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. 2018 Apr 27;16(4):e2002468.
doi: 10.1371/journal.pbio.2002468. eCollection 2018 Apr.

Assessing the stability of polio eradication after the withdrawal of oral polio vaccine

Michael Famulare  1 , Christian Selinger  1 , Kevin A McCarthy  1 , Philip A Eckhoff  1 , Guillaume Chabot-Couture  1
Affiliations

Assessing the stability of polio eradication after the withdrawal of oral polio vaccine

Michael Famulare et al. PLoS Biol. .

Abstract

The oral polio vaccine (OPV) contains live-attenuated polioviruses that induce immunity by causing low virulence infections in vaccine recipients and their close contacts. Widespread immunization with OPV has reduced the annual global burden of paralytic poliomyelitis by a factor of 10,000 or more and has driven wild poliovirus (WPV) to the brink of eradication. However, in instances that have so far been rare, OPV can paralyze vaccine recipients and generate vaccine-derived polio outbreaks. To complete polio eradication, OPV use should eventually cease, but doing so will leave a growing population fully susceptible to infection. If poliovirus is reintroduced after OPV cessation, under what conditions will OPV vaccination be required to interrupt transmission? Can conditions exist in which OPV and WPV reintroduction present similar risks of transmission? To answer these questions, we built a multi-scale mathematical model of infection and transmission calibrated to data from clinical trials and field epidemiology studies. At the within-host level, the model describes the effects of vaccination and waning immunity on shedding and oral susceptibility to infection. At the between-host level, the model emulates the interaction of shedding and oral susceptibility with sanitation and person-to-person contact patterns to determine the transmission rate in communities. Our results show that inactivated polio vaccine (IPV) is sufficient to prevent outbreaks in low transmission rate settings and that OPV can be reintroduced and withdrawn as needed in moderate transmission rate settings. However, in high transmission rate settings, the conditions that support vaccine-derived outbreaks have only been rare because population immunity has been high. Absent population immunity, the Sabin strains from OPV will be nearly as capable of causing outbreaks as WPV. If post-cessation outbreak responses are followed by new vaccine-derived outbreaks, strategies to restore population immunity will be required to ensure the stability of polio eradication.

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Conflict of interest statement

The authors have the following interest: this work was supported by Global Good, Bellevue, WA, USA. The authors are employees of the Institute for Disease Modeling, which is funded by Global Good. This does not alter the authors’ adherence to PLOS policies on sharing data and materials.

Figures

Fig 1
Fig 1. Effect of vaccination on shedding duration after OPV challenge and pre-challenge immunity.
Labels describe vaccines received and number of doses (i.e., bOPV×2 and IPV×1: two doses of bOPV and one dose of IPV). (A) Shedding duration after OPV challenge: shedding duration survival curves from aggregated trial data (solid lines) and maximum likelihood model fit (dashed) for each immunization schedule and poliovirus type. (Infection with Sabin 1, blue; Sabin 2, red; Sabin 3, orange; WPV, black). (B) Median shedding durations after infection because of OPV challenge or WPV transmission estimated from model fits in panels A and (C), corresponding pre-challenge homotypic OPV-equivalent antibody titers (see, also, S1 Text Fig A, and an interactive visualization of shedding duration data is available at https://famulare.github.io/cessationStability/). bOPV, bivalent type 1 and 3 OPV; IPV, inactivated polio vaccine; OPV, oral polio vaccine; WPV, wild poliovirus.
Fig 2
Fig 2. Concentration of poliovirus in stool: effects of age and immunity.
(A) Mean concentration of polivirus in stool (CID50/g) versus time after OPV challenge for immunologically naive subjects (color by age at challenge). (B) Peak concentration depends on age (dot color by age at challenge, corresponding to data from panel A at 1 week post-challenge; green line, model MLE and 95% CI, S1 Text Eq B). (C) Mean concentration after mOPV2 challenge for subjects with various vaccination histories (dashed, model MLE; solid, trial data age adjusted to 12 months using S1 Text Eq C). The concentration of poliovirus in stool depends on pre-challenge vaccination history. (D) The mean daily concentration (culture infectious doses per gram per day; CID50/g/day) declines by one order of magnitude for every 8-fold increase in OPV-equivalent antibody titer (OPV-equivalent titers [color, MLE, and 95% CI] for each trial arm shown in panel C; black, model [S1 Text Eq D, MLE, and 95% CI]). Interactive data visualization is available at https://famulare.github.io/cessationStability/. CI, confidence interval; CID50, the culture infectious dose that induces a cytopathic effect in 50% of infected cell or tissue cultures; IPV, inactivated polio vaccine; MLE, maximum likelihood estimate; mOPV, monovalent OPV; OPV, oral polio vaccine; tOPV, trivalent OPV.
Fig 3
Fig 3. Oral susceptibility to infection after OPV challenge.
(A) Fraction shedding after Sabin 1 oral challenge at different doses (color by trial arm, symbol by source study). (B) Fraction shedding after Sabin 2 oral challenge at different doses (color by trial arm, symbol by source study; data for doses ≤103 CID50 are for human-passaged Sabin 2 isolated from stool 5 days after vaccination). (C) Fraction shedding at vaccine doses (105–6 CID50) decreases with increasing OPV-equivalent antibody titer (color and symbols as in panels A–B; black lines are model MLE and 95% CI using S1 Text Eq E). (D) Beta-Poisson dose–response model MLE and 95% CI. Three model scenarios shown correspond to immunologically naive (NAb = 1, red), heterotypic bOPV and upper-bound IPV-only (NAb = 8, green), and typical tOPV or post-IPV-boosting (NAb = 256, blue). Data from panels A–B (symbols as above, colored by corresponding model scenario). bOPV, bivalent type 1 and 3 OPV; CI, confidence interval; CID50, the culture infectious dose that induces a cytopathic effect in 50% of infected cell or tissue cultures; IPV, inactivated polio vaccine; MLE, maximum likelihood estimate; OPV, oral polio vaccine; tOPV, trivalent OPV.
Fig 4
Fig 4. Waning immunity against infection.
OPV-equivalent antibody titer versus time between last exposure and mOPV challenge (color by serotype and symbol by source of immunity). Power-law model of waning from peak homotypic immunity (MLE and 95% CI, black lines) and heterotypic immunity against type 2 from bOPV (MLE and 95% CI assuming homotypic waning exponent, green lines). bOPV, bivalent type 1 and 3 OPV; CI, confidence interval; MLE, maximum likelihood estimate; mOPV, monovalent OPV; OPV, oral polio vaccine; tOPV, trivalent OPV; WPV, wild poliovirus.
Fig 5
Fig 5. Network motifs of poliovirus transmission.
(A) The essential motif of poliovirus transmission is index person to household member to close social contacts (dot color gives subject type; line color describes relationship). (B) The local reproduction number describes the expected number of secondary households infected by an index person based on sanitation, individual immunity, and the number of close social contacts. The house-to-house transmission motif represents this first generation of local transmission (color as in panel A; gray boxes denote households, and dashed lines indicate relationships beyond the first generation). (C) Our definition of the local reproduction number captures transmission among household members and close social contacts (solid colored lines) but does not include all relationships that may contribute to transmission (dashed black).
Fig 6
Fig 6. Transmission model calibration.
Each study measured the amount of transmission from index persons in different ways. (A) Houston 1960: fraction of children under 5 years of age shedding each week after mOPV challenge to an index child and subsequent transmission. (Color by subject type; weekly data MLE and 95% CI, dot and whiskers; model MLE and 95% CI, lines). Eight free parameters are jointly identified across the nine calibration targets. (B) Louisiana 1953–1955: incidence in household contacts of index children naturally infected by WPV, measured by seroconversion approximately 30 days after the index child became infected. Three free parameters are jointly identified by the five calibration targets. (C) Uttar Pradesh and Bihar 2003–2008: mean prevalence of WPV in stool measured in household contacts after the onset of paralysis in index children. One free parameter is jointly identified by the two calibration targets. See S1 Text Fig C for additional information about model fit. CI, confidence interval; MLE, maximum likelihood estimate; mOPV, monovalent OPV; WPV, wild poliovirus.
Fig 7
Fig 7. The effects of pre-exposure immunity on shedding and oral susceptibility to infection in children.
(A) Shedding index versus pre-challenge OPV-equivalent antibody titer (black, model MLE and 95% CI; color, range of immunities expected from vaccination). In the legend, the number of OPV doses equivalent to a titer range assumes healthy child (typical clinical trial) vaccine take rates. (B) Dose–response model versus OPV-equivalent titer (dose measured in culture infectious doses [CID50]). Pre-exposure immunity reduces susceptibility at all doses. bOPV, bivalent type 1 and 3 OPV; CI, confidence interval; CID50, the culture infectious dose that induces a cytopathic effect in 50% of infected cell or tissue cultures; IPV, inactivated polio vaccine; MLE, maximum likelihood estimate; OPV, oral polio vaccine.
Fig 8
Fig 8. WPV local reproduction number depends on immunity, sanitation, and contact network size.
(A) Local reproduction number versus immunity and fecal–oral dose (assuming 12 close social contacts outside the household per index child and that everyone has equal immunity) (color map, Rloc; dashed lines, transmission rate category boundaries). (B) Local reproduction number versus fecal–oral dose and number of close social contacts (assuming all are immunologically naive; legend as in panel A). HL, Houston/Louisiana; OPV, oral polio vaccine; UP, Uttar Pradesh and Bihar; WPV, wild poliovirus.
Fig 9
Fig 9. Effects of poliovirus strain on the local reproduction number.
Rloc versus HID50 and OPV-equivalent antibody titer for low (fecal–oral dose Tih = 0.5 μg/day and number of close social contacts Ns = 3), moderate (Houston 1960, Tih = 5 μg/day and Ns = 3), and high (UP and Bihar, Tih = 230 μg/day and Ns = 10) transmission rate settings (color map, Rloc; dashed lines, MLE for the HID50 of each strain [Table 1]). HID50, the dose (measured in CID50) that infects 50% of orally-exposed and immunologically-naive humans; MLE, maximum likelihood estimate; OPV, oral polio vaccine; UP, Uttar Pradesh; WPV, wild poliovirus.
Fig 10
Fig 10. The effects of vaccination policy on Sabin 2 transmission for four immunity scenarios: tOPV×3 (index and household/social contact NAb = 512), bOPV and tOPV×3 (index NAb = 512 and household/social contact NAb = 256), bOPV (index NAb = 8 and household/social contact NAb = 2), and naive (index and household/social contact NAb = 1).
(A) Local reproduction number versus fecal–oral dose and number of close social contacts (color map, Rloc; dashed lines, transmission rate category boundaries from Fig 8B; symbols, example low, moderate, and high transmission rate settings). (B) Maximum likelihood estimates of the fraction shedding for each subject type after mOPV2 challenge in young index children, for each immunity scenario and example transmission rate setting in panel A. bOPV, bivalent type 1 and 3 OPV; mOPV, monovalent OPV; tOPV, trivalent OPV.
Fig 11
Fig 11. Effects of increasing social distance on the local reproduction number of Sabin 2 in immunologically naive populations (NAb = 1).
Local reproduction number versus household member to social contact interaction rate and fecal–oral dose for moderate (Ns = 4, Tih = 5 μg/day, Tih ≤ 5 μg/day) and high (Ns = 10, Tih = 230 μg/day, Tih ≤ 230 μg/day) transmission rate settings (color map, Rloc; symbols, example parameter values from Fig 10).
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Global Good. This work was supported by Bill and Melinda Gates through Global Good, Bellevue, WA, USA. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.