolates

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2.78% changes/year

0

1

2

3

4

5

6

0 150 300 450 600Time post-vaccination

(days)

Perc

enta

ge o

f cha

nges

Molecular clock for poliovirus evolution

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Neurovirulence test

MeanClinical LesionScore Score

Sabin 2 attenuated 0/4 0.27117 neurovirulent 8/8 1.80102050/98 neurovirulent 4/4 1.60

117 - virus isolated from a fatal case.

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Excretion of poliovirus type 2 by an immunodeficient patient

0

1

2

3

4

5

6

28-Jan-99

3-Feb-99

30-Mar-99

21-Mar-99

23-Mar-99

24-Mar-99

2-Apr-99

3-Apr-99

6-Apr-99

8-Apr-99

19-Apr-99

19-Apr-99

20-Apr-99

22-Apr-99

23-Apr-99

05-Aug-99

19-Jan-00

01-Mar-00

22-Aug-00

10-Jan-01

06-Apr-01

Date of Sample

Titr

e of

vir

us p

fu/m

l (lo

g)

1st dose of immunoglobulin 2nd dose of immunoglobulin

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Effect of Pleconaril on SK isolates

0

0.5

1

1.5

2

2.5

3

1µg/ml0.1µg/ml0.01µg/ml0.001µg/ml0.0001µg/ml

Concentration of pleconaril

Log

diffe

renc

e in

vir

us ti

tre

Sabin 2

10/01/01

22/08/00

102050

102893

103408

101850

101547

100747

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Titre of virus excreted during treatment with Breast milk

0.0

1.0

2.0

3.0

4.0

5.0

-20 -10 0 10 20 30 40 50 60 70Days after commencement of treatment

Viru

s ex

cret

ed (l

og p

fu/g

of fa

eces

)1710 1180

End of first round 1311 3011 2012 1812

End of second round

Breast milk batch number

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Birmingham man : The type 2 paradox

OPV use has lead to the eradication of polio type 2

BUT OPV has caused the persistence of polio type 2 in a form that (to date) cannot be eradicated

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Genetically stabilised Sabin type 3 strains S15 & S16

C G

A

U

G

GA

A C G C GC

AAUG

CU

AGGC

AGCCU

ACG

CCU

GC

GA

CG

A A C

C C A

G G U C C

C G

A

U G G C

A A UC

G C U G U

A A

A

500

490

510

520

480

530 470

U

A A

Uor

S15 S16

A A

Courtesy of A. Macadam

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Conclusions on OPV

OPV trivalent and recently monovalent have been paramount in driving the GPEI and has brought use to the brink of eradication. BUT

OPV strains can :Through replication in the gut of the vaccinees - revert directly to a virulent phenotype, causing VAPP in vaccinee (type 3) and contacts (type 2)Recombine with other enteroviruses to give neurotropic viruses of unpredictable fitness that can spread in a partially vaccinated community and cause disease (Haiti experience).Establish chronic infections in immunodeficient individuals and drift in genotype and phenotype in an unpredictable way.

Bottom line : OPV strains are live polioviruses and ultimately become part of the eradication problem. Disseminating them in a post-eradication environment (global or regional) no longer makes sense. Disseminating them in the pre-eradication environment risks the events above and should be phased out as soon as alternatives are available.

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What Role for IPV in the End Game

and beyond?

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WPV Containment& Certification

VAPP/VDPV Elim. & Verification

'Post OPV'Era

Pre-eradication will be extended as Wild Polio Virus cases continue to be reported

WHO’s Strategic Advisory Group of Experts [SAGE] on IPV immunization will issue revised guidelines on IPV use in Pre-eradication period (expected April 2010)

WHO’s Strategic Advisory Group of Experts [SAGE] on IPV immunization will issue revised guidelines on IPV use in Pre-eradication period (expected April 2010)

2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

Last WPV case

Fill mOPV stockpile Stop tOPV

Today

Stockpile maintenance

IPV ?

Adapted from WHO GPEI communication

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9 month-old Ivory Coast Children

Seronegative after 3 Doses of OPV and Then Given 1 Dose of OPV or IPV

OPV IPV

Type 1 4/28 (14%) 22/27 (81%)

Type 2 4/15 (27%) 12/12 (100%)

Type 3 2/43 (5%) 28/42 (67%)

Morinier, Lancet 1993

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Seroconversion rates for poliovirus types 1,2,3 after 3 doses of inactivated poliovirus vaccine, Puerto Rico

Day

an G

H, e

t al.

JID

195

:12-

20, 2

007

20

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WPV Containment& Certification

VAPP/VDPV Elim. & Verification

'Post OPV'Era

WHO is now foreseeing universal use of IPV in the post-erdication era and is pushing for “affordable” IPV options

In addition to its use in pre-eradication setting, IPV is to become the polio immunization pillar once WPV circulation is controlled

In addition to its use in pre-eradication setting, IPV is to become the polio immunization pillar once WPV circulation is controlled

2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

Last WPV case

Fill mOPV stockpile Stop tOPV

Today

Refine options for IPV use

Optimize IPV use

Stockpile maintenance

Pursue IPV use

Adapted from WHO GPEI communication

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Sabin IPV?

Can Sabin IPV allow new manufacturers to enter in the field of IPV manufacturing with minimal containment risk?

The manufacturing facility escape of Sabin virus leading to emergence of virulent cVDPVs still remains a risk

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IPV-Containing Combinations for Infantssp (only) Product Portfolio : complexity ...

monovalent

bivalent

trivalent

tetravalent

pentavalent

hexavalent

OPVI

mI

T Polio

DT Polio

Td Polio

DTmI

TdmIWI2I

Td5I

5mI

WI//A

2I//A

A5I

5mI//AAR2I

17 Formulations

monovalent

bivalent

t i l t

tetravalent

pentavalent

hexavalent

OPV

I

mI

T PolioDT Polio

Td PolioDTmITdmIWI

2I

Td5I

5mI

WI//A

2I//A

A5I

5mI//A AR2I

30 Filled Products

monovalent

bivalent

trivalent

tetravalent

pentavalent

hexavalent

OPV

I

mIT PolioDT Polio

Td PolioDTmITdmIWI

2I

Td5I

5mI

WI//A

2I//A

A5I

5mI//AAR2I

450 Finished Products

OPV

IPV mrc5

IPV vero

ProductPortfolio

IPV OPV

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IPV reduced schedule is promoted by WHO as a way to implement more easily IM-based vaccination programs

There is no doubt that the concept is valid from a clinical standpoint

« modern » IPV has been developed (Ag content) with the objective of having a vaccine working with 2 doses given six month apart in tropical settings

Implementing such an approach would necessitate the use of two separate vaccines

Penta (IPV-free) and hexa products to be used in mixed hexa-penta schedulesPenta (IPV-free) and IPV standalone products to be used in co-administration mode

While this approach is relevant, the programmatic constrains might be difficult versus a hexa-based program

While this approach is relevant, the programmatic constrains might be difficult versus a hexa-based program

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Supply and cost

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Single layer of Vero cells on micro beads

Electronic microscopy J. Tektoff, IM*VERO chosen with J. Salk, J. Petricciani (NIH, P. Albrecht lab.) and P. Stœckel as part of a FAIR assessment of continuously cell lines candidates for vaccine production; see Cell Substrates for Biologics Production : factors affecting acceptability in Cell Substrates , John Petricciani, BOB, FDA (Plenum Publ. 1979).

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Recent third party assessment suggests that IPV capacity will be adequate to meet demand

Salk IPV remains the most viable option and capacity will meet the post eradication worldwide demand

Salk IPV remains the most viable option and capacity will meet the post eradication worldwide demand

IPV capacity has the potential to expand to ~ 400 million doses if demand materializes

IPV demand will raise from 80 to 425 million annual doses in the post

eradication era

Source : O.WYMAN report

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Source: Department of Health, South AfricaGriffiths UK, et al. Vaccine 24:5670-5678, 2006

“Break-even” IPV prices

Polio vaccine alternative

2 doses IPV in a 10-dose vial3 doses IPV in single-dose vial3 doses IPV in 10-dose vial3 doses IPV-DTPa-Hib3 doses IPV-DTPa-Hib-hepB4 doses IPV in single dose vial4 doses IPV in a 10 dose vial

Break-even price per dose0.410.390.244.114.680.260.16

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1985 81986 101987 91988 91989 111990 61991 101992 61993 41994 81995 7 ← IPV use increasing1996 51997 5 ← IPV/OPV recommended1998 11999 0 ← IPV alone recommended

VAPP Cases in USA

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Availability of an affordable hexavalent IPV solution will be critical to ensure that polio is contained

Availability of an affordable hexavalent IPV solution will be critical to ensure that polio is contained

When seeking for an affordable IPV option, 6 in 1 combination seems the most logical solution

Currently, the vast majority of IPV is delivered through combination vaccines

Ease acceptability of additional injectionsMinimize the impact on price

IPV universal immunization via combination vaccines would provide significant benefits

Programmatic sustainability, in countries already using 5 in 1Coverage enhancement for all diseases

The success of the Hib Initiative reinforces the value of combination vaccines42 GAVI eligible countries received support for Hib introduction with pentavalent combosMore than 30 millions children will be vaccinated representing 2/3 of GAVI eligible countries birth cohort

Hib initiative benchmarck (as of May 2008) Birth cohort vaccinated (excluding India)

30 949 000

0

5000000

10000000

15000000

20000000

25000000

30000000

35000000

2000 2001 2002 2003 2004 2005 2006 2007 2008 20090%

10%

20%

30%

40%

50%

60%

70%

25

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Conclusions on IPV

IPV is very safe and highly effective.

In some highly endemic areas IPV provides protection superior to that provided by OPV

Global supply can meet global demand

Schedule changes could be accommodated if really needed

Other new developments such as Sabin IPV, ID administration and adjuvantation are late, less effective and probably not required.

Although more expensive than OPV can be readily incorporated into pediatric combination vaccines (Hexavalent) where increased cost would be modest.

IPV use does not risk VAPP, cVDPV, or establishing chronic excretors.

Can be used in post eradication setting without risking the return of virulent derivative polio strains

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Acknowledgements

For slides:E. VidorG.Galy, F.SandreP.MorgonStanley PlotkinAndrew MacadamPhil Minor

For Early work on Polio genetics:

Phil Minor et al.Geoffrey SchildAndrew MacadamRudi Hauptmann et al.And many others