Polio Eradication: The Difficult Inclusion of IPV Research, Policy and Product Development (RAP), Polio Operations & Research Department (POL)
Overview Historical context Early inequality in case burden Recent divergence in control Current status of vaccine used Barriers to wider IPV use New endgame deliberations (Sabin 2 cessation) SAGE recommendations 6 November 2012
Historical context inactivated poliovirus vaccine (IPV), developed by Jonas Salk, first licensed on 12 April 1955 in the United States problems with early IPV use: incompletely inactivated IPV caused "Cutter incidence" in April 1955 potency quite low (compared to current product) as a consequence relative upswing in cases in 1958-1959 (curbing enthusiasm / confidence in IPV)
Introduction of Oral Poliovirus Vaccine field experience with OPV in massive campaigns late 1950s in Soviet Union created enthusiasm licensure of OPV starting in 1961 in United States (mopvs, then topv) consequently, a large-scale shift to replacing IPV with OPV in most of the world, except 4 countries (Iceland, Finland, Norway & Sweden)
San Antonio, 1962
Inequality in polio burden as a consequence of OPV use, polio disappeared in most of industrialized world in 1960s and 1970s however, in many developing countries polio continued unabated, and remained the major cause of permanent disability (in 1988, 350,000 cases were still estimated to occur)
Polio Eradication Initiative to address inequality, the World Health Assembly, resolved in 1988 to eradicate polio by the year 2000 subsequently, OPV was selected as the vaccineof-choice for polio eradication because of: ease of administration Superior mucosal immunity secondary transmission to unvaccinated contacts lower price rapid progress in controlling polio (by 2000, a decrease of >99% cases was reported)
8 Nov 2011 8 Nov 2012
Adverse events associated with OPV Longstanding: vaccine-associated paralytic poliomyelitis (VAPP), recognized since 1963 More recent: vaccine-derived poliovirus (VDPVs) causing outbreaks (cvdpvs), first recognized in 2000 in Hispaniola causing prolonged or chronic poliovirus infection in immunodeficient individuals (ivdpvs)
Recent divergence in control measures with progress toward polio eradication (decrease of 99% in polio cases by 2000), industrialized countries opted to include IPV in routine schedules primarily to prevent VAPP either with all-ipv schedules or sequential schedules of first IPV followed by OPV (73 countries) very few developing countries introduced IPV because either VAPP was not perceived as a public health problem, high IPV price, or OPV benefits
Barriers to IPV use in polio eradication programmatic imperative (WHY, WHEN, WHERE, HOW ) absence of convincing scientific data
What has changed? wild poliovirus type 2 was last detected in 1999 in India therefore, more than a decade without wild poliovirus type 2 yet, approximately 40% of global VAPP burden is due to Sabin type 2 (100-200 cases annually), and, >95% of cvdpv cases are due to type 2 relevant scientific data generated on IPV SAGE Working Group process to look at polio vaccines and new endgame strategy (Sabin 2 cessation)
circulating Vaccine-Derived Poliovirus Outbreaks (cvdpvs), 2000-2011 Type 1 (79 cases) Type 2 (478 cases) Type 3 (9 cases)
VAPP number Evidence: 'prevent polio if exposed to a VDPV2 or WPV2' In 1992, single-dose IPV at 3 mos before OPV Hungary: no VAPP reported In 2006, after IPV-only introduction of 1 IPV schedule dose in sequential schedule in 1992 US: no VAPP reported in infants who received at least 1 IPV dose in IPV/OPV schedule Year
Percent seroconversion Evidence: 'improve response to mopv2 in an outbreak' IPV priming effect, Cuba, 2010 100% 80% 60% 40% 20% P1 P2 P3 Cuba: single IPV dose in naive 4-mo old infants seroconverts 47%-63% against type 2 Not immune 94%-98% of infants who didn't seroconvert after single IPV dose 2nd dose Priming responded with priming response 1st dose PV 2 (Accepted for publication) 0% ID IM ID IM ID IM
Percent seroconversion Evidence: 'Improve response to mopv2 in an outbreak' Comparison of 2-dose response, Faden et al, JID, 1990 Impact on seroconversion of IPV followed by OPV similar to IPV-IPV or OPV-OPV Findings are consistent with priming through a single dose of IPV
P1 excretion after day 28 challenge (%) Evidence: 'reduce transmission of a re-introduced type 2' Impact of IPV vs. bopv booster, Moradabad, India, 2012 0 10 20 30 40 6-11 months Moradabad, India: single IPV dose to infants and older children with history of multiple OPV doses dramatically boosts intestinal mucosal immunity 5-6 years 10-11 years Effect is larger than with a bopv dose Day 31 Day 35 Day 42
Evidence: 'reduce transmission of a reintroduced type 2' IPV & mucosal immunity, Cuba, 2012 topv challenges after 2 x IPV IPV doses given ID and given ID vs. IM IM have similar impact on mucosal immunity
Percent Evidence: 'boost immunity to wild poliovirus 1 & 3' Impact of IPV vs. OPV booster after OPV3 in seronegative individuals at 9 months of age, Côte d'ivoire (Lancet, 1993) 100 90 80 70 60 50 40 30 20 10 0 81 14 27 100 In previously 67 OPV-immunized children, an IPV booster dose OPV Booster has greater impact IPV Booster than an OPV booster in closing immunity gap to all 3 serotypes 5 Type 1 Type 2 Type 3
Potential benefits of 'at least 1 IPV dose prior to OPV2 cessation' a) prevent polio if exposed to a VDPV2 or WPV2 b) improve response to mopv2 in an outbreak c) reduce transmission of a reintroduced type 2 d) boost immunity to WPV1 & 3
IPV Product & prices Volume purchasing and guaranteed procurement can substantially reduce the price of current IPV products below the current 'UNICEF price' (US$2.75/dose) However, volume purchasing alone cannot achieve a target price substantially below US$1.00/dose Only options are: 1) intradermal (ID) fractional dose IPV (1/5 dose); and 2) intramuscular (IM) adjuvanted IPV
Standalone IPV prices/dose Existing product (2012) Whole-dose IM Salk IPV US$1.25 US$2.75 Pipeline products (2015-17) Adjuvanted (1/5 th ) dose IM Salk IPV Fractional (1/5 th ) intradermal IPV dose US$0.40 US$1.00 Clear policy is essential to accelerate product US$0.50 development and licensure and establishing firm pricing US$0.50 NOTE: prices & timelines are best 10-dose vial estimates at Oct 2012
SAGE Recommendations (draft 6 Nov): Universal IPV (at least 1 dose) Timing, asap, contingent on pre-requisites for Sabin 2 cessation (incl. 'affordable IPV') Contingency, transition plan for early introduction of IPV with whole-dose products WHO to establish IPV introduction capacity
Next steps: Apr 2013: Working Group to report back to SAGE on further review of pre-requisites for Sabin 2 cessation (affordable IPV, interruption of persistent cvdpv, laboratory containment, surveillance and outbreak response capacity) towards establishing the time frame for OPV2 cessation - WG to conduct 6-monthly review of main prerequisites and 'triggers' for OPV2 cessation until all are in place
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Consultative process with IPV manufacturers and regulatory authorities 3-4 Sept: WG meeting - consultation with IPV manufacturers Four manufacturers invited, list of key questions shared ahead of time 45-min discussions between WG and each manufacturer Also: update from GATES foundation on their IPV-related activities Follow-up letter to manufacturers requesting plans on IPV products and pricing in writing; detailed responses received from all 4 manufacturers 28 Sept: WG conference call 26 Oct: WG conference call (after receiving manufacturers replies) 25 Oct: Follow-up meeting of ADG + POL/WHO with manufacturers and regulatory authorities (global polio vaccine manufacturer's meeting) 31 Oct: ADG, POL + IVD/WHO meet with French and Belgian national regulatory authorities
Programmatic consultations to date 4 Sept: Review of implications of IM vs ID application of IPV (based interviews with EPI managers of selected countries), SAGE Polio WG meeting, Geneva 19 Sept: Consultation on OPV2 cessation and IPV introduction at EMRO EPI managers meeting, Sharm-el-Sheikh, Egypt 2 Oct: IPAC session on programmatic aspects of IPV introduction, Geneva 10 Oct: Discussion on OPV2 cessation at SEARO EPI TAG meeting, New Delhi, India 16 Oct: WHO/AFRO expert consultation on regional perspectives for the use of IPV in routine immunization, Luanda, Angola 18 Oct: Consultation on OPV2 cessation and introduction of IPV at the PAHO EPI TAG meeting, Washington, USA D R A F T - N O T F O R D I S T R I B U T I O N
Rationale for introduction of 'at least 1 IPV dose prior to OPV2 cessation' possibility of continued silent circulation of cvdpv2 and of new cvpdv2 emergences following OPV2 cessation low but real risk of type 2 polio outbreaks following OPV2 cessation (i.e. due to cvdpv, chronic VDPV excretors, containment failure)