Community transmission of type 2 poliovirus after cessation of trivalent oral polio vaccine in Bangladesh: an open-label cluster-randomised trial and modelling study

Abstract

SummaryBackgroundTrivalent oral polio vaccine (tOPV) was replaced worldwide from April, 2016, by bivalent types 1 and 3 oral polio vaccine (bOPV) and one dose of inactivated polio vaccine (IPV) where available. The risk of transmission of type 2 poliovirus or Sabin 2 virus on re-introduction or resurgence of type 2 poliovirus after this switch is not understood completely. We aimed to assess the risk of Sabin 2 transmission after a polio vaccination campaign with a monovalent type 2 oral polio vaccine (mOPV2).MethodsWe did an open-label cluster-randomised trial in villages in the Matlab region of Bangladesh. We randomly allocated villages (clusters) to either: tOPV at age 6 weeks, 10 weeks, and 14 weeks; or bOPV at age 6 weeks, 10 weeks, and 14 weeks and either one dose of IPV at age 14 weeks or two doses of IPV at age 14 weeks and 18 weeks. After completion of enrolment, we implemented an mOPV2 vaccination campaign that targeted 40% of children younger than 5 years, regardless of enrolment status. The primary outcome was Sabin 2 incidence in the 10 weeks after the campaign in per-protocol infants who did not receive mOPV2, as assessed by faecal shedding of Sabin 2 by reverse transcriptase quantitative PCR (RT-qPCR). The effect of previous immunity on incidence was also investigated with a dynamical model of poliovirus transmission to observe prevalence and incidence of Sabin 2 virus. This trial is registered at ClinicalTrials.gov, number NCT02477046.FindingsBetween April 30, 2015, and Jan 14, 2016, individuals from 67 villages were enrolled to the study. 22 villages (300 infants) were randomly assigned tOPV, 23 villages (310 infants) were allocated bOPV and one dose of IPV, and 22 villages (329 infants) were assigned bOPV and two doses of IPV. Faecal shedding of Sabin 2 in infants who did not receive the mOPV2 challenge did not differ between children immunised with bOPV and one or two doses of IPV and those who received tOPV (15 of 252 [6%] vs six of 122 [4%]; odds ratio [OR] 1·29, 95% CI 0·45–3·72; p=0·310). However, faecal shedding of Sabin 2 in household contacts was increased significantly with bOPV and one or two doses of IPV compared with tOPV (17 of 751 [2%] vs three of 353 [1%]; OR 3·60, 95% CI 0·82–15·9; p=0·045). Dynamical modelling of within-household incidence showed that immunity in household contacts limited transmission.InterpretationIn this study, simulating 1 year of tOPV cessation, Sabin 2 transmission was higher in household contacts of mOPV2 recipients in villages receiving bOPV and either one or two doses of IPV, but transmission was not increased in the community as a whole as shown by the non-significant difference in incidence among infants. Dynamical modelling indicates that transmission risk will be higher with more time since cessation.FundingBill & Melinda Gates Foundation.

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

“…In addition to novel results for dose response and 521 waning, the key innovation of our work is its direct connection from individual-level measures of 522 shedding and susceptibility obtained by stool surveys to assessment of community susceptibility 523 (Fig 10). A recent application of this model to a field transmission study in Matlab, Bangladesh [86] assumptions and calibration data about socially-distant transmission. We discuss the relevance of 530 our results for interpreting the history of and implications for vaccination policy in the polio 531 eradication endgame [95] below.…”

“…First, calibration showed 381 that changes in childhood immunity from vaccination policy choices have larger effects on immunity 382 than waning ( Fig 1C and Fig 4), and so typical adults alive near OPV cessation will make small 383 contributions to the local transmission rate relative to children. Second, unimmunized adult family 384 members of infected children have similar (albeit slightly lower) likelihood of infection from index 385 persons than unimmunized children ( Fig 6B) [35,86]. Absent immunity, including adults in our 386 model is roughly equivalent to increasing the number of child contacts.…”

The early evolution of oral poliovirus vaccine is shaped by strong positive selection and tight transmission bottlenecks

“…We used high depth of coverage sequencing on the Illumina platform to define the within-host diversity of mOPV2 in samples from vaccinated individuals and their household contacts (29). These samples were collected as part of a cluster-randomized trial of OPV in the rural Matlab region, where the International Centre for Diarrheal Disease Research, Bangladesh (icddr,b) has conducted demographic and public health research since the 1960s (30).…”

“…However, few samples contained U2909C and no samples contained U398C. The majority of transmission events occurred within the first two weeks after the vaccination campaign, prior to when most vaccine recipients acquired U2909C and U398C (29). These data suggest that the three gatekeeper mutations were not preferentially transmitted; instead, they suggest that mutations must rise to an appreciable frequency early enough within a donor population to be frequently transmitted through a narrow bottleneck.…”

“…We developed an approach for sequencing OPV genomes directly from primary stool samples and validated its accuracy for identification of intrahost single nucleotide variants (iSNV). We applied this approach to samples from a recent trial that investigated the effect of tOPV cessation on the transmission of type 2 OPV (29). The trial included a defined point of introduction of monovalent type 2 OPV (mOPV2) and weekly longitudinal sampling of vaccine recipients and their household contacts; it therefore represents an opportunity to investigate the early evolutionary dynamics of OPV2 in a community setting.…”