the genetics of polio eradication - meduni wien · the genetics of polio eradication ... certified...

1

The Genetics of The Genetics of Polio EradicationPolio Eradication

Olen KewOlen KewDivision of Viral DiseasesDivision of Viral Diseases

Centers for Disease ControlCenters for Disease Control––AtlantaAtlanta

•• Background, molecular epidemiologyBackground, molecular epidemiology•• Eradication milestonesEradication milestones

OverviewOverview

Eradication milestonesEradication milestones–– Genetic indicators of progressGenetic indicators of progress

•• Current challengesCurrent challenges–– Countries with unbroken wild poliovirus (WPV) Countries with unbroken wild poliovirus (WPV)

endemicityendemicityReinfected countriesReinfected countries

2

–– Reinfected countriesReinfected countries•• VaccineVaccine--derived polioviruses (VDPVs)derived polioviruses (VDPVs)

–– cVDPVscVDPVs–– iVDPVsiVDPVs

2

AAAnVP2 2BVP3 3D2A 2C 3A 3CVP4 VP1

5´-UTR P1/CAPSID P2/NONCAPSID P3/NONCAPSID 3´-UTR

Poliovirus Genomic OrganizationPoliovirus Genomic Organization

• Single ORF, "polyprotein" proteolytically processed

• Single-stranded RNA genome (~7500 nt) has mRNA polarity

0 1 2 3 4 5 6 7kb

• Recombination between capsid/noncapsid regions

• VP1 gene (~900 nt) sequences used for molecular epidemiologic surveys; wider windows (up to complete genomes) for high-resolution analyses

•• Three serotypes: PV1 PV2 PV3Three serotypes: PV1 PV2 PV3

Epidemiologic Properties of Epidemiologic Properties of Wild Polioviruses (WPVs)Wild Polioviruses (WPVs)

•• Three serotypes: PV1, PV2, PV3Three serotypes: PV1, PV2, PV3

•• Paralytic attack rate: PV1>PV3>PV2Paralytic attack rate: PV1>PV3>PV2

–– PV1: ~1 case/200 naPV1: ~1 case/200 naïïve infectionsve infections

–– PV2: ~1 case/1000 naPV2: ~1 case/1000 naïïve infectionsve infections

–– PV3: <1 case/1000 naPV3: <1 case/1000 naïïve infectionsve infections

•• Transmissibility: PV1>PV2, PV3Transmissibility: PV1>PV2, PV3

•• ""NaturalNatural"" prevalenceprevalence: PV1>PV3>PV2: PV1>PV3>PV2

3

•• Stability of Stability of attenuatedattenuated phenotype: PV1>PV2, PV3phenotype: PV1>PV2, PV3

Biological Properties of Biological Properties of Sabin OPV StrainsSabin OPV Strains

•• Replicative fitness in gut: PV2>PV1>PV3Replicative fitness in gut: PV2>PV1>PV3

•• Immunogenicity: PV2>>PV1>PV3Immunogenicity: PV2>>PV1>PV3

•• Secondary Spread: PV2>PV3>PV1Secondary Spread: PV2>PV3>PV1

•• cVDPV emergence: PV2>>PV1>PV3cVDPV emergence: PV2>>PV1>PV3

•• iVDPV emergence: PV2>PV1, PV3iVDPV emergence: PV2>PV1, PV3

•• Eradication order (tOPV): PV2Eradication order (tOPV): PV2→PV3→PV1→PV3→PV1

•• Eradication of WPV2Eradication of WPV2•• Certification of three WHO Regions (AMR, 1994;Certification of three WHO Regions (AMR, 1994;

Eradication MilestonesEradication Milestones

Certification of three WHO Regions (AMR, 1994; Certification of three WHO Regions (AMR, 1994; WPR, 2000; EUR, 2002)WPR, 2000; EUR, 2002)–– Regional WPV certifications have stood test of timeRegional WPV certifications have stood test of time

•• Eradication of indigenous WPV1 and WPV3 in Eradication of indigenous WPV1 and WPV3 in very challenging settings:very challenging settings:–– Very high biological risk (Bangladesh, Egypt,…)Very high biological risk (Bangladesh, Egypt,…)

6

e y g b o og ca s ( a g ades , gyp , )e y g b o og ca s ( a g ades , gyp , )–– Conflict countries (Somalia [twice!], Angola, Sudan,…)Conflict countries (Somalia [twice!], Angola, Sudan,…)–– Poor infrastructure (most of subPoor infrastructure (most of sub--Saharan Africa, Saharan Africa,

Yemen, Cambodia,…)Yemen, Cambodia,…)•• Platform for other immunization initiativesPlatform for other immunization initiatives

4

19881988350 000 cases350 000 cases

Progress Since 1988 WHA Resolution Progress Since 1988 WHA Resolution to Eradicate Polioto Eradicate Polio

125 countries125 countries

2009 (YTD)2009 (YTD)

~40 cases/hr~40 cases/hr

1337 cases1337 cases1051 1051 -- 4 “endemic” countries4 “endemic” countries286 286 -- 23 reinfected countries23 reinfected countries

* Data as of 15 May 2008Data as of 12 November 2009

Certified polioCertified polio--freefree

ReinfectedReinfectedContinuously endemicContinuously endemic

Polio Eradication ProgressPolio Eradication ProgressEstimated and Reported Polio Cases, 1985Estimated and Reported Polio Cases, 1985––20092009

1997: Last Case fromWild Type 2 Poliovirus

Uttar Pradesh, India

1988: WHA Resolution to

Eradicate Polio

200

300

400

er (t

hous

ands

)

WPREUR

AMR2000: Original Target

Date for Interruption of Transmission

(134

,000

)

0)000)

,000

),0

00)

(137

,000

)

0

100

Num

be

1985

1987

1989

1991

1993

1995

1997

1999

2001

2003

2005

2007

2009

Reported EstimatedSource: WHO/IVB database

192 WHO Member States.

1337

1997

1979

560

1255

1922

784

(200

0)(1

0,00

0)(1

0,00

0)(1

8,00

0)(3

3,00

0(6

0,0

(75,

(76

1651

1315

5

Wild Poliovirus*, 11 Nov 2008 Wild Poliovirus*, 11 Nov 2008 –– 10 Nov 200910 Nov 2009

*Excludes viruses detected from environmentalsurveillance and vaccine derived polioviruses

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. © WHO 2009. All rights reserved

Case or outbreak following importation (0 - 6 months)Endemic countries

Case or outbreak following importation (6 - 12 months)

Wild virus type 1Wild virus type 3Wild virus type 1/3

Data in WHO HQ as of 10 Nov 2009

•• Rapid poliovirus screening methods used in WHO Global Rapid poliovirus screening methods used in WHO Global Polio LabNetPolio LabNet

Global Poliovirus SurveillanceGlobal Poliovirus Surveillance

•• All WPV and VDPV isolates sequenced (VP1)All WPV and VDPV isolates sequenced (VP1)

•• Phylogenetic trees/maps sent to WHO monthlyPhylogenetic trees/maps sent to WHO monthly

•• Trees reflect current conditions (Trees reflect current conditions (≤60 days after case)≤60 days after case)

•• Phylogenetic analysis used to distinguish Phylogenetic analysis used to distinguish ""source source reservoirs" from nonreservoirs" from non--reservoir reservoir ""indicator communitiesindicator communities""

•• Sequence data used to drive eradication Program (target Sequence data used to drive eradication Program (target reservoirs) and identify surveillance gapsreservoirs) and identify surveillance gaps

6

Global Polio Laboratory Network, 2009Global Polio Laboratory Network, 2009

Specialized Reference LaboratoryRegional Reference LaboratoryNational/ Sub-national Laboratory

n=144

•• Declining genetic diversityDeclining genetic diversity

•• Disappearing genotypes (>15% nt divergence)Disappearing genotypes (>15% nt divergence)

Genetic Indicators of EradicationGenetic Indicators of Eradication

–– Genotypes distributed geographicallyGenotypes distributed geographically

•• Disappearing clusters (~5% nt divergence)Disappearing clusters (~5% nt divergence)

–– Clusters are geographically localized (spotClusters are geographically localized (spot--mapped)mapped)

Di i li (Di i li ( h i f t i ih i f t i i ))•• Disappearing lineages (Disappearing lineages (≈chains of transmission≈chains of transmission))

–– Surviving lineages stretch over increasingly wide Surviving lineages stretch over increasingly wide geographic areasgeographic areas

–– Competing lineages goneCompeting lineages gone

7

India/99

Vietnam/89

STOP

STOP

Eradication of Wild Type 2 GenotypesEradication of Wild Type 2 Genotypes

Côte d’Ivoirie/94STOP

0.1

Sabin 2

Peru/89STOP

Type 2 Wild Poliovirus Genotypes:Type 2 Wild Poliovirus Genotypes:19791979––19991999

STOP 99STOP 79

STOP 94STOP 89

Genotypes Eradicated, YearSTOP

STOP89

SOURCE: WHO POLIO LABNET

8

Mexico/90Pakistan/09India/09

Sabin 3Nigeria/09

DR Congo/09

STOP


Sudan/04

Somalia/02

Turkey/90

Philippines/93Egypt/00

Vietnam/93

Colombia/88STOP

STOP

STOP

STOP

STOP

STOP

Brazil/88

Syria/91

Indonesia/95

Turkmenistan/90 China/93

Colombia/88

Angola/00STOP

STOPSTOP

STOP

STOP

STOP

STOP


STOP 88

STOP90STOP 88

STOP 92

STOP 95

STOP 93

STOP 00

STOP 93

STOP 02

STOP 04

STOP 95STOP 90

STOP 91

Endemic/Epidemic GenotypeNo Known Endemic GenotypesGenotypes Eradicated, YearSTOP

88


STOP8695

STOP 00

9

China/94

India/09

Nigeria/01Nigeria09 Afghanistan/09

Angola/09

Sudan/09STOP STOP

Eradication of Wild Type 1 Genotypes

China/93

Guatemala/87

Indonesia/95

South Africa/89

Zambia/02

Philippines/93

Brazil/88

STOP

STOP

STOP

STOPSTOP

STOP

STOP

Somalia/00Ethiopia/01

Iraq/00 Vietnam/92

Sabin 1

Peru/91

Tunisia/85

Myanmar/96

Egypt/04STOPSTOP

STOP

STOP

STOP

STOP

STOP

STOP


STOP 97STOP87

STOP 93

STOP 89 STOP 95

STOP 94STOP 95

STOP 96

STOP 01

STOP 85

STOP 00

STOP 93STOP 04

STOP 01

STOP 00


STOP91STOP 89 95

STOP 89

STOP 97

Endemic/Epidemic GenotypeNo Known Endemic GenotypesGenotypes Eradicated, YearSTOP

STOP 02

10

Mexico/90Pakistan/09India/09

Sabin 3Nigeria/09

DR Congo/09

STOP


Sudan/04

Somalia/02

Turkey/90

Philippines/93Egypt/00

Vietnam/93

Colombia/88STOP

STOP

STOP

STOP

STOP

STOP

Brazil/88

Syria/91

Indonesia/95

Turkmenistan/90 China/93

Colombia/88

Angola/00STOP

STOPSTOP

STOP

STOP

STOP

STOP

Eradication of WPV3 from Egypt, 1994Eradication of WPV3 from Egypt, 1994––20002000VP1 Sequence Relationships

STOP

Year

11

•• Natural evolution rate:Natural evolution rate:

–– ~1%/yr; clocklike accumulation of nt substitutions (sub)~1%/yr; clocklike accumulation of nt substitutions (sub)

11 2 b/ k (f ll )2 b/ k (f ll )

Poliovirus Molecular ClocksPoliovirus Molecular Clocks

–– 11––2 sub/week (full genome)2 sub/week (full genome)

–– ~1 sub/6 weeks (VP1; routine global PV surveillance)~1 sub/6 weeks (VP1; routine global PV surveillance)

•• Multiple molecular clocks (~30Multiple molecular clocks (~30--fold fold ""ticktick"" range)range)

–– Fast clocks:Fast clocks: highhigh--resolution molecular epidemiologyresolution molecular epidemiology

•• Dating recent importations, VDPV emergencesDating recent importations, VDPV emergences

•• PV genomic evolution in individualsPV genomic evolution in individuals

–– Slower clocks:Slower clocks: deeper evolutionary relationshipsdeeper evolutionary relationships

•• Dating older importations, VDPV emergences (>15 yr)Dating older importations, VDPV emergences (>15 yr)

Poliovirus Capsid Region Molecular ClocksPoliovirus Capsid Region Molecular Clocks

Synonymous SubstitutionsSynonymous Substitutions

Nonsynonymous SubstitutionsTotal SubstitutionsTotal Substitutions

Synonymous Transversions

Synonymous TransitionsSynonymous Transitions

12

•• Four countries have never eradicated Four countries have never eradicated indigenous WPV genotypesindigenous WPV genotypes

Challenges: Endemic CountriesChallenges: Endemic Countries

g g ypg g yp•• Key reasons differKey reasons differ

–– India:India: very high biological risks, large birth very high biological risks, large birth cohorts, low OPV immunogenicity, migrationcohorts, low OPV immunogenicity, migration

–– Afghanistan:Afghanistan: Active conflict, insecurity, hardActive conflict, insecurity, hard--toto--reach populationsreach populationsreach populationsreach populations

–– Pakistan:Pakistan: Conflict areas, epidemiologic linkage to Conflict areas, epidemiologic linkage to Afghanistan, local operational gapsAfghanistan, local operational gaps

–– Nigeria:Nigeria: low OPV coverage in northern states, low OPV coverage in northern states, political impediments, local operational gapspolitical impediments, local operational gaps

•• Key reservoirs: Uttar Pradesh (UP) (~180 Key reservoirs: Uttar Pradesh (UP) (~180 million), Bihar (~100 million)million), Bihar (~100 million)

UP + Bihar birth cohort : 500 000/monthUP + Bihar birth cohort : 500 000/month

Northern IndiaNorthern India

–– UP + Bihar birth cohort : ~500,000/monthUP + Bihar birth cohort : ~500,000/month–– Lower per dose efficacy of OPVLower per dose efficacy of OPV

•• Hyperendemic in 1998 (WPV1, 2, 3)Hyperendemic in 1998 (WPV1, 2, 3)–– Most clusters eradicatedMost clusters eradicated–– Both UP and Bihar have stopped WPV1 Both UP and Bihar have stopped WPV1

t i i ( i t it i i ( i t i f WPV1)f WPV1)transmission (migrants, pingtransmission (migrants, ping--pong of WPV1)pong of WPV1)•• WPV3 reduced to four lineages in 2005WPV3 reduced to four lineages in 2005

–– WPV3 expansion with emphasis on mOPV1WPV3 expansion with emphasis on mOPV1•• Decreasing WPV1 genetic diversityDecreasing WPV1 genetic diversity

13

Wild Poliovirus, India, 2008Wild Poliovirus, India, 2008––0909

P1= 67P3=462

20082008P1= 75P3= 484

2009*2009*

2000

0

250

500

750

1000

1250

1500

1750

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

*

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WPV1 – Sewage 2008WPV1 – 2009

WPV1 – Sewage 2009

*as of 26th Oct, 2009

14

20072006

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Disappearing WPV1 Clusters, India, 2006Disappearing WPV1 Clusters, India, 2006––0909

Grey 1 Grey 189 29 Grey 1 2

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*as of 26th Oct, 2009SOURCE: Enterovirus Research Centre, Mumbai

•• Widespread WPV 1, 2, 3 circulation in 1998Widespread WPV 1, 2, 3 circulation in 1998–– Multiple clustersMultiple clusters

M t WPV1 d WPV3 l t di t dM t WPV1 d WPV3 l t di t d

Pakistan/AfghanistanPakistan/Afghanistan

•• Most WPV1 and WPV3 clusters eradicatedMost WPV1 and WPV3 clusters eradicated•• Active conflict, attacks on UN staff, facilities, Active conflict, attacks on UN staff, facilities,

vehicles (especially AFG)vehicles (especially AFG)•• Residual endemicity in conflict areas (south Residual endemicity in conflict areas (south

and along shared border in north)and along shared border in north)g )g )•• Single epidemiologic blockSingle epidemiologic block

–– Migrating populations carry WPV from endemic Migrating populations carry WPV from endemic zones to poliozones to polio--free communitiesfree communities

–– Gradual decline in WPV genetic diversityGradual decline in WPV genetic diversity

15

WPV1 Pakistan/Afghanistan,WPV1 Pakistan/Afghanistan,20082008––0909

20092008

•• Wide “immunity gaps” in northern statesWide “immunity gaps” in northern states–– Poor routine immunizationPoor routine immunization–– Low OPV coverage in mass campaignsLow OPV coverage in mass campaigns

Northern NigeriaNorthern Nigeria

•• Indigenous polioviruses eradicated by 2003 from Indigenous polioviruses eradicated by 2003 from more populous (highmore populous (high--risk) southrisk) south

•• Widespread, continuous WPV1 and WPV3 Widespread, continuous WPV1 and WPV3 circulation in northcirculation in north–– AntiAnti--OPV rumorsOPV rumors

•• Major WPV exportationsMajor WPV exportationsj pj p–– WPV1: 2003, north, west, east; 2008, north, westWPV1: 2003, north, west, east; 2008, north, west–– WPV3: 2008, eastWPV3: 2008, east

•• Revitalized national commitment, 2009Revitalized national commitment, 2009•• Biological risks only moderate: expanding WPV Biological risks only moderate: expanding WPV

diversity can be stopped by good OPV coveragediversity can be stopped by good OPV coverage

16

Decreasing WPV1 DiversityDecreasing WPV1 DiversityNigeria, 2008Nigeria, 2008––0909

•• Poor infrastructure (most)Poor infrastructure (most)•• Ongoing or recent conflict (Chad, Sudan,Ongoing or recent conflict (Chad, Sudan,

Challenges: ReChallenges: Re--infected Countriesinfected Countries

Ongoing or recent conflict (Chad, Sudan, Ongoing or recent conflict (Chad, Sudan, Somalia, Angola, DR Congo, …)Somalia, Angola, DR Congo, …)

•• National immunization programs fragileNational immunization programs fragile•• Inattention to polio after first successful Inattention to polio after first successful

nationwide controlnationwide control–– Widening immunity gapsWidening immunity gaps–– Surveillance gaps (“orphan” lineages)Surveillance gaps (“orphan” lineages)

•• Adjoin endemic areas (Chad, Nepal, …)Adjoin endemic areas (Chad, Nepal, …)

17

Wild Poliovirus*, 11 Nov 2008 Wild Poliovirus*, 11 Nov 2008 –– 10 Nov 200910 Nov 2009

Indigenous Poliovirus

Int'l Spread of Polio

from Nigeria (& Chad, Sudan)

*Excludes viruses detected from environmentalsurveillance and vaccine derived polioviruses

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. © WHO 2009. All rights reserved

Case or outbreak following importation (0 - 6 months)Endemic countries

Case or outbreak following importation (6 - 12 months)

Wild virus type 1Wild virus type 3Wild virus type 1/3

Data in WHO HQ as of 10 Nov 2009

from India (& Angola)

Nigerian WPV1 Moves WestNigerian WPV1 Moves West

18

Nigerian WPV1 Moves WestNigerian WPV1 Moves West

Nigerian WPV3 Moves EastNigerian WPV3 Moves East

19

Kano Root, 2001Kano to Borno, 01-02

NIE to CAF, 2003NIE to CAE, 2003NIE to CHA, 2003

CHA to SUD-WDA, 2007

CHA to SUD-WDA, 2004

SUD RED to ETH 2004 05

SUD to SAA, 2004SAA to INO, 2004-05

SUD-RED to ERI, 2004-05

SUD-RED to ETH, 2004-05

SUD to YEM, 2004-05

SOM to KEN, 2006

SUD to SAA, 2004

Last SOM WPV1 isolate, 2007

SUD + ETH, CommonReservoir (2004)-08

to SUD-RED, 08-09

YEM to SOM, 2005

Undetected WPV1Transmission, 2004-08

SOM to ETH, 2005-06

SUD to [EGY], 08SUD to UGA, 2008-09

SUD to KEN, 08-09Current

•• Continued use of OPV carries continued risksContinued use of OPV carries continued risks–– 250250––500 cases of500 cases of VAPPVAPP/yr worldwide/yr worldwide

OPVOPV--Derived Viruses are PoliovirusesDerived Viruses are Polioviruses

250250 500 cases of 500 cases of VAPPVAPP/yr worldwide/yr worldwide–– Excretion of virulent derivatives by many healthy Excretion of virulent derivatives by many healthy

OPV recipientsOPV recipients–– cVDPVcVDPV outbreaks in areas with low coverageoutbreaks in areas with low coverage–– Chronic Chronic iVDPViVDPV infections among a subpopulation infections among a subpopulation

of persons with defects in Ab production (primaryof persons with defects in Ab production (primaryof persons with defects in Ab production (primary of persons with defects in Ab production (primary immunodeficiencies)immunodeficiencies)

•• Polio eradication means cessation of all Polio eradication means cessation of all poliovirus circulation (infection)poliovirus circulation (infection)

20

AAAnVP2 2BVP3 3D2A 2C 3A 3C

5'-UTR CAPSID NONCAPSID 3'-UTR

VP4 VP1

Attenuating Substitutions in Sabin OPV StrainsAttenuating Substitutions in Sabin OPV Strains

C2909U

T1143I

G481A

SABIN 2

I1006TS3091FSABIN 3

G2795AA480G U6203C

A4065S L3225M

G935U

A1106T

U2438A

Y3D073H

C2879U

L1134FSABIN 1

0 1 2 3 4 5 6 7kb

U2493CC472U C2034U

Circulating VaccineCirculating Vaccine--Derived PoliovirusDerived PoliovirusOutbreaks, 1988Outbreaks, 1988––20092009

Type 21988-93

30 CasesType 12000-01

21 Cases

Type 3

Type 12001

3 Cases

Type 12004

2 Cases

Type 22008 09

Type 12006-075 Cases

Type 22005-09

>300 Cases

Type 2Type 12005

46 Cases

yp2005-062 Cases

Type 22001-025 Cases

20053 Cases

Type 32005

1 Case7 Contacts

2008-094 Cases

Type 22005-09

20 Cases


21

20082007

Type 2 cVDPV Outbreaks, Nigeria, 2007Type 2 cVDPV Outbreaks, Nigeria, 2007––20092009

Sep-Oct 20092009

ImmunodeficiencyImmunodeficiency--Associated VaccineAssociated Vaccine--DerivedDerivedPoliovirus Isolates, 1962Poliovirus Isolates, 1962––20092009

SOURCE: WHO POLIO LABNETType 3Type 2Type 1

22

•• WPV genotypes eradicated since 1985:WPV genotypes eradicated since 1985:–– All WPV2 (4/4)All WPV2 (4/4)

82% f WPV3 (14/17)82% f WPV3 (14/17)

SummarySummary

–– 82% of WPV3 (14/17)82% of WPV3 (14/17)–– 85% of WPV1 (17/20)85% of WPV1 (17/20)

•• Decreasing genetic diversity within most Decreasing genetic diversity within most genotypesgenotypes–– Disappearing clusters and lineagesDisappearing clusters and lineages

M j h llM j h ll•• Major challenges:Major challenges:–– Operations in conflict areasOperations in conflict areas–– Widening immunity gaps in some polioWidening immunity gaps in some polio--free countriesfree countries–– Continuing emergence of cVDPVs and iVDPVsContinuing emergence of cVDPVs and iVDPVs–– Developing/implementing safe endgame strategiesDeveloping/implementing safe endgame strategies

AcknowledgmentsAcknowledgmentsWHOWHO--GPLNGPLNEsther de Gourville Esther de Gourville Humayun AsgharHumayun Asghar

CDCCDCCara BurnsCara BurnsJane IberJane Iber Humayun AsgharHumayun Asghar

Sohail ZaidiSohail ZaidiNicksy GumedeNicksy GumedeFestus AduFestus AduJagadish DeshpandeJagadish Deshpande

Jane IberJane IberQi ChenQi ChenJing ShawJing ShawElizabeth HendersonElizabeth Henderson

Jaume JorbaJaume JorbaDave KilpatrickDave Kilpatrick

WHO/HQ and RegionsWHO/HQ and Regions

National and WHO PolioNational and WHO PolioSurveillance Officers Surveillance Officers

SuSu--Ju YangJu YangPaul ChenowethPaul ChenowethMark PallanschMark PallanschA.J. WilliamsA.J. WilliamsNaomi DybdahlNaomi Dybdahl--SissokoSissoko

23

Thank You!Thank You!

24

2000

2250 mOPV1

Wild Virus Polio Cases by Serotype, 2001Wild Virus Polio Cases by Serotype, 2001––20092009

750

1000

1250

1500

1750

0

250

500

2001 2002 2003 2004 2005 2006 2007 2008 2009*

WPV3WPV1

Countries Currently Using IPVCountries Currently Using IPVin National Immunization Programsin National Immunization Programs

OPV

IPV then OPV

IPV

25

Routine OPV3 CoverageRoutine OPV3 CoverageUNICEF/WHO Estimates, 2006UNICEF/WHO Estimates, 2006

≤50%

51-79%

≥80%

SOURCE: UNICEF/WHO, 2006 Global Summary

Potential Antiviral CompoundsPotential Antiviral CompoundsInhibitor Class Compound Poliovirus Activity

(EC50, µM)Original Indication(route of delivery) Current Status

PV1 PV2 PV3PV1 PV2 PV3

ReplicationMRL 1237 5.3 4.6 3.8 Research Research lead

Enviroxime1 0.20 0.06 0.04 Rhino (oral/IN) Discontinued at Phase 2

Capsid

Disoxaril1 1.8 0.10 0.10 NPEV (oral) Discontinued at Phase 1

Pleconaril1 10 1.1 0.22 Rhino/NPEV (oral) In Phase 2 for rhino (IN)

Pirodavir1 10 1.7 0.56 Rhino (IN) Discontinued at Phase 2

R757612 0.03 0.003 0.02 Research Research lead

BTA1883 0.08 >4.6 >4.6 Rhino (oral) Replaced by BTA798

BTA798 nt nt nt Rhino (oral) In Phase 2 for rhino

V-0734 0.02 0.05 0.02 NPEV (oral) In preclinical for polio

3C ProteaseRupintrivir1 0.02 0.04 0.01 Rhino (IN) Discontinued at Phase 2

Compound 11 0.26 0.31 0.06 Rhino (oral) Discontinued at Phase 1

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