Update on Vaccine-Derived Poliovirus Outbreaks - Worldwide, July 2019-February 2020.
ABSTRACT: Circulating vaccine-derived polioviruses (cVDPVs) can emerge in areas with low poliovirus immunity and cause outbreaks* of paralytic polio (1-5). Among the three types of wild poliovirus, type 2 was declared eradicated in 2015 (1,2). The use of trivalent oral poliovirus vaccine (tOPV; types 1, 2, and 3 Sabin strains) ceased in April 2016 via a 1-month-long, global synchronized switch to bivalent OPV (bOPV; types 1 and 3 Sabin strains) in immunization activities (1-4). Monovalent type 2 OPV (mOPV2; type 2 Sabin strain) is available for cVDPV type 2 (cVDPV2) outbreak response immunization (1-5). The number and geographic breadth of post-switch cVDPV2 outbreaks have exceeded forecasts that trended toward zero outbreaks 4 years after the switch and assumed rapid and effective control of any that occurred (4). New cVDPV2 outbreaks have been seeded by mOPV2 use, by both suboptimal mOPV2 coverage within response zones and recently mOPV2-vaccinated children or contacts traveling outside of response zones, where children born after the global switch are fully susceptible to poliovirus type 2 transmission (2-4). In addition, new emergences can develop by inadvertent exposure to Sabin OPV2-containing vaccine (i.e., residual response mOPV2 or tOPV) (4). This report updates the January 2018-June 2019 report with information on global cVDPV outbreaks during July 2019-February 2020 (as of March 25, 2020)† (2). Among 33 cVDPV outbreaks reported during July 2019-February 2020, 31 (94%) were cVDPV2; 18 (58%) of these followed new emergences. In mid-2020, the Global Polio Eradication Initiative (GPEI) plans to introduce a genetically stabilized, novel OPV type 2 (nOPV2) that has a lower risk for generating VDPV2 than does Sabin mOPV2; if nOPV2 is successful in limiting new VDPV2 emergences, GPEI foresees the replacement of Sabin mOPV2 with nOPV2 for cVDPV2 outbreak responses during 2021 (2,4,6).
Project description: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.
Project description:Since the Global Polio Eradication Initiative (GPEI) was established in 1988, two of the three wild poliovirus (WPV) serotypes (types 2 and 3) have been eradicated.* Transmission of WPV type 1 (WPV1) remains uninterrupted only in Afghanistan and Pakistan. This report summarizes progress toward global polio eradication during January 1, 2018-March 31, 2020 and updates previous reports (1,2). In 2019, Afghanistan and Pakistan reported the highest number of WPV1 cases (176) since 2014. During January 1-March 31, 2020 (as of June 19), 54 WPV1 cases were reported, an approximate fourfold increase from 12 cases during the corresponding period in 2019. Paralytic poliomyelitis can also be caused by circulating vaccine-derived poliovirus (cVDPV), which emerges when attenuated oral poliovirus vaccine (OPV) virus reverts to neurovirulence following prolonged circulation in underimmunized populations (3). Since the global withdrawal of type 2-containing OPV (OPV2) in April 2016, cVDPV type 2 (cVDPV2) outbreaks have increased in number and geographic extent (4). During January 2018-March 2020, 21 countries reported 547 cVDPV2 cases. Complicating increased poliovirus transmission during 2020, the coronavirus disease 2019 (COVID-19) pandemic and mitigation efforts have resulted in suspension of immunization activities and disruptions to poliovirus surveillance. When the COVID-19 emergency subsides, enhanced support will be needed to resume polio eradication field activities.
Project description: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 22?weeks 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.
Project description:BACKGROUND:Mass campaigns with oral poliovirus vaccine (OPV) have brought the world close to the eradication of wild poliovirus. However, to complete eradication, OPV must itself be withdrawn to prevent outbreaks of vaccine-derived poliovirus (VDPV). Synchronized global withdrawal of OPV began with serotype 2 OPV (OPV2) in April 2016, which presented the first test of the feasibility of eradicating all polioviruses. METHODS:We analyzed global surveillance data on the detection of serotype 2 Sabin vaccine (Sabin-2) poliovirus and serotype 2 vaccine-derived poliovirus (VDPV2, defined as vaccine strains that are at least 0.6% divergent from Sabin-2 poliovirus in the viral protein 1 genomic region) in stool samples from 495,035 children with acute flaccid paralysis in 118 countries and in 8528 sewage samples from four countries at high risk for transmission; the samples were collected from January 1, 2013, through July 11, 2018. We used Bayesian spatiotemporal smoothing and logistic regression to identify and map risk factors for persistent detection of Sabin-2 poliovirus and VDPV2. RESULTS:The prevalence of Sabin-2 poliovirus in stool samples declined from 3.9% (95% confidence interval [CI], 3.5 to 4.3) at the time of OPV2 withdrawal to 0.2% (95% CI, 0.1 to 2.7) at 2 months after withdrawal, and the detection rate in sewage samples declined from 71.0% (95% CI, 61.0 to 80.0) to 13.0% (95% CI, 8.0 to 20.0) during the same period. However, 12 months after OPV2 withdrawal, Sabin-2 poliovirus continued to be detected in stool samples (<0.1%; 95% CI, <0.1 to 0.1) and sewage samples (8.0%; 95% CI, 5.0 to 13.0) because of the use of OPV2 in response to VDPV2 outbreaks. Nine outbreaks were reported after OPV2 withdrawal and were associated with low coverage of routine immunization (odds ratio, 1.64 [95% CI, 1.14 to 2.54] per 10% absolute decrease) and low levels of population immunity (odds ratio, 2.60 [95% CI, 1.35 to 5.59] per 10% absolute decrease) within affected countries. CONCLUSIONS:High population immunity has facilitated the decline in the prevalence of Sabin-2 poliovirus after OPV2 withdrawal and restricted the circulation of VDPV2 to areas known to be at high risk for transmission. The prevention of VDPV2 outbreaks in these known areas before the accumulation of substantial cohorts of children susceptible to type 2 poliovirus remains a high priority. (Funded by the Bill and Melinda Gates Foundation and the World Health Organization.).
Project description:Enormous progress has been made in global efforts to eradicate poliovirus, using live-attenuated Sabin oral poliovirus vaccine (OPV). However, as the incidence of disease due to wild poliovirus has declined, vaccine-derived poliovirus (VDPV) has emerged in areas of low-vaccine coverage. Coordinated global cessation of routine, type 2 Sabin OPV (OPV2) use has not resulted in fewer VDPV outbreaks, and continued OPV use in outbreak-response campaigns has seeded new emergences in low-coverage areas. The limitations of existing vaccines and current eradication challenges warranted development of more genetically stable OPV strains, most urgently for OPV2. Here, we report using codon deoptimization to further attenuate Sabin OPV2 by changing preferred codons across the capsid to non-preferred, synonymous codons. Additional modifications to the 5' untranslated region stabilized known virulence determinants. Testing of this codon-deoptimized new OPV2 candidate (nOPV2-CD) in cell and animal models demonstrated that nOPV2-CD is highly attenuated, grows sufficiently for vaccine manufacture, is antigenically indistinguishable from Sabin OPV2, induces neutralizing antibodies as effectively as Sabin OPV2, and unlike Sabin OPV2 is genetically stable and maintains an attenuation phenotype. In-human clinical trials of nOPV2-CD are ongoing, with potential for nOPV strains to serve as critical vaccine tools for achieving and maintaining polio eradication.
Project description:In 2001, highly evolved type 1 circulating vaccine-derived poliovirus (cVDPV) was isolated from three acute flaccid paralysis patients and one contact from three separate communities in the Philippines. Complete genomic sequencing of these four cVDPV isolates revealed that the capsid region was derived from the Sabin 1 vaccine strain but most of the noncapsid region was derived from an unidentified enterovirus unrelated to the oral poliovirus vaccine (OPV) strains. The sequences of the cVDPV isolates were closely related to each other, and the isolates had a common recombination site. Most of the genetic and biological properties of the cVDPV isolates were indistinguishable from those of wild polioviruses. However, the most recently identified cVDPV isolate from a healthy contact retained the temperature sensitivity and partial attenuation phenotypes. The sequence relationships among the isolates and Sabin 1 suggested that cVDPV originated from an OPV dose given in 1998 to 1999 and that cVDPV circulated along a narrow chain of transmission. Type 1 cVDPV was last detected in the Philippines in September 2001, and population immunity to polio was raised by extensive OPV campaigns in late 2001 and early 2002.
Project description:Background:The Polio Eradication and Endgame Strategic Plan 2013-2018 calls for the gradual withdrawal of oral poliovirus vaccine (OPV) from routine immunization. We aimed to quantify the transmission potential of Sabin strains from OPV when it is reintroduced, accidentally or deliberately, in a community vaccinated with inactivated poliovirus vaccine alone. Methods:We built an individual-based stochastic epidemiological model that allows independent spread of 3 Sabin serotypes and differential transmission rates within versus between households. Model parameters were estimated by fitting to data from a prospective cohort in Mexico. We calculated the effective reproductive number for the Mexico cohort and simulated scenarios of Sabin strain resurgence under postcessation conditions, projecting the risk of prolonged circulation, which could lead to circulating vaccine-derived poliovirus (cVDPV). Results:The estimated effective reproductive number for naturally infected individuals was about 1 for Sabin 2 and Sabin 3 (OPV2 and OPV3) in a postcessation setting. Most transmission events occurred between households. We estimated the probability of circulation for >9 months to be (1) <<1% for all 3 serotypes when 90% of children <5 years of age were vaccinated in a hypothetical outbreak control campaign; (2) 45% and 24% for Sabin 2 and Sabin 3, respectively, when vaccine coverage dropped to 10%; (3) 37% and 8% for Sabin 2 and Sabin 3, respectively, when a single active shedder appeared in a community. Conclusions:Critical factors determining the risk of cVDPV emergence are the scale at which OPV is reintroduced and the between-household transmission rate for poliovirus, with intermediate values posing the greatest risk.
Project description:To assess the dynamics of genetic reversion of live poliovirus vaccine in humans, we studied molecular evolution in Sabin-like poliovirus isolates from Nigerian acute flaccid paralysis cases obtained from routine surveillance. We employed a novel modeling approach to infer substitution and recombination rates from whole-genome sequences and information about poliovirus infection dynamics and the individual vaccination history. We confirmed observations from a recent vaccine trial that VP1 substitution rates are increased for Sabin-like isolates relative to the rate for the wild type due to increased nonsynonymous substitution rates. We also inferred substitution rates for attenuating nucleotides and confirmed that reversion can occur in days to weeks after vaccination. We combine our observations for Sabin-like virus evolution with the molecular clock for VP1 of circulating wild-type strains to infer that the mean time from the initiating vaccine dose to the earliest detection of circulating vaccine-derived poliovirus (cVDPV) is 300 days for Sabin-like virus type 1, 210 days for Sabin-like virus type 2, and 390 days for Sabin-like virus type 3. Phylogenetic relationships indicated transient local transmission of Sabin-like virus type 3 and, possibly, Sabin-like virus type 1 during periods of low wild polio incidence. Comparison of Sabin-like virus recombinants with known Nigerian vaccine-derived poliovirus recombinants shows that while recombination with non-Sabin enteroviruses is associated with cVDPV, the recombination rates are similar for Sabin isolate-Sabin isolate and Sabin isolate-non-Sabin enterovirus recombination after accounting for the time from dosing to the time of detection. Our study provides a comprehensive picture of the evolutionary dynamics of the oral polio vaccine in the field.The global polio eradication effort has completed its 26th year. Despite success in eliminating wild poliovirus from most of the world, polio persists in populations where logistical, social, and political factors have not allowed vaccination programs of sustained high quality. One issue of critical importance is eliminating circulating vaccine-derived polioviruses (cVDPVs) that have properties indistinguishable from those of wild poliovirus and can cause paralytic disease. cVDPV emerges due to the genetic instability of the Sabin viruses used in the oral polio vaccine (OPV) in populations that have low levels of immunity to poliovirus. However, the dynamics responsible are incompletely understood because it has historically been difficult to gather and interpret data about evolution of the Sabin viruses used in OPV in regions where cVDPV has occurred. This study is the first to combine whole-genome sequencing of poliovirus isolates collected during routine surveillance with knowledge about the intrahost dynamics of poliovirus to provide quantitative insight into polio vaccine evolution in the field.
Project description:Reversion and spread of vaccine-derived poliovirus (VDPV) to cause outbreaks of poliomyelitis is a rare outcome resulting from immunisation with the live-attenuated oral poliovirus vaccines (OPVs). Global withdrawal of all three OPV serotypes is therefore a key objective of the polio endgame strategic plan, starting with serotype 2 (OPV2) in April 2016. Supplementary immunisation activities (SIAs) with trivalent OPV (tOPV) in advance of this date could mitigate the risks of OPV2 withdrawal by increasing serotype-2 immunity, but may also create new serotype-2 VDPV (VDPV2). Here, we examine the risk factors for VDPV2 emergence and implications for the strategy of tOPV SIAs prior to OPV2 withdrawal. We first developed mathematical models of VDPV2 emergence and spread. We found that in settings with low routine immunisation coverage, the implementation of a single SIA increases the risk of VDPV2 emergence. If routine coverage is 20%, at least 3 SIAs are needed to bring that risk close to zero, and if SIA coverage is low or there are persistently "missed" groups, the risk remains high despite the implementation of multiple SIAs. We then analysed data from Nigeria on the 29 VDPV2 emergences that occurred during 2004-2014. Districts reporting the first case of poliomyelitis associated with a VDPV2 emergence were compared to districts with no VDPV2 emergence in the same 6-month period using conditional logistic regression. In agreement with the model results, the odds of VDPV2 emergence decreased with higher routine immunisation coverage (odds ratio 0.67 for a 10% absolute increase in coverage [95% confidence interval 0.55-0.82]). We also found that the probability of a VDPV2 emergence resulting in poliomyelitis in >1 child was significantly higher in districts with low serotype-2 population immunity. Our results support a strategy of focused tOPV SIAs before OPV2 withdrawal in areas at risk of VDPV2 emergence and in sufficient number to raise population immunity above the threshold permitting VDPV2 circulation. A failure to implement this risk-based approach could mean these SIAs actually increase the risk of VDPV2 emergence and spread.
Project description:Public health response to vaccine-derived poliovirus (VDPV) that is transmitted from person to person (circulating VDPV [cVDPV]) differs significantly from response to virus that replicates in individuals with primary immunodeficiency (immunodeficiency-associated VDPV [iVDPV]). cVDPV outbreaks require a community immunization response, whereas iVDPV chronic infections require careful patient monitoring and appropriate individual treatment. To support poliovirus outbreak response, particularly for type 2 VDPV, we investigated the genetic distinctions between cVDPV2 and iVDPV2 sequences. We observed that simple genetic measurements of nucleotide and amino acid substitutions are sufficient for distinguishing highly divergent iVDPV2 from cVDPV2 sequences, but are insufficient to make a clear distinction between the two categories among less divergent sequences. We presented quantitative approaches using genetic information as a surveillance tool for early detection of VDPV outbreaks. This work suggests that genetic variations between cVDPV2 and iVDPV2 may reflect differences in viral micro-environments, host-virus interactions, and selective pressures during person-to-person transmission compared with chronic infections in immunodeficient patients.