#EV-71 #seroepidemiology in #Taiwan in 2017 and comparison of those rates in 1997, 1999 and 2007 (PLoS One, abstract)

[Source: PLoS One, full page: (LINK). Abstract, edited.]


Enterovirus 71 seroepidemiology in Taiwan in 2017 and comparison of those rates in 1997, 1999 and 2007

Jian-Te Lee, Ting-Yu Yen, Wei-Liang Shih, Chun-Yi Lu, Ding-Ping Liu, Yi-Chuan Huang, Luan-Yin Chang , Li-Min Huang, Tzou-Yien Lin

Published: October 17, 2019 / DOI: https://doi.org/10.1371/journal.pone.0224110




During recent 20 years, enterovirus 71 (EV71) has emerged as a major concern among children, particularly in the Asia-Pacific region. To understand current EV71 serostatus, to find risk factors associated with EV71 infection and to establish future EV71 vaccine policy, we performed a seroepidemiology study in Taiwan in 2017.


After informed consent was obtained, we enrolled preschool children, 6–15-year-old students, 16–50-year-old people. They received a questionnaire and a blood sample was collected to measure the EV71 neutralization antibody.


Altogether, 920 subjects were enrolled with a male-to-female ratio of 1.03. The EV71 seropositive rate was 10% (8/82) in infants, 4% (6/153) in 1-year-old children, 8% (7/83) in 2-year-old children, 8% (13/156) in 3–5-year-old children, 31% (38/122) in 6–11-year-old primary school students, 45% (54/121) in 12–15-year-old high school students and 75% (152/203) in 16-50-year-old people. Risk factors associated with EV71 seropositivity in preschool children were female gender, having siblings, more siblings, and contact with herpangina or hand-foot-and-mouth disease. The risk factor with EV71 seropositivity in 16–50-year-old people was having children in their families in addition to older age (p<0.001). Compared with the rates in 1997, 1999 and 2007, the rates in children were significantly lower in 2017.


EV71 seropositive rates were very low, at 4% to 10%, in preschool children and not high, at 31%, in primary school students. Preschool children are highly susceptible and need EV71 vaccine most.


Citation: Lee J-T, Yen T-Y, Shih W-L, Lu C-Y, Liu D-P, Huang Y-C, et al. (2019) Enterovirus 71 seroepidemiology in Taiwan in 2017 and comparison of those rates in 1997, 1999 and 2007. PLoS ONE 14(10): e0224110. https://doi.org/10.1371/journal.pone.0224110

Editor: Dong-Yan Jin, University of Hong Kong, HONG KONG

Received: August 13, 2019; Accepted: October 4, 2019; Published: October 17, 2019

Copyright: © 2019 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: This study was supported by grants from the Taiwan Centers for Disease Control, the Ministry of Health and Welfare, Taiwan (grant number MOHW 106-CDC-C-114-000117 to L-YC) and the Ministry of Science and Technology, Taiwan (grant numbers MOST 105-2320-B-002-016 and 105-2314-B-002-139-MY3) to L-YC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Enterovirus; EV-71; Taiwan; Serology; Seroprevalence.



#Genetic and #phenotypic characterization of recently discovered #EV-D111 (PLoS Negl Trop Dis., abstract)

[Source: PLoS Neglected Tropical Diseases, full page: (LINK). Abstract, edited.]


Genetic and phenotypic characterization of recently discovered enterovirus D type 111

Serge Alain Sadeuh-Mba , Marie-Line Joffret , Arthur Mazitchi, Marie-Claire Endegue-Zanga, Richard Njouom, Francis Delpeyroux, Ionela Gouandjika-Vasilache , Maël Bessaud

Published: October 17, 2019 / DOI: https://doi.org/10.1371/journal.pntd.0007797 / This is an uncorrected proof.



Members of the species Enterovirus D (EV-D) remain poorly studied. The two first EV-D types (EV-D68 and EV-D70) have regularly caused outbreaks in humans since their discovery five decades ago but have been neglected until the recent occurrence of severe respiratory diseases due to EV-D68. The three other known EV-D types (EV-D94, EV-D111 and EV-D120) were discovered in the 2000s-2010s in Africa and have never been observed elsewhere. One strain of EV-D111 and all known EV-D120s were detected in stool samples of wild non-human primates, suggesting that these viruses could be zoonotic viruses. To date, EV-D111s are only known through partial genetic sequences of the few strains that have been identified so far. In an attempt to bring new pieces to the puzzle, we genetically characterized four EV-D111 strains (among the seven that have been reported until now). We observed that the EV-D111 strains from human samples and the unique simian EV-D111 strain were not phylogenetically distinct, thus suggesting a recent zoonotic transmission. We also discovered evidences of probable intertypic genetic recombination events between EV-D111s and EV-D94s. As recombination can only happen in co-infected cells, this suggests that EV-D94s and EV-D111s share common replication sites in the infected hosts. These sites could be located in the gut since the phenotypic analysis we performed showed that, contrary to EV-D68s and like EV-D94s, EV-D111s are resistant to acid pHs. We also found that EV-D111s induce strong cytopathic effects on L20B cells, a cell line routinely used to specifically detect polioviruses. An active circulation of EV-D111s among humans could then induce a high number of false-positive detection of polioviruses, which could be particularly problematic in Central Africa, where EV-D111 circulates and which is a key region for poliovirus eradication.


Author summary

Many examples of emergence of viruses that trigger severe diseases in humans are known. Emergence can be due to the sudden increase of the pathogenic power of a virus that had silently circulated into human populations for a long period; it can also be due to the cross-species transmission of a virus from its animal host to humans. The recent outbreaks of severe respiratory diseases due to enteroviruses D68 (EV-D68) brought to the light to potency of members of the species Enterovirus D (EV-D) to emerge as severe human pathogens.

By many aspects, EV-Ds are still mysterious: their natural history and epidemiology are poorly studied and even their main hosts remain unknown. For decades, EV-Ds were believed to infect mainly humans but recent data about EV-Ds identified in sub-Saharan Africa support their zoonotic origin. In an attempt to increase our knowledge about EV-Ds, we undertook genetic and phenotypic characterization of four EV-D111 isolates, a virus type that was recently uncovered in humans and in non-human primates in Central Africa. Our results show that EV-D111s are probably enteric viruses and evolve by exchanging genetic sequences with EV-D94.


Citation: Sadeuh-Mba SA, Joffret M-L, Mazitchi A, Endegue-Zanga M-C, Njouom R, Delpeyroux F, et al. (2019) Genetic and phenotypic characterization of recently discovered enterovirus D type 111. PLoS Negl Trop Dis 13(10): e0007797. https://doi.org/10.1371/journal.pntd.0007797

Editor: Abdallah M. Samy, Faculty of Science, Ain Shams University (ASU), EGYPT

Received: December 12, 2018; Accepted: September 18, 2019; Published: October 17, 2019

Copyright: © 2019 Sadeuh-Mba et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All sequence data are available at GenBank (accession numbers: MK032892-MK032898).

Funding: We are grateful for the financial support of the Institut Pasteur (PTR-276) and for the financial support of the World Health Organization. This work was supported by the European Virus Archive goes Global project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Enterovirus; EV-D111; EV-D94; Recombination.


#Enterovirus D68 #serosurvey: evidence for #endemic circulation in the #Netherlands, 2006 to 2016 (Euro Surveill., abstract)

[Source: Eurosurveillance, full page: (LINK). Abstract, edited.]

Enterovirus D68 serosurvey: evidence for endemic circulation in the Netherlands, 2006 to 2016

Eveliina Karelehto1, Gerrit Koen1, Kimberley Benschop2, Fiona van der Klis2, Dasja Pajkrt3, Katja Wolthers1

Affiliations: 1 Department of Medical Microbiology, Laboratory of Clinical Virology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 2 National Institute for Public Health and the Environment, Bilthoven, the Netherlands; 3 Department of Pediatric Infectious Diseases, Emma Children’s Hospital, University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

Correspondence:  Katja C Wolthers

Citation style for this article: Karelehto Eveliina, Koen Gerrit, Benschop Kimberley, van der Klis Fiona, Pajkrt Dasja, Wolthers Katja. Enterovirus D68 serosurvey: evidence for endemic circulation in the Netherlands, 2006 to 2016. Euro Surveill. 2019;24(35):pii=1800671. https://doi.org/10.2807/1560-7917.ES.2019.24.35.1800671

Received: 12 Dec 2018;   Accepted: 05 Jun 2019




Enterovirus D68 (EV-D68) has caused major outbreaks of severe respiratory illness worldwide since 2010.


Our aim was to evaluate EV-D68 circulation in the Netherlands by conducting a serosurvey of EV-D68 neutralising antibodies (nAb) among the Dutch general population.


We screened 280 sera from children and adults in the Netherlands and used two independent sets of samples collected in the years 2006 and 2007 and in the years 2015 and 2016, time points before and after the first EV-D68 upsurge in 2010. Neutralisation capacity of the sera was tested against the prototype Fermon EV-D68 strain isolated in 1962 and against a recent EV-D68 strain (genotype B3) isolated in France in 2016.


Regardless of the time of serum collection, we found remarkably high overall seropositivity (94.3–98.3%) for nAb against both EV-D68 strains. Geometric mean titres increased in an age-dependent manner.


Our data suggest that EV-D68 has been circulating in the Netherlands for decades and that the enterovirus surveillance does not accurately capture the prevalence of this clinically relevant pathogen.

©  This work is licensed under a Creative Commons Attribution 4.0 International License.

Keywords: Enterovirus; EV-D68; Pediatrics; Netherlands; Seroprevalence.


Cryo-EM #structure of #pleconaril-resistant #rhinovirus-B5 complexed to the #antiviral OBR-5-340 reveals unexpected binding site (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Cryo-EM structure of pleconaril-resistant rhinovirus-B5 complexed to the antiviral OBR-5-340 reveals unexpected binding site

Jiri Wald, Marion Pasin, Martina Richter, Christin Walther, Neann Mathai, Johannes Kirchmair, Vadim A. Makarov, Nikolaus Goessweiner-Mohr, Thomas C. Marlovits, Irene Zanella, Antonio Real-Hohn, Nuria Verdaguer, Dieter Blaas, and Michaela Schmidtke

PNAS first published August 28, 2019 / DOI: https://doi.org/10.1073/pnas.1904732116

Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved August 1, 2019 (received for review March 29, 2019)



More than 160 rhinovirus (RV) types cause about a billion respiratory infections annually in the United States alone, contributing to influenza-like illness. This diversity makes vaccination impractical. Existing small-molecule inhibitors target RVs by binding to a hydrophobic pocket in the capsid but exhibit side effects, resistance, and/or mutational escape, impeding registration as drugs. The pyrazolopyrimidine OBR-5-340 acts like other capsid binders by preventing conformational changes required for genome release. However, by using cryo-EM, we show that OBR-5-340 inhibits the naturally pleconaril-resistant RV-B5 by attaching close to the pocket entrance in a binding geometry different from that of most capsid binders. Combinations of inhibitors with disparate binding modes might thus effectively combat RVs while reducing the risk of resistance development.



Viral inhibitors, such as pleconaril and vapendavir, target conserved regions in the capsids of rhinoviruses (RVs) and enteroviruses (EVs) by binding to a hydrophobic pocket in viral capsid protein 1 (VP1). In resistant RVs and EVs, bulky residues in this pocket prevent their binding. However, recently developed pyrazolopyrimidines inhibit pleconaril-resistant RVs and EVs, and computational modeling has suggested that they also bind to the hydrophobic pocket in VP1. We studied the mechanism of inhibition of pleconaril-resistant RVs using RV-B5 (1 of the 7 naturally pleconaril-resistant rhinoviruses) and OBR-5-340, a bioavailable pyrazolopyrimidine with proven in vivo activity, and determined the 3D-structure of the protein-ligand complex to 3.6 Å with cryoelectron microscopy. Our data indicate that, similar to other capsid binders, OBR-5-340 induces thermostability and inhibits viral adsorption and uncoating. However, we found that OBR-5-340 attaches closer to the entrance of the pocket than most other capsid binders, whose viral complexes have been studied so far, showing only marginal overlaps of the attachment sites. Comparing the experimentally determined 3D structure with the control, RV-B5 incubated with solvent only and determined to 3.2 Å, revealed no gross conformational changes upon OBR-5-340 binding. The pocket of the naturally OBR-5-340-resistant RV-A89 likewise incubated with OBR-5-340 and solved to 2.9 Å was empty. Pyrazolopyrimidines have a rigid molecular scaffold and may thus be less affected by a loss of entropy upon binding. They interact with less-conserved regions than known capsid binders. Overall, pyrazolopyrimidines could be more suitable for the development of new, broadly active inhibitors.

rhinovirus – capsid binder – inhibitor – 3D structure – cryo-EM



1 J.W., M.P., M.R., and C.W. contributed equally to this work.

2 To whom correspondence may be addressed. Email: dieter.blaas@meduniwien.ac.at or michaela.schmidtke@med.uni-jena.de.

Author contributions: J.K., T.C.M., A.R-H., N.V., D.B., and M.S. designed research; J.K, T.C.M, D.B., and M.S. supervised research; J.W., M.P., M.R., C.W., N.M., J.K., I.Z., A.R-H., and D.B. performed research; V.A.M. contributed new reagents/analytic tools; J.W., M.P., M.R., C.W., N.M., J.K., N.G-M., A.R-H., D.B., and M.S. analyzed data; D.B. reconstructed and refined the cryo-EM data; M.P. reconstructed and refined the cryo-EM data and carried out the thermal stability assays; M.R., C.W., and M.S. carried out the antiviral tests; N.M. analyzed binding sites of all compounds; I.Z. carried out stability assays; N.V. critically assessed the manuscript; and N.M., J.K., D.B., and M.S. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

Data deposition: The 3D structures reported in this paper have been deposited in the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank, http://www.rcsb.org/ and the Electron Microscopy Data Bank, https://www.ebi.ac.uk/pdbe/emdb/ (accession nos.: RV-B5 complexed to OBR-5-340, PDB 6SK5 and EMD-10220; RV-B5, PDB 6SK6 and EMD-10221; RV-A89, PDB 6SK7and EMD-10222).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1904732116/-/DCSupplemental.

Published under the PNAS license.

Keywords: Antivirals; Drugs Resistance; Pleconaril; Enterovirus; Rhinovirus.


#Molecular and #Clinical #Comparison of #Enterovirus D68 #Outbreaks among Hospitalized #Children, #Ohio, #USA, 2014 and 2018 (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 11—November 2019 / Research

Molecular and Clinical Comparison of Enterovirus D68 Outbreaks among Hospitalized Children, Ohio, USA, 2014 and 2018

Huanyu Wang, Alejandro Diaz, Katherine Moyer1, Maria Mele-Casas2, Maria Fatima Ara-Montojo3, Isabel Torrus2, Karen McCoy, Asuncion Mejias, and Amy L. Leber

Author affiliations: Nationwide Children’s Hospital, Columbus, Ohio, USA (H. Wang, A. Diaz, K. Moyer, M. Mele-Casas, M.F. Ara-Montojo, I. Torrus, K. McCoy, A. Mejias, A.L. Leber); The Ohio State University, Columbus, Ohio, USA (H. Wang, A. Mejias, A.L. Leber).



Enterovirus D68 (EV-D68) causes respiratory tract infections and neurologic manifestations. We compared the clinical manifestations from 2 EV-D68 outbreaks in 2014 and 2018 and a low-activity period in 2016 among hospitalized children in central Ohio, USA, and used PCR and sequencing to enable phylogenetic comparisons. During both outbreak periods, infected children had respiratory manifestations that led to an increase in hospital admissions for asthma. The 2018 EV-D68 outbreak appeared to be milder in terms of respiratory illness, as shown by lower rates of pediatric intensive care unit admission. However, the frequency of severe neurologic manifestations was higher in 2018 than in 2014. During the same period in 2016, we noted neither an increase in EV-D68 nor a significant increase in asthma-related admissions. Phylogenetic analyses showed that EV-D68 isolates from 2018 clustered differently within clade B than did isolates from 2014 and are perhaps associated with a different EV-D68 subclade.

Keywords: Enterovirus; EV-D68; Neurology; Pediatrics; Ohio; USA.


Prospective Research of #Human #Parechovirus and #Cytokines in #CSF of Young #Children Less than One Year with #Sepsis-like Illness: Comparison with #Enterovirus (J Clin Virol., abstract)

[Source: Journal of Clinical Virology, full page: (LINK). Abstract, edited.]

Journal of Clinical Virology / Available online 15 August 2019 / In Press, Journal Pre-proof

Prospective Research of Human Parechovirus and Cytokines in Cerebrospinal Fluid of Young Children Less than One Year with Sepsis-like Illness: Comparison with Enterovirus

Su Eun Park ab1, Duyeal Song c1, Kyunghwa Shin c, Sang Ook Nam ab, Ara Ko ab, Ju Hyun Kong ab, Young Mi Kim d, Gyu Min Yeon e, Yun-Jin Lee ab

{a} Department of Pediatrics, Pusan National University Children’s Hospital, Pusan National University School of Medicine – 20 Geumoro, Mulgeumeup, 50612, Yangsan, South Korea; {b} Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital – 20 Geumoro, Mulgeumeup, 50612, Yangsan, South Korea; {c} Department of Laboratory Medicine, Pusan National University Yangsan Hospital – 20 Geumoro, Mulgeumeup, 50612, Yangsan, South Korea; {d} Department of Pediatrics, Pusan National University Hospital – 179, Gudeok-ro, 49241, Busan, South Korea; {e} Department of Pediatrics, Kosin University Gospel Hospital, Kosin University – 262, Gamcheon-ro, 49267, Busan, South Korea

Received 26 December 2018, Revised 12 March 2019, Accepted 14 August 2019, Available online 15 August 2019. DOI: https://doi.org/10.1016/j.jcv.2019.08.006



  • HPeV meningitis was found in 11.1% of sepsis-like children less than 12 months.
  • CSF findings were significantly different between HPeV and enteroviral meningitis.
  • CSF cytokine profiles noticeably differed between HPeV and enteroviral meningitis.


{1} Su Eun Park and Duyeal Song were equally responsible for the work described in this paper.

© 2019 Elsevier B.V. All rights reserved.

Keywords: Parechovirus; Enterovirus; Sepsis; Pediatrics.


#Antibodies to #Enteroviruses in #CSF of #Patients with Acute Flaccid #Myelitis (mBio, abstract)

[Source: mBio, full page: (LINK). Abstract, edited.]

Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis

Nischay Mishra, Terry Fei Fan Ng, Rachel L. Marine, Komal Jain, James Ng, Riddhi Thakkar, Adrian Caciula, Adam Price, Joel A. Garcia, Jane C. Burns, Kiran T. Thakur, Kimbell L. Hetzler,Janell A. Routh, Jennifer L. Konopka-Anstadt, W. Allan Nix, Rafal Tokarz, Thomas Briese, M. Steven Oberste, W. Ian Lipkin

Christine A. Biron, Editor

DOI: 10.1128/mBio.01903-19



Acute flaccid myelitis (AFM) has caused motor paralysis in >560 children in the United States since 2014. The temporal association of enterovirus (EV) outbreaks with increases in AFM cases and reports of fever, respiratory, or gastrointestinal illness prior to AFM in >90% of cases suggest a role for infectious agents. Cerebrospinal fluid (CSF) from 14 AFM and 5 non-AFM patients with central nervous system (CNS) diseases in 2018 were investigated by viral-capture high-throughput sequencing (VirCapSeq-VERT system). These CSF and serum samples, as well as multiple controls, were tested for antibodies to human EVs using peptide microarrays. EV RNA was confirmed in CSF from only 1 adult AFM case and 1 non-AFM case. In contrast, antibodies to EV peptides were present in CSF of 11 of 14 AFM patients (79%), significantly higher than controls, including non-AFM patients (1/5 [20%]), children with Kawasaki disease (0/10), and adults with non-AFM CNS diseases (2/11 [18%]) (P = 0.023, 0.0001, and 0.0028, respectively). Six of 14 CSF samples (43%) and 8 of 11 sera (73%) from AFM patients were immunoreactive to an EV-D68-specific peptide, whereas the three control groups were not immunoreactive in either CSF (0/5, 0/10, and 0/11; P = 0.008, 0.0003, and 0.035, respectively) or sera (0/2, 0/8, and 0/5; P = 0.139, 0.002, and 0.009, respectively).



The presence in cerebrospinal fluid of antibodies to EV peptides at higher levels than non-AFM controls supports the plausibility of a link between EV infection and AFM that warrants further investigation and has the potential to lead to strategies for diagnosis and prevention of disease.

Keywords: Enterovirus; EV-D68; Serology; USA.