IPV – Need of the hour

Dr Gaurav GuptaPediatrician, Charak Clinics, Mohali

drgaurav@charakclinics.com

A brief history of Polio

• First described by Michael Underwood in 1789• First outbreak described in U.S. in 1843• 21,000 paralytic cases reported in the U. S. in

1952• Global eradication in near future

A brief history of Polio Vaccine• 1955 Inactivated vaccine

• 1961 Types 1 and 2 monovalent OPV

• 1962 Type 3 monovalent OPV

• 1963 Trivalent OPV

• 1987 Enhanced-potency IPV (eIPV)

Adapted from 1, 11

Summary of Key Attributes of OPV and IPV

Sutter et al. Vaccines, 2008

Plotkin & Vidor . Vaccines, 2008

Despite Significant Progress, 4 Countries Still Remain Endemic for Polio

WHO. Poliomyelitis Fact sheet. Available at: http://www.who.int/mediacentre/factsheets/fs114/en/print.html, 2009

WHO. Polio Case Count. Available at: http://www.who.int/immunization_monitoring/en/diseases/poliomyelitis/case_count.cfm, 2009

Graph adapted from WHO. Progress Towards Global Immunization Goals. Available at:http://www.who.int/immunization_monitoring/data/SlidesGlobalImmunization.pdf, 2009

Polio Eradication Progress, 1988-2008

• 1988: 350,000 estimated cases

>125 endemic countries

• 2008: 1,652 cases

4 endemic countries– India, Nigeria, Afghanistan, Pakistan

Endemic with wild polio virus (4 Countries)

Certified polio-free regions (114 countries)

Not certified but non-endemic (73 countries)

Polio Eradication: A Godzilla of Campaigns

Just think…..• In 2008, India administered more than one billion doses of

OPV during polio vaccination campaigns. • On any given National Immunization Day (NID), more than 72

million children were immunized across a single weekend, making these regular occurrences repeatedly the largest immunizations in history !

• And somewhere in India, polio campaigns were conducted in 24 out of the 52 weeks in the year.

SEARO, New Delhi, 2011

Immunization and VaccineDevelopment (IVD) SEARO

Protecting People from Vaccine Preventable

Diseases

Weekly AFP and VPD Update for Week 48, 2011

Data as of 05 December 2011

8

Wild Polio VirusIndia, 2010

*Dots are randomly placed within blocks (Sub-districts) Data as of 05 Dec 2011

= Most recent P1 Wild polio case

Districts with cases in 2010

India

18244217

P1 Wild13-Dec-2010; District Murshidabad, West Bengal

P3 Wild22-Oct-2010; District Pakur, Jharkhand

Date and location of most recent case

Wild Polio Cases, 2010

Total P3 Wild cases

Total districts with wild cases

Total P1 Wild cases

Total wild polio cases

= Most recent P3 Wild polio case

9

Wild Polio VirusIndia, 2011

*Dots are randomly placed within blocks (Sub-districts)

Data as of 05 Dec 2011

= Most recent P1 Wild polio case

101

1

P1 Wild13-Jan-2011; District Howra, West Bengal

P3 Wild -

Date and location of most recent case

Wild Polio Cases, 2011Total P1 Wild cases

Total polio cases

Total districts with wild cases

Total P3 Wild cases

Districts with cases in 2011

Districts with cases in current week

10

Vaccine Derived Polio Virus (VDPV)India, 2011

*Dots are randomly placed within blocks (Sub-districts)

Data as of 05 Dec 2011

Districts with cases in 2011

Districts with cases in current week

5166

P2 VDPV22-Jun-2011; District Barnala, Punjab

P3 VDPV07-Oct-2011; District Jajpur, Orissa

Date and location of most recent case

VDPV Cases, India, 2011

Total VDPV cases Total districts with VDPV cases

Total P3 VDPV casesTotal P2 VDPV cases

= Most recent P2 VDPV case

= Most recent P3 VDPV case

11

Wild Polio Cases by Type (P1, P3) and Month of OnsetIndia, 2007-2011

Data as of 05 Dec 2011

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But why talk about IPV now?

“The primary challenge to India’s energetic and comprehensive polio eradication efforts is

the failure of the vaccine to optimally protect children in the remaining infected areas of

the country.”

WHO (GPEI. Annual Report 2008)

• Concerns about VAPP is being increasingly realized.

• Reemergence of type 2 poliovirus in the form of VDPV

• Reintroduction of wild PV circulation in previously polio-free countries through

importations

GOI has recognized the need for IPV in our country and granted license for use in India

(50 years after its development).

Role of IPV in ‘Polio End Game’ – WHO position

IAP recommendations

– Suboptimal OPV efficacy– Inadequate Herd effect– Vaccine Associated Paralytic

Poliomyelitis (VAPP)– Vaccine Derived Polio Virus

(VDPV)

Issues Surrounding the Use of OPV

Polio is Still Endemic in 4 Countries, Reflecting both “Failure to Vaccinate” and “Vaccine Failure”

WHO. Polio Case count. Available at: http://www.who.int/immunization_monitoring/en/diseases/poliomyelitis/case_count.cfm, 2009

Graphs from WHO. Polioeradication. Progress & Prospect. 2008

Roberts. Science, 2009

W. Uttar Pradesh Bihar Rest of countryHigh risk Medium risk Rest of country

In Nigeria, high “failure to vaccinate”

In Nigeria, high “failure to vaccinate”

In India, polio cases despite high coverage, thus “high vaccine failure”

In India, polio cases despite high coverage, thus “high vaccine failure”

0 doses 1-3 doses4-6 doses 7+ doses

OPV doses administrated per area in Nigeria 2003-2008 OPV doses administrated per area in India 2003-2008

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Seroconversion after 3 doses of OPV

• Industrialized versus low-income countries– 95% Seroconversion in industrialized countries

• Seroconversion in low-income countries

Review of 32 studies. Patriarca, Wright & John. Rev Infect Dis 1991; 13:926-39

Type Weighted average seroconversion

1

2

3

73%

90%

70%

Paralytic polio cases are occurring predominantly among the children who had received 4 or more doses of vaccine, and lately among those who had received more than 7 doses of OPV. On the other hand among the polio cases percentage ofunvaccinated children is very low. In case children develop paralytic disease after taking many doses of OPV, it means that many doses of vaccine had failedto provide protection.

VAPP: A Rare But Serious and Inevitable Adverse Event Associated

with OPV

• Vaccine-Associated Paralytic Polio:– Definition: PP in vaccinee following OPV administration

– Cause: Mutation of vaccine virus during replication in the gut of vaccinee (reversion to neurovirulence)

– Form: VAPP undistinguishable from naturally occurring polio• Same incubation period, range of severity and Case Fatality Rate

– May affect both vaccinees & close contacts

Sutter et al. Vaccines, 2008

Paul. Vaccine, 2004

John. Bull of the WHO, 2004

VDPV: No Longer Just a Theoretical Concern

• Vaccine Derived Polio Virus or VDPVs:– Definition: derivatives of Sabin OPV strains exhibiting 1-15% divergence in the

sequence of viral protein vp1 – Origin: accumulation of mutations by

• Replication of the live vaccine strains within the vaccinee’s guts • Recombination with other enteroviruses

– Potential to cause paralytic polio in humans and sustained circulation – Factor favoring emergence & spread are same as for wPV:

• Low OPV coverage• Poor sanitation• High population density• Tropical conditions

– 3 Types cVDPV, iVDPV, aVDPVWHO. WER, 2006

• Particular concern: re-emergence of type 2 (as VDPV) whereas the wild type was declared eradicated in 2002 and reported in 5 independent cVDPV outbreaks since then

• According to some experts: “more likely several million individuals were infected during these events, and many thousand more have been infected by VDPV lineages within outbreaks which have escape detection”

DOR / HAITI2000-01VDPV 121 cases

DOR / HAITI2000-01VDPV 121 cases

NIGER2006

VDPV 22 cases

NIGER2006

VDPV 22 cases

NIGERIA2005-08VDPV 2

148 cases

NIGERIA2005-08VDPV 2

148 cases

DR CONGO2008

VDPV 211 cases

DR CONGO2008

VDPV 211 cases

MADAGASCARVDPV 22001-025 cases

20053 cases

MADAGASCARVDPV 22001-025 cases

20053 cases

MYANMAR2006-07VDPV 15 cases

MYANMAR2006-07VDPV 15 cases

INDONESIA2005

VDPV 146 cases

INDONESIA2005

VDPV 146 cases

CHINA2004

VDPV 12 cases

CHINA2004

VDPV 12 cases

CAMBODIA2005-06VDPV 32 cases

CAMBODIA2005-06VDPV 32 cases

PHILIPPINES2001

VDPV 13 cases

PHILIPPINES2001

VDPV 13 cases

ETHIOPIA2008-09VDPV 24 cases

ETHIOPIA2008-09VDPV 24 cases

2000- July 2009: At Least 13 cVDPV Outbreaks in 12 Countries Caused et Least of 300 Paralytic

Polio cases

WHO. cVDPV 2000-2008. Available at: http://www.polioeradication.org/content/general/cvdpv_count.pdf, 2009

GPEI.Strategic Plan 2009-2013. Available at: http://www.polioeradication.org/content/publications/PolioStrategicPlan09-13_Framework.pdf,2009

Wringe et al. Plos One, 2008

INDIA2009

VDPV 1, 2 2 & 18 cases

INDIA2009

VDPV 1, 2 2 & 18 cases

The OPV Paradox – how OPV Use May Compromise the Final Goal of Eradication

– Given risk of VAPP and VDPV associated with OPV, continued use of OPV may end up causing more cases of polio than wild polio virus (OPV paradox)

WHO. cVDPV 2000-2008. Available at: http://www.polioeradication.org/content/general/cvdpv_count.pdf, 2009

GPEI. Strategic Plan 2009-2013. Available at:http://www.polioeradication.org/content/publications/PolioStrategicPlan09-13_Framework.pdf,2009

WHO. WER, 2004 Jacob. Bull of the WHO, 2002 Dowdle et al. Rev Med Virol, 2003

RISK FREQUENCY GLOBAL ESTIMATES

VAPP 2-4 per million birth cohort

250-500 cases/year (WHO)400-800 cases/year (other experts’ estimate)

cVDPV13 independent cVDPV outbreaks in 12 countries since 2000

iVDPV 33 cases since 1962

eIPV: The Vaccine of Choice for Today and the Future

–High Immunogenicity Even After 2 Doses–Long-term Persistence of Antibodies

–Good Efficacy / Effectiveness–Good Herd Immunity –Favorable Health Economics

eIPV: High Immunogenicity, Even After 2 Doses

– High immunogenicity of IPV even in developing and tropical countries where OPV is suboptimal

– High immunogenicity after 2 doses (including 27 developing countries) : • In 30 trials involving >4500 subjects, seroprotection against poliovirus:

– 89-100% against type 1– 92-100% against type 2– 70-100% against type 3

– Immunogenicity expectedly reinforced after 3rd dose • In 48 trials involving >6000 subjects

– 95-100% seroprotection rates against all 3 types

– Comparative study in India, 1990s 92% efficacy of IPV vs 66% for OPV(3 doses of respective vaccines)

Polio Eradication Committee et al. Indian Pediatr, 2008

Plotkin & Vidor. Vaccines, 2008

IPV Provides Good Herd Immunity

• Herd immunity: – Protection of the population to a greater extent than that expected by the actual

population vaccination coverage

• Excellent herd immunity reported wherever IPV used on large scale – e.g. : USA

John. Expert Rev Vaccines, 2009

Stickle. Am J Public Health, 1954

Observed

Expected in absence of vaccine use

Expected with vaccine effect limitedto vaccinees

Paralytic Poliomyelitis Cases Expected with orwithout Vaccine use, 1951-1954

Role of OPV + eIPV

• Better mucosal immunity of OPV + IPV• Very low risk of VAPP – early OPV protection against VAPP by

maternal antibodies. Subsequently protected by IPV. IPV alone may not be enough.

• Higher seropositivity of OPV + IPV in multiple trials in Gambia, Oman, Thailand, Israel & Pakistan.

• Benefit of continuing the government policy regarding OPV with highly predictable immunogenicity & efficacy of IPV.

OPV & IPV are not contradictory but complementary !

Indian Academy of Pediatrics: Schedules

OPV at birth, OPV and IPV at 6, 10 and 14 weeks.OPV and IPV at 15-18 mths and OPV at 5 years. OPV on all NID’s and SNID’s.

Indian Pediatrics 2008; 45: 635-648

Polio immunization naïve child

Child has received OPV primary series

IPV given as two doses at 2 month interval Continue OPV with DPT booster, and on all NID’s and SNID’s

– IPV should be the preferred vaccine– The schedules are as before with a

booster dose of IPV at 5 years

Immunocompromised child

Indian Pediatrics 2008; 45: 635-648

Indian Academy of Pediatrics: Schedules

‘End game’ & ‘Post –eradication’ strategy – IAP PEC

• End game - Use b-OPV for SIA’s, and add IPV for highly endemic region.

• Post eradication – Introduce IPV and try to achieve high coverage before discontinuing OPV. Start with south states free of wild polio gradually universal use. Continue OPV through 3 Pulse NIDs until WPV transmission stopped.