Comprehensive technical module R ationale for IPV introduction amp OPV withdrawal in relation to Objective 2 of The Polio Eradication amp Endgame Strategic Plan Immunization Systems Management Group IMG ID: 759923
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Inactivated Polio Vaccine (IPV)Comprehensive technical moduleRationale for IPV introduction & OPV withdrawal in relation to Objective 2 of The Polio Eradication & Endgame Strategic Plan
Immunization Systems Management Group (IMG)
Version date: February 10, 2014
Slide2Glossary of terms & abbreviations
cVDPV Circulating Vaccine-Derived PoliovirusDTP3 Diphtheria Tetanus Pertussis (third dose)GPEI Global Polio Eradication InitiativeIMG Immunization Systems Management GroupIPV Inactivated Polio VaccineOPV Oral polio vaccinebOPV (bivalent, contains types 1 and 3)mOPV (monovalent)OPV1 (type 1 component of OPV) OPV2 (type 2 component of OPV)OPV3 (type 3 component of OPV)SAGE Strategic Advisory Group of Experts on ImmunizationVAPP Vaccine-associated paralytic poliomyelitisVDPV Vaccine-derived poliovirusWHA World Health AssemblyWHO World Health OrganizationWPV Wild poliovirus
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Slide3Definitions
Technical termDefinition (in the context of these slides)Fractional DoseA fractional dose is a dose that uses less antigen (1/5th or 1/3rd) for cost or supply sparing measures. With IPV, fractional doses are being evaluated by administration into the skin (intradermal, ID). In contrast, full dose is usually administered into the muscle (intramuscular, IM) or subcutaneous tissue (SC or SQ).Intestinal ImmunityIntestinal shedding refers to the amount of virus an infected person “sheds” or passes on through their intestine (and fecal matter). Wild polioviruses and vaccine viruses can be spread from person to person this way, if there is no intestinal immunity. In developing countries the major mode of transmission is thought to be fecal shedding to others with oral ingestion.Oral-pharyngeal sheddingOral-pharyngeal shedding refers to the amount of virus an infected person “sheds” or passes on through their oral secretions (nose and mouth). In industrialized countries the major mode of transmission is thought to be oral secretion to oral ingestion.PrimingChildren who do not seroconvert after a first dose are considered primed if they seroconvert within 7 days of a 2nd dose.SeroconversionSeroconversion is defined as the development of antibodies in blood serum as a result of infection or immunization and is correlated with protection
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Slide4Provide Technical background on Polio & Polio vaccines as it relates to Objective 2 of GPEI’s Polio Eradication & Endgame Strategic PlanReview Rationale for OPV cessationReview Rationale for IPV introductionReview of SAGE recommendations for IPV introduction
Objectives of this module
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Note
: this is a comprehensive stand-alone deck of slides with an accompanying document
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Key messages for IPV introduction & OPV cessation
All countries introduce at least one dose of IPV into the routine immunization system before the tOPV-bOPV switch
IPV recommended by SAGE
OPV cessation must occur for the world to be polio free because OPV in rare cases can cause paralytic disease
OPV cessation crucial
Removal of type 2 in 2016 (tOPV to bOPV switch globally)bOPV cessation in 2018-2019 (complete cessation of OPV)
OPV cessation--2 phases
Ensures that a substantial proportion of the population is protected against type 2 polio after OPV2 cessation
IPV rationale
Mitigates risks of type 2 reintroduction in association with OPV2 cessation & facilitates polio eradication by boosting immunity to types 1&3
Added IPV benefits
Recommended for routine immunization…not campaignsRecommended in addition to OPV…not replacing any OPV
IPV clarifications
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GPEI Accomplishment: Significant Decline in Polio-paralyzed Children, 1988-2013*
*as of 31 December 2013
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Slide7As wild polioviruses are eradicated, number of vaccine-derived cases exceeds wild poliovirus cases
A hypothetical scenario of estimated VDPV cases compared to reported cases of wild poliovirus (as of 31 December, 2013)
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Slide88
The Polio Eradication & Endgame Strategic Plan 2013-2018
“complete the eradication and containment of all wild, vaccine-related, and Sabin polioviruses such that no child ever again suffers paralytic poliomyelitis.”
The Plan differs from previous eradication plans
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The Plan has four objectives
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Objective 2 of The Plan addresses the Endgame through three distinct stages
Before
end 2015
2016
2019-2020
Ongoing STRENGTHENING of routine immunization services
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Timeline for implementation of Objective 2, the Endgame
Last wild polio
case
IPV in routine immunization
2013 2014 2015 2016 2017 2018
2019-2020
Anticipated timeline
Phase in IPV
Before
end of 2015
: introduce one dose of IPV in immunization programs of all countries, prior to tOPV-bOPV switch
tOPV-bOPV switch
2016
:
tOPV-bOPV switch globally
Global certification
Stop
bOPV
2019-2020
: withdrawal of bOPV
after the world is certified polio-free in 2018
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Slide12Technical Rationale for Oral Polio Vaccine (OPV) Cessation
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Key Messages
Because
OPV in rare cases can cause paralytic disease,
OPV cessation must occur
for the world to be polio free.
OPV cessation will occur globally in two phases:
removal of type 2 component (switch from
tOPV
to
bOPV
) in 2016
followed by
bOPV
withdrawal and cessation of OPV use in 2018-2019
.
Slide13Oral Polio Vaccines (OPV) in routine and supplementary immunization activities globally
Types of OPVTrivalent OPV (tOPV): types 1, 2, and 3Bivalent OPV (bOPV): types 1 and 3Monovalent OPV (mOPV): types 1 or 2 or 3Currently, TRIVALENT is the most commonly used OPV in routine immunization globally, while BIVALENT is more commonly used in supplementary immunization activities.
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Slide14Types of polioviruses
99% reduction in cases of wild poliovirus since 1988Type 1 (341 cases as of 20 November 2013†)Type 2 (eliminated worldwide in 1999)Type 3 (none detected since November 2012)
Wild
Vaccine derived polioviruses (VDPV)Most are circulating VDPVs (cVDPVs)*~49-184 per year since 2008 (through 20 Nov 2013)Type 2 cVDPVs account for 97% of cVDPVs
VDPVs*
Vaccine-associated paralytic poliomyelitis (VAPP)**Estimated ~250-500 globally per yearType 2 accounts for about 40% of VAPP
VAPP**
† More up-to-date numbers can be found at http://www.polioeradication.org/Dataandmonitoring/Poliothisweek.aspx*Other extremely rare VDPVs include primary immunodeficiency VDPVs (iVDPVs) and ambiguous VDPVs (aVDPVs)**Refers to spontaneous reversion to neurovirulence of one of the attenuated viruses in OPV. VAPP occurs in OPV recipients or their close contacts in contrast to cVDPVs which are widely transmitted in a community and are not likely to be related to contact with a recent vaccine recipient.
OPV related
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Slide15What does it mean for the world to be polio-free?
Complete interruption of transmission and elimination of all polio diseaseWild poliovirusesVaccine-derived polioviruses (VDPVs)Vaccine-associated paralytic poliomyelitis (VAPP)Eradication & Endgame Strategic Plan 2013-2028 refers to both wild and vaccine-derived polioviruses
Eradication
Plan refers to
wild virus
Endgame
Plan refers to management of
VDPVs and VAPP
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Slide16Rationale for continuing use of OPV until Polio Eradication & Global Certification
As long as there are susceptible persons in other countries, there is risk of export of the virus to these countries.”
Endemic in 3 countries – reservoirs for re-infecting others (Pakistan, Afghanistan, Nigeria)In 2013, polio cases in 5 other countries previously polio free countries (Somalia, Kenya, Ethiopia, Cameroon, Syria)
Wild poliovirus still circulating
OPV is a critical component of the eradication strategy until polio transmission is interrupted
globally & the world is certified polio-free, Risk of polio spread into other regions of the world is real without the continued use of OPV
Eradication requires OPV
InexpensiveEasy to administerOffers good oral and intestinal immunity—needed for interruption of person to person transmission
OPV is appropriate for eradication
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Slide17Objective 2 of the Plan calls for a phased withdrawal and containment of OPV globally
OPV withdrawal
Remove type 2
by switch from tOPV to
bOPV…
Phase 1 2016
Type 2
…followed
by
bOPV withdrawal and cessation of OPV use in 2019-2020
Phase 22019-2020
All OPV
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Slide18Rationale for removing type 2 component of OPV (OPV2)
Risks of OPV2 far outweigh the benefitsThus, need to remove OPV2, but need to maintain population immunity against type 2 with IPV prior to OPV2 cessation Type 2 poliovirus apparently eradicated since 1999 (last case detected in Aligarh, India)New diagnostics and experience suggest that type 2 cause >95% of cVDPVs Type 2 causes 40% of VAPP todayType 2 component of OPV interferes with immune response to types 1 and types 3
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Slide19Rationale for retaining Types 1 & Types 3 components of OPV (bivalent OPV) until global certification of polio eradication
Type 1 causes all polio cases related to wild virus todayFew VDPV cases are type 1Few VAPP cases in immunocompetent individualsType 3 last detected in November, 2012 (as of 20 November 2013)Few VDPV cases are type 3Most VAPP cases (60%) in immunocompetent persons are type 3While lack of detection since November 2012 is promising, the period without detection to date is not long enough to assume eradication—due to potential silent transmission, certification of eradication requires at least 3 years without detection of virus.
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Slide20Risks associated with OPV2 cessation
Two main risks are associated with OPV2 cessationThese risks are mitigated by strengthening routine immunization and introduction of IPV
Short-term risks
Time-limited risk of cVDPV2 emergence, highest 1-2 years after OPV2 cessation
Medium & long term risks
Poliovirus re-introduction from a vaccine manufacturing site, research facility, immune deficient persons, diagnostic laboratory, or bioterrorism
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Slide21Role of OPV post-eradication
Maintaining a stockpile of monovalent OPVs (mOPV1, mOPV2, mOPV3)Using mOPVs to control outbreaks of cVDPVs or re-introduction from a manufacturing site, research facility, or diagnostic laboratoryStockpile of mOPVs would allow a type-specific response for rapid interruption of outbreak
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Slide22Technical Rationale for Introduction for Inactivated Polio Vaccine (IPV)
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Key Messages
Introducing
IPV
before the
tOPV-bOPV
switch in 2016 will ensure that a substantial proportion of the population is
protected against type 2 polio after OPV2 cessation and mitigate risks
associated with OPV2 cessation
IPV is recommended for
routine immunization
programmes
& not campaigns
IPV is given
in addition to OPV doses
and does not replace any OPV doses
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Planned use of IPV: SAGE Recommendations
Single dose of IPV at 14 weeks of age with DTP3, in addition to OPV3 or OPV4.
Countries have flexibility to consider alternative schedules
All endemic and other high risk countries should develop a plan for IPV introduction by mid-2014 and all OPV-only using countries by end-2014
WER, 3 Jan 2014, vol. 89, 1 (pp 1-20): at http://www.who.int/wer/2014/wer8901/en/index.html
SAGE recommended that all countries
introduce at least 1 dose of
IPV
in
their routine immunization programmes to mitigate the risks associated with the withdrawal of type 2 component of
OPV
Slide24Features of Inactivated Polio Vaccine (IPV)
Not a live vaccine – no risk of VAPP or VDPVsMust be administered by intramuscular or subcutaneous injectionTrivalent – produces antibodies to types 1, 2 and 3 poliovirusA high proportion of vaccinees, generally > 95% of children, have serum neutralizing antibodies after 3 doses to all three polio serotypesAppears equivalent to OPV in inducing pharyngeal immunityInferior to OPV in inducing gut immunityMore costly to produce than OPVPartners are working towards achieving the lowest possible price for GAVI and non-GAVI countries.Collaborations & investigations underway to explore two “low cost” IPV options:fractional dose intradermal adjuvanted intramuscular IPV GAVI will cover the full cost of purchase for GAVI eligible and graduating countries
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Slide25Rationale for introducing at least one dose of IPV prior to the tOPV-bOPV switch
Reduce risks associated with OPV2 cessation Lower risk of re-emergence of type 2 poliovirusesFacilitate interruption of transmission with the use of monovalent OPV2 if type 2 outbreaks occurBoost immunity against types 1 & 3 thus hastening polio eradication
IPV
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Introducing
IPV before the
tOPV-bOPV
switch in 2016 will ensure that a substantial proportion of the population is protected against type 2 polio after OPV2
cessation. One dose of IPV will:
Slide26Individual protection against paralytic disease induced by IPV – REDUCE RISKS
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IPV
Slide27Impact of one dose of IPV*
Primary role of one dose of IPV is intended to be a RISK MITIGATION strategy to reduce risk of re-emergence of type 2 polioviruses after OPV2 cessationSeroconversion against type 2 after one dose of IPV ranges from 32-63%. Persons who seroconvert should be protected against paralytic polioSeroconversion rates are higher when vaccine is administered later in infancy presumably because of waning maternal antibodyPersons who seroconvert should be protected against paralytic polio
Author yearCountry ScheduleType 2 SeroconversionIntramuscular administration of 1 dose of IPVMcBean 1988US2 mo35%Simasathien 1994 Thailand2 mo39%Resik 2010Cuba6 wk36%Mohammed 2010Oman2 mo32%Resik 2013Cuba4 mo63%
* Estı´variz CF et al. Lancet 2012; 12(2):128-35
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Slide28Rationale for administering IPV after 14 weeks of age, in the context of the Endgame Plan
The immune response to intramuscularly administered IPV varies based on the number of administered doses (higher with more doses) and the age at vaccination (higher with delayed immunization). 3 doses: ~100% against all 3 serotypes2 doses: ~90% against all 3 serotypes, when administered >8 weeks of age1 dose: ~19%-46% against Type 1, 32%-63% against Type 2, and 28%-54% against Type 3 poliovirus. It is important to note that immune response to one dose of IPV is substantially higher, particularly against Type 2 poliovirus (63%) when administered at 4 months of age compared to 6 weeks to 2 months of age (32%-39%). Thus, SAGE recommends a single dose of IPV at 14 weeks or first contact afterwards, or with DTP3/OPV3 or for countries administering a birth dose of OPV, at the time of the OPV4 dose
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Slide29Poliovirus type 2 seroconversion & priming
IPV administered at 4 months of age (n=153)1st dose seroconversion 63%Priming 98%1st dose seroconversion & priming99%
Sutter RW – Presentation to SAGE IPV Working Group June 2013 based on: Resik S et al N Engl J Med 2013;368:416-24
In a study from Cuba, among those who did not seroconvert after 1 dose of IPV, 98% had a priming response to a subsequent dose of IPV--that is, they developed significant antibody responses within 7 days of subsequent exposure to IPV. Persons without priming who are seronegative would not be expected to make detectable antibody for at least 10-14 days or longer after immunization.Persons who are seronegative but primed may also be protected against paralytic polio although data are conflicting as to whether priming alone is protective.
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Slide30IPV Evidence: One IPV dose prevents VAPP in Hungary. Implies priming induces clinical protection.
VAPP
number of cases
Year
In 1992,
single-dose IPV at 3 mos of age,before OPV receipt
In 2006,
IPV-only schedule
Sutter RW – Presentation to SAGE IPV Working Group
June 2013
In contrast, effectiveness against type 1 in Senegal was 36% (0%-67%) implying that seroconversion is the predictor of immunity.
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Slide31Outbreak control with mOPV2 in a population which previously received IPV -- REDUCE RISKS
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IPV
Slide32IPV Evidence: What impact is one dose of IPV in routine immunization likely to have during SIAs in outbreak situations?
Impact on seroconversion of IPV followed by OPV is similar to IPV-IPV or OPV-OPVThus, with one dose of IPV a proportion of the population is already immune. Use of mOPV in an outbreak control setting in a population who received a dose of IPV is likely to lead to higher immunity levels than a single dose of mOPV in a completely susceptible populationThus, population immunity thresholds to terminate poliovirus transmission are more likely to be reached after a dose of IPV followed by mOPV compared to a single dose of mOPV only in response to an outbreak.
Comparison of 2-dose response, Faden et al, JID,
1990**These data are based on a US study in Baltimore and Buffalo.
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Slide33IPV in reducing transmission of polioviruses – Interrupt Transmission
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IPV
Slide34OPV challenge studies: Shedding of poliovirus in IPV versus OPV vaccinees
From Vidor E et. al, Poliovirus Vaccine – Inactivated, Vaccines 6
th edition, Elsevier, 2013
IPV is equivalent to OPV in reducing oral shedding but is inferior to OPV in reducing intestinal shedding.To the degree that polioviruses are transmitted orally, IPV should be equivalent to OPV. To the extent that polioviruses are transmitted via the fecal-oral route, IPV is likely to be inferior to OPV.
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Slide35Although IPV may not be as effective as OPV in decreasing prevalence of poliovirus excretion in stool, IPV may still decrease transmission
IPV does reduce the duration of shedding and the amount of virus shed in the stool.Thus, IPV should decrease the spread of polioviruses if they are introduced, compared to a fully unvaccinated population.
From Sutter et al. Poliovirus vaccine-live, Vaccines 6
th ed, Elsevier, 2013
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Slide36IPV in boosting immunity in OPV primed individuals – Hastens Eradication
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IPV
Slide37A single dose of IPV after prior doses of tOPV boosts immunity to types 1 & 3
*Moriniere BJ et al. Lancet 1993;341:1545-50, ** Estı´variz CF et al. Lancet 2012; 12(2):128-35,
Seroconversion after one dose of IPV in seronegative children with prior OPV substantially higher than would be expected with one dose of IPV in polio vaccine naïve children. Further, IPV in persons with prior OPV induces boosts in mucosal immunity.Results from a similar study in Moradabad showed 91%-100% seroconversion for types 3 and 2 respectively among those who received IPV**
IPV could also play a role in the eradication efforts, in conjunction with bOPV, by boosting immunity against type 1 and 3 polioviruses in polio endemic countries and countries where poliovirus circulation has been reestablished. Immune response to Types 1 & 3 significantly better with IPV at 6 months of age in children who received three prior doses of tOPV in Ivory Coast but were still seronegative*
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3 tOPV + IPV**3 tOPV + tOPV**Type 1 seroconversion80%40%Type 3 seroconversion76%22%
** Fourth dose at 6 months
Slide38Type 2
Type 3
Type 1
tOPV
: 3 rings
of protection against types 1, 2, and 3
mOPV2
bOPV + mOPV2
Protection
against type 2 provided by supplementary use of mOPV2
in the setting of an outbreak
mOPV2
bOPV + IPV + mOPV2
bOPV
& mOPV2
effect is enhanced in an IPV population thus facilitating outbreak control
bOPV
+
IPV
bOPV + IPV
IPV adds protection against type 2 & boosts immunity to 1 & 3 (enhancing
bOPV
effect)
Potential Type 2 outbreak requiring mOPV2
b
OPV
2 rings of protection
against types 1 and 3
tOPV-bOPV
switch
Schematic description of technical rationale for use of at least one dose of IPV as part of the Endgame Strategy
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IPV Presentations and Formulations
Only WHO prequalified formulation
1-dose and 10-dose available now5-dose expected in late 2014Preservative : 2PE does not allow for Multi dose vial Policy application
Stand-alone IPV
Tetravalent,
pentavalent, hexavalent available Combination with whole-cell pertussis not currently availableSubstantially higher cost than stand-alone IPV
Combination products
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Example 6-10-14 week schedule with IPV
VaccineBirth6 weeks10 weeks14 weeksBCG√DTP-HepB-Hib√√√Pneumococcal√√√Rotavirus*√√√OPV√√√Stand-alone IPV√
1st contact after 14 weeks
Single dose of IPV at 14 weeks or first contact afterwardsAll children who are behind on their schedule should receive one dose of the IPV at the first immunization contact after 14 weeksCountries have flexibility to consider alternative schedules (e.g. earlier IPV administration based on local conditions)
*
Rotavirus vaccine may be administered in 2 or 3 doses, depending on the country schedule
Slide41Administration of Inactivated Polio Vaccine (IPV)
IPV is administered by intramuscular injection (IM) or subcutaneously (SQ) in a dose of 0.5 ml into the outer part of the thighWhen given at the same visit, IPV and other injectable vaccines should be given at different injection sites at least 2 cm apart For example, if IPV, Pentavalent vaccine, and Pneumococcal vaccine are to be given during the same visit, IPV and Pneumococcal should be in one thigh 2 cm apart and the Pentavalent vaccine (more reactogenic) in the other thighIPV should not be mixed with other vaccines in the same vial or syringe IPV can be administered to prematurely born infants and children with immunodeficiencies (e.g., HIV, congenital or acquired immunodeficiency, sickle cell disease)
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Multiple Injections: Acceptability and Safety
Recently, more low and middle income countries have begun using multiple vaccine injections with the addition of pneumococcal vaccine and IPV Substantial evidence has reinforced the well-established record of safety and acceptance of multiple injections from countries using multiple injections*For example, US infants often receive 3 or more injections during each of the primary series vaccination visitsGiving a child several vaccinations during the same visit offers three major advantages:Immunizing children as soon as possible provides protection during the vulnerable early months of their lives. Giving several vaccinations at the same time means parents and caregivers do not need to make as many vaccination visits. 1It means that health care providers are able to more efficiently provide and deliver other health services by reducing the time they need to spend providing vaccinations.
*http://www.cdc.gov/vaccinesafety/Vaccines/multiplevaccines.html
*http
://www.cmaj.ca/content/182/18/E843.full
Slide43Specific notes on the recommended IPV schedule*
*from 7th Meeting of the SAGE Polio Working Group, October 18-19, 2013
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IPV does not replace ANY of the OPV doses
– that is, IPV will be given in addition to OPV and OPV will continue to be used per current practice for now
IPV is recommended for routine immunization programmes
and not campaigns because injections are difficult to accommodate in campaigns against polio
The higher the IPV coverage the better, but
even low coverage will provide direct benefit
to those vaccinated and greatly facilitate building population immunity in an emergency response
Slide44Planned use of IPV: IPV Rationale Summary
IPV induces immunity in a proportion of children which will protect them against polio caused by vaccine viruses (VAPP and cVDPVs) and polio caused by wild poliovirusIPV should lower risk of re-emergence of type 2 poliovirusesIPV in conjunction with bOPV will decrease the number of cases of VAPP caused by types 1 and 3IPV will boost immunity to types 1 and 3 which should hasten eradication of types 1 and 3 wild polioviruses and reduce polio disease caused by types 1 and 3 cVDPVsIPV by inducing immunity to type 2 will facilitate outbreak control with mOPV2 should type 2 viruses be reintroducedA proportion of the population will already be immune resulting in a higher level of immunity after a dose of mOPV2 in outbreak control than after a dose of mOPV2 to contain an outbreak in a completely susceptible populationThe higher the IPV coverage the better, but even low coverage will provide direct benefit to those vaccinated and greatly facilitate building population immunity in an emergency response
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