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A novel, genetically-stabilized type 2 oral polio vaccine (nOPV2), developed to assist in the global polio eradication program, was recently the first-ever vaccine granted Emergency Use Listing by the WHO. Lot release tests for this vaccine included-for the first time to our knowledge-the assessment of genetic heterogeneity using next-generation sequencing (NGS). NGS ensures that the genetically-modified regions of the vaccine virus genome remain as designed and that levels of polymorphisms which may impact safety or efficacy are controlled during routine production. The variants present in nOPV2 lots were first assessed for temperature sensitivity and neurovirulence using molecular clones to inform which polymorphisms warranted formal evaluation during lot release. The novel use of NGS as a lot release test required formal validation of the method. Analysis of an nOPV2 lot spiked with the parental Sabin-2 strain enabled performance characteristics of the method to be assessed simultaneously at over 40 positions in the genome. These characteristics included repeatability and intermediate precision of polymorphism measurement, linearity of both spike-induced and nOPV2 lot-specific polymorphisms, and the limit-of-detection of spike-induced polymorphisms. The performance characteristics of the method met pre-defined criteria for 34 spike-induced polymorphic sites and 8 polymorphisms associated with the nOPV2 preparation; these sites collectively spanned most of the viral genome. Finally, the co-location of variants of interest on genomes was evaluated, with implications for the interpretation of NGS discussed.
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INTRODUCTION: Inactivated poliovirus vaccine (IPV) shortages and evidence of improved immunogenicity of two intradermal (ID) fractional IPV (fIPV) doses compared with one full intramuscular dose led to recommendations for fIPV delivery. To provide evidence on the economics of fIPV, we estimated the cost per child vaccinated using full-dose IPV compared with fIPV in routine and campaign settings. We evaluated the impact on costs of alternative devices facilitating ID administration, vaccine vial sizes, and prices. METHODS: We used an Excel-based model to estimate the commodity and delivery costs for providing IPV. Commodity costs included vaccine price per dose adjusted for wastage, prices for vaccine administration devices, and safety boxes. Delivery costs included storage costs at each level of the supply chain, transport costs for commodities between levels, and human resource costs for vaccine administration. Model inputs were obtained from various databases and published literature. All costs are reported in 2018 US dollars. RESULTS: In both campaign and routine settings, fIPV had a lower cost per child vaccinated than full dosing, despite the assumed higher vaccine wastage with fIPV in routine settings, and even when novel ID administration devices were used. In routine settings, costs per child fully vaccinated with fractional doses were 15% to 48% lower than those with full-dose delivery across different vial sizes. The cost per child vaccinated ranged from $1.84 to $2.65 for fractional doses, depending on the administration device, compared with $3.57 for full dose, when using 5-dose vials. The magnitude of cost reductions with fIPV relative to full-dose IPV was largest with smaller vial sizes and higher vaccine price. CONCLUSION: Adopting fIPV can reduce costs per child vaccinated compared with using full doses, especially as IPV prices increase in the short term and more so when two full doses could be recommended in the future.
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BACKGROUND: Silent circulation of polioviruses complicates the polio endgame and motivates analyses that explore the probability of undetected circulation for different scenarios. A recent analysis suggested a relatively high probability of unusually long silent circulation of polioviruses in small populations (defined as 10,000 people or smaller). METHODS: We independently replicated the simple, hypothetical model by Vallejo et al. (2017) and repeated their analyses to explore the model behavior, interpretation of the results, and implications of simplifying assumptions. RESULTS: We found a similar trend of increasing times between detected cases with increasing basic reproduction number (R0) and population size. However, we found substantially lower estimates of the probability of at least 3 years between successive polio cases than they reported, which appear more consistent with the prior literature. While small and isolated populations may sustain prolonged silent circulation, our reanalysis suggests that the existing rule of thumb of less than a 5% chance of 3 or more years of undetected circulation with perfect surveillance holds for most conditions of the model used by Vallejo et al. and most realistic conditions. CONCLUSIONS: Avoiding gaps in surveillance remains critical to declaring wild poliovirus elimination with high confidence as soon as possible after the last detected poliovirus, but concern about transmission in small populations with adequate surveillance should not significantly change the criteria for the certification of wild polioviruses.
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Administering vaccines directly to mucosal surfaces can induce both serum and mucosal immune responses. Mucosal responses may prevent establishment of initial infection at the port of entry and subsequent dissemination to other sites. The sublingual route is attractive for mucosal vaccination, but both a safe, potent adjuvant and a novel formulation are needed to achieve an adequate immune response. We report the use of a thermoresponsive gel (TRG) combined with a double mutant of a bacterial heat-labile toxin (dmLT) for sublingual immunization with a trivalent inactivated poliovirus vaccine (IPV) in mice. This TRG delivery system, which changes from aqueous solution to viscous gel upon contact with the mucosa at body temperature, helps to retain the formulation at the site of delivery and has functional adjuvant activity from the inclusion of dmLT. IPV was administered to mice either sublingually in the TRG delivery system or intramuscularly in phosphate-buffered saline. We measured poliovirus type-specific serum neutralizing antibodies as well as polio-specific serum Ig and IgA antibodies in serum, saliva, and fecal samples using enzyme-linked immunosorbent assays. Mice receiving sublingual vaccination via the TRG delivery system produced both mucosal and serum antibodies, including IgA. Intramuscularly immunized animals produced only serum neutralizing and binding Ig but no detectable IgA. This study provides proof of concept for sublingual immunization using the TRG delivery system, comprising a thermoresponsive gel and dmLT adjuvant.