Importation and Circulation of Vaccine-Derived Poliovirus Serotype 2, Senegal, 2020–2021

Faye, Martin; Kébé, Ousmane; Diop, Boly; Ndiaye, Ndack; Dosseh, Annick; Sam, Abdoulaye; Diallo, Aliou; Dia, Hamet; Diallo, Jean Pierre; Dia, Ndongo; Kiori, Davy; Diop, Ousmane M.; Sall, Amadou Alpha; Faye, Ousmane

doi:10.3201/eid2810.220847

Cited by 3 publications

(6 citation statements)

References 24 publications

(39 reference statements)

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“…The Bayesian phylogenetic analysis suggests that the most probable origin of all VDPV2 isolates circulating in Senegal, Guinea, Gambia, and Mauritania was Senegal around 2015. Our results are consistent with previous findings that suggest that VDPV2s in Senegal in 2021 will spread to Gambia ( Faye. et al., 2022 ), given that all VDPV2 strains from the Gambia branch are in the SEN1 lineage, which has Senegal as the most likely origin with a very high probability.…”

Section: Discussionsupporting

confidence: 93%

“…et al., 2022 ), given that all VDPV2 strains from the Gambia branch are in the SEN1 lineage, which has Senegal as the most likely origin with a very high probability. Similarly, these results do not contradict the possibility that the origin of some independent VDPV2 introductions observed in Senegal recorded during 2020–21 was Guinea, Mali, and Côte d’Ivoire, as previously suggested ( Faye. et al., 2022 ).…”

Section: Discussionsupporting

confidence: 87%

“…Analysis of complete VP1 coding sequences showed that strain SPA866 branched closely (bootstrap value of 98%) with cVDPV2 strains obtained in Senegal in 2021, more precisely with those strains previously defined in clade 2 by Faye et al ( Faye. et al., 2022 ).…”

Section: Resultssupporting

confidence: 78%

“…We estimated that the initiating OPV dose for VDPV2s circulating in west Africa in 2020–21 was given around 2015 in Senegal, and it disseminated in early 2018 within the country and lately to nearby countries such as Mauritania, Guinea, and Gambia. Thus, the widespread circulation of cVDPV2s reveals gaps in immunity to PV2 in children across all these countries and their silent circulation until the first detection in wastewater samples in Dakar, Senegal, in December 2020 ( Faye. et al., 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…Finally, characterization of the detected poliovirus (WPV, OPV, or VDPV) was carried out using intratypic differentiation (ITD) assays ( Gerloff et al., 2018 ), as was amplification and sequencing of the complete VP1 region of the viral genome. In Senegal, 25 contacts of the AFP case were studied by the WHO-accredited reference polio laboratory at the Institut Pasteur of Dakar, as previously described ( Faye. et al., 2022 ).…”

Section: Methodsmentioning

confidence: 99%

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Metagenomic sequencing, molecular characterization, and Bayesian phylogenetics of imported type 2 vaccine-derived poliovirus, Spain, 2021

Fernández-García

Faye

Díez-Fuertes

et al. 2023

Front. Cell. Infect. Microbiol.

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IntroductionIn 2021, a type 2 vaccine-derived poliovirus (VDPV2) was isolated from the stool of a patient with acute flaccid paralysis (AFP) admitted to Spain from Senegal. A virological investigation was conducted to characterize and trace the origin of VDPV2.MethodsWe used an unbiased metagenomic approach for the whole-genome sequencing of VDPV2 from the stool (pre-treated with chloroform) and from the poliovirus-positive supernatant. Phylogenetic analyses and molecular epidemiological analyses relying on the Bayesian Markov Chain Monte Carlo methodology were used to determine the geographical origin and estimate the date of the initiating dose of the oral poliovirus vaccine for the imported VDPV2.ResultsWe obtained a high percentage of viral reads per total reads mapped to the poliovirus genome (69.5% for pre-treated stool and 75.8% for isolate) with a great depth of sequencing coverage (5,931 and 11,581, respectively) and complete genome coverage (100%). The two key attenuating mutations in the Sabin 2 strain had reverted (A481G in the 5’UTR and Ile143Thr in VP1). In addition, the genome had a recombinant structure between type-2 poliovirus and an unidentified non-polio enterovirus-C (NPEV-C) strain with a crossover point in the protease-2A genomic region. VP1 phylogenetic analysis revealed that this strain is closely related to VDPV2 strains circulating in Senegal in 2021. According to Bayesian phylogenetics, the most recent common ancestor of the imported VDPV2 could date back 2.6 years (95% HPD: 1.7–3.7) in Senegal. We suggest that all VDPV2s circulating in 2020–21 in Senegal, Guinea, Gambia, and Mauritania have an ancestral origin in Senegal estimated around 2015. All 50 stool samples from healthy case contacts collected in Spain (n = 25) and Senegal (n = 25) and four wastewater samples collected in Spain were poliovirus negative.DiscussionBy using a whole-genome sequencing protocol with unbiased metagenomics from the clinical sample and viral isolate with high sequence coverage, efficiency, and throughput, we confirmed the classification of VDPV as a circulating type. The close genomic linkage with strains from Senegal was consistent with their classification as imported. Given the scarce number of complete genome sequences for NPEV-C in public databases, this protocol could help expand poliovirus and NPEV-C sequencing capacity worldwide.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 87%

Section: Resultssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Metagenomic sequencing, molecular characterization, and Bayesian phylogenetics of imported type 2 vaccine-derived poliovirus, Spain, 2021

Fernández-García

Faye

Díez-Fuertes

et al. 2023

Front. Cell. Infect. Microbiol.

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Differential Inhibition of Intra- and Inter-molecular Protease Cleavages by Antiviral Compounds

Doherty¹,

Kirkegaard

2023

Preprint

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Differential inhibition of intra- and inter-molecular protease cleavages by antiviral compounds

Doherty,

Kirkegaard

2023

J Virol

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Enteroviruses encode two protease active sites, in the 2A and 3C coding regions. While they target many host proteins, they first need to be excised from the viral polyprotein in which they are embedded. Polyprotein cleavage can occur either intra-molecularly (in cis ) or inter-molecularly (in trans ). Previous work suggested that antivirals targeting intra-molecular cleavages could generate inhibitory precursors that can suppress the outgrowth of drug-resistant variants. Therefore, we wanted to evaluate enteroviral cleavage patterns to identify such obligate intra-molecular cleavages as a method of drug target selection. Using translation extracts, we show that cis cleavage of the 2A protease N-terminal junction is conserved across three enterovirus clades, while the mechanism for the N-terminal junction of 3C varies, with enterovirus D68 3C cleavage occurring in cis and poliovirus 3C cleavage occurring in trans . Antiviral agents targeting proteases are generally identified via their ability to block the cleavage of artificial peptide substrates. Here, we show that antivirals identified for their ability to block inter-molecular cleavage can sometimes block intra-molecular cleavage of the protease from its polyprotein but with widely varying efficacy. Additionally, we demonstrate that for three enteroviral species, genomes defective in 2A protease activity suppress the growth of wild-type virus in mixed populations, supporting the hypothesis that preventing intra-molecular cleavage at the VP1·2A junction can create dominantly inhibitory precursors. These data argue that, to reduce the likelihood of drug resistance, protease-targeted antivirals should be evaluated for their ability to block intra-molecular polyprotein cleavages in addition to inter-molecular cleavage of other substrates. IMPORTANCE Most protease-targeted antiviral development evaluates the ability of small molecules to inhibit the cleavage of artificial substrates. However, before they can cleave any other substrates, viral proteases need to cleave themselves out of the viral polyprotein in which they have been translated. This can occur either intra- or inter-molecularly. Whether this process occurs intra- or inter-molecularly has implications for the potential for precursors to accumulate and for the effectiveness of antiviral drugs. We argue that evaluating candidate antivirals for their ability to block these cleavages is vital to drug development because the buildup of uncleaved precursors can be inhibitory to the virus and potentially suppress the selection of drug-resistant variants.

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Importation and Circulation of Vaccine-Derived Poliovirus Serotype 2, Senegal, 2020–2021

Cited by 3 publications

References 24 publications

Metagenomic sequencing, molecular characterization, and Bayesian phylogenetics of imported type 2 vaccine-derived poliovirus, Spain, 2021

Metagenomic sequencing, molecular characterization, and Bayesian phylogenetics of imported type 2 vaccine-derived poliovirus, Spain, 2021

Differential Inhibition of Intra- and Inter-molecular Protease Cleavages by Antiviral Compounds

Differential inhibition of intra- and inter-molecular protease cleavages by antiviral compounds

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