SUPPLEMENT ARTICLE

Modeling the Potential Role of Inactivated Poliovirus Vaccine to Manage the Risks of Oral Poliovirus Vaccine Cessation Radboud J. Duintjer Tebbens1 and Kimberly M. Thompson1,2 1

Kid Risk, Inc, and 2College of Medicine, University of Central Florida, Orlando

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Background. The Global Polio Eradication Initiative plans to stop all oral poliovirus vaccine (OPV) after wild poliovirus eradication, starting with serotype 2. Stakeholders continue to discuss the role of using inactivated poliovirus vaccine (IPV) to manage the risks of circulating vaccine-derived polioviruses (cVDPVs) during the end game. Methods. We use a poliovirus transmission and OPV evolution model to explore the impact of various routine immunization policies involving IPV on population immunity dynamics and the probability and magnitude of cVDPV emergences following OPV cessation. Results. Adding a single IPV dose to an OPV-only routine immunization schedule at or just before OPV cessation produces very limited impact on the probability of cVDPV emergences and the number of expected polio cases in settings in which we expect cVDPVs in the absence of IPV use. The highest-cost option of switching to a 3-dose IPV schedule only marginally decreases cVDPV risks. Discontinuing supplemental immunization activities while introducing IPV prior to OPV cessation leads to an increase in cVDPV risks. Conclusions. Introducing a dose of IPV in countries currently using OPV only for routine immunization offers protection from paralysis to successfully vaccinated recipients, but it does little to protect high-risk populations from cVDPV risks. Keywords. polio; eradication; dynamic modeling; disease outbreaks; inactivated poliovirus vaccine; oral poliovirus vaccine. Global polio eradication requires interrupting the transmission of all wild polioviruses (WPVs) followed by discontinuation of the live, attenuated oral poliovirus vaccine (OPV) to eliminate vaccine-associated paralytic poliomyelitis (VAPP) and the risk of outbreaks due to circulating vaccine-derived polioviruses (cVDPVs) [1, 2]. The last reported type 2 WPV (WPV2) case occurred in 1999 [3], while WPV1 continues to circulate and WPV3-confirmed paralysis still occurred in 2012 [4]. The Global Polio Eradication Initiative (GPEI) plans for global coordinated cessation of type 2containing OPV (OPV2 cessation) [5]. The current strategy calls for the addition of at least 1 dose of

Correspondence: Kimberly Thompson, DR (ScD), Kid Risk, Inc, 10524 Moss Park Rd, Ste 204–364, Orlando, FL 32832 ([email protected]). The Journal of Infectious Diseases® 2014;210(S1):S485–97 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/infdis/jit838

inactivated poliovirus vaccine (IPV) into the routine immunization (RI) schedule of all countries currently using OPV-only prior to or at the time of coordinated OPV2 cessation. The inclusion of IPV would provide protection from paralysis for successfully IPV-vaccinated children in the event of a post-cessation cVDPV outbreak. Even if the low take of the first IPV dose does not result in measurable serum antibodies, some children may experience a priming immune response [6], which could protect them from paralysis and lead to better and faster response to a subsequent IPV or OPV dose during outbreak response activities. Clinical data provide some indication of the effect of IPV on individual protection to paralysis, but its impact on the probability of cVDPV emergence and transmission remains uncertain. This article uses a differential-equation based poliovirus transmission and OPV evolution model [7, 8] to explore the potential impact of IPV use during the end game on the probability and expected size of cVDPV outbreaks after OPV2 cessation. We previously explored the dynamics of OPV cessation in Modeling the Role of IPV in OPV Cessation

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countries using OPV-only RI schedules without the introduction of IPV [9]. We use a similar analytical framework and the same sample of hypothetical populations to assess the impact of IPV on post-cessation cVDPV risks. METHODS Background

Poliovirus Transmission and OPV Evolution Model

The model includes multiple immunity states (eg, maternal immunity, different numbers of prior live poliovirus infections or successful IPV vaccinations, and waning stages for immunity to poliovirus transmission but not to poliomyelitis), preferential age-heterogeneous mixing, and explicit consideration of fecaloral and oropharyngeal transmission [7, 8]. Only fully susceptible individuals and children born with maternal antibodies who no longer possess protective levels can contract paralytic poliomyelitis, while individuals in all other immunity states remain fully and permanently protected from paralysis. The model simulates evolution over 20 stages from fully attenuated OPV (with low basic reproduction number (R0) and paralysisto-infection ratio) to fully reverted cVDPV with the same R0 and paralysis-to-infection ratio as homotypic WPVs, and dieout of transmission when the prevalence of a virus drops S486

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Successful vaccination with the live, attenuated OPV leads to infection and humoral and mucosal immune response that permanently protect the individual from paralytic poliomyelitis and significantly reduce the probability of re-infection and the amount of virus shed from the intestines or oropharynx if reinfected, at least for several years [10, 11]. Live virus infection also implies some chance of immunizing susceptible contacts or boosting the intestinal immunity of immune contacts [12– 15]. However, OPV leads to rare cases of VAPP [16, 17], can evolve to acquire WPV-like properties and cause cVDPV outbreaks in places with low population immunity [18–20], and provides suboptimal seroconversion in poor hygiene settings [21, 22], which implies the need for many repeated doses to achieve “take” of the vaccine. IPV does not cause infection in recipients or contacts and does not cause paralysis. IPV provides high seroconversion for all serotypes after 2 or more doses across different settings [22, 23], which permanently protects the recipient from paralytic poliomyelitis and significantly reduces oropharyngeal reinfection or excretion [10, 24]. However, studies that challenged IPV vaccine recipients with OPV showed a very limited effect on intestinal re-infection and excretion, which implies limited impact on fecal-oral transmission [10, 11, 25]. Based on a comprehensive expert literature review and elicitation process [10, 11] and an extensive model calibration process [7, 8, 11], we use the inputs in Table 1 to characterize the immunity to poliovirus transmission provided by IPV and OPV.

below a certain threshold [7, 8]. Consistent with the evidence [20] the model allows the transmission of more evolved OPVrelated viruses and ultimately cVDPV emergence when population immunity remains low. With high population immunity more evolved OPV-related viruses die out (ie, their prevalence never exceeds the threshold) and only OPV and closely related viruses transmit to a limited extent given sufficient OPV inflow from immunization. Although the OPV evolution process in the model mimics the true complexities involved in cVDPV emergence and ignores stochasticity and microdynamics, it reproduced field experiences with and without cVDPV emergences [7, 8]. We define the effective proportion infectious with OPVrelated viruses (EPIORV) as the infectiousness-weighted prevalence of virus in all stages of OPV evolution [9]. We characterize population immunity to poliovirus transmission as the mixingadjusted effective immune proportion (EPIM), which equals one minus the proportion of all infectible individuals in the population, weighted by their inherent potential to participate in transmission (ie, based on the properties of their immunity states) and age-heterogeneous mixing rates [26]. EIP* = 1–1/R0 represents the threshold population immunity level above which viral transmission will eventually die out [12, 26, 27]. We characterize RI coverage with 3 or more doses and ignore the impact of any birth dose or partial coverage that might in reality occur when some individuals receive less than three doses [9]. We varied the OPV take rate when exploring cVDPV risks, but we used a fixed per-dose IPV take rate of 0.63, which implies 0.95 cumulative take after 3 doses, given the small impact of this assumption [26, 28]. We assume the IPV take rate accounts for any priming effect (ie, a first dose that stimulates the immune system but does not manifest in detectable serum antibodies) and that primed individuals remain protected from paralytic poliomyelitis even in the absence of detectable serum antibodies [6]. For a schedule of 1 IPV dose that represents the only exposure to the serotype, we assume that all vaccine recipients who take or prime move to the 1 successful IPV immunity state at the time of vaccination (assumed to occur at age 3 months). For a schedule of 3 IPV doses, we compute the fraction that takes with 1, 2, or 3 IPV doses and transfer these fractions to the appropriate immunity states [28]. For a schedule that adds 1 IPV dose to the 3 OPV doses, we assume that administration of the IPV dose occurs at the time of the third OPV dose. We assume that all children who would take the OPV dose do so (ie, IPV does not negatively impact the OPV take rate or the associated acquisition of better intestinal immunity) [28]. Those who receive 3 OPV doses without taking then take the IPV according to the IPV take rate. For example, with a trivalent OPV (tOPV) per-dose take rate of 0.50 (ie, the lower bound for type 2 that we considered in an analysis of cVDPV risks [9]), 87.5% will take after 3 OPV doses. This leaves only 12.5% potentially immunized with the added IPV dose at the 0.63 take rate, which implies fewer than 8% of individuals

Table 1. Work

Model Inputs Used for the Different Analyses (Not Including Previously Published Generic Model Inputs [7]), Based on Prior

Fixed Model Inputs Across All Runs

Value 0–2, 3–11 mo; 1–4, 5–9, 10–14, 15–39a; ≥40 ya

Age groups Years before R0 seasonality starts Years before RI starts

5 15

Years before regular SIAs start

25

Years before regular SIAs end Duration of each regular SIA (days)

35 5

Timing of SIAs (day nos. in the year)

0, 60, 120, . . .

RI coverageb before SIAs start Relative total contribution to oropharyngeal transmission (Duintjer Tebbens, Kalkowska, Wassilak, et al, in preparation) [6, 8–10] (recent to last waning stage)c

Linear ramp from 0 (at start of RI) to .5 (at start of regular SIAs)

1 successful IPV dose 2 successful IPV doses

.20–.36 .07–.13

3 or more successful IPV doses

.04–.06

1 live poliovirus infection 2 or more live poliovirus infections

.05–.18 .01–.07

Impact of IPV on OPV Cessation Dynamics

Impact of IPV on Outbreak Response Dynamics

Impact of Later IPV Introduction With Reduced OPV Use and Comparison of IPV Before or After OPV in the RI Schedule

Exploration of Uncertain Assumptions Related to Transmission

.67d

.67d

.67d

.67d

1 successful IPV dose 2 successful IPV doses

.74–.90 .41–.81

.74–.90 .41–.81

.74–.90 .41–.81

.37–.45; .74–.90; 1 .21–.41; .74–.90; 1

3 or more successful IPV doses

.27–.72

.27–.72

.27–.72

.14–.36; .27–.72; 1

1 live poliovirus infection 2 or more live poliovirus infections

.07–.18 .02–.10

.07–.18 .02–.10

.07–.18 .02–.10

.07–.18 .02–.10

.3

.3

.3

.3; .6; .7

13 × .9 .1

13 × .9 .1

13 × .9 .1

13 × .9 .1

180

180

180

180

Analysis-specific Model Inputs (Symbol and/or Unit) Relative total contribution to fecal-oral transmission (Duintjer Tebbens, Kalkowska, Wassilak, et al, in preparation) [6, 8–10] (recent to last waning stage)c Maternally immune

Proportion of transmissions via oropharyngeal route (poro) Basic reproductive no. (R0) (PV1)* R0 amplitude (α)*e Season at cessation (days between seasonal R0 peak and OPV cessation) (sc)* Birth and mortality rate (b and μ, per person per year)*

.04

.04

.04

.04

Strength of preferential mixing (κ)*f

.3

.3

.3

.3

Average per-dose take rate of type 2 tOPV or mOPV (tr)*

.6

.6

.5

.6

Years without SIAs before OPV cessation**

1

1

0 or 1

1

RI coverageb from start of SIAs** Annual no. of SIA rounds**

.6 3

.6 3

.6 1

.6 3

Mediumg

Mediumg

Mediumg

Mediumg

No. of cumulative paralytic cVDPV cases per million people until outbreak detection

NA

1 or 5

NA

NA

Time from outbreak detection until the first oSIA (days)

NA

45

NA

NA

Duration of each oSIA round (days)

NA

5

NA

NA

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.48d

Maternally immune

Table 1 continued.

Impact of IPV on OPV Cessation Dynamics

Analysis-specific Model Inputs (Symbol and/or Unit)

Impact of IPV on Outbreak Response Dynamics

Impact of Later IPV Introduction With Reduced OPV Use and Comparison of IPV Before or After OPV in the RI Schedule

Exploration of Uncertain Assumptions Related to Transmission

Interval between oSIA rounds (days)

NA

30

NA

NA

oSIA impact No. of oSIA rounds

NA NA

Mediumg 4

NA NA

NA NA

Based on prior work [7–12]. Abbreviations: cVDPV, circulating vaccine-derived poliovirus; IPV, inactivated poliovirus vaccine; mo, months; mOPV, monovalent; no, number; OPV; NA, not applicable; OPV, oral poliovirus vaccine; oSIA, outbreak response SIA; PV1, poliovirus type 1; R0, basic reproductive number; RI, routine immunization; SIA, supplemental immunization activity; tOPV, trivalent OPV; y, years.

**Indicates a policy input selected deterministically for the analysis of the impact of IPV on post-cessation cVDPV risks, based the subsample of runs that led to a post-cessation cVDPV emergence in the absence of any IPV use [9]. a

Age groups whose immunity levels impact the fraction of newborns born into the maternally immune state [7].

b

Coverage with exactly 3 RI doses or 4 RI doses (in the event of simultaneous administration of IPV and OPV with the third dose), assuming no partial coverage, birth doses, or booster doses. c

Defined as the product of relative susceptibility, relative infectiousness, and relative duration of infectiousness compared to fully susceptible individuals (eg, value of .1 for a given immunity state means that an individual in that immunity state generates .1 times as many secondary infections given exposure to poliovirus as a fully susceptible individual given the same exposure) [12]. The values in the table reflect the best estimates for type 2 [7, 11].

d

No range from recent to last waning stage specified because maternally immune individuals wane directly to the fully susceptible state.

e

Defined as the “proportional change in R0 due to seasonality” [7, p. 717].

f

Defined as the “proportion of contacts reserved for individuals within the same mixing age group”[7, p. 717].

g

Medium SIA impact assumes true coverage of .8 and repeated missed probability of .85 for each SIA [9].

take due to the added IPV dose. With a higher tOPV take rate (which probably occurs in most settings for type 2 [22]) of, for example, 0.7 the cumulative OPV take equals 0.973, leaving only 0.63 of the remaining 2.7% (ie, 1.7%) to take due to the added IPV dose. We also consider schedules that substitute IPV for the first or third OPV dose. For these schedules, we assume the fraction that takes to OPV at 3 months corresponds to the cumulative take rate of 2 OPV doses, and the fraction of nontakers to the OPV doses that moves to the 1 successful IPV immunity state corresponds to the per-dose IPV take rate. For a first IPV dose schedule we conservatively multiply by the relative susceptibility of maternally immunes (ie, 0.79 for type 2 [7]) to account for the potential interference of maternal antibodies with IPV seroconversion if given around 6 weeks of age. This approach does not consider the impacts of decreased coverage that occurs with later doses in the schedule due to dropout. Analytical Framework

We extend the approach of a previous analysis that explored the dynamics of OPV cessation and cVDPV risks in the absence of IPV use for (1) a relatively high-risk setting without outbreak response, (2) the large space of possible settings for all countries for 16 policies, and (3) the use of OPV for outbreak response after OPV cessation [9]. Table 1 shows the model inputs for S488

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the different analyses of the impact of IPV on OPV cessation behavior. We focus on OPV2 cessation and use model inputs consistent with type 2. For the impact of IPV on OPV2 cessation dynamics, we use the same hypothetical population for which we previously modeled outbreak response to a cVDPV emergence after OPV2 cessation in the absence of any IPV use [9]. We consider various possible scenarios for IPV use, including adding 1 IPV dose to tOPV-only RI 6 months before OPV cessation, adding or substituting 1 IPV dose at OPV cessation, and making a switch to IPV-only RI with OPV cessation. The scenarios of adding and substituting 1 IPV dose at OPV2 cessation remain identical for type 2, although they differ for the other serotypes [26, 28]. We ignore outbreak response except for the analysis of the impact of IPV on outbreak response dynamics, which assumes 4 monovalent OPV (mOPV) outbreak response SIAs (oSIAs) as used previously [9]. We varied the outbreak detection threshold to correspond to the occurrence of either 1 or 5 cumulative paralytic cases per million people [29]. We explored the impact of introducing IPV just before OPV cessation compared to earlier IPV introduction combined with either discontinuing SIAs or discontinuing the third OPV RI dose. For this analysis, we conservatively used the lower bound OPV take rate [7, 9] to maximize the marginal improvement of a single IPV RI dose on overall take and one annual pre-OPV

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*Indicates a setting-specific input varied probabilistically for the analysis of the impact of IPV on post-cessation cVDPV risks, based the subsample of runs that led to a post-cessation cVDPV emergence in the absence of any IPV use [9].

RESULTS Impact of IPV on OPV Cessation Dynamics

Figure 1 shows how IPV use around the time of OPV cessation influences population immunity, the prevalence of OPV-related viruses, and cVDPV emergences. The dotted curve with a 1-year period due to seasonality in R0 shows the threshold population immunity level (EIP*). The solid line shows the population immunity level (EIPM) without IPV, and the dashed lines show the population immunity for the IPV policy scenarios. Die-out eventually occurs when the population immunity curves stay above the threshold, but polioviruses may circulate when the EIPM falls below the EIP*. The model aggregates individual immunity to poliovirus transmission derived from RI, SIAs, and exposure to live polioviruses to determine overall population immunity (ie, EIPM). Relatively large increases in EIPM reflect intense transmission, including outbreaks and SIAs. Introducing an additional IPV dose 6 months before or at OPV cessation

slows down the decrease in population immunity following OPV cessation (Figure 1A). However, the small improvement in the per-dose take rate for IPV compared to tOPV does not offset the significant loss of intestinal immunity and secondary transmission associated with stopping OPV in this example (Table 1). The slower loss of population immunity with IPV than without IPV translates into a slightly faster initial decay of OPV-related virus prevalence (Figure 1B), but using 1 or 3 IPV doses does not slow down population immunity loss enough to avoid the cVDPV emergences (Figure 1C). The model shows that IPV use somewhat delays the cVDPV outbreak, and the switch to 3 IPV doses delays the second epidemic peak by a year. Given the RI coverage in this example (ie, 0.6), the individual immunity induced by IPV-only moderately reduces the expected paralytic incidence (Figure 1C). The difference between adding 1 IPV dose at OPV cessation or 6 months before OPV cessation remains very small, because the relatively high OPV take rate leaves little potential role for IPV to marginally increase the overall fraction of children that take and thus the overall population immunity. Impact of IPV on Post-cessation cVDPV Risks

Table 2 shows how IPV use impacts cVDPV risks based on a sample of 540 runs that reflect different conditions for which cVDPVs emerged following OPV cessation in the absence of any IPV use [9]. A single IPV dose added 6 months before OPV cessation prevented the cVDPV emergence in 73 (14%) runs. Consistent with the behavior in Figure 1, adding 1 IPV dose at OPV cessation led to a very similar result, whereas switching to IPV-only RI at OPV cessation prevented cVDPV emergences in 145 (27%) runs. In the absence of outbreak response activities, the model yields modest reductions in the expected annual paralytic poliomyelitis incidence from cVDPVs for the different IPV options compared to no IPV use. Switching to IPV-only RI at OPV cessation provides the greatest reduction (ie, 52% reduction for all runs and 33% reduction for only those runs in which an outbreak occurs despite IPV use). Table 2 also shows a very small increase in the timing of cVDPV emergence and up to a 1-month delay in outbreak detection for the switch to IPV-only RI at OPV2 cessation. Impact of IPV on Outbreak Response Dynamics

Figure 2 shows how the use of IPV influences the outbreak size in the context of aggressive outbreak response with 4 mOPV oSIAs. In Figure 2A, the oSIA response occurs 45 days after the cumulative incidence per million people first exceeds 1 paralytic case in the model, assuming active surveillance. The response controls the cVDPV outbreak in all scenarios. IPV use in RI slows down the outbreak dynamics and shifts the outbreaks out in time but does not prevent them. The slower dynamics of the cVDPV outbreak with increased IPV use allows the outbreak response rounds to control the outbreak relatively

Modeling the Role of IPV in OPV Cessation

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cessation SIA round to minimize the impact of discontinuing SIAs (Table 1). For the same population, we also compared substituting 1 IPV dose for the first or third OPV dose. We also explored the population immunity behavior resulting from different assumptions about the proportion of transmissions via the oropharyngeal route ( poro) and the impact of IPV-induced immunity on fecal-oral transmission. Although we fixed the setting-specific poro input [7] at 30% (ie, 0.3) [9] to reflect typical conditions in developing countries in general [11], we explored the impact of adding IPV to RI for higher oropharyngeal transmission rates (0.6 or 0.7) [7, 10, 11]. We also considered the assumption that IPV does not impact fecaloral transmission (ie, IPV immunity state properties related to transmission equal fully susceptible immunity state properties with the relative contribution to oropharyngeal transmission held constant), and alternatively that IPV-induced immunity reduces the relative contribution to transmission by twice our best estimates in Table 1 (ie, by multiplying relative infectiousness by 0.5). In addition to the analyses that consider 1 hypothetical population to illustrate behavior (Table 1), we also assess the impact of various IPV scenarios on the probability of cVDPV emergences and potential paralytic cases assuming no outbreak response for the 540 runs we previously found led to cVDPVs after OPV2 cessation in the absence of any IPV use [9]. These 540 runs (ie, 7% of the 8000 total runs [9]) include combinations of variability and policy inputs that represent places most likely to experience cVDPVs after OPV cessation (ie, IPV introduction will not impact cVDPVs risks for the 93% of runs that did not produce cVDPVs, although IPV use in places represented by these runs may reduce other post-eradication risks [2] or the impact of importations from failures to control cVDPVs elsewhere [30]).

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Figure 1. Impact of IPV on the behavior of population immunity, OPV-related prevalence, and cVDPV emergence. A, Population immunity in terms of EIPM and compared to threshold EIP*. B, OPV-related virus prevalence in terms of EPIORV). C, Paralytic poliomyelitis incidence due to fully reverted cVDPVs. Abbreviations: cVDPV, circulating vaccine-derived poliovirus; EIP, effective immune proportion; EIPM, mixing-adjusted effective immune proportion; EPIORV, effective proportion infectious with OPV-related virus; IPV, inactivated poliovirus vaccine; OPV, oral poliovirus vaccine.

earlier compared to the peak, which reduces the expected number of cumulative cases per million people. If outbreak detection occurs when the cumulative incidence per million people first exceeds 5 paralytic cases, then the outbreak response begins S490

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after the outbreak peaks, which leads to similar case estimates with or without IPV. The expected number of cases depends on the population immunity at the time of the outbreak and the timing of the outbreak relative to the peak seasonal

transmission timing. In this example, the outbreak for the scenario that uses the most IPV shows the most intense transmission, which reflects the combination of relatively lower population immunity due to a longer time period without OPV and the outbreak occurring at a time of increasing R0 due to seasonality. Impact of Later IPV Introduction With Reduced OPV Use

Figure 3A highlights the high risk associated with reducing OPV use before OPV cessation, even in the context of increased IPV use. The first scenario in Figure 3A introduces IPV at OPV cessation and continues annual tOPV SIAs up until just before OPV2 cessation in a setting of poor OPV take rates, high R0, and moderate RI coverage (Table 1). This strategy leads to sufficient population immunity at the time of OPV2 cessation to prevent a cVDPV emergence. The second scenario substitutes 1 IPV dose for 1 OPV dose 12 months before OPV cessation but continues annual tOPV SIAs up until OPV2 cessation. The substitution of an IPV dose for an OPV dose leads to losses of secondary and intestinal immunity between the last 2 SIAs. However, the tOPV SIA that occurs just before OPV2 cessation offsets the minimal loss and increases population immunity high enough to prevent a cVDPV emergence. The last scenario in Figure 3A shows that adding 1 IPV dose and stopping tOPV SIAs 12 months before OPV2 cessation leads to a net loss of population immunity and a cVDPV emergence shortly before OPV2 cessation, with

continued.

detection shortly after OPV2 cessation. The corresponding curve in Figure 3A shows an increase in population immunity due to the outbreak at the end of the first year after OPV cessation. Comparison of IPV Before or After OPV in the RI Schedule

Figure 3B shows that substituting IPV for the first instead of the third OPV dose leads to a negligible decrease in population immunity due to the assumed lower take. However, using IPV first will prevent some of the expected 0.02 VAPP cases per million total people or 0.4 per million births associated with the OPVOPV-IPV schedule [16]. Exploration of Uncertain Assumptions Related to Transmission

For the overall variability and policy space, some combinations of assumptions do not lead to cVDPV emergence [9]. Changing the values of one or more inputs may change the scenario from one that leads to cVDPV emergence to one that does not. Unlike more generic assumptions like R0, poro differentially impacts IPV compared to OPV. Figure 4 shows some impact of the assumptions about the uncertain role of oropharyngeal transmission and IPV-induced immunity to fecal-oral poliovirus transmission. For the thick curves in Figure 4A with the best estimate of poro = 0.3, which correspond to identical curves in Figure 1, postcessation cVDPVs emerge regardless of IPV use. In contrast, increasing the relative importance of oropharyngeal transmission implies more impact of both IPV and

Modeling the Role of IPV in OPV Cessation

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Figure 1

Table 2. Results From the Analysis of the Impact of IPV Options on the Number of cVDPV Emergences, Expected Paralytic Cases Based on the Full Sample of 540 Runs, or Only on the Runs That Led to cVDPV Emergence for the IPV Policy Scenario, Outbreak Detection for Only the Runs With cVDPV Emergence for the IPV Policy Scenario, and Detection Timing for Only the Runs With cVDPV Detection for the IPV Policy Scenario Average Annual Incidence (cVDPV Paralytic Cases per Million People per Year) [% Reduction Compared to No IPV Use]a Values for Scenario Indicated for All Runs (n = 540)

No IPV use [7]

540 [100%]

9 [Ref.]

Add 1 IPV dose 6 mo before OPV cessation

467 [86%]

6 [34%]

Add/substitute 1 IPV dose at the time of OPV cessation

473 [88%]

Switch to IPVonly RI with OPV cessation

395 [73%]

Values for No IPV Use vs Indicated IPV Scenario for Runs With cVDPV Emergence Only (n in Column 2)

Average No. of Years Between cVDPV Emergence and Outbreak Detection for No IPV Use vs Indicated IPV Scenario for Runs With cVDPV Detection (n)

.49b

.45b (n = 533)c

9 vs 7 [24%]

.45 vs .48

.46 vs .49 (n = 460)c

6 [33%]

9 vs 7 [24%]

.45 vs .48

.46 vs .49 (n = 467)c

5 [52%]

9 vs 6 [33%]

.42 vs .46

.46 vs .53 (n = 395)c

Abbbreviations: cVDPV, circulating vaccine-derived poliovirus; IPV, inactivated poliovirus vaccine; mo, months; OPV, oral poliovirus vaccine; RI, routine immunization; SIA, supplemental immunization activity. a

Average taken from OPV cessation through 10 years after the last SIA, with no postcessation cVDPV outbreak response SIAs.

b

No comparison made to itself.

c

Slightly fewer runs that the total no. of runs with cVDPV emergences (see second column) because for some runs the outbreak died out naturally before detection of the cVDPV (eg, 7 of the 540 runs died out prior to detection for the No IPV use scenario).

OPV on population immunity to poliovirus transmission. Consequently, with very high poro of 0.7, population immunity increases before OPV cessation such that no cVDPVs emerge regardless of IPV use (dash-dotted curves in Figure 4B). With poro = 0.6, the greater population immunity induced by OPV-only remains insufficient to prevent the cVDPV emergence, whereas adding a dose of IPV in this case increases population immunity enough to prevent the cVDPV emergence (dashed curves in Figure 4B). Figure 4B shows that the assumed impact of IPV-induced immunity on fecal-oral transmission influences the level of population immunity after IPV becomes the only poliovirus vaccine available. However, in this example, cVDPV emergences occurred for the entire wide range of assumptions about the impact of IPV on fecaloral transmission. Figure 4A and 4B show that the benefit of IPV use increases if oropharyngeal transmission dominates even in high R0 settings and/or if IPV substantially reduces participation in fecal-oral poliovirus transmission. Overall, the time since the last OPV SIAs relative to OPV cessation, the RI coverage level, and R0 remain much more important drivers of cVDPV risks [9]. S492

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DISCUSSION The results from this deterministic differential-equation based model for hypothetical populations suggest a small impact of IPV use with respect to mitigating the cVDPV risks in highrisk settings in the absence of IPV use. Model results [7–9, 12, 26, 28, 29] and empirical evidence [18–20, 31, 32] strongly suggest that population immunity to poliovirus transmission will determine the risk of cVDPV emergence and the dynamics of outbreaks. Population immunity to poliovirus transmission may correlate strongly with the level of individual immunity to paralytic poliomyelitis disease in settings with only live poliovirus-induced immunity (ie, WPV and OPV-related viruses). However, re-infection waning immunity, and potential participation in transmission of disease-immune individuals for polioviruses make the distinction between individual protection from disease and population immunity to transmission matter. Poliovirus vaccination does not prevent infection or viral excretion, and individuals with IPV-only induced immunity become infected and excrete much more virus in their feces than OPV-vaccinated individuals [10, 24, 33–35]. The recent widespread environmental

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IPV Policy Scenario

No. [% of Sample] of Runs With cVDPV Emergence

Average No. of Years From OPV Cessation Until cVDPV Emergence for No IPV Use vs Indicated IPV Scenario for Runs With cVDPV Emergence (n in Column 2)

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Figure 2. Impact of IPV options on paralytic poliomyelitis incidence due to fully reverted cVDPVs (no. in parentheses give the cumulative no. of cases per million people) as a function of the timing of detection that triggers outbreak response. A, Outbreak detection on day when cumulative incidence exceeds 1. B, Outbreak detection on day when cumulative incidence exceeds 5. Abbreviations: cVDPV, circulating vaccine-derived poliovirus; IPV, inactivated poliovirus vaccine; OPV, oral poliovirus vaccine; RI, routine immunization.

isolations of WPV1 in Israel [36] despite very high IPV RI coverage demonstrates that IPV does not provide absolute herd immunity to poliovirus transmission, even if some level of herd immunity probably exists based on settings with likely more

prominent oropharyngeal transmission [10, 31, 37, 38]. Any model findings depend on the inputs and assumptions, and our findings reflect closed populations with limited heterogeneity and other limitations related to the deterministic transmission model

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Figure 3. Impact of earlier IPV introduction with reduced OPV use in SIAs or RI and comparison of IPV before or after OPV in the RI schedule in terms mixing-adjusted EIPM relative to the threshold EIP*. A, Impact of earlier IPV introduction with reduced OPV use. B, Comparison of IPV before or after OPV in the RI schedule. Abbreviations: EIP, effective immune proportion; EIPM, mixing-adjusted effective immune proportion; IPV, inactivated poliovirus vaccine; OPV, oral poliovirus vaccine; RI, routine immunization; SIA, supplemental immunization activity.

[7, 9]. However, our results remain relatively robust for a wide range of assumptions and consistent with the available evidence [7–11, 20]. While no direct evidence exists to support our S494

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assumption that priming prevents paralytic poliomyelitis for individuals that receive only 1 IPV dose, assuming no or only limited protection from paralysis for these individuals will not affect the

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Figure 4. Exploration of assumptions about the relative importance of oropharyngeal transmission and IPV-induced immunity to fecal-oral transmission on the mixing-adjusted EIPM. A, Impact of proportion of transmissions via oropharyngeal mode ( poro, or p_oro in the legend). B, Impact of wide range of assumption about IPV-induced immunity to fecal-oral transmission. Abbreviations: EIP, effective immune proportion; EIPM, mixing-adjusted effective immune proportion; IPV, inactivated poliovirus vaccine; OPV, oral poliovirus vaccine; RI, routine immunization.

results much given that a single IPV dose prevents very few expected paralytic cases. Our numerical results apply directly to serotype 2 and the concepts apply to serotypes 1 and 3, although

differences for some model inputs (eg, OPV take rates, R0, paralysis-to-infection ratio, and OPV evolution dynamics) [7] will lead to different results.

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Notes Financial support. The authors thank the Bill & Melinda Gates Foundation for providing a contract to Kid Risk, Inc., to support completion of this work under Work Order 4533–23446. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the Bill and Melinda Gates Foundation. Supplement sponsorship. This article is part of a supplement entitled “The Final Phase of Polio Eradication and Endgame Strategies for the Post-Eradication Era,” which was sponsored by the Centers for Disease Control and Prevention. Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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The settings with the highest cVDPV risks most likely coincide with settings of intense fecal-oral transmission, for which we expect the least impact of IPV on population immunity to poliovirus transmission [39]. The settings also coincide with low RI coverage and longer times without SIAs prior to OPV cessation. IPV use will provide more impact on population immunity in settings with higher RI coverage and less intense fecal-oral transmission. Moreover, scheduling IPV before OPV instead of at the third OPV dose may minimally reduce population immunity (depending on interference with maternal immunity) while preventing some VAPP cases. Our analyses focused on settings with the highest cVDPV risks and suggest a relatively small reduction in cVDPV risk or expected cases in the outbreak population associated with the use of IPV for those settings (Table 2). These results underscore the importance of not deriving a false sense of security associated with the introduction of IPV. The model results also demonstrate that under some circumstances, IPV use might slow down the dynamics of cVDPV emergences and delay the detection of the outbreak while allowing a wider spread of virus and asymptomatic participation in transmission by individuals with IPV-only induced immunity. The slower dynamics of the outbreak and response could potentially lead to more paralytic cases in the outbreak population and delay in detection, which may also increase the risks of exportation of the circulating live poliovirus to other areas. Relying on IPV rather than OPV to maintain high population immunity prior to OPV cessation represents a very risky and costly [39] strategy in settings at the greatest risk of cVDPV emergences. These results reaffirm that the best strategy to minimize cVDPV risks involves maximizing OPV use right up until OPV cessation [9, 26, 28]. In conclusion, introducing IPV around the time of OPV cessation provides a modest reduction in the probability of cVDPV outbreaks and their size, particularly in settings most at risk of cVDPV emergence. Policy makers must carefully consider the trade-off between the costs of IPV and its potential impact on cVDPV risk management, and they should not derive a false sense of security associated with the introduction of IPV. Achieving global interruption of the circulation of WPVs followed by successful management of coordinated OPV cessation should remain the primary priority for the GPEI partners.

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