After the 2015 documentation of global eradication of wild poliovirus type 2,* Sabin type 2 oral poliovirus vaccine (OPV) was withdrawn from routine immunization (RI) in all OPV-using countries in 2016, in a global synchronized switch from trivalent OPV (containing vaccine virus serotypes 1, 2, and 3) to bivalent OPV (containing serotypes 1 and 3), to reduce the rare risks for type 2 vaccine-associated paralytic poliomyelitis. Concurrently, the Global Polio Eradication Initiative (GPEI) recommended that all OPV-using countries introduce ≥1 dose of inactivated poliovirus vaccine (IPV) into RI programs; IPV protects against paralysis caused by all three serotypes but cannot be transmitted from person to person or cause paralysis. Use of OPV, especially in areas with low vaccination coverage, is associated with low risk of emergence of vaccine-derived polioviruses (VDPVs). As susceptible persons in new birth cohorts accumulated after withdrawal of OPV type 2, population immunity against infection with serotype 2 declined (1), facilitating the emergence of circulating VDPV type 2 (cVDPV2). During the previous 7 years, cVDPV2 outbreaks required response supplementary immunization activities (SIAs) with monovalent type 2 OPV (mOPV2); however, if SIAs were not of sufficiently high quality and did not achieve high enough coverage, new emergences of cVDPV2 occurred.

BACKGROUND: The polio eradication endgame required the withdrawal of Sabin type 2 from the oral poliovirus vaccine and introduction of one or more dose of inactivated poliovirus vaccine (IPV) into routine immunisation schedules. However, the duration of single-dose IPV immunity is unknown. We aimed to address this deficiency. METHODS: In this phase 4, open-label, non-randomised clinical trial, we assessed single-dose IPV immunity. Two groups of infants or children were screened: the first group had previously received IPV at 14 weeks of age or older (previous IPV group; age >2 years); the second had not previously received IPV (no previous IPV group; age 7-12 months). At enrolment, all participants received an IPV dose. Children in the no previous IPV group received a second IPV dose at day 30. Blood was collected three times in each group: on days 0, 7, and 30 in the previous IPV group and on days 0, 30, and 37 in the no previous IPV group. Poliovirus antibody was measured by microneutralisation assay. Immunity was defined as the presence of a detectable antibody or a rapid anamnestic response (ie, priming). We used the χ(2) to compare proportions and the Mann-Whitney U test to assess continuous variables. To assess safety, vaccinees were observed for 30 min, caregivers for each participating child reported adverse events after each follow-up visit and were questioned during each follow-up visit regarding any adverse events during the intervening period. Adverse events were recorded and graded according to the severity of clinical symptoms. The study is registered with ClinicalTrials.gov, NCT03723837. FINDINGS: From Nov 18, 2018, to July 31, 2019, 502 participants enrolled in the study, 458 (255 [65%] boys and 203 [44%] girls) were included in the per protocol analysis: 234 (93%) in the previous IPV group and 224 (90%) in the no previous IPV group. In the previous IPV group, 28 months after one IPV dose 233 (>99%) of 234 children had persistence of poliovirus type 2 immunity (100 [43%] of 234 children were seropositive; 133 [99%] of 134 were seronegative and primed). In the no previous IPV group, 30 days after one IPV dose all 224 (100%) children who were type 2 poliovirus naive had seroconverted (223 [>99%] children) or were primed (one [<1%]). No adverse events were deemed attributable to study interventions. INTERPRETATION: A single IPV dose administered at 14 weeks of age or older is highly immunogenic and induces nearly universal type 2 immunity (seroconversion and priming), with immunity persisting for at least 28 months. The polio eradication initiative should prioritise first IPV dose administration to mitigate the paralytic burden caused by poliovirus type 2. FUNDING: WHO and Rotary International.

BACKGROUND: The polio eradication endgame called for the removal of trivalent oral poliovirus vaccine and introduction of bivalent (types 1&3) OPV (bOPV) and inactivated poliovirus vaccine (IPV). However, supply shortages have delayed IPV administration to tens of millions of infants, and immunogenicity data are currently lacking to guide catch-up vaccination policies. METHODS: We conducted an open-label randomized clinical trial assessing two interventions, full or fractional-dose IPV (fIPV, 1/5 of IPV), administered at age 9-13 months with a second dose given two-months later. Serum was collected at days 0, 60, 67, and 90 to assess seroconversion, priming, and antibody titer. None received IPV or poliovirus type 2-containing vaccines before enrolment. RESULTS: A single fIPV dose at age 9-13 months yielded 75% (95%CI:68-82) seroconversion against type 2, whereas two fIPV doses resulted in 100% seroconversion compared with 94% (95%CI: 89-97) after a single full dose (p < 0.001). Two doses of IPV resulted in 100% seroconversion. CONCLUSIONS: Our study confirmed increased IPV immunogenicity when administered at an older age, likely due to reduced interference from maternally derived antibodies. Either one full dose of IPV or two doses of fIPV could be used to vaccinate missed cohorts, two fIPV doses being antigen-sparing and more immunogenic. CLINICAL TRIAL REGISTRY: This trial was registered with ClinicalTrials.gov, number NCT03890497.

BACKGROUND: A rapid increase in circulating vaccine-derived poliovirus type 2 outbreaks, and the need to reserve inactivated poliovirus vaccine (IPV) for routine immunisation, has increased the value of fractional dose IPV (fIPV) as a measure to prevent acute flaccid paralysis. However, the intradermal route of administration has been viewed as prohibitive to outbreak response campaigns. We aimed to establish the immunogenicity and safety of administering intradermal fIPV with a disposable syringe jet injector (DSJI) or an intradermal adaptor (IDA) compared with standard administration with a BCG needle and syringe (N&S). METHODS: This pragmatic, non-inferiority trial was undertaken in a campaign setting in communities in The Gambia. Children aged 4-59 months without contraindication to vaccination were eligible. Children were not individually randomly assigned; instead, the vaccination teams were randomly assigned (1:1:1) to one of three administration methods. Parents and the field team were not masked, but laboratory personnel were masked. Baseline demographic and anthropometric data were collected from the participants. Public health officers experienced at intradermal immunisation, and nurses without experience, had 2 h of training on each of the administration methods before the campaign. Participants were vaccinated using the administration method in use by the vaccination team in their community. Poliovirus serum neutralising antibodies (SNA) were measured in children aged 24-59 months before and 4 weeks after vaccination. Adverse events and data on injection quality were collected from all participants. The primary outcome was the type 2 immune response rate (seroconversion in seronegative [SNA titre <8] children plus a 4-fold titre rise in seropositive children). Adjusted differences in the immune response between the DSJI or IDA group versus the N&S group were calculated with 97·5% CIs. A margin of -10% was used to define the non-inferiority of DSJI or IDA compared to N&S. Immunogenicity analysis was done per protocol. The trial is registered with ClinicalTrials.govNCT02967783 and has been completed. FINDINGS: Between Oct 28 and Dec 29, 2016, 3189 children aged 4-59 months were recruited, of whom 3170 were eligible. Over 3 days, 2720 children were vaccinated (N&S, 917; IDA, 874; and DSJI, 929). Among 992 children aged 25-59 months with a baseline SNA available, 90·1% (95% CI 86·1-92·9; 281/312) of those vaccinated using the DSJI had an immune response to type 2 compared with 93·8% (90·6-95·8; 331/353) of those vaccinated with N&S and 96·6% (94·0-98·0; 316/327) of those vaccinated with IDA. All (53/53) type 2 seronegative children seroconverted. For polio type 2, non-inferiority was shown for both the IDA (adjusted difference 0·7% [97·5% CI -3·3 to 4·7], unadjusted difference 2·9% [-0·9 to 6·8]) and DSJI (adjusted difference -3·3% [-8·3 to 1·5], unadjusted difference -3·7% [-8·7 to 1·1]) compared with N&S. Non-inferiority was shown for type 1 and 3 for the IDA and DSJI. Neither injection quality nor the training and experience of the vaccinators had an effect on immune response. No safety concerns were reported. INTERPRETATION: In a campaign, intradermal fIPV is safe and generates consistent immune responses that are not dependent on vaccinator experience or injection quality when administered using an N&S, DSJI, or IDA. Countries facing vaccine-derived poliovirus type 2 outbreaks should consider fIPV campaigns to boost population immunity and prevent cases of acute flaccid paralysis. FUNDING: World Health Organization and the Medical Research Council.

BACKGROUND: We conducted a trial in Nigeria to assess the immunogenicity of the new bOPV + IPV immunization schedule and gains in type 2 immunity with addition of second dose of IPV. The trial was conducted in August 2016-March 2017 period, well past the tOPV-bOPV switch in April 2016. METHODS: This was an open-label, two-arm, non-inferiority, multi-center, randomized controlled trial. We enrolled 572 infants of age ≤14 days and randomized them into two arms. Arm A received bOPV at birth, 6 and 10 weeks, bOPV+IPV at week 14 and IPV at week 18. Arm B received IPV each at 6, 10, 14 weeks and bOPV at 18 weeks of age. RESULTS: Seroconversion rates for poliovirus types 1 and 3, respectively, were 98.9% (95%CI:96.7-99.8) and 98.1% (95%CI:88.2-94.8) in Arm A, and 89.6% (95%CI:85.4-93.0) and 98.5% (95%CI:96.3-99.6) in Arm B. Type 2 seroconversion with one dose IPV in Arm A was 72.0% (95%CI:66.2-77.3), which increased significantly with addition of second dose to 95.9% (95%CI:92.8-97.9). CONCLUSION: This first trial on the new EPI schedule in a sub-Saharan African country demonstrated excellent immunogenicity against poliovirus types 1 and 3, and substantial/enhanced immunogenicity against poliovirus type 2 after 1 to 2 doses of IPV respectively.

BACKGROUND: Monovalent type 2 oral poliovirus vaccine (mOPV2) stockpile is low. One potential strategy to stretch the existing mOPV2 supply is to administer a reduced dose: one-drop instead of two-drops. METHODS: We conducted a randomized, controlled, open-label, non-inferiority trial (10% margin) to compared immunogenicity following administration of one versus two-drops of mOPV2. We enrolled 9-22-months old infants from Mocuba district of Mozambique. Poliovirus neutralizing antibodies were measured in sera collected before and one month after mOPV2 administration. Immune response was defined as seroconversion from seronegative (<1:8) at baseline to seropositive (>1:8) after vaccination or boosting titers by >4-fold for those with titers between 1:8 and 1:362 at baseline. The trial was registered at anzctr.org.au (number ACTRN12619000184178p). RESULTS: We enrolled 378 children and 262 (69%) completed per-protocol requirements. Immune response of mOPV2 was 53.6% (95% confidence interval [CI]: 44.9%-62.1%) and 60.6% (95% CI: 52.2%-68.4%) in 1-drop and 2-drops recipients, respectively. The non-inferiority margin of the 10% was not reached (difference=7.0%; 95%CI= -5.0-19.0). CONCLUSION: A small loss of immunogenicity of reduced mOPV2 was observed. Although the non-inferiority target was not achieved, the Strategic Advisory Group of Experts on Immunization, recommended the 1-drop strategy as a dose-sparing measure if mOPV2 supplies deteriorate further.

While there have been no cases of type-2 wild poliovirus for over 20 years, transmission of type-2 vaccine-derived poliovirus (VDPV2) and associated paralytic cases in several continents represent a threat to eradication. The withdrawal of the type-2 component of oral poliovirus vaccine (OPV2) was implemented in April 2016 to stop VDPV2 emergence and secure eradication of all poliovirus type 2. Globally, children born after this date have limited immunity to prevent transmission. Using a statistical model, we estimate the emergence date and source of VDPV2s detected between May 2016 and November 2019. Outbreak response campaigns with monovalent OPV2 are the only available method to induce immunity to prevent transmission. Yet, our analysis shows that using monovalent OPV2 is generating more paralytic VDPV2 outbreaks with the potential for establishing endemic transmission. The novel OPV2 is urgently required, alongside a contingency strategy if this vaccine does not materialize or perform as anticipated.

Among the three wild poliovirus (WPV) types, type 2 (WPV2) was declared eradicated globally by the Global Commission for the Certification of Poliomyelitis Eradication (GCC) in 2015. Subsequently, in 2016, a global withdrawal of Sabin type 2 oral poliovirus vaccine (OPV2) from routine use, through a synchronized switch from the trivalent formulation of oral poliovirus vaccine (tOPV, containing vaccine virus types 1, 2, and 3) to the bivalent form (bOPV, containing types 1 and 3), was implemented. WPV type 3 (WPV3), last detected in 2012 (1), will possibly be declared eradicated in late 2019.* To ensure that polioviruses are not reintroduced to the human population after eradication, World Health Organization (WHO) Member States committed in 2015 to containing all polioviruses in poliovirus-essential facilities (PEFs) that are certified to meet stringent containment criteria; implementation of containment activities began that year for facilities retaining type 2 polioviruses (PV2), including type 2 oral poliovirus vaccine (OPV) materials (2). As of August 1, 2019, 26 countries have nominated 74 PEFs to retain PV2 materials. Twenty-five of these countries have established national authorities for containment (NACs), which are institutions nominated by ministries of health or equivalent bodies to be responsible for poliovirus containment certification. All designated PEFs are required to be enrolled in the certification process by December 31, 2019 (3). When GCC certifies WPV3 eradication, WPV3 and vaccine-derived poliovirus (VDPV) type 3 materials will also be required to be contained, leading to a temporary increase in the number of designated PEFs. When safer alternatives to wild and OPV/Sabin strains that do not require containment conditions are available for diagnostic and serologic testing, the number of PEFs will decrease. Facilities continuing to work with polioviruses after global eradication must minimize the risk for reintroduction into communities by adopting effective biorisk management practices.

The Global Polio Eradication Initiative continues to make progress toward the eradication target. Indigenous wild poliovirus (WPV) type 2 was last detected in 1999, WPV type 3 was last detected in 2012, and over the past 2 years WPV type 1 has been detected only in parts of 2 countries (Afghanistan and Pakistan). Once the eradication of poliomyelitis is achieved, infectious and potentially infectious poliovirus materials retained in laboratories, vaccine production sites, and other storage facilities will continue to pose a risk for poliovirus reintroduction into communities. The recent breach in containment of WPV type 2 in an inactivated poliovirus vaccine manufacturing site in the Netherlands prompted this review, which summarizes information on facility-associated release of polioviruses into communities reported over >8 decades. Successful polio eradication requires the management of poliovirus containment posteradication to prevent the consequences of the reestablishment of poliovirus transmission.

In April 2016, all 155 oral poliovirus vaccine (OPV)–using countries and territories in the world discontinued use of Sabin poliovirus type 2 by switching from trivalent OPV (tOPV) to bivalent OPV (bOPV), containing Sabin poliovirus types 1 and 3, in their national immunization schedules [1]. This event was the largest recall of a medicinal product in history and the fastest introduction of a new vaccine—bOPV. At the same time, all OPV-using countries attempted to introduce at least 1 dose of inactivated poliovirus vaccine (IPV) into the childhood immunization schedule for risk mitigation, primarily to minimize the number of paralytic poliomyelitis cases, should poliovirus type 2 be reintroduced or emerge [2].

BACKGROUND: Due to global shortage of inactivated poliovirus vaccine and global withdrawal of poliovirus type-2 (PV2) containing oral vaccine in May 2016, Vietnam has not used any PV2-containing vaccine between May 2016-October 2018. We assessed population immunity gap to PV2. METHODS: A cross-sectional survey in children 1-18 months of age was carried out in January 2018: one blood sample was obtained and analysed for the presence of poliovirus neutralizing antibodies. In children with detectable anti-PV2 antibodies, a second blood sample was obtained and analysed four months later to distinguish between passive (maternally-derived) and active (induced by secondary transmission or vaccination) immunity. RESULTS: Analysable sera were obtained from 1,106/1,110 enrolled children. Seroprevalence of PV2 antibodies was 87/368 (23.6%) among 1-7-month-old; 27/471 (5.7%) in the 8-15-month-old; and 19/267 (7.1%) in the 16-18-month-old. Seroprevalence declined with age in the 1-7 month-old group, and in children 8-18 months it remained without significant change by age. Four months later, 11/87 (14%), 9/27 (32%), and 12/19 (37%) remained seropositive in the 1-7, 8-15, and 16-18-month groups, respectively. INTERPRETATION: We found declining immunity to PV2, suggesting that Vietnam is at risk for an outbreak of type 2 vaccine-derived poliovirus in case of importation or new emergence.

Background: In July 2016, Sri Lanka replaced one intramuscular dose of inactivated poliovirus vaccine (IPV) with two doses of intradermal fractional IPV (fIPV) in its routine immunization schedule. We carried out a survey of seroprevalence of anti-polio antibodies in children who received two fIPV doses and compared it with those who received one full IPV dose. Methods: Children born between March and December 2016 were randomly selected from three Sri Lankan districts (Colombo, Badulla, Anuradhapura). Sera were collected and tested for presence of neutralizing antibodies to poliovirus types 1, 2, and 3. Results: Seroprevalence of anti-polio antibodies was 100% in all districts for poliovirus type 1 (PV1) and PV3; it ranged between 90-93% for PV2 in children who received one full IPV dose and between 78-100% in those receiving two fIPV doses (p=0.217). Median reciprocal titers of anti-PV2 antibodies were similar in those who received full IPV vs fIPV (1:64 vs 1:45 respectively; p=0.110). Interpretation: Our study demonstrated that Sri Lanka not only succeeded in maintaining very high primary immunization coverage but that it is feasible for a national immunization program to implement fIPV immunization and achieve high coverage with intradermal application. The seroprevalence of anti-PV2 antibodies did not decrease after the introduction of fIPV.

Background: Kano state has been a protracted reservoir of poliovirus in Nigeria. Immunity trends have been monitored through seroprevalence surveys since 2011. The survey in 2015 was, in addition, intended to assess the impact of use of inactivated poliovirus vaccine (IPV). Methods: It was a health facility based seroprevalence survey. Eligible children aged 6-9, 12-15 and 19-22 months of age brought to the paediatrics outpatient department of Murtala Mohammad Specialist Hospital between 19 October and 6 November 2015, were screened for eligibility. Eligible children were enrolled after parental consent, history taken, physical examination conducted, and a blood sample collected to test for neutralizing antibody titres against the three poliovirus serotypes. Results: Overall, 365 results were available in the three age groups. In the 6-9-month-old age group, the seroprevalence was 73% (95% confidence interval [CI] 64-80%), 83% (95% CI 75-88%), and 66% (95% CI 57-73%) for serotypes 1, 2, and 3, respectively. In the 12-15- and 19-22-month-old age groups, seroprevalence was higher but still remained <90% across serotypes. Seroprevalence to serotypes 1 and 3 in 2015 was similar to 2014; however, for serotype 2 there was a significant improvement. IPV received in supplemental immunization activities was found to be a significant predictor of seropositivity among 6-9-month-old infants for serotypes 1 and 2. Conclusions: Seroprevalence for serotypes 1 and 3 remains low (<80%) in 6-9-month-olds. This poses a significant risk for poliovirus spread if reintroduced into the population. Efforts to strengthen immunization coverage are imperative to secure and sustain high population immunity.

Since the Global Polio Eradication Initiative was launched in 1988 (1), the number of polio cases worldwide has declined by >99.99%. Among the three wild poliovirus (WPV) serotypes, only type 1 (WPV1) has been detected since 2012. This decline is attributable primarily to use of the live, attenuated oral poliovirus vaccine (OPV) in national routine immunization schedules and mass vaccination campaigns. The success and safety record of OPV use is offset by the rare emergence of genetically divergent vaccine-derived polioviruses (VDPVs), whose genetic drift from the parental OPV strains indicates prolonged replication or circulation (2). Circulating VDPVs (cVDPVs) can emerge in areas with low immunization coverage and can cause outbreaks of paralytic polio. In addition, immunodeficiency-associated VDPVs (iVDPVs) can emerge in persons with primary immunodeficiencies and can replicate and be excreted for years. This report presents data on VDPVs detected during January 2017-June 2018 and updates previous VDPV summaries (3). During this reporting period, new cVDPV outbreaks were detected in five countries. Fourteen newly identified persons in nine countries were found to excrete iVDPVs. Ambiguous VDPVs (aVDPVs), isolates that cannot be classified definitively, were found among immunocompetent persons and environmental samples in seven countries.

Substantial progress has been made since the World Health Assembly (WHA) resolved to eradicate poliomyelitis in 1988 (1). Among the three wild poliovirus (WPV) types, type 2 (WPV2) was declared eradicated in 2015, and type 3 (WPV3) has not been reported since 2012 (1). In 2017 and 2018, only Afghanistan and Pakistan have reported WPV type 1 (WPV1) transmission (1). When global eradication of poliomyelitis is achieved, facilities retaining poliovirus materials need to minimize the risk for reintroduction of poliovirus into communities and reestablishment of transmission. Poliovirus containment includes biorisk management requirements for laboratories, vaccine production sites, and other facilities that retain polioviruses after eradication; the initial milestones are for containment of type 2 polioviruses (PV2s). At the 71st WHA in 2018, World Health Organization (WHO) Member States adopted a resolution urging acceleration of poliovirus containment activities globally, including establishment by the end of 2018 of national authorities for containment (NACs) to oversee poliovirus containment (2). This report summarizes containment progress since the previous report (3) and outlines remaining challenges. As of August 2018, 29 countries had designated 81 facilities to retain PV2 materials; 22 of these countries had established NACs. Although there has been substantial progress, intensification of containment measures is needed.

Background: Full-dose inactivated poliovirus vaccine (IPV) boosts mucosal immunity in persons previously vaccinated with oral poliovirus vaccine (OPV). We assessed whether fractional-dose IPV (fIPV, 1/5th of a full dose) administered intradermally also boosts mucosal immunity. Methods: Children 10-12 years of age, previously vaccinated with OPV, were enrolled in Sri Lanka and randomized to receive one dose of IPV, fIPV, or no IPV vaccine. One month later, they received a challenge dose of trivalent OPV (tOPV). Blood was collected at enrolment and before tOPV challenge; and stool was collected at 3, 7 and 14 days post OPV challenge. Sera were analysed for presence of poliovirus neutralizing antibodies; stool was analysed for presence of poliovirus. Results: We analysed 304/309 (98%) enrolled subjects. The serum antibody response in the IPV and fIPV study arms was 98-100% for all 3 poliovirus serotypes with no difference between arms. There were 16/97 (16%), 9/99 (9%), and 72/95 (76%) subjects excreting poliovirus at any time-point after tOPV challenge in the IPV, fIPV and "No IPV Vaccine" study arms, respectively (p<0.001 for comparison of IPV [or fIPV] vs "No IPV Vaccine"; p=0.1 for comparisons of fIPV vs IPV). These percentages translate in relative decreases in excretion prevalence of 80% and 88% to IPV and fIPV, respectively, compared with the "No IPV Vaccine" control arm. Interpretation: Our study demonstrated that a single fIPV dose boosts mucosal immunity to a similar degree as does a single full dose of IPV. This finding provides further evidence in support of fIPV for poliovirus outbreak response at the time of IPV global supply shortage.

Background: Vaccine-derived polioviruses (VDPV) outbreaks typically occur in areas of low poliovirus immunity. Madagascar successfully eradicated wild poliovirus in 1997; however, multiple VDPV outbreaks have occurred since then, and numerous vaccination campaigns have been carried out to control the VDPV outbreaks. We conducted a survey of poliovirus neutralizing antibodies among Malagasy children to assess performance of vaccination campaigns and estimate the risk of future VDPV outbreaks. Methods: This was a random community survey in children aged 6-11 months, 36-59 months and 5-14 years of age in high risk areas of Madagascar (Mahajanga, Toliara, Antsalova, and Midongy-atsimo); and in a reference area (Antananarivo). After obtaining informed consent, basic demographic and vaccination history, 2 mL of peripheral blood were collected. Neutralizing antibodies against all three poliovirus serotypes were detected by using a standard microneutralization assay. Results: There were 1500 children enrolled and 1496 (>99%) provided sufficient quantity of blood for analysis. Seroprevalence for poliovirus type 1 (PV1) was >90% in all age groups and study areas. PV2 seroprevalence ranged between 75-100%; it was lowest in the youngest age group in Midongy and Toliara. PV3 seroprevalence ranged between 79-100%. Seroprevalence in the reference area was not significantly different from polio high risk sites. Discussion: Madagascar achieved high population immunity. In order to preserve these gains, routine immunization needs to be strengthened. Currently, the risk of new VDPV emergences in Madagascar appears low.

BACKGROUND: Afghanistan is one of the remaining wild-poliovirus (WPV) endemic countries. We conducted a seroprevalence survey of anti-poliovirus antibodies in Kandahar Province. METHODS: Children in two age groups (6-11months and 36-48months) visiting Mirwais hospital in Kandahar for minor ailments unrelated to polio were enrolled. After obtaining informed consent, we collected venous blood and conducted neutralization assay to detect poliovirus neutralizing antibodies. RESULTS: A total of 420 children were enrolled and 409/420 (97%) were analysed. Seroprevalence to poliovirus type 1 (PV1) was 97% and 100% in the younger and older age groups respectively; it was 71% and 91% for PV2; 93% and 98% for PV3. Age group (RR=3.6, CI 95%=2.2-5.6) and place of residence outside of Kandahar city (RR=1.8, CI 95%=1.2-2.6) were found to be significant risk factors for seronegativity. CONCLUSIONS: The polio eradication program in Kandahar achieved high serological protection, especially against PV1 and PV3. Lower PV2 seroprevalence in the younger age group is a result of a withdrawal of live type 2 vaccine in 2016 and is expected. Ability to reach all children with poliovirus vaccines is a pre-requisite for achieving poliovirus eradication.

BACKGROUND: Outbreaks of circulating vaccine derived polioviruses type 2 (cVDPV2) remain a risk to poliovirus eradication in an era without live poliovirus vaccine containing type 2 in routine immunization. We evaluated existing outbreak response strategies recommended by the World Health Organization (WHO) for control of cVDPV2 outbreaks. METHODS: Seronegative children for poliovirus type 2 (PV2) at 22weeks of life were assigned to one of four study groups and received respectively (1) one dose of trivalent oral poliovirus vaccine (tOPV); (2) monovalent OPV 2 (mOPV2); (3) tOPV together with a dose of inactivated poliovirus vaccine (IPV); or (4) mOPV2 with monovalent high-potency IPV type 2. Stool and blood samples were collected and assessed for presence of PV2 (stool) and anti-polio antibodies (sera). RESULTS: We analyzed data from 265 children seronegative for PV2. Seroconversion to PV2 was achieved in 48, 76, 98 and 100% in Groups 1-4 respectively. mOPV2 was more immunogenic than tOPV alone (p<0.001); and OPV in combination with IPV was more immunogenic than OPV alone (p<0.001). There were 33%, 67%, 20% and 43% PV2 excretors in Groups 1-4 respectively. mOPV2 resulted in more prevalent shedding of PV2 than when tOPV was used (p<0.001); and tOPV together with IPV resulted in lower excretion of PV2 than tOPV alone (p=0.046). CONCLUSION: mOPV2 was a more potent vaccine than tOPV. Adding IPV to OPV improved immunological response; adding IPV also seemed to have shortened the duration of PV2 shedding. mIPV2 did not provide measurable improvement of immune response when compared to conventional IPV. WHO recommendation to use mOPV2 as a vaccine of first choice in cVDPV2 outbreak response was supported by our findings. Clinical Trial registry number: NCT02189811.

We conducted a serological survey of anti-polio antibodies in polio high-risk areas of Mali, Guinea and Cote d'Ivoire to assess risk of future poliovirus outbreaks. Random community sampling of children 6-11 and 36-48months-old was conducted; neutralizing antibodies against poliovirus were detected using microneutralization assay. We analysed 1059/1064 (99.5%) of enrolled children. Seroprevalence to poliovirus type 1 (PV1) across all age groups and locations ranged between 92 and 100%, for PV2 it was 77-100%, and 89-95% for PV3. PV2 seroprevalence in the younger age group in Guinea and Cote d'Ivoire was<80%. History of<4 polio vaccine doses and acute malnutrition were associated with seronegativity (OR=2.1 CI95%=1.5-3.1, OR=1.8 CI95%=1.1-3.3 respectively). The risk of poliovirus outbreak following importation is low because of high population immunity to PV1, however, due to large cohort of PV2 seronegative children any future detection of vaccine-derived poliovirus type 2 requires urgent response to arrest rapid spread.

Background: We assessed immunity against polioviruses induced with new Pakistani immunization schedule and compared it with alternative immunization schedules. Methods: Newborns were randomized to receive one of the following vaccination schedules, administered at birth, 6, 10, and 14 weeks of age. Arm A: 4x IPV; Arm B: 4x bOPV; Arm C and D: bOPV, bOPV, bOPV, bOPV+ inactivated poliovirus vaccine (IPV); Arm E: 4x trivalent oral poliovirus vaccine (tOPV). At 22 weeks of age, children received one challenge dose of tOPV, and children in arm D received one additional IPV dose. Sera were analyzed for presence of polio neutralizing antibodies at birth, 14, and 22 weeks of age. Results: Study arms A-E, the seroconversion for PV1 at 22 weeks of age was 80%, 97%, 94%, 96%, 94% respectively; for PV2: 84%, 19%, 53%, 49%, 93%; and for PV3: 93%, 94%, 98%, 94%, 85%. Interpretation: Current immunization schedule in Pakistan induced high seroconversion rates for PV1 and PV3; however, it induced PV2 seroconversion in only half of study subjects. There is a growing cohort of young children in Pakistan who are unprotected against PV2; and this creates an increasing risk of a large-scale outbreak of poliomyelitis caused by circulating vaccine-derived PV2.

In 1988, the World Health Assembly launched the Global Polio Eradication Initiative (GPEI) (1). Among the three wild poliovirus (WPV) serotypes, only type 1 (WPV1) has been detected since 2012. Since 2014, detection of WPV1 has been limited to three countries, with 37 cases in 2016 and 11 cases in 2017 as of September 27. The >99.99% decline worldwide in polio cases since the launch of the GPEI is attributable to the extensive use of the live, attenuated oral poliovirus vaccine (OPV) in mass vaccination campaigns and comprehensive national routine immunization programs. Despite its well-established safety record, OPV use can be associated with rare emergence of genetically divergent vaccine-derived polioviruses (VDPVs) whose genetic drift from the parental OPV strains indicates prolonged replication or circulation (2). VDPVs can also emerge among persons with primary immunodeficiencies (PIDs). Immunodeficiency-associated VDPVs (iVDPVs) can replicate for years in some persons with PIDs. In addition, circulating vaccine-derived polioviruses (cVDPVs) can emerge very rarely among immunologically normal vaccine recipients and their contacts in areas with inadequate OPV coverage and can cause outbreaks of paralytic polio. This report updates previous summaries regarding VDPVs (3). During January 2016-June 2017, new cVDPV outbreaks were identified, including two in the Democratic Republic of the Congo (DRC) (eight cases), and another in Syria (35 cases), whereas the circulation of cVDPV type 2 (cVDPV2) in Nigeria resulted in cVDPV2 detection linked to a previous emergence. The last confirmed case from the 2015-2016 cVDPV type 1 (cVDPV1) outbreak in Laos occurred in January 2016. Fourteen newly identified persons in 10 countries were found to excrete iVDPVs, and three previously reported patients in the United Kingdom and Iran (3) were still excreting type 2 iVDPV (iVDPV2) during the reporting period. Ambiguous VDPVs (aVDPVs), isolates that cannot be classified definitively, were found among immunocompetent persons and environmental samples in 10 countries. Cessation of all OPV use after certification of polio eradication will eliminate the risk for new VDPV infections.

Individuals with primary immunodeficiency disorder may excrete poliovirus for extended periods and will constitute the only remaining reservoir of virus after eradication and withdrawal of oral poliovirus vaccine. Here, we analyzed the epidemiology of prolonged and chronic immunodeficiency-related vaccine-derived poliovirus cases in a registry maintained by the World Health Organization, to identify risk factors and determine the length of excretion. Between 1962 and 2016, there were 101 cases, with 94/101 (93%) prolonged excretors and 7/101 (7%) chronic excretors. We documented an increase in incidence in recent decades, with a shift toward middle-income countries, and a predominance of poliovirus type 2 in 73/101 (72%) cases. The median length of excretion was 1.3 years (95% confidence interval: 1.0, 1.4) and 90% of individuals stopped excreting after 3.7 years. Common variable immunodeficiency syndrome and residence in high-income countries were risk factors for long-term excretion. The changing epidemiology of cases, manifested by the greater incidence in recent decades and a shift to from high- to middle-income countries, highlights the expanding risk of poliovirus transmission after oral poliovirus vaccine cessation. To better quantify and reduce this risk, more sensitive surveillance and effective antiviral therapies are needed.

BACKGROUND: Nigeria remains one of only three polio-endemic countries in the world. In 2016, after an absence of 2 years, wild poliovirus serotype 1 was again detected in North-Eastern Nigeria. To better guide programmatic action, we assessed the immunity status of infants and children in Borno and Yobe states, and evaluated the impact of recently introduced inactivated poliovirus vaccine (IPV) on antibody seroprevalence. METHODS AND FINDINGS: We conducted a facility-based study of seroprevalence to poliovirus serotypes 1, 2 and 3 among health-seeking patients in two sites each of Borno and Yobe States. Enrolment was conducted amongst children 6-9 and 36-47 months of age attending the paediatrics outpatient department of the selected hospitals in the two states between 11 January and 5 February 2016. Detailed demographic and immunization history of the child was taken and an assessment of the child's health and nutritional state was conducted via physical examination. Blood was collected to test for levels of neutralizing antibody titres against the three poliovirus serotypes. The seroprevalence in the two age groups, potential determinants of seropositivity and the impact of one dose of IPV on humoral immunity were assessed. A total of 583 subjects were enrolled and provided sufficient quantities of serum for testing. Among 6-9-month-old infants, the seroprevalence was 81% (74-87%), 86% (79-91%), and 72% (65-79%) in Borno State, and 75% (67-81%), 74% (66-81%) and 69% (61-76%) in Yobe States, for serotypes-1, 2 and 3, respectively. Among children aged 36-47 months, the seroprevalence was >90% in both states for all three serotypes, with the exception of type 3 seroprevalence in Borno [87% (80-91%)]. Median reciprocal anti-polio neutralizing antibody titers were consistently >900 for serotypes 1 and 2 across age groups and states; with lower estimates for serotype 3, particularly in Borno. IPV received in routine immunization was found to be a significant determinant of seropositivity and anti-polio neutralizing antibodies among 6-9-month-old infants for serotypes 1 and 3, but demonstrated a non-significant positive association for serotype 2. Children receiving IPV through SIAs demonstrated significantly higher anti-polio neutralizing antibodies for serotypes 1 and 3. CONCLUSIONS: The seroprevalence to poliovirus remains suboptimal in both Borno and Yobe States in Nigeria. The low seroprevalence facilitated the continued transmission of both wild serotype 1 and serotype 2 circulating vaccine-derived poliovirus detected in Borno State in 2016. Further efforts are necessary to improve the immunity status of these populations to ensure sufficient population immunity to interrupt transmission.

BACKGROUND: Pakistan is one of the 3 remaining wild poliovirus endemic countries. We collected sera from children to assess the prevalence of poliovirus antibodies in selected high-risk areas for poliovirus transmission. METHODS: Children in 2 age groups (6-11 and 36-48 months) were randomly selected between November 2015 and March 2016 in 6 areas of Pakistan (Sindh Province: Karachi and Kashmore; Khyber Pakhtunkhwa Province: Peshawar, Bannu and Nowshera; Punjab Province: Faisalabad). After obtaining informed consent, basic demographic and vaccination history data were collected, 1 peripheral venipuncture was obtained, and assays to detect poliovirus (PV)-neutralizing antibodies were performed. RESULTS: A total of 1301 children were enrolled and had peripheral blood drawn that analyzed. Study subjects were evenly distributed among survey sites and age groups. Anti-polio seroprevalence differed significantly among geographic areas (P < 0.001); in the 6-11 months group, it ranged between 89% and 98%, 58% and 95%, and 74% and 96% for PV serotypes 1, 2 and 3, respectively; in 36-48 months group, it ranged between 99% and 100%, 95% and 100%, and 92% and 100% for PV 1, 2, and 3, respectively. Having received inactivate poliovirus vaccine, malnourishment (stunting) and educational level of parents were found to be associated with presence of anti-polio antibodies. CONCLUSION: The polio eradication program achieved overall high serologic protection; however, immunity gaps in young children in the high polio risk areas remain. These gaps enable sustained circulation of wild poliovirus type 1, and pose risk for emergence of vaccine-derived polioviruses. Focusing on the lowest socioeconomic strata of society, where malnutrition is most prevalent, could accelerate poliovirus eradication.

The Global Polio Eradication Initiative (GPEI) continues to make progress toward the eradication target. Only one of the three serotypes, wild poliovirus (WPV) type 1 (WPV1), is still circulating, and the numbers of cases and countries with endemic transmission are at record lows. With the certification of wild poliovirus type 2 (WPV2) eradication in 2015 and the global replacement of trivalent oral poliovirus vaccine (tOPV) containing Sabin poliovirus types 1, 2, and 3 with bivalent OPV containing only Sabin poliovirus types 1 and 3 during April-May 2016, poliovirus type 2 (PV2) is now an eradicated pathogen. However, in eight countries (Cameroon, Chad, Democratic Republic of Congo, Mozambique, Niger, Nigeria, Pakistan, and Syria), monovalent type 2 OPV (mOPV2) was authorized for large-scale outbreak control after tOPV withdrawal (1). Poliovirus containment, an evolving area of work that affects every country, aims to ensure that all PV2 specimens are safely contained to minimize the risk for reintroducing the virus into communities. This report summarizes the current status of poliovirus containment and progress since the last report (2), and outlines remaining challenges. Within 30 countries, 86 facilities have been designated by the relevant national authorities (usually the Ministry of Health) to become poliovirus-essential facilities for the continued storage or handling of PV2 materials; each country is responsible for ensuring that these facilities meet all biorisk management requirements.

Immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) have been isolated from primary immunodeficiency (PID) patients exposed to oral poliovirus vaccine (OPV). Patients may excrete poliovirus strains for months or years; the excreted viruses are frequently highly divergent from the parental OPV and have been shown to be as neurovirulent as wild virus. Thus, these patients represent a potential reservoir for transmission of neurovirulent polioviruses in the post-eradication era. In support of WHO recommendations to better estimate the prevalence of poliovirus excreters among PIDs and characterize genetic evolution of these strains, 635 patients including 570 with primary antibody deficiencies and 65 combined immunodeficiencies were studied from 13 OPV-using countries. Two stool samples were collected over 4 days, tested for enterovirus, and the poliovirus positive samples were sequenced. Thirteen patients (2%) excreted polioviruses, most for less than 2 months following identification of infection. Five (0.8%) were classified as iVDPVs (only in combined immunodeficiencies and mostly poliovirus serotype 2). Non-polio enteroviruses were detected in 30 patients (4.7%). Patients with combined immunodeficiencies had increased risk of delayed poliovirus clearance compared to primary antibody deficiencies. Usually, iVDPV was detected in subjects with combined immunodeficiencies in a short period of time after OPV exposure, most for less than 6 months. Surveillance for poliovirus excretion among PID patients should be reinforced until polio eradication is certified and the use of OPV is stopped. Survival rates among PID patients are improving in lower and middle income countries, and iVDPV excreters are identified more frequently. Antivirals or enhanced immunotherapies presently in development represent the only potential means to manage the treatment of prolonged excreters and the risk they present to the polio endgame.

Administration of 1/5th dose of Inactivated poliovirus vaccine intradermally (fIPV) provides similar immune response as full-dose intramuscular IPV, however, fIPV administration with BCG needle and syringe (BCG NS) is technically difficult. We compared immune response after one fIPV dose administered with BCG NS to administration with intradermal devices, referred to as Device A and B; and assessed feasibility of conducting a door-to-door vaccination campaign with fIPV. In Phase I, 452 children 6-12months old from Karachi were randomized to receive one fIPV dose either with BCG NS, Device A or Device B in a health facility. Immune response was defined as seroconversion or fourfold rise in polio neutralizing antibody titer 28days after fIPV among children whose baseline titer ≤362. In Phase II, fIPV was administered during one-day door-to-door campaign to assess programmatic feasibility by evaluating vaccinators' experience. For all three poliovirus (PV) serotypes, the immune response after BCG NS and Device A was similar, however it was lower with Device B (34/44 (77%), 31/45 (69%), 16/30 (53%) respectively for PV1; 53/78 (68%), 61/83 (74%), 42/80 (53%) for PV2; and; 58/76 (76%), 56/80 (70%), 43/77 (56%) for PV3; p<0.05 for all three serotypes). Vaccinators reported problems filling Device B in both Phases; no other operational challenges were reported during Phase II. Use of fIPV offers a dose-saving alternative to full-dose IPV.

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.

This report updates previous surveillance summaries and describes vaccine-derived polioviruses (VDPVs) detected worldwide during January 2015-May 2016. The update includes new circulating VDPV (cVDPV) outbreaks in Myanmar, Laos, Ukraine and Guinea, and sharply reduced cVDPV2 in Nigeria and Pakistan. 21 newly identified persons in 10 countries were found to excrete immunodeficiency-associated VDPVs (iVDPVs), and a patient in the UK was still excreting an iVDPV in 2015 after >29 years of chronic infection. Ambiguous VDPVs (aVDPVs) were found among immunocompetent persons and environmental samples in 19 countries. In response to the observation that the large majority of VDPV isolates are type 2, WHO coordinated the worldwide replacement of trivalent OPV (tOPV) with bivalent OPV (bOPV; types 1 and 3) in April 2016, preceded by the introduction of at least one dose of inactivated poliovirus vaccine (IPV) into routine immunization schedules in all high-risk countries.