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Perspective

National choices related to inactivated poliovirus vaccine, innovation and the endgame of global polio eradication Expert Rev. Vaccines 13(2), 221–234 (2014)

Kimberly M Thompson* and Radboud J Duintjer Tebbens Kid Risk, Inc., 10524 Moss Park Rd., Ste. 204-364, Orlando, FL 32832, USA *Author for correspondence: Tel.: +1 617 680 2836 Fax: +1 407 668 4831 [email protected]

Achieving the goal of a world free of poliomyelitis still requires significant effort. Although polio immunization represents a mature area, the polio endgame will require new tools and strategies, particularly as national and global health leaders coordinate the cessation of all three serotypes of oral poliovirus vaccine and increasingly adopt inactivated poliovirus vaccine (IPV). Poliovirus epidemiology and the global options for managing polioviruses continue to evolve, along with our understanding and appreciation of the resources needed and the risks that require management. Based on insights from modeling, we offer some perspective on the current status of plans and opportunities to achieve and maintain a world free of wild polioviruses and to successfully implement oral poliovirus vaccine cessation. IPV costs and potential wastage will represent an important consideration for national policy makers. Innovations may reduce future IPV costs, but the world urgently needs lower-cost IPV options. KEYWORDS: cost • eradication • inactivated poliovirus vaccine • oral poliovirus vaccine • polio

As the Global Polio Eradication Initiative (GPEI) works to stop the remaining circulation of wild poliovirus (WPV) type 1 (WPV1) in endemic countries and respond to outbreaks of WPVs and circulating vaccine-derived polioviruses (cVDPVs), national and global policy makers must plan for the polio endgame, which requires the active engagement of multiple stakeholders and global coordination and management [1]. All countries currently include multiple doses of oral poliovirus vaccine (OPV), inactivated poliovirus vaccine (IPV) or both in their routine immunization schedules, and some countries also conduct supplemental immunization activities (SIAs) using OPV [2]. Several recent reviews discuss the complex landscape of global and national poliovirus vaccination policy options, which continue to evolve [1–3]. Although current national polio vaccine schedules vary considerably [2], all routine immunization doses involve trivalent formulations (i.e., tOPV or IPV) that can induce immunity for any or all of the three poliovirus serotypes in the vaccine recipient. All routine immunization schedules include three or more

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poliovirus vaccine doses, because of differential seroconversion and interference between various OPV serotypes and the need to prime and boost to achieve and sustain high antibody titers for IPV. We assume that all IPV will remain trivalent (i.e., IPV always includes all three poliovirus serotypes such that we do not need to label it as trivalent). IPV vaccine formulations may also include other antigens (i.e., combination vaccines), which reduces the overall number of injections that children receive and facilitates sharing vaccine administration costs over multiple antigens. All SIAs currently use OPV, for which countries may use trivalent OPV (tOPV), bivalent OPV (bOPV, including types 1 and 3) or a monovalent OPV (mOPV1 or mOPV3) [2]. In the absence of naturally occurring WPV2 (since 2000) [4] and with the emergence of type 2 cVDPVs (cVDPV2s) and ongoing risks associated with the type 2 component of tOPV (OPV2) [5], the current GPEI strategy aims to globally coordinate the cessation of each OPV serotype, starting with OPV2 [6–8]. The implementation of this strategy depends on prior

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interruption of the known transmission of cVDPV2s, and the development of preparedness strategies and a sufficient stockpile of mOPV2 to respond to any outbreaks of cVDPV2s that may emerge following OPV2 cessation [1]. The GPEI recommends the introduction of at least one dose of IPV into the routine immunization schedules of all countries, ideally prior to OPV2 cessation, but the role of IPV in national immunization schedules remains a topic of much discussion. With the changing epidemiology of WPVs and ongoing discussions about the global strategy and the role of IPV in national immunization programs, we recognize the opportunity to provide additional perspective on the current situation, future options and key constraints that impact current and future choices. Scope

This article reviews the current epidemiological picture for polio and vaccine options for managing polioviruses during and after OPV cessation. We focus particularly on the costs of IPV as a critical factor that will determine its role in national immunization programs, and we discuss potential opportunities to reduce IPV production and administration costs and how IPV use will most likely impact population immunity. Considering qualitative insights from experience modeling polioviruses [9], we demonstrate the importance of maintaining high population immunity through the final stages of polio eradication, and we discuss some of the implications of the innovations developed to meet the challenges in the polio endgame for other vaccine-preventable diseases. Polio epidemiology as of 2013

Despite missing the original target of eradicating all WPVs by 2000 [10], the GPEI successfully eradicated WPV2 by 2000 [4] and it continues to make progress toward the eradication of WPV1 and WPV3 [2]. As of December 2013, most of the countries in the world successfully maintain sufficiently high population immunity to prevent the sustained transmission of all 3 serotypes of virulent live polioviruses (LPVs, which include WPV, cVDPVs, OPV and OPV-related viruses). However, the last reservoirs of WPV1 in the remaining endemic areas of a few countries continue to experience cases and to export viruses that cause outbreaks (defined as one or more linked paralytic cases) in previously-polio free areas that achieved, but failed to maintain, high population immunity. Thus, after reaching its lowest ever annual global number of countries reporting WPV cases and total reported WPV cases to date in 2012 [2], importations of WPV1 into countries with insufficient population immunity to prevent transmission (e.g., Somalia, Kenya and Syria) led to outbreaks in 2013 [101]. In addition, cVDPV2s circulated in six countries in 2013, including five countries that sustained circulation of the virus that began at least 6 months earlier [102]. In 2013, Israel also reported numerous isolations of WPV1 from sewage samples collected throughout the country in the absence of any symptomatic poliomyelitis cases [11]. Given that Israel used IPV exclusively and with high coverage since 2005, this event suggests 222

that IPV use does not preclude and may mask extended asymptomatic poliovirus transmission, and it highlights the potential value of environmental surveillance in the polio endgame. The increased use of bOPV in SIAs since 2010 apparently increased population immunity in the last WPV3 reservoirs high enough to interrupt the remaining chains of transmission. Although silent circulation can occur (i.e., the virus can continue to transmit without the appearance of cases, because only a relatively small fraction of infections leads to a case), after a sufficient period of time with no observed cases [12,13], world health leaders will most likely begin preparations to declare WPV3 eradication completed. Remarkably, we may observe the outcome of apparent WPV3 eradication prior to successfully stopping the current cVDPV2s, and this may impact perceptions about the desirability of coordinating OPV2 and OPV3 cessation [1]. Current GPEI strategy

The current GPEI strategy focuses on coordinated OPV2 cessation, presumably followed by coordinated OPV3 and OPV1 cessation, although the actual timing remains uncertain and depends on the epidemiological situation [6–8]. The strategy involves a coordinated switch from tOPV to bOPV in all countries that currently use tOPV (i.e., all countries will plan to stop using OPV2 on the same day) and it recommends the introduction of at least one dose of IPV into the routine immunization schedules of these countries, ideally prior to OPV2 cessation. Although a single dose of IPV will not prevent infection, it may offer protection from paralysis and prime vaccine recipients to mount an immunological response more quickly if exposed to a subsequent IPV dose or an LPV infection [14]. Thus, the use of IPV in this context would provide protection from paralysis to successfully-vaccinated children from LPV2, and add to the population immunity for type 2 after OPV2 cessation, which may help to mitigate cVDPV2 risks. This would increase the chances that any circulating LPV2s brewing prior to OPV2 cessation die out, and extend the time between OPV2 cessation and the time at which the population includes enough effectively susceptible people to sustain LPV2 transmission. The GPEI strategy recognizes that national interests align with respect to the coordination of OPV cessation. Any country can decide to switch from the use of tOPV to IPV in its routine immunization program at any time [1]. However, unilateral cessation of any serotype of OPV (e.g., OPV2 cessation or OPV2 and OPV3 cessation, or OPV cessation altogether) without replacement by IPV carries significant risks of importation of OPV-related viruses from countries that continue to use those OPVs [15]. Up to the point of coordinated cessation of one or more serotypes of OPV, some countries will continue to use tOPV, ideally with a goal of maximizing coverage and their population immunity. At the time of cessation, all countries using tOPV will need to switch to an OPV formulation that contains only the remaining serotypes (i.e., bOPV for OPV2 cessation, mOPV1 for OPV2 and OPV3 cessation, or Expert Rev. Vaccines 13(2), (2014)

IPV, innovation & the endgame of global polio eradication

no OPV in the case of tOPV cessation) [2], with or without also introducing at least one dose of IPV.

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National IPV choices for countries currently using tOPV

Perspective

Switch to IPV-only schedule

Switch to 2 doses of IPV Introduce IPV in primary schedule prior to OPV cessation

IPV/OPV sequential schedule OPV/IPV sequential schedule

Full IM IPV dose We assume that countries that already use IPV in their routine immunization Full ID IPV dose Substitute 1 IPV dose for 1 OPV schedules will continue to do so. These Fractional IM IPV dose dose countries must maintain consistently high Fractional ID IPV dose population immunity, and they will need to recognize that failing to do so will put Full IM IPV dose them at risk for sustained transmission Full ID IPV dose and a potential outbreak following the Add 1 IPV dose Fractional IM IPV dose importation of an LPV [11,16,17]. Fractional ID IPV dose We focus on the choices of countries that currently use tOPV. FIGURE 1 presents Switch to IPV-only schedule the decision tree of their choices prior to Add IPV after Switch to 2 doses of IPV-only schedule and after the time of coordinated global OPV cessation Substitute 1 IPV dose for 1 OPV dose Continue tOPVcessation of one or more OPV serotypes. only until OPV Add 1 IPV dose The status quo in these countries involves cessation three primary doses of tOPV with or without an OPV birth dose and in some No IPV cases additional booster doses [2]. The Figure 1. Decision tree of potential options for countries currently using tOPVchoices include switching to an IPV-only only in routine immunization to introduce IPV. schedule (i.e., three or more doses) [2], ID: Intradermal; IM: Intramuscular; IPV: Inactivated poliovirus vaccine; OPV: Oral switching more than one of the doses in poliovirus vaccine. their entire schedule from OPV to IPV, switching one dose of OPV in their schedule to one dose of IPV, or adding one dose of IPV to to use an OPV2-containing vaccine in its routine immunitheir existing schedule. The switch to an IPV-only or a sequen- zation program, all countries will need to maintain high tial IPV/OPV schedule both represent paths used by many population immunity for type 2 to prevent cVDPV2s. other countries, and we assume that these use full intramuscular doses [2]. The current GPEI strategy proposes adding a sin- Impact of IPV choices on immunity gle dose of IPV to the status quo schedule of three primary Adding or substituting one or more doses of IPV into the routOPV doses prior to OPV2 cessation (defined as switching tine immunization schedule will impact population immunity, from tOPV to bOPV for all routine immunization and SIA because poliovirus vaccines differ with respect to the nature of OPV doses on a specific date), which implies an extra dose in immunological protection that they provide. Specifically, OPV the routine immunization schedule reportable to the WHO on doses that ‘take’ cause an infection in the recipient that leads to the joint reporting form. The extra reportable dose implies a mucosal and humoral immunity and can spread to others leadfour-dose primary schedule for poliovirus vaccine (not includ- ing to secondary protection (i.e., infection and immunity in ing a birth dose if given). The GPEI continues to explore contacts). However, the take rates of OPV vary by serotype potential options to reduce the costs associated with introduc- and setting due to interference between OPV serotypes, interacing IPV into countries that currently use tOPV, including tions with non-polio enteroviruses, and other factors (i.e., after dose-sparing (i.e., fractional doses) and/or intradermal adminis- three tOPV doses, take rates vary over a wide range) [2]. In tration, which may save on vaccine costs and administration contrast, full intramuscular IPV induces humoral immunity in costs, respectively [14,18–20]. Consequently, for both of the a consistently high fraction of recipients of two or more doses options that involve a single IPV dose, FIGURE 1 includes possible started at or after 8 weeks of age (i.e., take rates of 89% or combinations of full, fractional, intramuscular (IM) and intra- more) [2,3,21,22]. IPV protects the vaccine recipient from paralydermal (ID) administration. sis, but does not protect the individual as well from re-infection Although some countries currently perform SIAs to increase or reduce fecal excretion following re-infection as much as population immunity in the context of eradication efforts, we OPV (i.e., IPV provides much weaker intestinal immunassume that a change in the routine immunization schedule ity) [23,24]. In the absence of any known paralytic cases with a will not impact the conduct of SIAs, and consequently we do history of successful IPV vaccination, we assume that IPVnot include SIAs in FIGURE 1. As long as any country continues induced seroconversion provides permanent protection from

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paralytic poliomyelitis [23]. However, substantial uncertainty exists related to the duration of protection for primed IPV recipients who did not seroconvert or receive additional doses to follow priming [23,24]. Maternal immunity impacts the immunogenicity of IPV [3,25], which means the vaccine schedule for IPV doses must balance the trade-off between giving doses to infants that do not take due to maternal antibodies versus leaving infants with insufficient or no maternal antibodies unprotected. Studies demonstrate higher take rates for IPV given at 8 weeks than at 6 weeks [3], which leads to the recommendation to delay the first dose of IPV until after 2 months of age [26]. For countries using a 6, 10, 14-week tOPV schedule, introducing IPV along with an OPV dose would need to occur after the first dose, or else countries would need to shift their poliovirus vaccine schedule to older ages. Introducing IPV after OPV in the routine immunization schedule will still allow for the OPV infections to cause VAPP. Thus, although many countries switched from a schedule with OPV-only to one with IPV-only or sequential IPV/OPV to eliminate VAPP, countries that add a dose of IPV after doses of OPV will not benefit from the same reduction of VAPP. This suggests that countries concerned with VAPP may want to consider a sequential IPV/OPV schedule, which may require shifting the timing of the doses. OPV2 cessation will end cases of VAPP associated with type 2, but it will not prevent VAPP associated with OPV1 and OPV3, and the rates of these types of VAPP may change in the absence of OPV2. TABLE 1 shows the potential impact on VAPP, individual immunity for the vaccine recipient, and population immunity of different national routine immunization IPV choices for countries that currently use tOPV for routine immunization. A full IPV schedule will eliminate VAPP and provide better seroconversion of all serotypes than a full tOPV schedule and thus better individual protection from disease [2,3,21,22], particularly in settings of intense exposure to enteroviruses (i.e., settings of intense fecal-oral transmission). Therefore, switching the entire routine immunization schedule from tOPV to IPV with no changes in SIAs provides an improvement in individual immunity for vaccine recipients. At the population level, relatively higher seroconversion rates for IPV imply that a higher fraction of routine immunization vaccine recipients will acquire partial protection from participation in poliovirus transmission. However, with respect to population immunity to poliovirus transmission (i.e., the aggregate potential of all members of a population to participate in poliovirus transmission, including asymptomatic participation on transmission) [18,24,27], the evidence suggests that IPVimmunes exhibit a much higher potential to participate in fecal-oral transmission than OPV-immunes [24,27] and a relatively smaller fraction of the total population may benefit from vaccine-induced immunity. Consequently, a switch to IPV may potentially decrease population immunity to poliovirus transmission despite the relatively better individual seroconversion rates of IPV than OPV, particularly in settings of intense fecal224

oral transmission. Recent isolations of WPV1 from sewage samples throughout Israel demonstrate the possibility of widespread poliovirus transmission despite high IPV coverage [11]. Because IPV does not secondarily immunize contacts of vaccine recipients, all unvaccinated children will remain susceptible in an all-IPV schedule (in the absence of OPV SIAs or outbreaks with LPVs). In a schedule that includes OPV, some fraction of children not reached by vaccination directly become secondarily immunized if their contacts receive OPV, particularly for type 2 [24,27]. In addition, if the introduction of IPV diverts resources such that SIAs occur with reduced intensity for one or more serotypes (e.g., fewer SIAs or reliance on bOPV SIAs exclusively), then this could lead to individual immunity gaps for non-targeted serotypes in areas that rely on SIAs to sustain sufficiently high population immunity to prevent transmission. TABLE 1 shows this by separately including consideration of SIAs for the IPV-only strategy, with limited impact of switching to IPV on population immunity in areas that continue OPV SIAs targeting all serotypes. The net effect will depend on the conditions in individual countries, and it remains uncertain given the absence of substantial field experience with IPV in settings of intense fecal-oral transmission. Recent modeling results provide specific examples and further insights into how routine immunization coverage in schedules with IPV may interact with population immunity thresholds, particularly in the context of coordinated OPV2 cessation [28,29, DUINTJER TEBBENS RJ, THOMPSON KM. MODELING THE POTENTIAL ROLE OF INACTIVATED POLIOVIRUS VACCINE TO MANAGE THE RISKS OF ORAL POLIOVIRUS VACCINE CESSATION.

J. Infect. Dis. (2013) (SUBMITTED); KALKOWSKA D, DUINTJER TEBBENS RJ, THOMPSON KM. MODELING

STRATEGIES TO INCREASE POPULATION IMMUNITY AND PREVENT THE TRANSMISSION OF

POLIOVIRUS INFECTIONS IN THE HIGH-RISK AREA OF NORTHWEST

NIGERIA. J Infect Dis. (2013)

(SUBMITTED)].

Substituting one or more doses of IPV for OPV doses (i.e., a sequential schedule of IPV/OPV or OPV/IPV or an OPV schedule with one IPV dose substituted in) would lead to an expected increase in individual immunity for vaccine recipients and will significantly reduce or even eliminate VAPP if the IPV doses precede the OPV doses [30]. The sequential schedule may still decrease population immunity in settings of intense fecaloral transmission, because children who do not take the OPV doses will not acquire the enhanced intestinal immunity associated with OPV, and the population will not benefit from as much immunity derived from secondary OPV. Similarly, if the substitution of an IPV dose for an OPV dose occurs with reduced SIAs for one or more serotypes in a setting of suboptimal routine coverage, then this also will decrease population immunity for those types. Although a single IPV dose in previously-susceptible vaccine recipients induces relatively low rates of seroconversion, it may successfully prime these individuals to induce good seroconversion and higher antibodies after receipt of a subsequent IPV or OPV dose [2,3,21,22,24,27]. We assume that substituting one IPV dose for one OPV dose also improves individual immunity for vaccine recipients, which may or may not increase overall population immunity depending on the coverage, take rates and current role of secondary OPV in providing immunity. Expert Rev. Vaccines 13(2), (2014)

IPV, innovation & the endgame of global polio eradication

Perspective

Table 1. Impact of different IPV choices on individual immunity to paralytic poliomyelitis for vaccine recipients and population immunity to poliovirus transmission, based on reviews of OPV and IPV seroconversion studies, an expert literature review on immunity to poliovirus transmission and modeling. Impact on VAPP

Impact on individual immunity to paralytic poliomyelitis

Impact on population immunity to poliovirus transmission and cVDPV risk

Switch to IPV-only schedule (in countries with no SIAs)

Elimination

Increase

Potential decrease, particularly in settings of intense fecal-oral transmission (see text)

Switch to IPV-only schedule and continue OPV SIAs targeting all serotypes (in countries with suboptimal routine coverage that need SIAs)

Reduction

Increase

Limited impact

Switch to IPV-only schedule and decrease OPV SIAs of one or more serotypes (in countries with suboptimal routine coverage that need SIAs)

Reduction

Possible type-specific immunity gaps

Type-specific decrease regardless of intensity of fecal-oral transmission

Substitute one or more doses of IPV for OPV (in countries with no SIAs)

Reduction if IPV precedes OPV

Increase

Potential decrease, particularly in settings of intense fecal-oral transmission (see text)

Substitute one or more doses of IPV for OPV and continue OPV SIAs targeting all serotypes (in countries with sub-optimal routine coverage that need SIAs)

Reduction if IPV precedes OPV

Increase

Limited impact

Substitute one or more doses of IPV for OPV and decrease OPV SIAs of one or more serotypes (in countries with no SIAs)

Reduction if IPV precedes OPV

Possible type-specific immunity gaps

Type-specific decrease regardless of intensity of fecal-oral transmission

Add one IPV dose

Reduction if IPV precedes OPV

Increase (less increase if IPV precedes OPV)

Increase (unless OPV SIAs decrease for 1 or more serotypes)

Any IPV schedule (in any combination with OPV serotypes still in use, analogous to schedules in the top of the table)

Elimination/reduction

Increase, unless sub-optimal routine coverage no longer supplemented with IPV SIAs

Probable decrease, particularly in settings of intense fecal-oral transmission (see text)

No IPV

Depends on continued OPV serotypes

No protection for serotypes not covered by a vaccine

Significant decrease, population at increased risk for cVDPVs

IPV choice

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Introduce IPV prior to OPV cessation

Introduce IPV at OPV cessation

cVDPVs: Circulating vaccine-derived polioviruses; IPV: Inactivated poliovirus vaccine; OPV: Oral poliovirus vaccine; SIAs: Supplemental immunization activities; VAPP: Vaccine-associated paralytic poliomyelitis. Data taken from [2,3,5,16,21–24,27].

Adding an IPV dose to the existing routine schedule and assuming no impact on SIAs improves overall individual and population immunity by providing an extra opportunity for vaccine recipients to develop immunity. The dependence on the timing and ordering of the single IPV dose remains unknown, with earlier administration of the IPV dose potentially leading to more interference by maternal antibodies, but providing some reduction in VAPP cases (although the same www.expert-reviews.com

maternal immunity that interferes with IPV seroconversion may also reduce VAPP). Recent studies demonstrate the potential to use fractional doses of IPV instead of full doses, with relatively small, but measurable impacts on seroconversion and immunogenicity associated with lower levels of titers in the vaccine [14,18–20]. The relatively lower seroconversion rates associated with fractional doses lead to some decrease in individual immunity, 225

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Perspective

Thompson & Duintjer Tebbens

which will translate to decreases in population immunity. The method of administration may also impact the titers of vaccine received, and consequently cost-reduction measures will on-net lead to an expected reduction in individual and population immunity relative to the potential impacts shown in TABLE 1, with the amount of reduction depending on the actual choices made and conditions that exist in the country. Introducing IPV after OPV cessation will improve individual immunity, unless it implies that areas that rely on SIAs for their immunity would reduce or stop these SIAs. The introduction of IPV will potentially decrease population immunity to poliovirus transmission compared to OPV use in settings of intense fecal-oral transmission (particularly if coupled with reduced SIAs), but it will provide more population immunity to poliovirus transmission for serotypes stopped compared to no IPV use after OPV cessation of one or more serotypes [28,29, DUINTJER TEBBENS RJ, THOMPSON KM. MODELING

THE POTENTIAL ROLE OF INACTIVATED

POLIOVIRUS VACCINE TO MANAGE THE RISKS OF ORAL POLIOVIRUS VACCINE CESSATION.

J. Infect.

Dis. (2013) (SUBMITTED); KALKOWSKA D, DUINTJER TEBBENS RJ, THOMPSON KM. MODELING STRATEGIES TO INCREASE POPULATION IMMUNITY AND PREVENT THE TRANSMISSION OF POLIOVIRUS INFECTIONS IN THE HIGH-RISK AREA OF NORTHWEST

NIGERIA. J Infect Dis. (2013)

(SUBMITTED)].

The timing of IPV introduction will impact the dynamics of population immunity, which should represent an important consideration for all national policy makers. Adding an IPV dose will increase population immunity to all three serotypes (including types 1 and 3), and it will reduce the rate of decline in population immunity to type 2 following OPV2 cessation (if added prior to OPV2 cessation), although in most cases not enough to keep population immunity above the threshold required to prevent cVDPV2 emergence [28,29,

DUINTJER TEBBENS RJ, THOMPSON KM. MODELING

THE POTENTIAL ROLE OF INACTIVATED

POLIOVIRUS VACCINE TO MANAGE THE RISKS OF ORAL POLIOVIRUS VACCINE CESSATION.

J. Infect.

Dis. (2013) (SUBMITTED); KALKOWSKA D, DUINTJER TEBBENS RJ, THOMPSON KM. MODELING STRATEGIES TO INCREASE POPULATION IMMUNITY AND PREVENT THE TRANSMISSION OF POLIOVIRUS INFECTIONS IN THE HIGH-RISK AREA OF NORTHWEST NIGERIA. J Infect Dis. (2013) (SUBMITTED)]. Population immunity levels impact the transmission and die out of OPV [5,16,27–29, DUINTJER TEBBENS RJ, THOMPSON KM. MODELING THE POTENTIAL ROLE OF INACTIVATED POLIOVIRUS VACCINE TO MANAGE THE RISKS OF ORAL POLIOVIRUS VACCINE CESSATION.

J. Infect. Dis. (2013) (SUBMITTED); KALKOWSKA D, DUINTJER

TEBBENS RJ, THOMPSON KM. MODELING

STRATEGIES TO INCREASE POPULATION IMMUNITY AND

PREVENT THE TRANSMISSION OF POLIOVIRUS INFECTIONS IN THE HIGH-RISK AREA OF NORTHWEST

NIGERIA. J Infect Dis. (2013) (SUBMITTED)],

and increasing population immunity for a specific serotype prior to OPV cessation of that serotype above the threshold required to prevent sustained transmission represents the best strategy to prevent cVDPVs. Countries with population immunity levels close to the threshold that add IPV doses prior to OPV cessation may get the boost required to prevent the development of cVDPV2s and/or sustained transmission of any imported LPV2s, but this will depend on the level of coverage achieved. The introduction of insufficient levels of IPV at the time of OPV2 cessation may leave countries vulnerable to the emergence of cVDPV2s, which may then take longer to emerge and to get detected [11,13]. Thus, prior to OPV2 cessation, countries

226

currently using tOPV will likely find it in their interest to maximize their population immunity to type 2, by maximizing their use of tOPV in SIAs and potentially by adding IPV to their routine immunization schedules if they obtain high routine immunization coverage, because this will give them the best chances of observing die out following coordinated OPV2 cessation. The impact of replacing OPV doses with IPV doses (i.e., as opposed to adding extra IPV doses) remains uncertain and the timing also represents an important consideration. While immunogenicity remains higher for at least two IPV doses than for at least two tOPV doses, particularly in countries with intense fecal-oral transmission leading to interference of OPV take with other enteroviruses, those same countries also experience the lowest impact of IPV on population immunity to poliovirus transmission. This occurs because IPV does not provide as much protection against (asymptomatic) intestinal infections and fecal excretion as OPV and IPV-only provides immunity to vaccine recipients. Thus, introducing IPV before or after OPV2 cessation would prevent some cases of paralysis in vaccine recipients and prime vaccine recipients such that they may not need two doses before they respond if later exposed to another dose of IPV or to an LPV, assuming sufficient duration of priming. If the IPV coverage leads to a net increase in population immunity (i.e., if increased take with IPV offsets reductions in population immunity associated with the lack of secondary OPV infections and reduced intestinal immunity induction), then its use should reduce transmission of any circulating or imported LPVs. With respect to cVDPVs, we must appreciate that IPV may reduce cases of paralysis, which we observe, while still allowing for sustained transmission [11]. Impact of IPV choices on costs

The impacts of vaccine choices on population immunity represent one consideration for national immunization programs, but costs typically emerge as the most important consideration, particularly given competition for limited resources. Currently UNICEF procures IPV for approximately US$3.00/dose [3] and PAHO for approximately US$6.00/dose [31] which represents a significantly higher vaccine price than the US$0.10–US $0.20 price/dose of tOPV [103]. We previously considered the risks, costs and benefits of switching to IPV or stopping poliovirus vaccination after the successful eradication of all three WPV serotypes [32]. Based on this analysis, we found that switching to IPV offered the lowest risk option, but not the lowest cost option, and we recommended that the GPEI and manufacturers invest in efforts to reduce IPV costs to improve the cost–effectiveness of IPV. Any option of substituting one dose (or more) of IPV for OPV or adding a dose of IPV in an existing schedule implies incremental costs related to the difference between vaccine and administration costs for the IPV dose(s) compared to the current schedule of OPV dose(s). The relatively higher vaccine and administration costs of IPV compared to OPV mean that national immunization budgets must increase to support the Expert Rev. Vaccines 13(2), (2014)

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IPV, innovation & the endgame of global polio eradication

change, which motivates efforts to get IPV costs as close to OPV costs as possible by seeking reductions in the costs of the vaccine, the amount of vaccine used per dose and administration. Investment in efforts to decrease the costs of IPV production and/or administration yielded some innovations in the past several years. Multiple studies support the potential use of fractional doses of IPV and administration using alternative mechanisms (e.g., ID IPV) [14,18–20], although few estimates of cost exist for these studies and some regulatory issues remain, which will likely impact the cost per dose. Using fractional doses at the level of one-fifth the full dose (i.e., five fractional doses per single full-dose vial of IPV) appears to yield promising results, with relatively small but measurable impacts on immunogenicity associated with lower levels of titers in the vaccine [14,18–20], as reviewed, discussed and further interpreted elsewhere [3]. As a result, fractional dosing currently represents the leading strategy to reduce IPV vaccine costs, although currently it would require ‘off-label’ use of IPV based on the existing studies. Stretching IPV to get five fractional doses per fulldose vial would reduce the costs per dose by approximately a factor of 5. In the context of IPV multi-use vials, we must account for the high likelihood of increased wastage, because routine immunization programs will most likely need to discard opened IPV vials at the end of an immunization session or within 6 h of opening (whichever occurs sooner) based on existing WHO policy [33]. This contrasts significantly with OPV multi-dose vials, which can remain in use until 4 weeks (28 days) after opening as long as proper handling and storage occurs between doses [33]. Several studies demonstrate the significant increase in wastage that can occur in the context of switching from single dose to multi-dose vials [34,35]. Changing the vial size also implies logistical and training challenges to ensure proper discarding of opened vials while minimizing wastage. The use of fractional doses will also raise issues for manufacturers, due to the lower immunogenicity of the lower-titer dose, which differs from the labeled use. Concurrent administration of IPV with OPV also represents a new use of IPV in most countries that may require additional studies to demonstrate safety and efficacy for regulatory purposes, although some clinical data already exist with concurrent IPV and OPV administration in various schedules [36–40]. Manufacturers lack incentives to support the use of fractional doses, particularly if relabeling for this use would require them to conduct additional studies and seek regulatory approval for a product that represents an inferior option to their existing, licensed full dose product. Manufacturers also would most likely prefer to increase overall production of IPV, which would allow them to reduce the costs per dose due to production economies of scale. At this point, manufacturers expect that most of the IPV they will sell to UNICEF will come in multi-dose vials, with the October 2013 UNICEF tender requesting 10-dose and 5-dose presentations of WHO prequalified IPV [104], and the list of WHO prequalified vaccines currently including a 10-dose vial presentation from one manufacturer [105]. www.expert-reviews.com

Perspective

Multi-dose vials decrease finish and filling costs and lead to a lower price per dose, but they also lead to increased wastage in practice, which may offset some (and potentially all) [34,35] of the benefits derived from increasing the vial size. Given the expectation of multi-full-dose vials and the potential consideration of the use of fractional doses in national immunization programs, this raises the possibility of relatively large numbers of fractional doses per vial (e.g., 50 fractional (1/5th) doses from a 10-fulldose vial), and the possibility of very high wastage, safety concerns and/or missed children, due to reluctance of routine immunization providers to open vials to vaccinate a few children in order to avoid large amounts of wastage at the end of the day. Manufacturers continue to explore opportunities for dosesparing using adjuvants [41,42] and/or ways to increase yields in production through biotechnological innovations, but the impact of these approaches on IPV costs remains uncertain. Several groups developed the technology to produce IPV from Sabin (i.e., OPV) seed strains [43,44]. Using OPV seed strains may offer some savings, because the Sabin seed strains represent less virulent strains than the WPV seed strains used to produce conventional IPV, but both LPV seed strains pose real risks if released and require the same aggressive containment [45]. Using Sabin seed strains does not appear to decrease the IPV vaccine cost per dose [43,44]. We currently assume no expected reduction in IPV costs associated with manufacturing, although we see significant potential benefits associated with innovations that could potentially reduce future costs. With respect to administration costs, three innovations may reduce or eliminate the use of needles and eliminate the associated costs for needles and their disposal. First, increased adoption of IPV-containing combination vaccines will reduce the administration costs attributable to IPV by sharing them with other antigens in the vaccine [46]. However, using IPV in combination vaccines impacts the formulation of the pertussis component in pertussis-containing combination vaccines (i.e., whole-cell or acellular), which may impact vaccine cost, safety and/or immunogenicity [32,47]. Second, fractional dosing administered with a jet injector may make it easier to administer IPV [18], which may decrease the level of staff required, although the net impact on costs of this strategy remains difficult to estimate in the absence of a specific licensed technology. Third, efforts to develop a microneedle patch technology for vaccine administration could revolutionize vaccine administration, particularly if the patches allow for dose sparing and/or if the use of dissolving polymers for the patch essentially eliminates the need for waste disposal [48,49]. At this point, combination vaccines and jet injectors for intradermal administration represent the most mature approaches, and combination vaccines will most likely emerge as the preferred long-term option, although they will not become available for all markets for several years. However, the development of a microneedle patch could make it cheaper and easier to deliver poliovirus vaccine separately. We could even imagine the development of an ‘eradicated virus’ combination vaccine patch, which might ultimately contain antigens for polio, measles and rubella. 227

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Estimates of the costs associated with introducing IPV into current OPV-only routine immunization schedules

Despite all of the innovations to date, prior estimates of the vaccine costs [46], adjusted to US$ 2013 accounting for inflation, appear to still represent the best available estimates for the projected costs, with the assumption that the prior estimates represent vaccine prices for a 10-dose vial presentation. We use the estimated costs of the IPV component of combination vaccines as the basis for our estimate of cost for IPV in a stand alone 1-dose vial (e.g., costs associated with the pertussis component of the combination vaccine offset costs associated with finish and fill capacity increases). TABLE 2 summarizes our current best estimates of average vaccine cost, wastage and administration costs per dose for different presentations and administration strategies for countries characterized as within the low-, lower middle- and upper middle-income groups defined by the World Bank [106]. TABLE 2 does not include high-income countries, because they all currently use IPV [2,32] and, thus, we do not anticipate any incremental costs for these countries. We assume that vaccine cost per dose covers the cost of the packaged vaccine, wastage per dose equals one minus the fraction of

distributed doses to the country (D) that get administered (A) (i.e., 1-A/D) [50] and administration costs per dose cover all non-vaccine materials, delivery and logistics costs paid to vaccinate an individual (e.g., injection supplies, waste disposal, personnel, training, reporting, etc.) [46]. The estimates in TABLE 2 do not account for any real reduction in costs that may occur in the future associated with manufacturing process changes or global economies of scale that would result from all countries adopting more than one dose of IPV in their routine immunization schedules. The estimates of administration costs attribute a fraction of all routine immunization program costs to polio using data from 13 low- and lower middle-income countries as described elsewhere [46]. We assume that the multi-dose vial presentations of IPV will lead to increased wastage due to the current open vial policy [33]. In its tender, UNICEF assumes 10% and 50% wastage associated with unused opened 5- and 10-dose vials, respectively [104]. We assume that these estimates do not include other types of wastage that occur throughout the system even with 1-dose vials, which we previously estimated as 10%, 10% and 5% for low-, lower middle- and upper middle-income countries,

Table 2. Estimated vaccine costs, vaccine wastage, and administration costs per dose for polio routine immunization options in US$ 2013 based on prior cost estimates and assumptions regarding wastage and prices for number of IPV doses in the routine immunization schedule, vial size and administration strategy as outlined in the text. Inputs (per dose) by World Bank income group [104]

IPV doses†

Vial size

Inflation-adjusted prior estimates

Vaccine cost per dose (US$)

Vaccine wastage per dose‡ (%)

Administration cost per dose (US$)

LOW

LMI

UMI

LOW

LMI

UMI

LOW

LMI

UMI

OPV

0

‡ 10

0.12

0.12

0.13

20

20

15

0.87

0.87

1.86

Stand alone, full IM IPV

any

1

2.5

4.5

6.0

10

10

5

1.08

1.08

2.86

Combination, full IM IPV

any

1

2.5

4.5

6.0

10

10

5

0.27

0.27

0.69

Stand alone, full IM IPV

3+

5

2.0

3.5

4.6

20

20

15

1.08

1.08

2.86

Stand alone, full IM IPV

2

5

2.0

3.5

4.6

30

30

25

1.08

1.08

2.86

Stand alone, full IM IPV

1

5

2.0

3.5

4.6

40

40

35

1.08

1.08

2.86

Stand alone, full IM IPV

3+

10

1.3

2.3

3.2

60

60

55

1.08

1.08

2.86

Stand alone, full IM IPV

2

10

1.3

2.3

3.2

70

70

65

1.08

1.08

2.86

Stand alone, full IM IPV

1

10

1.3

2.3

3.2

80

80

75

1.08

1.08

2.86

Stand alone, full ID IPV

1

1

2.5

4.5

6.0

20

20

15

0.98

0.98

2.36

0.5

0.9

1.2

50

50

45

0.98

0.98

2.36

Assumptions for new options

Stand alone, fractional (1/5 full) ID IPV

1

§

1



Number of IPV doses in the national immunization schedule (impacts arrival rate of eligible children) Defined as one minus the fraction of distributed doses (D) that get administered (A) (i.e., 1-A/D) [50] Vial containing one full dose of IPV, corresponding to five fractional doses administered from each vial ID: Intradermal; IM: Intramuscular; IPV: Inactivated poliovirus vaccine; LMI: Lower middle-income country; LOW: Low income country; OPV: Oral poliovirus vaccine; UMI: Upper middle-income country. Data taken from [46]. ‡ §

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IPV, innovation & the endgame of global polio eradication

respectively (TABLE 2) [46]. Thus, we use the UNICEF estimates of wastage for unused opened vials as our estimated increased absolute wastage for these presentations compared to 1-dose vials for national immunization schedules with more than one dose of IPV (e.g., IPV-only and sequential schedules). In countries using multi-dose vials within national immunization schedules that include one or two doses of IPV in their schedules, we account for the less frequent arrival rate of eligible children to vaccinate in a routine immunization session [35] by increasing the absolute wastage by an additional 20% or 10%, respectively. We assume the cost of ID IPV administration falls halfway between the cost of OPV and IM IPV (i.e., it will require more trained staff and lead to more non-vaccine administration materials costs than required for OPV, but not as much as for IM IPV), with 20% higher wastage due to more challenges in administration. Although the cost may fall anywhere between the OPV and IM IPV administration costs, if ID IPV administration costs more than IM IPV administration, then we assume that countries will not use it. The estimates in TABLE 2 assume that national immunization programs would only use fractional doses from 1-dose vials, which would allow for division of the per dose vaccine cost by a factor of five. In the context of availability of only multi-dose vials, we assume that fractional IPV would not represent a reasonable strategy for national immunization programs due to excessive wastage (e.g., routine immunization programs would need to use 25–50 fractional IPV doses per session or within 6 h to use all of the vaccine in the 5-dose or 10-dose vial). The cost and wastage estimates in TABLE 2 represent uncertain values that reflect the available information, and future efforts should revisit these estimates as more information becomes available. In addition, if WHO provides an open-vial policy that will allow for longer use of IPV from opened multi-dose vials of IPV, then this could significantly decrease the impacts of wastage. Using the estimates in TABLES 2 & 3 provides estimates of the incremental costs associated with many of the IPV routine immunization options shown in FIGURE 1 with consideration of schedule and vaccine presentation (i.e., vial size, stand alone and combination) compared to three doses of tOPV. We assume that countries reach the same levels of coverage independent of vaccine choice without any difference in routine immunization system costs. The results in TABLE 3 show that IPV vaccine costs and wastage assumptions drive the total costs, and they suggest that 1-dose and 5-dose vials represent better options than 10-dose vials with respect to total costs due to relatively large expected wastage. The ability to use 1-dose vials for ID IPV and fractional ID IPV administration will depend on access to 1-dose vials by all countries that may wish to use these strategies. Considering current discussions, we do not anticipate a large global supply of 1-dose IPV vials, at least not available from UNICEF, and this may significantly impact the ability of countries who wish to use fractional ID IPV doses. The costs in TABLE 3 suggest significant increases in national routine immunization costs associated with the adoption of IPV by countries that currently use tOPV only. These results www.expert-reviews.com

Perspective

indicate the need for ongoing and urgent efforts to decrease IPV costs. The use of adjuvants and/or other manufacturing strategies to increase yield may decrease the vaccine cost of IPV substantially, and although these efforts represent critical areas for innovation, we cannot currently quantify their potential impact. The estimates reveal the significance of better understanding the potential for wastage in the context of the selected schedule and the need for better information about costs. In many countries strengthening routine immunization represents an overall aspiration, which extends beyond polio, but impacts polio immunization. Any costs, incurred to strengthen routine immunization specific to polio may also provide external benefits for other vaccines, and vice versa. Our simplistic discussion does not capture these costs. In addition, we implicitly assumed that the existing routine immunization infrastructure in each country could deliver the IPV doses, including an additional dose of IPV in the schedule, at a constant cost per dose by vaccine type without additional resources related to infrastructure (i.e., without the need to expand the cold chain). Additional research will need to characterize the impacts of any additional routine immunization infrastructure costs required to actually change polio immunization policy. Managing chronic excretors & immunodeficiencyassociated vaccine-derived poliovirus risks

The transition to IPV will also prevent new LPV infections in a small number of individuals with some types of primary immunodeficiencies which can become chronic or prolonged excretors of LPVs, if infected (i.e., immunodeficiency-associated vaccinederived poliovirus [iVDPV] extretors) [51]. As the world eliminates the circulation of LPVs following WPV eradication and OPV cessation of each serotype, the possibility of reintroduction of a LPV from a chronic excretor represents a very small, but real risk [52]. The benefits of IPV relate to the reduction of new iVDPV excretors, but IPV does not clear infections in existing iVDPV excretors. Innovations related to the development of antiviral compounds may provide an option to treat infections in iVDPV excretors [53], but until such compounds become available, efforts to reduce the number of new iVDPV excretors (e.g., using IPV instead of OPV for individuals with primary immunodeficiencies) represent important risk management opportunities. Discussion

The polio endgame continues to evolve, with efforts to reduce IPV costs representing a priority for multiple stakeholders. Switching from OPV to IPV represents the best opportunity to reduce risks after WPV eradication and OPV cessation, but it comes at a cost and does not substitute for efforts to manage risks aggressively before OPV cessation (i.e., prevention) [16,28]. Current innovation efforts promise to reduce IPV vaccine and administration costs, but we cannot accurately forecast either the timing of the availability or costs of lower-cost IPV options. The world urgently needs a low-cost IPV option, and efforts to reduce IPV vaccine and administration costs should accelerate as much as possible so that national policy makers 229

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Table 3. Numbers of OPV and IPV doses in the schedule, IPV vial size & estimated incremental costs (US$ 2013) per immunized child (i.e., including all doses in the routine immunization schedule) for vaccine (including adjustment for wastage), administration and the total compared to three doses of OPV (reference) by World Bank Income Group.

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Options

OPV total cost (reference case)†

OPV doses

3

IPV doses

IPV vial size

Incremental vaccine cost per immunized child (US$)

Incremental administration cost per immunized child (US$)

Incremental total cost per immunized child (US$)

LOW

LOW

LOW

LMI

0

0

Reference

UMI

LMI

UMI

Reference

LMI

UMI

Reference

Stand alone, full IM IPV Switch to IPV-only

0

3

1

7.88

14.55

18.49

0.63

0.63

3.00

8.51

15.18

21.49

Switch to IPV-only

0

3

5

7.05

12.68

15.78

0.63

0.63

3.00

7.68

13.31

18.78

Switch to IPV-only

0

3

10

9.30

16.80

20.87

0.63

0.63

3.00

9.93

17.43

23.87

Switch to IPV/OPV sequential‡

1

2

1

5.26

9.70

12.33

0.42

0.42

2.00

5.68

10.12

14.33

Switch to IPV/OPV sequential‡

1

2

5

5.41

9.70

11.96

0.42

0.42

2.00

5.83

10.12

13.96

Switch to IPV/OPV sequential‡

1

2

10

8.37

15.03

17.98

0.42

0.42

2.00

8.79

15.45

19.98

Substitute one IPV dose for one OPV dose

2

1

1

2.63

4.85

6.16

0.21

0.21

1.00

2.84

5.06

7.16

Substitute one IPV dose for one OPV dose

2

1

5

3.18

5.68

6.92

0.21

0.21

1.00

3.39

5.89

7.92

Substitute one IPV dose for one OPV dose

2

1

10

6.35

11.35

12.65

0.21

0.21

1.00

6.56

11.56

13.65

Add one IPV dose

3

1

1

2.78

5.00

6.32

1.08

1.08

2.86

3.86

6.08

9.18

Add one IPV dose

3

1

5

3.33

5.83

7.08

1.08

1.08

2.86

4.41

6.91

9.94

Add one IPV dose

3

1

10

6.50

11.50

12.80

1.08

1.08

2.86

7.58

12.58

15.66

Add one full ID IPV dose

3

1

1

3.13

5.63

7.06

0.98

0.98

2.36

4.10

6.60

9.42

Add one fractional ID IPV dose§

3

1

1

1.00

1.80

2.18

0.98

0.98

2.36

1.98

2.78

4.54

3

1

7.88

14.55

18.49

-1.80

-1.80

-3.51

6.08

12.75

14.98

Stand alone, ID IPV

Combination, full IM IPV{ Use combination IPV

0



Vaccine costs (including adjustment for wastage) for the reference of 3 doses of OPV: US$0.45, US$0.45 and US$0.46 for LOW, LMI and UMI, respectively and administration costs: US$2.61, US$2.61, US$5.58 for LOW, LMI and UMI, respectively. Add this amount to all of the other options to get the associated non-incremental cost estimate per immunized child. ‡ Same costs with either order IPV/OPV or OPV/IPV. § May not represent a real option if manufacturers do not produce and/or if UNICEF does not tender sufficient quantities of 1-dose vials. { We assume that these estimates include the potentially significant costs associated with any needed switches from whole cell to acellular pertussis vaccine. Current combination vaccines with IPV generally use acellular pertussis for increased safety, which adds some cost to the vaccines because acellular pertussis costs more to produce on its own than whole-cell pertussis. Recent concerns about effectiveness of acellular pertussis vaccine have emerged due to some resurgence of pertussis, which may lead to a preference by some countries for a combination vaccine with IPV to contain a whole-cell pertussis component, which will require manufacturers to overcome some technical challenges and will add costs. ID: Intradermal; IM: Intramuscular; IPV: Inactivated poliovirus vaccine; LMI: Lower middle-income country; LOW: Low income country; OPV: Oral poliovirus vaccine; UMI: Upper middle-income country.

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IPV, innovation & the endgame of global polio eradication

can decide on their preferred strategy with respect to IPV. We hope that our analysis provides helpful context to policy makers about the trade-offs associated with some of the options. We focus on estimating the total costs independent of who pays the cost, which may help national immunization programs in estimating their costs and also may help other stakeholders as they consider the path ahead. Our analysis remains limited by a lack of information, but it demonstrates the importance of IPV costs in national and global policy making. Some stakeholders may not consider the comparison to OPV costs relevant, or they may prefer to focus on the total costs of all immunization efforts, including routine immunization and SIAs. However, national policy makers will compare the costs and overall budget implications of a new policy for routine immunization to those of the existing policy, and those countries which are conducting SIAs due to insufficient routine immunization coverage should expect to continue them after the introduction of IPV (i.e., if they need SIAs while using tOPV, then they most likely still will need them with IPV). National policy makers should also consider the implications of different IPV options for population immunity, because managing population immunity ultimately represents the key to an eradication program. We see the interdependency that emerges as critical: national policy makers will impact manufacturer choices by the immunization strategies they choose; and manufacturers will impact national immunization options as they determine their IPV products, production capacity and pricing. Charting the course for the polio endgame requires ensuring sufficient quantities of the vaccines needed, including oversupply of tOPV up until the time of OPV cessation of one or more serotypes and then sufficient supplies of licensed bOPV for all OPV-using countries. As we approach the epidemiological situation of no circulation of each serotype of LPV, national and global health leaders will need to work with manufacturers, donors and other stakeholders to ensure smooth and successful transitions and to manage the timing and logistics of supplying the appropriate mixture of poliovirus vaccines. Innovations related to IPV production and administration for poliovirus could potentially impact other vaccines. For example, if manufacturers pursue rapid development of the microneedle patch technology for IPV, then this could provide a platform for more rapid adoption of this potentially valuable administration technology for many vaccines, and perhaps other pharmaceutical products. This investment for polio could potentially decrease the costs of administering vaccines significantly and eliminate the use of needles and syringes, and it could also reduce administration costs if volunteers can administer the microneedle patch (in contrast to requiring highlytrained health care workers to provide injections with needles). Efforts to improve routine immunization coverage for poliovirus vaccines will also potentially improve coverage for other vaccines. Improving the attribution of the costs of routine immunization to individual vaccines may improve overall appreciation of the significant amount of cost-sharing that currently occurs in national routine immunization programs. The www.expert-reviews.com

Perspective

GPEI began conducting SIAs in part due to inadequacies in routine immunization coverage to rapidly achieve and maintain sufficiently high population immunity, and ideally we should seek to improve routine immunization beyond the point at which countries require SIAs to sustain sufficient population immunity. Innovations with respect to the development of polio antiviral compounds may also open up a pathway for further development of antiviral and other compounds that may complement the benefits of vaccines, and these compounds may also play a role in responding to outbreaks. Expert commentary: advice to national immunization program managers using tOPV-only schedules as they consider adding IPV

National immunization program managers face significant challenges as they protect their populations from vaccinepreventable diseases while balancing their budgets. OPV offers a much less expensive option than IPV for routine immunization, and consequently including one or more doses of IPV in the national routine immunization schedule will lead to overall increases in costs. The optimal routine immunization strategy for each country depends on coverage achieved in the existing routine immunization program and in any SIAs used to increase national population immunity. Countries that conduct SIAs should continue campaigns independent of any decision to introduce IPV, because IPV use in routine immunization will not replace the population immunity benefits provided by SIAs. All else equal, adding a dose of IPV to an existing routine immunization schedule will lead to an overall small increase in population immunity, but substituting a dose of IPV in place of a dose of OPV may not lead to a net increase in population immunity. Despite the increase in immunogenicity of an IPV dose to individual vaccine recipients, the loss of intestinal immunity and secondary spread to contacts implies that IPV may represent a better option for individuals who receive vaccine, but a worse option for the population as a whole. Once OPV cessation occurs, IPV will represent the only vaccine option available for routine immunization, so all countries must decide whether and how they want to include IPV in their vaccine schedules or stop poliovirus vaccination for the OPV serotypes. Given the relatively aggressive potential timing for the current strategy of OPV2 cessation, which we assume may occur as early as April 2016, all countries should evaluate their options and develop implementation plans. Countries will need to secure sufficient supplies of tOPV until the point of OPV2 cessation and supplies of licensed bOPV for use in routine immunization after OPV2 cessation is achieved. Those countries that self-produce OPV will need to coordinate the timing of their production of tOPV and bOPV with the global strategy. If countries decide to add IPV to their schedules, then they will need to determine the available vaccine vial size and estimate wastage and costs to order sufficient numbers of vials and ensure sufficient funds. Any national and WHO policies related to the use of doses from 231

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Thompson & Duintjer Tebbens

opened multi-dose vials represent an important consideration with respect to wastage, and immunization program managers should seek to minimize wastage.

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Five-year view

As the near-term IPV options become more clearly defined, analysts will need to refine estimates of the financial costs and immunological benefits of the options. Many uncertainties persist about the cost of the IPV options and the timing of the availability of lower-cost IPV options, and countries will continue to make choices about how they use their limited resources for vaccines. As the world gets closer to WPV eradication, we see a need for rapid innovation to reduce IPV costs. Over the course of the next several years, we will observe the relative success or failure of manufacturers to develop and license IPV formulations that will offer a much lower-cost option for countries currently using tOPV for routine immunization, and we will also observe the choices that countries will make with respect to the adoption of IPV as we move into the polio endgame. We anticipate that by 2018, global health leaders will certify the world free of wild poliovirus type 3 (WPV3), and we hope that we will see the successful elimination of all WPVs and cVPDV2s. We hope that global and national health leaders will succeed with respect to OPV cessation for one or more serotypes, and that the experience will lead to confidence that we can work together on global public health major projects. The future path remains uncertain, but the need for coordination and planning stands out as a clear

requirement for success. If we can manage a successful transition to a world free of circulating LPVs, then this may set the stage for additional global disease coordination efforts. Encouraging national immunization programs to adopt a strategy of managing population immunity for polioviruses may also help to accelerate progress toward achieving WHO regional goals to eliminate measles. Although IPV immunization costs did not change significantly over the past few years, several innovations appear on the horizon that may potentially reduce costs. Acknowledgements

The authors wish to thank the stakeholders and anonymous reviewers who provided comments. Disclaimer

The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the Bill & Melinda Gates Foundation. Financial & competing interests disclosure

The authors thank the Bill & Melinda Gates Foundation for providing a contract to Kid Risk, Inc. to support the completion of this work under Work Order 4533-23446. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • The Global Polio Eradication Initiative continues to make progress toward achieving eradication of all three serotypes of wild polioviruses, which increases the need to prepare for the endgame. • Introducing a dose of inactivated poliovirus vaccine (IPV) as an additional dose in a three-dose tOPV schedule (i.e., adopting a four-dose schedule) increases individual and population immunity, but substituting one or more IPV doses for one or more tOPV doses in routine immunization may not increase population immunity to poliovirus transmission. • IPV and administration costs and wastage will determine the cost–effectiveness of IPV, which will ultimately influence decisions made by countries with respect to the role of IPV in their national immunization programs. • With the apparent disappearance of WPV3, global health leaders may want to consider simultaneous OPV2 and OPV3 cessation, particularly if delays occur with respect to ending cVDPV2 outbreaks.

Papers of special note have been highlighted as: • of interest •• of considerable interest 1

••

Thompson KM, Duintjer Tebbens RJ. Current polio global eradication and control policy options: Perspectives from modeling and prerequisites for OPV cessation. Expert Rev. Vaccines 11(4), 449–459 (2012). This study outlines the decisions and considerations for global polio management and presents a complete decision tree of

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vaccine choices. The study also reviews the literature related to seroconversion associated with different immunization schedules.

the options along with dynamic considerations.

References 2



Thompson KM, Pallansch MA, Duintjer Tebbens RJ, Wassilak SGF, Kim JH, Cochi SL. Pre-eradication national vaccine policy options for poliovirus infection and disease control. Risk Anal. 33(4), 516–543 (2013). This analysis documents the wide spectrum of current strategies that countries use to manage population immunity, including their routine immunization and supplemental immunization activities

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Estivariz C, Pallansch MA, Anand A et al. Poliovirus vaccination options for achieving eradication and securing the endgame. Curr. Opin. Virol. 3, 309–315 (2013).

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World Health Organization. Transmission of wild poliovirus type 2: Apparent global interruption. Wkly Epidemiol. Record. 76, 95–97 (2001).

Expert Rev. Vaccines 13(2), (2014)

IPV, innovation & the endgame of global polio eradication

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Expert Review of Vaccines Downloaded from informahealthcare.com by Nanyang Technological University on 04/27/15 For personal use only.

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Duintjer Tebbens RJ, Pallansch MA, Kim JH et al. Oral poliovirus vaccine evolution and insights relevant to modeling the risks of circulating vaccine-derived polioviruses. Risk Anal. 33(4), 680–702 (2013). WHO. Global Polio Eradication Initiative: Polio Eradication and Endgame Strategic Plan (2013–2018). Report No.: WHO/ POLIO/13.02, Geneva, Switzerland 2013. World Health Organization: Meeting of the Strategic Advisory Group of Experts on immunization. April 2012 — conclusions and recommendations. Wkly Epidemiol. Record 21, 201–216 (2012). World Health Organization: Meeting of the Strategic Advisory Group of Experts on immunization. November 2012: Conclusions and recommendations. Wkly Epidemiol. Record 88, 1–16 (2013).

polio outbreaks and poliovirus vaccine availability for response. Public Health Rep. 127(1), 23–37 (2012). 18

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Resik S, Tejeda A, Lago PM et al. Randomized controlled clinical trial of fractional doses of inactivated poliovirus vaccine administered intradermally by needle-free device in Cuba. J. Infect. Dis. 201(9), 1344–1352 (2011). Mohammed AJ, Al Awaidy S, Bawikar S et al. Fractional doses of inactivated poliovirus vaccine in Oman. N. Engl. J. Med. 362(25), 2351–2359 (2010). Cadorna-Carlos J, Vidor E, Bonnet MC. Randomized controlled study of fractional doses of inactivated poliovirus vaccine administered intradermally with a needle in the Philippines. Int. J. Infect. Dis. 16(2), e110–e116 (2012). Sutter RW, Ca´ceres VM, Ma´s Lago P. The role of routine immunization in the post-certification era. Bull. World Health Organ. 82(1), 31–38 (2004).

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Thompson KM. Modeling poliovirus risks and the legacy of polio eradication. Risk Anal. 33(4), 505–515 (2013).

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Plotkin SA, Vidor E. Poliovirus vaccine – inactivated. In: Vaccines (5th Edition). Plotkin SA, Orenstein WA, Offit PA (Eds). Saunders Elsevier, USA 605–630 (2008).

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Anis E, Kopel E, Singer S et al. Insidious reintroduction of wild poliovirus into Israel, 2013. Euro Surveill. 18, 20586 (2013).

Duintjer Tebbens RJ, Pallansch MA, Chumakov KM et al. Expert review on poliovirus immunity and transmission. Risk Anal. 33(4), 544–605 (2013).

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Eichner M, Dietz K. Eradication of poliomyelitis: When can one be sure that polio virus transmission has been terminated? Am. J. Epidemiol. 143(8), 816–822 (1996).

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Duintjer Tebbens RJ, Pallansch MA, Chumakov KM et al. Review and assessment of poliovirus immunity and transmission: Synthesis of knowledge gaps and identification of research needs. Risk Anal. 33(4), 606–646 (2013).

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Kalkowska D, Duintjer Tebbens RJ, Thompson KM. The probability of undetected wild poliovirus circulation after apparent global interruption of transmission. Am. J. Epidemiol. 175(9), 936–949 (2012). Resik S, Tejeda A, Sutter RW et al. Priming after a fractional dose of inactivated poliovirus vaccine. N. Engl. J. Med. 368(5), 416–424 (2013). Thompson KM, Duintjer Tebbens RJ. The case for cooperation in managing and maintaining the end of poliomyelitis: Stockpile needs and coordinated OPV cessation. Medscape J. Med. 10(8), 190 (2008). Thompson KM, Pallansch MA, Duintjer Tebbens RJ, Wassilak SGF, Cochi SL. Modeling population immunity to support efforts to end the transmission of live polioviruses. Risk Anal. 33(4), 647–663 (2013). Thompson KM, Wallace GS, Duintjer Tebbens RJ et al. Trends in the risk of U.S.

www.expert-reviews.com

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Mateen FJ, Shinohara RT, Sutter RW. Oral and inactivated poliovirus vaccines in the newborn: A review. Vaccine 31(21), 2517–2524 (2013).]

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World Health Organization. Polio vaccines and polio immunization in the pre-eradication era: WHO position paper. Wkly Epidemiol. Record 85(23), 213–228 (2010).

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Duintjer Tebbens RJ, Pallansch MA, Kalkowska DA, Wassilak SG, Cochi SL, Thompson KM. Characterizing poliovirus transmission and evolution: Insights from modeling experiences with wild and vaccine-related polioviruses. Risk Anal. 23(4), 703–749 (2013)

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Thompson KM, Duintjer Tebbens RJ. Modeling the dynamics of oral poliovirus vaccine cessation. J. Infect. Dis. (2014) (In Press).

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This study explores changes in population immunity as a result of OPV cessation.

Perspective

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Kalkowska D, Duintjer Tebbens RJ, Thompson KM. Modeling strategies to increase population immunity and prevent poliovirus transmission in two high-risk areas in northern India. J. Infect. Dis. (2014) (In Press).

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Alexander LN, Seward JF, Santibanez TA et al. Vaccine policy changes and epidemiology of poliomyelitis in the United States. JAMA 292(14), 1696–1701 (2004).

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Pan American Health Organization: Brazil’s Experience with the Development of a Vaccine-Wastage Evaluation System. Pan American Health Organization Immunization Newsletter. 34, 1–8 (2012).

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Thompson KM, Duintjer Tebbens RJ, Pallansch MA et al. The risks, costs, and benefits of future global policies for managing polioviruses. Am. J. Public Health 98(7), 1322–1330 (2008).

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This analysis considered post-WPV eradication vaccine policy options and explored the risks, costs, and benefits of IPV or no polio vaccination compared to continued use of OPV with or without SIAs. The study demonstrated that OPV cessation represented a better option than continued use of OPV after WPV eradication, with the incremental cost-effectiveness and net benefits of the options depending on assumptions made about whether to compare to OPV with or without SIAs as the comparator.

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WHO Policy Statement. The Use of Opened Multi-Dose Vials of Vaccine in Subsequent Immunization Sessions. WHO/V&B/00.09, WHO, Geneva, Switzerland.

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Drain PK, Nelson CM, Lloyd JS. Single-dose versus multi-dose vaccine vials for immunization programmes in developing countries. Bull. World Health Organ. 81, 726–731 (2003).

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This paper explores issues related to vaccine wastage associated with multi-dose vials.

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Lee BY, Norman BA, Assi TA et al. Single versus multi-dose vaccine vials: An economic computational model. Vaccine 28, 5292–5300 (2010).



This paper demonstrates trade-offs between arrival rates of individuals to immunization programs and wastage.

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Modlin JF, Halsey NA, Thoms ML, Meschievitz CK, Patriarca PA. Humoral and mucosal immunity in infants induced by three sequential inactivated poliovirus vaccine-live attenuated oral poliovirus vaccine immunization schedules. Baltimore

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Simizu B, Abe S, Yamamoto H et al. Development of inactivated poliovirus

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Duintjer Tebbens RJ, Sangrujee N, Thompson KM. The costs of polio risk management policies after eradication. Risk Anal. 26(6), 1507–1531 (2006).

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Jefferson R, Rudin M, DiPietranonj C. Systematic review of the effects of pertussis vaccines in children. Vacccine 21, 2003–2014 (2003).

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due to wild or vaccine-derived poliovirus after eradication. Risk Anal. 26(6), 1471–1505 (2006).

vaccine derived from Sabin strains. Biologicals 34(2), 151–154 (2006).

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Naito S, Ito Y, Kiyohara T, Kataoka M, Ochiai M, Takada K. Antigen-loaded dissolving microneedle array as a novel tool for percutaneous vaccination. Vaccine 30(6), 1191–1197 (2012). World Health Organization: Monitoring vaccine wastage at the country level: guidelines for programme managers. Report No.: WHO/V&B/03.18, World Health Organization, Geneva, Switzerland 2003. Kew OM, Sutter RW, de Gourville EM, Dowdle WR, Pallansch MA. Vaccine-derived polioviruses and the endgame strategy for global polio eradication. Ann. Rev. Microbiol. 59, 587–635 (2005). Duintjer Tebbens RJ, Pallansch MA, Kew OM et al. Risks of paralytic disease

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Collett MS, Neyts J, Modlin JF. A case for developing antiviral drugs against polio. Antiviral Res. 79(3), 179–187 (2008).

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Expert Rev. Vaccines 13(2), (2014)

National choices related to inactivated poliovirus vaccine, innovation and the endgame of global polio eradication.

Achieving the goal of a world free of poliomyelitis still requires significant effort. Although polio immunization represents a mature area, the polio...
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