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In May 2016, the Global Polio Eradication Initiative (GPEI) coordinated the cessation of all use of type 2 oral poliovirus vaccine (OPV2), except for emergency outbreak response. Since then, paralytic polio cases caused by type 2 vaccine-derived polioviruses now exceed 3,000 cases reported by 39 countries. In 2022 (as of April 25, 2023), 20 countries reported detection of cases and nine other countries reported environmental surveillance detection, but no reported cases. Recent development of a genetically modified novel type 2 OPV (nOPV2) may help curb the generation of neurovirulent vaccine-derived strains; its use since 2021 under Emergency Use Listing is limited to outbreak response activities. Prior modeling studies showed that the expected trajectory for global type 2 viruses does not appear headed toward eradication, even with the best possible properties of nOPV2 assuming current outbreak response performance. Continued persistence of type 2 poliovirus transmission exposes the world to the risks of potentially high-consequence events such as the importation of virus into high-transmission areas of India or Bangladesh. Building on prior polio endgame modeling and assuming current national and GPEI outbreak response performance, we show no probability of successfully eradicating type 2 polioviruses in the near term regardless of vaccine choice. We also demonstrate the possible worst-case scenarios could result in rapid expansion of paralytic cases and preclude the goal of permanently ending all cases of poliomyelitis in the foreseeable future. Avoiding such catastrophic scenarios will depend on the development of strategies that raise population immunity to type 2 polioviruses., (© 2023 Society for Risk Analysis.)

Due to the very low, but nonzero, paralysis risks associated with the use of oral poliovirus vaccine (OPV), eradicating poliomyelitis requires ending all OPV use globally. The Global Polio Eradication Initiative (GPEI) coordinated cessation of Sabin type 2 OPV (OPV2 cessation) in 2016, except for emergency outbreak response. However, as of early 2023, plans for cessation of bivalent OPV (bOPV, containing types 1 and 3 OPV) remain undefined, and OPV2 use for outbreak response continues due to ongoing transmission of type 2 polioviruses and reported type 2 cases. Recent development and use of a genetically stabilized novel type 2 OPV (nOPV2) leads to additional potential vaccine options and increasing complexity in strategies for the polio endgame. Prior applications of integrated global risk, economic, and poliovirus transmission modeling consistent with GPEI strategic plans that preceded OPV2 cessation explored OPV cessation dynamics and the evaluation of options to support globally coordinated risk management efforts. The 2022-2026 GPEI strategic plan highlighted the need for early bOPV cessation planning. We review the published modeling and explore bOPV cessation immunization options as of 2022, assuming that the GPEI partners will not support restart of the use of any OPV type in routine immunization after a globally coordinated cessation of such use. We model the potential consequences of globally coordinating bOPV cessation in 2027, as anticipated in the 2022-2026 GPEI strategic plan. We do not find any options for bOPV cessation likely to succeed without a strategy of bOPV intensification to increase population immunity prior to cessation., (© 2023 Society for Risk Analysis. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Novel oral poliovirus vaccine type 2 (nOPV2) was developed by modifying the Sabin strain to increase genetic stability and reduce risk of seeding new circulating vaccine-derived poliovirus type 2 outbreaks. Bivalent oral poliovirus vaccine (bOPV; containing Sabin types 1 and 3) is the vaccine of choice for type 1 and type 3 outbreak responses. We aimed to assess immunological interference between nOPV2 and bOPV when administered concomitantly., Methods: We conducted an open-label, non-inferiority, randomised, controlled trial at two clinical trial sites in Dhaka, Bangladesh. Healthy infants aged 6 weeks were randomly assigned (1:1:1) using block randomisation, stratified by site, to receive nOPV2 only, nOPV2 plus bOPV, or bOPV only, at the ages of 6 weeks, 10 weeks, and 14 weeks. Eligibility criteria included singleton and full term (≥37 weeks' gestation) birth and parents intending to remain in the study area for the duration of study follow-up activities. Poliovirus neutralising antibody titres were measured at the ages of 6 weeks, 10 weeks, 14 weeks, and 18 weeks. The primary outcome was cumulative immune response for all three poliovirus types at the age of 14 weeks (after two doses) and was assessed in the modified intention-to-treat population, which was restricted to participants with adequate blood specimens from all study visits. Safety was assessed in all participants who received at least one dose of study product. A non-inferiority margin of 10% was used to compare single and concomitant administration. This trial is registered with ClinicalTrials.gov, NCT04579510., Findings: Between Feb 8 and Sept 26, 2021, 736 participants (244 in the nOPV2 only group, 246 in the nOPV2 plus bOPV group, and 246 in the bOPV only group) were enrolled and included in the modified intention-to-treat analysis. After two doses, 209 (86%; 95% CI 81-90) participants in the nOPV2 only group and 159 (65%; 58-70) participants in the nOPV2 plus bOPV group had a type 2 poliovirus immune response; 227 (92%; 88-95) participants in the nOPV2 plus bOPV group and 229 (93%; 89-96) participants in the bOPV only group had a type 1 response; and 216 (88%; 83-91) participants in the nOPV2 plus bOPV group and 212 (86%; 81-90) participants in the bOPV only group had a type 3 response. Co-administration was non-inferior to single administration for types 1 and 3, but not for type 2. There were 15 serious adverse events (including three deaths, one in each group, all attributable to sudden infant death syndrome); none were attributed to vaccination., Interpretation: Co-administration of nOPV2 and bOPV interfered with immunogenicity for poliovirus type 2, but not for types 1 and 3. The blunted nOPV2 immunogenicity we observed would be a major drawback of using co-administration as a vaccination strategy., Funding: The US Centers for Disease Control and Prevention., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The Global Polio Eradication Initiative (GPEI) faces substantial challenges with managing outbreaks of serotype 2 circulating vaccine-derived polioviruses (cVDPV2s) in 2021. A full five years after the globally coordinated removal of serotype 2 oral poliovirus vaccine (OPV2) from trivalent oral poliovirus vaccine (tOPV) for use in national immunization programs, cVDPV2s did not die out. Since OPV2 cessation, responses to outbreaks caused by cVDPV2s mainly used serotype 2 monovalent OPV (mOPV2) from a stockpile. A novel vaccine developed from a genetically stabilized OPV2 strain (nOPV2) promises to potentially facilitate outbreak response with lower prospective risks, although its availability and properties in the field remain uncertain. Using an established global poliovirus transmission model and building on a related analysis that characterized the impacts of disruptions in GPEI activities caused by the COVID-19 pandemic, we explore the implications of trade-offs associated with delaying outbreak response to avoid using mOPV2 by waiting for nOPV2 availability (or equivalently, delayed responses waiting for national validation of meeting the criteria for nOPV2 initial use). Consistent with prior modeling, responding as quickly as possible with available mOPV2 promises to reduce the expected burden of disease in the outbreak population and to reduce the chances for the outbreak virus to spread to other areas. Delaying cVDPV2 outbreak response (e.g., modeled as no response January-June 2021) to wait for nOPV2 can considerably increase the total expected cases (e.g., by as many as 1,300 cVDPV2 cases in the African region during 2021-2023) and increases the likelihood of triggering the need to restart widescale preventive use of an OPV2-containing vaccine in national immunization programs that use OPV. Countries should respond to any cVDPV2 outbreaks quickly with rounds that achieve high coverage using any available OPV2, and plan to use nOPV2, if needed, once it becomes widely available based on evidence that it is as effective but safer in populations than mOPV2., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Despite exhaustive and fully-financed plans to manage the risks of globally coordinated cessation of oral poliovirus vaccine (OPV) containing type 2 (OPV2) prior to 2016, as of 2022, extensive, continued transmission of circulating vaccine-derived polioviruses (cVDPVs) type 2 (cVDPV2) remains. Notably, cumulative cases caused by cVDPV2 since 2016 now exceed 2,500. Earlier analyses explored the implications of using different vaccine formulations to respond to cVDPV2 outbreaks and demonstrated how different properties of novel OPV2 (nOPV2) might affect its performance compared to Sabin monovalent OPV2 (mOPV2). These prior analyses used fixed assumptions for how outbreak response would occur, but outbreak response implementation can change. We update an existing global poliovirus transmission model to explore different options for responding with different vaccines and assumptions about scope, delays, immunization intensity, target age groups, and number of rounds. Our findings suggest that in order to successfully stop all cVDPV2 transmission globally, countries and the Global Polio Eradication Initiative need to address the deficiencies in emergency outbreak response policy and implementation. The polio program must urgently act to substantially reduce response time, target larger populations - particularly in high transmission areas - and achieve high coverage with improved access to under-vaccinated subpopulations. Given the limited supplies of nOPV2 at the present, using mOPV2 intensively immediately, followed by nOPV2 intensively if needed and when sufficient quantities become available, substantially increases the probability of ending cVDPV2 transmission globally., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

In early 2020, the COVID-19 pandemic led to substantial disruptions in global activities. The disruptions also included intentional and unintentional reductions in health services, including immunization campaigns against the transmission of wild poliovirus (WPV) and persistent serotype 2 circulating vaccine-derived poliovirus (cVDPV2). Building on a recently updated global poliovirus transmission and Sabin-strain oral poliovirus vaccine (OPV) evolution model, we explored the implications of immunization disruption and restrictions of human interactions (i.e., population mixing) on the expected incidence of polio and on the resulting challenges faced by the Global Polio Eradication Initiative (GPEI). We demonstrate that with some resumption of activities in the fall of 2020 to respond to cVDPV2 outbreaks and full resumption on January 1, 2021 of all polio immunization activities to pre-COVID-19 levels, the GPEI could largely mitigate the impact of COVID-19 to the delays incurred. The relative importance of reduced mixing (leading to potentially decreased incidence) and reduced immunization (leading to potentially increased expected incidence) depends on the timing of the effects. Following resumption of immunization activities, the GPEI will likely face similar barriers to eradication of WPV and elimination of cVDPV2 as before COVID-19. The disruptions from the COVID-19 pandemic may further delay polio eradication due to indirect effects on vaccine and financial resources., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Trivalent oral poliovirus vaccine (tOPV) was globally replaced with bivalent oral poliovirus vaccine (bOPV) in April 2016 ("the switch"). Many outbreaks of paralytic poliomyelitis associated with type 2 circulating vaccine-derived poliovirus (cVDPV2) have been reported since this time. The Global Polio Eradication Initiative (GPEI) developed standard operating procedures (SOPs) to guide countries experiencing cVDPV2 outbreaks to implement timely and effective outbreak response (OBR). To assess the possible role of compliance with SOPs in successfully stopping cVDPV2 outbreaks, we analyzed data on critical timelines in the OBR process., Methods: Data were collected on all cVDPV2 outbreaks detected for the period April 1, 2016 and December 31, 2020 and all outbreak responses to those outbreaks between April 1, 2016 and December 31, 2021. We conducted secondary data analysis using the GPEI Polio Information System database, records from the U.S. Centers for Disease Control and Prevention Polio Laboratory, and meeting minutes of the monovalent OPV2 (mOPV2) Advisory Group. Date of notification of circulating virus was defined as Day 0 for this analysis. Extracted process variables were compared with indicators in the GPEI SOP version 3.1., Results: One hundred and eleven cVDPV2 outbreaks resulting from 67 distinct cVDPV2 emergences were reported during April 1, 2016-December 31, 2020, affecting 34 countries across four World Health Organization Regions. Out of 65 OBRs with the first large-scale campaign (R1) conducted after Day 0, only 12 (18.5%) R1s were conducted by the target of 28 days after Day 0. Of the 89 OBRs with the second large-scale campaign (R2) conducted after Day 0, 30 (33.7%) R2s were conducted by the target of 56 days after Day 0. Twenty-three (31.9%) of the 72 outbreaks with isolates dated after Day 0 were stopped within the 120-day target., Conclusion: Since "the switch", delays in OBR implementation were evident in many countries, which may be related to the persistence of cVDPV2 outbreaks >120 days. To achieve timely and effective response, countries should follow GPEI OBR guidelines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Pakistan and Afghanistan remain the only reservoirs of wild poliovirus transmission. Prior modeling suggested that before the coronavirus disease 2019 (COVID-19) pandemic, plans to stop the transmission of serotype 1 wild poliovirus (WPV1) and persistent serotype 2 circulating vaccine-derived poliovirus (cVDPV2) did not appear on track to succeed., Methods: We updated an existing poliovirus transmission and Sabin-strain oral poliovirus vaccine (OPV) evolution model for Pakistan and Afghanistan to characterize the impacts of immunization disruptions and restrictions on human interactions (ie, population mixing) due to the COVID-19 pandemic. We also consider different options for responding to outbreaks and for preventive supplementary immunization activities (SIAs)., Results: The modeling suggests that with some resumption of activities in the fall of 2020 to respond to cVDPV2 outbreaks and full resumption on 1 January 2021 of all polio immunization activities to pre-COVID-19 levels, Pakistan and Afghanistan would remain off-track for stopping all transmission through 2023 without improvements in quality., Conclusions: Using trivalent OPV (tOPV) for SIAs instead of serotype 2 monovalent OPV offers substantial benefits for ending the transmission of both WPV1 and cVDPV2, because tOPV increases population immunity for both serotypes 1 and 2 while requiring fewer SIA rounds, when effectively delivered in transmission areas., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Beginning in 2013, multiple local government areas (LGAs) in Borno and Yobe in northeast Nigeria and other parts of the Lake Chad basin experienced a violent insurgency that resulted in substantial numbers of isolated and displaced people. Northeast Nigeria represents the last known reservoir country of wild poliovirus (WPV) transmission in Africa, with detection of paralytic cases caused by serotype 1 WPV in 2016 in Borno and serotype 3 WPV in late 2012. Parts of Borno and Yobe are also problematic areas for transmission of serotype 2 circulating vaccine-derived polioviruses, and they continue to face challenges associated with conflict and inadequate health services in security-compromised areas that limit both immunization and surveillance activities. We model poliovirus transmission of all three serotypes for Borno and Yobe using a deterministic differential equation-based model that includes four subpopulations to account for limitations in access to immunization services and dynamic restrictions in population mixing. We find that accessibility issues and insufficient immunization allow for prolonged poliovirus transmission and potential undetected paralytic cases, although as of the end of 2019, including responsive program activities in the modeling suggest die out of indigenous serotypes 1 and 3 WPVs prior to 2020. Specifically, recent and current efforts to access isolated populations and provide oral poliovirus vaccine continue to reduce the risks of sustained and undetected transmission, although some uncertainty remains. Continued improvement in immunization and surveillance in the isolated subpopulations should minimize these risks. Stochastic modeling can build on this analysis to characterize the implications for undetected transmission and confidence about no circulation., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

Nearly 20 years after the year 2000 target for global wild poliovirus (WPV) eradication, live polioviruses continue to circulate with all three serotypes posing challenges for the polio endgame. We updated a global differential equation-based poliovirus transmission and stochastic risk model to include programmatic and epidemiological experience through January 2020. We used the model to explore the likely dynamics of poliovirus transmission for 2019-2023, which coincides with a new Global Polio Eradication Initiative Strategic Plan. The model stratifies the global population into 72 blocks, each containing 10 subpopulations of approximately 10.7 million people. Exported viruses go into subpopulations within the same block and within groups of blocks that represent large preferentially mixing geographical areas (e.g., continents). We assign representative World Bank income levels to the blocks along with polio immunization and transmission assumptions, which capture some of the heterogeneity across countries while still focusing on global poliovirus transmission dynamics. We also updated estimates of reintroduction risks using available evidence. The updated model characterizes transmission dynamics and resulting polio cases consistent with the evidence through 2019. Based on recent epidemiological experience and prospective immunization assumptions for the 2019-2023 Strategic Plan, the updated model does not show successful eradication of serotype 1 WPV by 2023 or successful cessation of oral poliovirus vaccine serotype 2-related viruses., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

After the globally coordinated cessation of any serotype of oral poliovirus vaccine (OPV), some risks remain from undetected, existing homotypic OPV-related transmission and/or restarting transmission due to several possible reintroduction risks. The Global Polio Eradication Initiative (GPEI) coordinated global cessation of serotype 2-containing OPV (OPV2) in 2016. Following OPV2 cessation, the GPEI and countries implemented activities to withdraw all the remaining trivalent OPV, which contains all three poliovirus serotypes (i.e., 1, 2, and 3), from the supply chain and replace it with bivalent OPV (containing only serotypes 1 and 3). However, as of early 2020, monovalent OPV2 use for outbreak response continues in many countries. In addition, outbreaks observed in 2019 demonstrated evidence of different types of risks than previously modeled. We briefly review the 2019 epidemiological experience with serotype 2 live poliovirus outbreaks and propose a new risk for unexpected OPV introduction for inclusion in global modeling of OPV cessation. Using an updated model of global poliovirus transmission and OPV evolution with and without consideration of this new risk, we explore the implications of the current global situation with respect to the likely need to restart preventive use of OPV2 in OPV-using countries. Simulation results without this new risk suggest OPV2 restart will likely need to occur (81% of 100 iterations) to manage the polio endgame based on the GPEI performance to date with existing vaccine tools, and with the new risk of unexpected OPV introduction the expected OPV2 restart probability increases to 89%. Contingency planning requires new OPV2 bulk production, including genetically stabilized OPV2 strains., (© 2019 Society for Risk Analysis. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Delays in achieving the global eradication of wild poliovirus transmission continue to postpone subsequent cessation of all oral poliovirus vaccine (OPV) use. Countries must stop OPV use to end all cases of poliomyelitis, including vaccine-associated paralytic polio (VAPP) and cases caused by vaccine-derived polioviruses (VDPVs). The Global Polio Eradication Initiative (GPEI) coordinated global cessation of all type 2 OPV (OPV2) use in routine immunization in 2016 but did not successfully end the transmission of type 2 VDPVs (VDPV2s), and consequently continues to use type 2 OPV (OPV2) for outbreak response activities. Using an updated global poliovirus transmission and OPV evolution model, we characterize outbreak response options for 2019-2029 related to responding to VDPV2 outbreaks with a genetically stabilized novel OPV (nOPV2) strain or with the currently licensed monovalent OPV2 (mOPV2). Given uncertainties about the properties of nOPV2, we model different assumptions that appear consistent with the evidence on nOPV2 to date. Using nOPV2 to respond to detected cases may reduce the expected VDPV and VAPP cases and the risk of needing to restart OPV2 use in routine immunization compared to mOPV2 use for outbreak response. The actual properties, availability, and use of nOPV2 will determine its effects on type 2 poliovirus transmission in populations. Even with optimal nOPV2 performance, countries and the GPEI would still likely need to restart OPV2 use in routine immunization in OPV-using countries if operational improvements in outbreak response to stop the transmission of cVDPV2s are not implemented effectively., (© 2020 Society for Risk Analysis.)

The use of the oral poliovirus vaccine (OPV) in developing countries has reduced the incidence of poliomyelitis by >99% since 1988 and is the primary tool for global polio eradication. Spontaneous reversions of the vaccine virus to a neurovirulent form can impede this effort. In persons with primary B-cell immunodeficiencies, exposure to OPV can result in chronic infection, mutation, and excretion of immunodeficiency-associated vaccine-derived polioviruses, (iVDPVs). These iVDPVs may have the potential for transmission in a susceptible population and cause paralysis. The extent to which sera from OPV recipients are able to neutralize iVDPVs with varying degrees of antigenic site substitutions is investigated here. We tested sera from a population immunized with a combination vaccine schedule (both OPV and inactivated polio vaccine) against a panel of iVDPVs and found that increases in amino acid substitution in the P1 capsid protein resulted in a decrease in the neutralizing capacity of the sera. This study underscores the importance of maintaining high vaccine coverage in areas of OPV use as well as active surveillance of those known to be immunocompromised., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Certification of global eradication of indigenous wild poliovirus type 2 occurred in 2015 and of type 3 in 2019. Since the launch of the Global Polio Eradication Initiative (GPEI) in 1988 and broad use of live, attenuated oral poliovirus vaccine (OPV), the number of wild poliovirus cases has declined >99.99% (1). Genetically divergent vaccine-derived poliovirus* (VDPV) strains can emerge during vaccine use and spread in underimmunized populations, becoming circulating VDPV (cVDPV) strains, and resulting in outbreaks of paralytic poliomyelitis. † In April 2016, all oral polio vaccination switched from trivalent OPV (tOPV; containing vaccine virus types 1, 2, and 3) to bivalent OPV (bOPV; containing types 1 and 3) (2). Monovalent type 2 OPV (mOPV2) is used in response campaigns to control type 2 cVDPV (cVDPV2) outbreaks. This report presents data on cVDPV outbreaks detected during January 2018-June 2019 (as of September 30, 2019). Compared with January 2017-June 2018 (3), the number of reported cVDPV outbreaks more than tripled, from nine to 29; 25 (86%) of the outbreaks were caused by cVDPV2. The increase in the number of outbreaks in 2019 resulted from VDPV2 both inside and outside of mOPV2 response areas. GPEI is planning future use of a novel type 2 OPV, stabilized to decrease the likelihood of reversion to neurovirulence. However, all countries must maintain high population immunity to decrease the risk for cVDPV emergence. Cessation of all OPV use after certification of polio eradication will eliminate the risk for VDPV emergence., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Background: Intradermal administration of fractional inactivated poliovirus vaccine (fIPV) is a dose-sparing alternative to the intramuscular full dose. We aimed to compare the immunogenicity of two fIPV doses versus one IPV dose for routine immunisation, and also assessed the immunogenicity of an fIPV booster dose for an outbreak response., Methods: We did an open-label, randomised, controlled, inequality, non-inferiority trial in two clinics in Dhaka, Bangladesh. Healthy infants were randomly assigned at 6 weeks to one of four groups: group A received IPV at age 14 weeks and IPV booster at age 22 weeks; group B received IPV at age 14 weeks and fIPV booster at age 22 weeks; group C received IPV at age 6 weeks and fIPV booster at age 22 weeks; and group D received fIPV at 6 weeks and 14 weeks and fIPV booster at age 22 weeks. IPV was administered by needle-syringe as an intramuscular full dose (0·5 mL), and fIPV was administered intradermally (0·1 mL of the IPV formulation was administered using the 0·1 mL HelmJect auto-disable syringe with a Helms intradermal adapter). Both IPV and fIPV were administered on the outer, upper right thigh of infants. The primary outcome was vaccine response to poliovirus types 1, 2, and 3 at age 22 weeks (routine immunisation) and age 26 weeks (outbreak response). Vaccine response was defined as seroconversion from seronegative (<1:8) at baseline to seropositive (≥1:8) or four-fold increase in reciprocal antibody titres adjusted for maternal antibody decay and was assessed in the modified intention-to-treat population (infants who received polio vaccines per group assignment and polio antibody titre results to serotypes 1, 2, and 3 at 6, 22, 23, and 26 weeks of age). The non-inferiority margin was 12·5%. This trial is registered with ClinicalTrials.gov, number NCT02847026., Findings: Between Sept 1, 2016 and May 2, 2017, 1076 participants were randomly assigned and included in the modified intention-to-treat analysis: 271 in Group A, 267 in group B, 268 in group C, and 270 in group D. Vaccine response at 22 weeks to two doses of fIPV (group D) was significantly higher (p<0·0001) than to one dose of IPV (groups A and B) for all three poliovirus serotypes: the type 1 response comprised 212 (79% [95% CI 73-83]) versus 305 (57% [53-61]) participants, the type 2 response comprised 173 (64% [58-70]) versus 249 (46% [42-51]) participants, and the type 3 response comprised 196 (73% [67-78]) versus 196 (36% [33-41]) participants. At 26 weeks, the fIPV booster was non-inferior to IPV (group B vs group A) for serotype 1 (-1·12% [90% CI -2·18 to -0·06]), serotype 2 (0·40%, [-2·22 to 1·42]), and serotype 3 (1·51% [-3·23 to -0·21]). Of 129 adverse events, 21 were classified as serious including one death; none were attributed to IPV or fIPV., Interpretation: fIPV appears to be an effective dose-sparing strategy for routine immunisation and outbreak responses., Funding: US Centers for Disease Control and Prevention., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: As a risk-mitigation strategy to minimize paralytic polio following withdrawal of Sabin type 2 from the oral poliovirus vaccine in April 2016, a single full dose or 2 fractional doses of inactivated poliovirus vaccine (IPV) are recommended. However, limited knowledge exists on long-term persistence of immune memory following 1- or 2-dose IPV schedules., Methods: We examined induction and maintenance of immune memory following single- vs 2-dose IPV schedules, either full-dose intramuscular or fractional-dose intradermal, in rhesus macaques. Humoral responses, bone marrow-homing antibody-secreting plasma cells, and blood-circulating/lymph node-homing memory B cells were examined longitudinally., Results: A single dose of IPV, either full or fractional, induced binding antibodies and memory B cells in all vaccinated macaques, despite failing to induce neutralizing antibodies (NT Abs) in many of them. However, these memory B cells declined rapidly, reaching below detection in the systemic circulation by 5 months; although a low frequency of memory B cells was detectable in draining lymph nodes of some, but not all, animals. By contrast, a 2-dose vaccination schedule, either full or fractional, efficiently induced NT Abs in all animals along with bone marrow-homing plasma cells and memory B cells. These memory B cells persisted in the systemic circulation for up to 16 months, the maximum duration tested after the second dose of vaccination., Conclusions: Two doses of IPV, regardless of whether fractional or full, are more effective than a single dose for inducing long-lasting memory B cells.

Poliovirus surveillance plays a critical role in achieving and certifying eradication and will play a key role in the polio endgame. Environmental surveillance can provide an opportunity to detect circulating polioviruses prior to the observation of any acute flaccid paralysis cases. We completed a systematic review of peer-reviewed publications on environmental surveillance for polio including the search terms "environmental surveillance" or "sewage," and "polio," "poliovirus," or "poliomyelitis," and compared characteristics of the resulting studies. The review included 146 studies representing 101 environmental surveillance activities from 48 countries published between 1975 and 2016. Studies reported taking samples from sewage treatment facilities, surface waters, and various other environmental sources, although they generally did not present sufficient details to thoroughly evaluate the sewage systems and catchment areas. When reported, catchment areas varied from 50 to over 7.3 million people (median of 500,000 for the 25% of activities that reported catchment areas, notably with 60% of the studies not reporting this information and 16% reporting insufficient information to estimate the catchment area population size). While numerous studies reported the ability of environmental surveillance to detect polioviruses in the absence of clinical cases, the review revealed very limited information about the costs and limited information to support quantitative population effectiveness of conducting environmental surveillance. This review motivates future studies to better characterize poliovirus environmental surveillance systems and the potential value of information that they may provide in the polio endgame.

Background: More than 99% of poliovirus infections are non-paralytic and therefore, not detected by acute flaccid paralysis (AFP) surveillance. Environmental surveillance (ES) can detect circulating polioviruses from sewage without relying on clinical presentation. With extensive ES and continued circulation of polioviruses, Pakistan presents a unique opportunity to quantify the impact of ES as a supplement to AFP surveillance on overall completeness and timeliness of poliovirus detection., Methods: Genetic, geographic and temporal data were obtained for all wild poliovirus (WPV) isolates detected in Pakistan from January 2011 through December 2013. We used viral genetics to assess gaps in AFP surveillance and ES as measured by detection of 'orphan viruses' (≥1.5% different in VP1 capsid nucleotide sequence). We compared preceding detection of closely related circulating isolates (≥99% identity) detected by AFP surveillance or ES to determine which surveillance system first detected circulation before the presentation of each polio case., Findings: A total of 1,127 WPV isolates were detected by AFP surveillance and ES in Pakistan from 2011-2013. AFP surveillance and ES combined exhibited fewer gaps (i.e., % orphan viruses) in detection than AFP surveillance alone (3.3% vs. 7.7%, respectively). ES detected circulation before AFP surveillance in nearly 60% of polio cases (200 of 346). For polio cases reported from provinces conducting ES, ES detected circulation nearly four months sooner on average (117.6 days) than did AFP surveillance., Interpretation: Our findings suggest ES in Pakistan is providing earlier, more sensitive detection of wild polioviruses than AFP surveillance alone. Overall, targeted ES through strategic selection of sites has important implications in the eradication endgame strategy.

Introduction: The polio eradication endgame strategic plan calls for the sequential removal of Sabin poliovirus serotypes from the trivalent oral poliovirus vaccine (tOPV), starting with type 2, and the introduction of ≥1 dose of inactivated poliovirus vaccine (IPV), to maintain an immunity base against poliovirus type 2. The global removal of oral poliovirus type 2 was successfully implemented in May 2016. However, IPV supply constraints has prevented introduction in 21 countries and led to complete stock-out in >20 countries., Methods: We conducted a literature review and contacted corresponding authors of recent studies with fractional-dose IPV (fIPV), one-fifth of intramuscular dose administered intradermally, to conduct additional type 2 immunogenicity analyses of two fIPV doses compared with one full-dose IPV., Results: Four studies were identified that assessed immunogenicity of two fIPV doses compared to one full-dose IPV. Two fractional doses are more immunogenic than 1 full-dose, with type 2 seroconversion rates improving between absolute 19-42% (median: 37%, p<0.001) and relative increase of 53-125% (median: 82%), and antibody titer to type 2 increasing by 2-32-fold (median: 10-fold). Early age of administration and shorter intervals between doses were associated with lower immunogenicity., Discussion: Overall, two fIPV doses are more immunogenic than a single full-dose, associated with significantly increased seroconversion rates and antibody titers. Two fIPV doses together use two-fifth of the vaccine compared to one full-dose IPV. In response to the current IPV shortage, a schedule of two fIPV doses at ages 6 and 14weekshas been endorsed by technical oversight committees and has been introduced in some affected countries., (Copyright © 2017. Published by Elsevier Ltd.)

Testing for neutralizing antibodies against polioviruses has been an established gold standard for assessing individual protection from disease, population immunity, vaccine efficacy studies, and other vaccine clinical trials. Detecting poliovirus specific IgM and IgA in sera and mucosal specimens has been proposed for evaluating the status of population mucosal immunity. More recently, there has been a renewed interest in using dried blood spot cards as a medium for sample collection to enhance surveillance of poliovirus immunity. Here, we describe the modified poliovirus microneutralization assay, poliovirus capture IgM and IgA ELISA assays, and dried blood spot polio serology procedures for the detection of antibodies against poliovirus serotypes 1, 2, and 3.

Background: The provision of several doses of monovalent type 1 oral poliovirus vaccine (mOPV1) and bivalent OPV1 and 3 (bOPV) vaccines through campaigns is essential to stop the circulation of remaining wild polioviruses. Our study aimed to assess the shortening of intervals between campaigns with bOPV and mOPV1 and to assess the immunogenicity of bOPV in routine immunisation schedules., Methods: We did an open-label, non-inferiority, five-arm, randomised controlled trial in Bangladesh. We recruited healthy infants aged 6 weeks at 42 immunisation clinics and randomly assigned them (with blocks of 15, three per group) to receive a short three-dose schedule of bOPV (bOPV short) or mOPV1 (mOPV1 short) with the first dose given at age 6 weeks, the second at age 8 weeks, and the third at age 10 weeks; or to a standard three-dose schedule of bOPV (bOPV standard) or mOPV1 (mOPV1 standard) or trivalent OPV (tOPV standard) with the first dose given at age 6 weeks, the second at 10 weeks, and the third at age 14 weeks. The primary outcome was the proportion of infants with antibody seroconversion for type 1, type 2, and type 3 polioviruses. The primary, modified intention-to-treat analysis included all patients who had testable serum samples before and after receiving at least one OPV dose. We used a 10% margin to establish non-inferiority for bOPV groups versus mOPV1 groups in seroconversion for type 1 poliovirus, and for bOPV1 short versus bOPV1 standard for types 1 and 3. This trial is registered at ClinicalTrials.gov, number NCT01633216, and is closed to new participants., Findings: Between May 13, 2012, and Jan 21, 2013, we randomly assigned 1000 infants to our study groups. 927 completed all study visits and were included in the primary analysis. Seroconversion for type-1 poliovirus was recorded in 183 (98%, 95% CI 95-100) of 186 infants given bOPV short, 179 (97%, 94-99) of 184 given bOPV standard, 180 (96%, 92-98) of 188 given mOPV short, 178 (99%, 97-100) of 179 given mOPV1 standard, and 175 (92%, 87-96) of 190 given tOPV standard. Seroconversion for type 2 was noted in 16 infants (9%, 5-14) on bOPV short, 29 (16%, 11-22) on bOPV standard, 19 (10%, 7-15) on mOPV short, 33 (18%, 13-25) on mOPV1 standard, and 182 (96%, 92-98) on tOPV standard. Seroconversion for type 3 was noted in 175 infants (94%, 90-97) on bOPV short, 176 (96%, 92-98) on bOPV standard, 18 (10%, 6-15) on mOPV short, 25 (14%, 10-20) on mOPV1 standard, and 167 (88%, 83-92) on tOPV standard. The short schedules for mOPV1 and bOPV elicited a non-inferior antibody response compared with the bOPV standard schedule. 104 adverse events were reported in 100 infants during follow up. 36 of these events needed admission to hospital (32 were pneumonia, two were vomiting or feeding disorders, one was septicaemia, and one was diarrhoea with severe malnutrition). One of the infants admitted to hospital for pneumonia died 5 days after admission. No adverse event was attributed to the vaccines., Interpretation: Our trial showed that three doses of mOPV1 or bOPV with a short schedule of 2 week intervals between doses induces an immune response similar to that obtained with the standard schedule of giving doses at 4 week intervals. These findings support the use of these vaccines in campaigns done at short intervals to rapidly increase population immunity against polioviruses to control outbreaks or prevent transmission in high-risk areas., Funding: Centers for Disease Control and Prevention and UNICEF., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The effect of transport temperature on the viability of poliovirus in stool specimens from paralyzed cases has not been tested. Quality assurance of programmatic indicators will be necessary in the final phase of polio eradication., Objective: To estimate the effect of time at elevated temperatures on wild poliovirus titers in stool specimens., Methods: We exposed aliquots of pooled wild poliovirus type 1 specimens to elevated temperatures (27 °C, 31 °C, and 35 °C) for varying time periods up to 14 days. We determined the virus titer of these aliquots and created decay curves at each temperature to estimate the relationship between time at temperature and virus titer., Results: We found significantly different slopes of decay at each temperature. The negative slopes increased as the temperature increased., Conclusions: While poliovirus in stool remains relatively stable at moderately elevated temperature, transport at higher temperatures could impact sample integrity and virus isolation results., (Published by Elsevier Inc.)

Background: Frequent supplemental immunization activities (SIAs) with the oral poliovirus vaccine (OPV) represent the primary strategy to interrupt poliovirus transmission in the last endemic areas., Materials and Methods: Using a differential-equation based poliovirus transmission model tailored to high-risk areas in Nigeria, we perform one-way and multi-way sensitivity analyses to demonstrate the impact of different assumptions about routine immunization (RI) and the frequency and quality of SIAs on population immunity to transmission and persistence or emergence of circulating vaccine-derived polioviruses (cVDPVs) after OPV cessation., Results: More trivalent OPV use remains critical to avoid serotype 2 cVDPVs. RI schedules with or without inactivated polio vaccine (IPV) could significantly improve population immunity if coverage increases well above current levels in under-vaccinated subpopulations. Similarly, the impact of SIAs on overall population immunity and cVDPV risks depends on their ability to reach under-vaccinated groups (i.e., SIA quality). Lower SIA coverage in the under-vaccinated subpopulation results in a higher frequency of SIAs needed to maintain high enough population immunity to avoid cVDPVs after OPV cessation., Conclusions: National immunization program managers in northwest Nigeria should recognize the benefits of increasing RI and SIA quality. Sufficiently improving RI coverage and improving SIA quality will reduce the frequency of SIAs required to stop and prevent future poliovirus transmission. Better information about the incremental costs to identify and reach under-vaccinated children would help determine the optimal balance between spending to increase SIA and RI quality and spending to increase SIA frequency.

Background: After 25 years without poliomyelitis cases caused by circulating wild poliovirus (WPV) in Israel, sewage sampling detected WPV type 1 (WPV1) in April 2013, despite high vaccination coverage with only inactivated poliovirus vaccine (IPV) since 2005., Methods: We used a differential equation-based model to simulate the dynamics of poliovirus transmission and population immunity in Israel due to past exposure to WPV and use of oral poliovirus vaccine (OPV) in addition to IPV. We explored the influences of various immunization options to stop imported WPV1 circulation in Israel., Results: We successfully modeled the potential for WPVs to circulate without detected cases in Israel. Maintaining a sequential IPV/OPV schedule instead of switching to an IPV-only schedule in 2005 would have kept population immunity high enough in Israel to prevent WPV1 circulation. The Israeli response to WPV1 detection prevented paralytic cases; a more rapid response might have interrupted transmission more quickly., Conclusions: IPV-based protection alone might not provide sufficient population immunity to prevent poliovirus transmission after an importation. As countries transition to IPV in immunization schedules, they may need to actively manage population immunity and consider continued use of OPV, to avoid the potential circulation of imported live polioviruses before globally coordinated cessation of OPV use., (© 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: journals.permissions@oup.com.)

Laboratory diagnosis has played a critical role in the Global Polio Eradication Initiative since 1988, by isolating and identifying poliovirus (PV) from stool specimens by using cell culture as a highly sensitive system to detect PV. In the present study, we aimed to develop a molecular method to detect PV directly from stool extracts, with a high efficiency comparable to that of cell culture. We developed a method to efficiently amplify the entire capsid coding region of human enteroviruses (EVs) including PV. cDNAs of the entire capsid coding region (3.9 kb) were obtained from as few as 50 copies of PV genomes. PV was detected from the cDNAs with an improved PV-specific real-time reverse transcription-PCR system and nucleotide sequence analysis of the VP1 coding region. For assay validation, we analyzed 84 stool extracts that were positive for PV in cell culture and detected PV genomes from 100% of the extracts (84/84 samples) with this method in combination with a PV-specific extraction method. PV could be detected in 2/4 stool extract samples that were negative for PV in cell culture. In PV-positive samples, EV species C viruses were also detected with high frequency (27% [23/86 samples]). This method would be useful for direct detection of PV from stool extracts without using cell culture., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Chronic prolonged excretion of vaccine-derived polioviruses by immunodeficient persons (iVDPV) presents a personal risk of poliomyelitis to the patient as well as a programmatic risk of delayed global eradication. Poliovirus antiviral drugs offer the only mitigation of these risks. Antiviral agents may also have a potential role in the management of accidental exposures and in certain outbreak scenarios. Efforts to discover and develop poliovirus antiviral agents have been ongoing in earnest since the formation in 2007 of the Poliovirus Antivirals Initiative. The most advanced antiviral, pocapavir (V-073), is a capsid inhibitor that has recently demonstrated activity in an oral poliovirus vaccine human challenge model. Additional antiviral candidates with differing mechanisms of action continue to be profiled and evaluated preclinically with the goal of having 2 antivirals available for use in combination to treat iVDPV excreters., (© 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: journals.permissions@oup.com.)

Background: Pockets of undervaccinated individuals continue to raise concerns about their potential to sustain epidemic transmission of vaccine-preventable diseases. Prior importations of live polioviruses (LPVs) into Amish communities in North America led to their recognition as a potential and identifiable linked network of undervaccinated individuals., Methods: We developed an individual-based model to explore the potential transmission of a LPV throughout the North American Amish population., Results: Our model demonstrates the expected limited impact associated with the historical importations, which occurred in isolated communities during the low season for poliovirus transmission. We show that some conditions could potentially lead to wider circulation of LPVs and cases of paralytic polio in Amish communities if an importation occurred during or after 2013. The impact will depend on the uncertain historical immunity to poliovirus infection among members of the community., Conclusions: Heterogeneity in immunization coverage represents a risk factor for potential outbreaks of polio if introduction of a LPV occurs, although overall high population immunity in North America suggests that transmission would remain relatively limited. Efforts to prevent spread between Amish church districts with any feasible measures may offer the best opportunity to contain an outbreak and limit its size., (© 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: journals.permissions@oup.com.)

Background: Early detection and control of vaccine-derived poliovirus (VDPV) emergences are essential to secure the gains of polio eradication., Methods: Serial sewage samples were collected in 4 towns of Mexico before, throughout, and after the May 2010 oral poliovirus vaccine (OPV) mass immunization campaign. Isolation and molecular analysis of polioviruses from sewage specimens monitored the duration of vaccine-related strains in the environment and emergence of vaccine-derived polioviruses in a population partially immunized with inactivated poliovirus vaccine (IPV)., Results: Sabin strains were identified up to 5-8 weeks after the campaign in all towns; in Aguascalientes, 1 Sabin 3 was isolated 16 weeks after the campaign, following 7 weeks with no Sabin strains detected. In Tuxtla Gutiérrez, type 2 VDPV was isolated from 4 samples collected before and during the campaign, and type 1 VDPV from 1 sample collected 19 weeks afterward. During 2009-2010, coverage in 4 OPV campaigns conducted averaged only 57% and surveillance for acute flaccid paralysis (AFP) was suboptimal (AFP rate<1 per 100,000 population<15 years of age) in Tuxtla Gutierrez., Conclusions: VDPVs may emerge and spread in settings with inadequate coverage with IPV/OPV vaccination. Environmental surveillance can facilitate early detection in these settings., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

A paralytic poliomyelitis outbreak occurred in Namibia in 2006, almost exclusively among adults. Nineteen cases were virologically confirmed as due to wild poliovirus type 1 (WPV1), and 26 were classified as polio compatible. Eleven deaths occurred among confirmed and compatible cases (24%). Of the confirmed cases, 97% were aged 15-45 years, 89% were male, and 71% lived in settlement areas in Windhoek. The virus was genetically related to a virus detected in 2005 in Angola, which had been imported earlier from India. The outbreak is likely due to immunity gaps among adults who were inadequately vaccinated during childhood. This outbreak underscores the ongoing risks posed by poliovirus importations, the importance of maintaining strong acute flaccid paralysis surveillance even in adults, and the need to maintain high population immunity to avoid polio outbreaks in the preeradication period and outbreaks due to vaccine-derived polioviruses in the posteradication era., (© 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: journals.permissions@oup.com.)

Background: Inactivated poliovirus vaccine (IPV) is rarely used in tropical developing countries. To generate additional scientific information, especially on the possible emergence of vaccine-derived polioviruses (VDPVs) in an IPV-only environment, we initiated an IPV introduction project in Yogyakarta, an Indonesian province. In this report, we present the coverage, immunity, and VDPV surveillance results., Methods: In Yogyakarta, we established environmental surveillance starting in 2004; and conducted routine immunization coverage and seroprevalence surveys before and after a September 2007 switch from oral poliovirus vaccine (OPV) to IPV, using standard coverage and serosurvey methods. Rates and types of polioviruses found in sewage samples were analyzed, and all poliovirus isolates after the switch were sequenced., Results: Vaccination coverage (>95%) and immunity (approximately 100%) did not change substantially before and after the IPV switch. No VDPVs were detected. Before the switch, 58% of environmental samples contained Sabin poliovirus; starting 6 weeks after the switch, Sabin polioviruses were rarely isolated, and if they were, genetic sequencing suggested recent introductions., Conclusions: This project demonstrated that under almost ideal conditions (good hygiene, maintenance of universally high IPV coverage, and corresponding high immunity against polioviruses), no emergence and circulation of VDPV could be detected in a tropical developing country setting., (© 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: journals.permissions@oup.com.)

Background: In 2009, enhanced poliovirus surveillance was established in polio-endemic areas of Uttar Pradesh and Bihar, India, to assess poliovirus infection in older individuals., Methods: In Uttar Pradesh, stool specimens from asymptomatic household and neighborhood contacts of patients with laboratory-confirmed polio were tested for polioviruses. In Bihar, in community-based surveillance, children and adults from 250 randomly selected households in the Kosi River area provided stool and pharyngeal swab samples that were tested for polioviruses. A descriptive analysis of surveillance data was performed., Results: In Uttar Pradesh, 89 of 1842 healthy contacts of case patients with polio (4.8%) were shedding wild poliovirus (WPV); 54 of 85 (63.5%) were ≥5 years of age. Shedding was significantly higher in index households than in neighborhood households (P<.05). In Bihar, 11 of 451 healthy persons (2.4%) were shedding WPV in their stool; 6 of 11 (54.5%) were ≥5 years of age. Mean viral titer was similar in older and younger children., Conclusions: A high proportion of persons≥5 years of age were asymptomatically shedding polioviruses. These findings provide indirect evidence that older individuals could have contributed to community transmission of WPV in India. Polio vaccination campaigns generally target children<5 years of age. Expanding this target age group in polio-endemic areas could accelerate polio eradication., (© 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: journals.permissions@oup.com.)

Inactivated poliovirus vaccine (IPV) is efficacious against paralytic disease, but its effect on mucosal immunity is debated. We assessed the efficacy of IPV in boosting mucosal immunity. Participants received IPV, bivalent 1 and 3 oral poliovirus vaccine (bOPV), or no vaccine. A bOPV challenge was administered 4 weeks later, and excretion was assessed 3, 7, and 14 days later. Nine hundred and fifty-four participants completed the study. Any fecal shedding of poliovirus type 1 was 8.8, 9.1, and 13.5% in the IPV group and 14.4, 24.1, and 52.4% in the control group by 6- to 11-month, 5-year, and 10-year groups, respectively (IPV versus control: Fisher's exact test P < 0.001). IPV reduced excretion for poliovirus types 1 and 3 between 38.9 and 74.2% and 52.8 and 75.7%, respectively. Thus, IPV in OPV-vaccinated individuals boosts intestinal mucosal immunity., (Copyright © 2014, American Association for the Advancement of Science.)

Background: Response to challenge with live, attenuated, oral polio vaccine (OPV) is a measure of immunity induced by prior immunization., Methods: Using stool samples from a study from Oman in which an initial schedule of inactivated polio vaccine (IPV) was followed by an OPV type 1 challenge, we quantitated virus shed, sequenced capsid proteins of recovered virus, and developed assays for neutralization of poliovirus and mucosal immunoglobulin A (IgA) detection., Results: Neutralizing activity correlated with detection of polio-specific IgA in stool suspensions collected 7 days after OPV type 1 challenge. Both neutralization and IgA in stool were associated with cessation of virus shedding by day 7. Rapid development of an IgA response with cessation of shedding suggests that IPV primed for the early response to challenge. Correlation of neutralization activity and IgA detection provides evidence that polio-specific IgA intestinal antibody is a determinant of mucosal shedding/transmission and that IgA functions through neutralization of virus. In contrast, neither presence nor quantity of serum or intestinal antibody induced by IPV prior to challenge correlated with cessation of shedding., Conclusions: These assays provide an opportunity to study other immunization schedules to gain a broader understanding of the appearance and duration of a protective mucosal response to polio vaccination.

Background: A serosurvey to evaluate population immunity to polioviruses (PVs) in the context of the importation-related wild PV1 outbreak in Tajikistan in 2010 (461 confirmed cases among children and young adults) was conducted., Methods: Serum specimens from a nationwide sample of 1-24 year-old persons selected through stratified cluster sampling (n=2447) were tested for neutralizing antibodies to all three PV types. Samples with titers<1:8 were considered seronegative. The serosurvey was conducted during the interval after mOPV1 supplementary immunization activities (SIAs) and before tOPV SIAs (targeting ages ≤ 15 years) implemented to control the outbreak. In the absence of pre-outbreak specimens, results for PV3 were used as a proxy for pre-outbreak PV1 immunity patterns., Results: Overall, PV1 seroprevalence was 98.9%, PV2 seroprevalence was 98.8%, and PV3 seroprevalence was 86.9%. PV1 and PV2 seroprevalence exceeded 95% in all age groups and regions. PV3 seroprevalence was <90% in all age groups and regions, except 15-19 year-olds (91.7%) and Dushanbe (90.0%). PV3 seroprevalence was lowest among 1-4 (82.7%) and 5-9 (84.4%) year-olds, particularly among 1-4 year-olds in Kurgan-Tube (76.3%) and RRS (80.0%) regions. Birth cohorts immunized only through routine services (ages, 1-7 years) had lower PV3 seroprevalence than birth cohorts targeted by the SIAs during 1995-2002 (8-19 years): 82.5% versus 89.3%, p<0.001., Conclusions: Suboptimal (<90%) PV3 seroprevalence across wide age range suggests the outbreak resulted from accumulation of susceptibles due to suboptimal coverage over a long time period, particularly in the birth cohorts immunized only through routine services and in areas where the outbreak began (Kurgan-Tube and RRS). High PV1 seroprevalence indicates that mOPV1 SIAs with expanded target age (≤ 15 years) succeeded in closing the immunity gap and ongoing WPV1 transmission is unlikely. To accelerate outbreak control in areas which have been polio-free for long time, expanding SIA target age should be considered., (Copyright © 2013. Published by Elsevier Ltd.)

Since 2005, a large poliomyelitis outbreak associated with type 2 circulating vaccine-derived poliovirus (cVDPV2) has occurred in northern Nigeria, where immunization coverage with trivalent oral poliovirus vaccine (tOPV) has been low. Phylogenetic analysis of P1/capsid region sequences of isolates from each of the 403 cases reported in 2005 to 2011 resolved the outbreak into 23 independent type 2 vaccine-derived poliovirus (VDPV2) emergences, at least 7 of which established circulating lineage groups. Virus from one emergence (lineage group 2005-8; 361 isolates) was estimated to have circulated for over 6 years. The population of the major cVDPV2 lineage group expanded rapidly in early 2009, fell sharply after two tOPV rounds in mid-2009, and gradually expanded again through 2011. The two major determinants of attenuation of the Sabin 2 oral poliovirus vaccine strain (A481 in the 5'-untranslated region [5'-UTR] and VP1-Ile143) had been replaced in all VDPV2 isolates; most A481 5'-UTR replacements occurred by recombination with other enteroviruses. cVDPV2 isolates representing different lineage groups had biological properties indistinguishable from those of wild polioviruses, including efficient growth in neuron-derived HEK293 cells, the capacity to cause paralytic disease in both humans and PVR-Tg21 transgenic mice, loss of the temperature-sensitive phenotype, and the capacity for sustained person-to-person transmission. We estimate from the poliomyelitis case count and the paralytic case-to-infection ratio for type 2 wild poliovirus infections that ∼700,000 cVDPV2 infections have occurred during the outbreak. The detection of multiple concurrent cVDPV2 outbreaks in northern Nigeria highlights the risks of cVDPV emergence accompanying tOPV use at low rates of coverage in developing countries.

With national and global health policymakers facing numerous complex decisions related to achieving and maintaining polio eradication, we expanded our previously developed dynamic poliovirus transmission model using information from an expert literature review process and including additional immunity states and the evolution of oral poliovirus vaccine (OPV). The model explicitly considers serotype differences and distinguishes fecal-oral and oropharyngeal transmission. We evaluated the model by simulating diverse historical experiences with polioviruses, including one country that eliminated wild poliovirus using both OPV and inactivated poliovirus vaccine (IPV) (USA), three importation outbreaks of wild poliovirus (Albania, the Netherlands, Tajikistan), one situation in which no circulating vaccine-derived polioviruses (cVDPVs) emerge despite annual OPV use and cessation (Cuba), three cVDPV outbreaks (Haiti, Madura Island in Indonesia, northern Nigeria), one area of current endemic circulation of all three serotypes (northern Nigeria), and one area with recent endemic circulation and subsequent elimination of multiple serotypes (northern India). We find that when sufficient information about the conditions exists, the model can reproduce the general behavior of poliovirus transmission and outbreaks while maintaining consistency in the generic model inputs. The assumption of spatially homogeneous mixing remains a significant limitation that affects the performance of the differential equation-based model when significant heterogeneities in immunity and mixing may exist. Further studies on OPV virus evolution and improved understanding of the mechanisms of mixing and transmission may help to better characterize poliovirus transmission in populations. Broad application of the model promises to offer insights in the context of global and national policy and economic models., (© 2013 Society for Risk Analysis.)

Eradication of wild poliovirus (WPV) types 1 and 3, prevention and cessation of circulating vaccine-derived polioviruses, and achievement and maintenance of a world free of paralytic polio cases requires active risk management by focusing on population immunity and coordinated cessation of oral poliovirus vaccine (OPV). We suggest the need for a complementary and different conceptual approach to achieve eradication compared to the current case-based approach using surveillance for acute flaccid paralysis (AFP) to identify symptomatic poliovirus infections. Specifically, we describe a modeling approach to characterize overall population immunity to poliovirus transmission. The approach deals with the realities that exposure to live polioviruses (e.g., WPV, OPV) and/or vaccination with inactivated poliovirus vaccine provides protection from paralytic polio (i.e., disease), but does not eliminate the potential for reinfection or asymptomatic participation in poliovirus transmission, which may increase with time because of waning immunity. The AFP surveillance system provides evidence of symptomatic poliovirus infections detected, which indicate immunity gaps after outbreaks occur, and this system represents an appropriate focus for controlling disease outbreaks. We describe a conceptual dynamic model to characterize population immunity to poliovirus transmission that helps identify risks created by immunity gaps before outbreaks occur, which provides an opportunity for national and global policymakers to manage the risk of poliovirus and prevent outbreaks before they occur. We suggest that dynamically modeling risk represents an essential tool as the number of cases approaches zero., (© 2012 Society for Risk Analysis.)

V-073, a small-molecule capsid inhibitor originally developed for nonpolio enterovirus indications is considerably more potent against polioviruses. All poliovirus isolates tested to date (n = 45), including wild, vaccine, vaccine-derived, and laboratory strains, are susceptible to the antiviral capsid inhibitor V-073. We grew poliovirus in the presence of V-073 to allow for the identification of variants with reduced susceptibility to the drug. Sequence analysis of 160 independent resistant variants (80 isolates of poliovirus type 1, 40 isolates each of types 2 and 3) established that V-073 resistance involved a single amino acid change in either of two virus capsid proteins, VP1 (67 of 160 [42%]) or VP3 (93 of 160 [58%]). In resistant variants with a VP1 change, the majority (53 of 67 [79%]) exhibited a substitution of isoleucine at position 194 (equivalent position 192 in type 3) with either methionine or phenylalanine. Of those with a VP3 change, alanine at position 24 was replaced with valine in all variants (n = 93). The resistance phenotype was relatively stable upon passage of viruses in cell culture in the absence of drug. Single-step growth studies showed no substantial differences between drug-resistant variants and the virus stocks from which they were derived, while the resistant viruses were generally more thermally labile than the corresponding drug-susceptible parental viruses. These studies provide a foundation from which to build a greater understanding of resistance to antiviral compound V-073.

Background: The continued presence of polio in northern India poses challenges to the interruption of wild poliovirus transmission and the management of poliovirus risks in the post-eradication era. We aimed to assess the current immunity profile after routine doses of trivalent oral poliovirus vaccine (OPV) and numerous supplemental doses of type-1 monovalent OPV (mOPV1), and compared the effect of five vaccine formulations and dosages on residual immunity gaps., Methods: We did a community-based, randomised controlled trial of healthy infants aged 6-9 months at ten sites in Moradabad, India. Serum neutralising antibody was measured before infants were randomly assigned to a study group and given standard-potency or higher-potency mOPV1, intradermal fractional-dose inactivated poliovirus vaccine (IPV, GlaxoSmithKline), or intramuscular full-dose IPV from two different manufacturers (GlaxoSmithKline or Panacea). Follow-up sera were taken at days 7 and 28. Our primary endpoint was an increase of more than four times in antibody titres. We did analyses by per-protocol in children with a blood sample available before, and 28 days after, receiving study vaccine (or who completed study procedures). This trial is registered with Current Controlled Trials, number ISRCTN90744784., Findings: Of 1002 children enrolled, 869 (87%) completed study procedures (ie, blood sample available at day 0 and day 28). At baseline, 862 (99%), 625 (72%), and 418 (48%) had detectable antibodies to poliovirus types 1, 2, and 3, respectively. In children who were type-1 seropositive, an increase of more than four times in antibody titre was detected 28 days after they were given standard-potency mOPV1 (5/13 [38%]), higher-potency mOPV1 (6/21 [29%]), intradermal IPV (9/16 [56%]), GlaxoSmithKline intramuscular IPV (19/22 [86%]), and Panacea intramuscular IPV (11/13 [85%]). In those who were type-2 seronegative, 42 (100%) of 42 seroconverted after GlaxoSmithKline intramuscular IPV, and 24 (59%) of 41 after intradermal IPV (p<0·0001). 87 (90%) of 97 infants who were type-3 seronegative seroconverted after intramuscular IPV, and 21 (36%) of 49 after intradermal IPV (p<0·0001)., Interpretation: Supplemental mOPV1 resulted in almost total seroprevalence against poliovirus type 1, which is consistent with recent absence of poliomyelitis cases; whereas seroprevalence against types 2 and 3 was expected for routine vaccination histories. The immunogenicity of IPV produced in India (Panacea) was similar to that of an internationally manufactured IPV (GSK). Intradermal IPV was less immunogenic., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The Global Polio Eradication Initiative aims to eradicate wild poliovirus by the end of 2012. Therefore, more-immunogenic polio vaccines, including monovalent oral poliovirus vaccines (mOPVs), are needed for supplemental immunization activities. This trial assessed the immunogenicity of monovalent types 1 and 3, compared with that of trivalent oral poliovirus vaccine (tOPV), in South Africa., Methods: We conducted a blinded, randomized, 4-arm controlled trial comparing the immunogenicity of a single dose of mOPV1 (from 2 manufacturers) and mOPV3 (from 1 manufacturer), given at birth, with the immunogenicity of tOPV., Results: Eight hundred newborns were enrolled; 762 (95%) were included in the analysis. At 30 days after vaccine administration, seroconversion to poliovirus type 1 was 73.4% and 76.4% in the 2 mOPV1 arms, compared with 39.1% in the tOPV arm (P < .0000001), and seroconversion to poliovirus type 3 was 58.0% in the mOPV3 arm, compared with 21.2% in the tOPV arm (P < .0000001). The vaccines were well tolerated, and no adverse events were attributed to trial interventions., Conclusion: A dose of mOPV1 or mOPV3 at birth was superior to that of tOPV in inducing type-specific seroconversion in this sub-Saharan African population. Our results support continued use of mOPVs in supplemental immunization activities in countries where poliovirus types 1 or 3 circulate. Clinical Trials Registration. ISRCTN18107202.

Objectives: The United States eliminated indigenous wild polioviruses (WPVs) in 1979 and switched to inactivated poliovirus vaccine in 2000, which quickly ended all indigenous live poliovirus transmission. Continued WPV circulation and use of oral poliovirus vaccine globally allow for the possibility of reintroduction of these viruses. We evaluated the risk of a U.S. polio outbreak and explored potential vaccine needs for outbreak response., Methods: We synthesized information available on vaccine coverage, exemptor populations, and population immunity. We used an infection transmission model to explore the potential dynamics of a U.S. polio outbreak and potential vaccine needs for outbreak response, and assessed the impacts of heterogeneity in population immunity for two different subpopulations with potentially low coverage., Results: Although the risk of poliovirus introduction remains real, widespread transmission of polioviruses appears unlikely in the U.S., given high routine coverage. However, clusters of un- or underimmunized children might create pockets of susceptibility that could potentially lead to one or more paralytic polio cases. We found that the shift toward combination vaccine utilization, with limited age indications for use, and other current trends (e.g., decreasing proportion of the population with immunity induced by live polioviruses and aging of vaccine exemptor populations) might increase the vulnerability to poliovirus reintroduction at the same time that the ability to respond may decrease., Conclusions: The U.S. poliovirus vaccine stockpile remains an important resource that may potentially be needed in the future to respond to an outbreak if a live poliovirus gets imported into a subpopulation with low vaccination coverage.

Background: To provide the polio eradication initiative with more immunogenic oral poliovirus vaccines (OPVs), we evaluated newly developed monovalent type 1 OPV (mOPV1) among infants in India., Methods: Two double-blind randomized controlled clinical trials compared two mOPV1s (mOPV1 A and mOPV1 B) versus trivalent OPV (tOPV X) given at birth (trial I), or assessed two products of higher-potency mOPV1 (mOPV1 C and mOPV1 D) versus regular-potency mOPV1 (mOPV1 B) or tOPV Y given at birth and at 30 days (trial II)., Results: In trial I, 597 newborns were enrolled, 66 withdrawn or excluded, leaving 531 (88.9%) subjects for analysis. Seroconversion to poliovirus type 1 was 10.4% for mOPV1 A, 15.6% for mOPV1 B and 10.2% for tOPV X. In trial II, 718 newborns were enrolled, 135 withdrawn or excluded, leaving 583 (81.2%) subjects for analysis. Seroconversion to poliovirus type 1 following a birth dose was 15.1%, 19.7%, 18.0% and 10.6%, following the 30-day dose 87.1%, 89.2%, 84.4%, or 55.9%, and cumulative for both doses 90.4%, 90.3%, 89.5% and 61.9% for mOPV1s B, C, and D and tOPV Y, respectively., Conclusions: In both studies, seronconversion rates were unexpectedly low to poliovirus type 1 after mOPV1 or tOPV given at birth but high for all formulations of mOPV1 given at age 30 days. The cause for low immunogenicity of OPV at birth in India is not known., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

V-073, an enterovirus capsid inhibitor, was evaluated for its spectrum of antipoliovirus activity. V-073 inhibited all 45 polioviruses tested in a virus-induced cytopathic effect protection assay, with 50% effective concentration (EC50) values ranging from 0.003 to 0.126 microM. Ninety percent of the polioviruses tested were inhibited at EC(50)s of < or = 0.076 microM (MIC90 = 32 ng/ml). V-073 is a promising antiviral candidate for the posteradication management of poliovirus incidents.

For the final stages in the eradication of poliovirus type 1 (P1), the World Health Organization advocates the selective use of monovalent type 1 oral poliovirus vaccine (mOPV1). To compare the immunogenicity of mOPV1 with that of trivalent OPV (tOPV) in infants, a study was performed in Egypt in 2005. Newborns were vaccinated with mOPV1 or tOPV immediately after birth and were challenged with mOPV1 after 1 month. Vaccination with mOPV1 at birth resulted in significantly higher seroconversion against P1 viruses and lower excretion of P1 viruses than vaccination with tOPV. Intratypic differentiation of the viruses shed by the newborns revealed the presence of remarkably high numbers of antigenically divergent (AD) P1 isolates, especially in the mOPV1 study group. The majority of these AD P1 isolates (71%) were mOPV1 challenge derived and were shed by newborns who did not seroconvert to P1 after the birth dose. Genetic characterization of the viruses revealed that amino acid 60 of the VP3 region was mutated in all AD P1 isolates. Isolates with substitution of residue 99 of the VP1 region had significantly higher numbers of nonsynonymous mutations in the VP1 region than isolates without this substitution and were preferentially shed in the mOPV1 study group. The widespread use of mOPV1 has proven to be a powerful tool for fighting poliovirus circulation in the remaining areas of endemicity. This study provides another justification for the need to achieve high vaccination coverage in order to prevent the circulation of AD strains.

Background: Oral poliovirus vaccine (OPV) has not been used in the United States since 2000. Type 1 vaccine-derived poliovirus (VDPV) was identified in September 2005, from an unvaccinated Amish infant hospitalized in Minnesota with severe combined immunodeficiency. An investigation was conducted to determine the source of the virus and its means of transmission., Methods: The infant was tested serially for poliovirus excretion. Investigations were conducted to detect poliovirus infections or paralytic poliomyelitis in Amish communities in Minnesota, neighboring states, and Ontario, Canada. Genomic sequences of poliovirus isolates were determined for phylogenetic analysis., Results: No source for the VDPV could be identified. In the index community, 8 (35%) of 23 children tested, including the infant, had evidence of type 1 poliovirus or VDPV infection. Phylogenetic analysis suggested that the VDPV circulated in the community for approximately 2 months before the infant's infection was detected and that the initiating OPV dose had been given before her birth. No paralytic disease was found in the community, and no poliovirus infections were found in other Amish communities investigated., Conclusions: This is the first demonstrated transmission of VDPV in an undervaccinated community in a developed country. Continued vigilance is needed in all countries to identify poliovirus infections in communities at high risk of poliovirus transmission.

Background: In 1988, the World Health Assembly resolved to eradicate poliomyelitis. Although substantial progress toward this goal has been made, eradication remains elusive. In 2004, the World Health Organization called for the development of a potentially more immunogenic monovalent type 1 oral poliovirus vaccine., Methods: We conducted a trial in Egypt to compare the immunogenicity of a newly licensed monovalent type 1 oral poliovirus vaccine with that of a trivalent oral poliovirus vaccine. Subjects were randomly assigned to receive one dose of monovalent type 1 oral poliovirus vaccine or trivalent oral poliovirus vaccine at birth. Thirty days after birth, a single challenge dose of monovalent type 1 oral poliovirus vaccine was administered in all subjects. Shedding of serotype 1 poliovirus was assessed through day 60., Results: A total of 530 subjects were enrolled, and 421 fulfilled the study requirements. Thirty days after the study vaccines were administered, the rate of seroconversion to type 1 poliovirus was 55.4% in the monovalent-vaccine group, as compared with 32.1% in the trivalent-vaccine group (P<0.001). Among those with a high reciprocal titer of maternally derived antibodies against type 1 poliovirus (>64), 46.0% of the subjects in the monovalent-vaccine group underwent seroconversion, as compared with 21.3% in the trivalent-vaccine group (P<0.001). Seven days after administration of the challenge dose of monovalent type 1 vaccine, a significantly lower proportion of subjects in the monovalent-vaccine group than in the trivalent-vaccine group excreted type 1 poliovirus (25.9% vs. 41.5%, P=0.001). None of the serious adverse events reported were attributed to the trial interventions., Conclusions: When given at birth, monovalent type 1 oral poliovirus vaccine is superior to trivalent oral poliovirus vaccine in inducing humoral antibodies against type 1 poliovirus, overcoming high preexisting levels of maternally derived antibodies, and increasing the resistance to excretion of type 1 poliovirus after administration of a challenge dose. (Current Controlled Trials number, ISRCTN76316509.), (2008 Massachusetts Medical Society)

From 2001 to 2004, Switzerland switched from routine vaccination with oral polio vaccine (OPV) to inactivated polio vaccine (IPV), using both vaccines in the intervening period. Since IPV is less effective at inducing mucosal immunity than OPV, this change might allow imported poliovirus to circulate undetected more easily in an increasingly IPV-immunized population. Environmental monitoring is a recognized tool for identifying polioviruses in a community. To look for evidence of poliovirus circulation following cessation of OPV use, two sewage treatment plants located in the Zurich area were sampled from 2004 to 2006. Following virus isolation using either RD or L20B cells, enteroviruses and polioviruses were identified by reverse transcription-PCR. A total of 20 out of 174 wastewater samples were positive for 62 Sabin-like isolates. One isolate from each poliovirus-positive sample was analyzed in more detail. Sequencing the complete viral protein 1 (VP1) capsid coding region, as well as intratypic differentiation (ITD), identified 3 Sabin type 1, 13 Sabin type 2, and 4 Sabin type 3 strains. One serotype 1 strain showed a discordant result in the ITD. Three-quarters of the strains showed mutations within the 5' untranslated region and VP1, known to be associated with reversion to virulence. Moreover, three strains showed heterotypic recombination (S2/S1 and S3/S2/S3). The low number of synonymous mutations and the partial temperature sensitivity are not consistent with extended circulation of these Sabin virus strains. Nevertheless, the continuous introduction of polioviruses into the community emphasizes the necessity for uninterrupted child vaccination to maintain high herd immunity.

Virological surveillance is an important element in the Polio Eradication Initiative to provide information rapidly about circulating wild polioviruses. Molecular tools have been developed to identify the serotype of the poliovirus strains and whether they are of vaccine or wild origin (intratypic differentiation) and to perform the molecular epidemiology of wild strains. The main objective of this study was to show that restriction fragment length polymorphism (RFLP) is a tool that can be used for molecular epidemiology of wild polioviruses. This is retrospective study of poliovirus type 1 strains received at the Institut Pasteur of Bangui (IPB), a WHO Regional Reference Laboratory for Africa, since 1994. We describe our experience with isolates from Western and Central Africa and show a positive correlation between the genotypes as determined by sequencing the gene for the VP1 capsid protein and the RFLP patterns. Although genomic sequencing is the gold standard method for detailed molecular epidemiology analysis of poliovirus isolates, these results show that RFLP is a potentially valuable tool for molecular epidemiological analysis of poliovirus type 1 strains: it could be used by many laboratories as a rapid method for ITD and genotype screening where sequencing capacity is not readily available.