Susceptibilities of #enterovirus D68, enterovirus 71, and #rhinovirus 87 strains to various #antiviral #compounds (Antiviral Res., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Antiviral Res. 2016 Apr 7. pii: S0166-3542(16)30203-0. doi: 10.1016/j.antiviral.2016.04.003. [Epub ahead of print]

Susceptibilities of enterovirus D68, enterovirus 71, and rhinovirus 87 strains to various antiviral compounds.

Smee DF1, Evans WJ1, Nicolaou KC2, Tarbet EB1, Day CW3.

Author information: 1Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, USA. 2The Scripps Research Institute, La Jolla, California, USA. 3Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, USA. Electronic address: craig.day@usu.edu.

 

Abstract

Compounds were evaluated for antiviral activity in rhabdomyosarcoma (RD) cells against a recent 2014 clinical isolate of enterovirus D68 (EV-D68), a 1962 strain of EV-68D, rhinovirus 87 (RV-87, serologically the same as EV-D68), and enterovirus 71 (EV-71). Test substances included known-active antipicornavirus agents (enviroxime, guanidine HCl, pirodavir, pleconaril, and rupintrivir), nucleobase/nucleoside analogs (3-deazaguanine and ribavirin), and three novel epidithiodiketopiperazines (KCN-2,2′-epi-19, KCN-19, and KCN-21). Of these, rupintrivir was the most potent, with 50% inhibition of viral cytopathic effect (EC50) and 90% inhibition (EC90) of virus yield at 0.0022-0.0053 μM against EV-D68. Enviroxime, pleconaril and the KCN compounds showed efficacy at 0.01-0.3 μM; 3-deazaguanine and pirodavir inhibited EV-D68 at 7-13 μM, and guanidine HCl and ribavirin were inhibitory at 80-135 μM. Pirodavir was active against EV-71 (EC50 of 0.78 μM) but not against RV-87 or EV-D68, and all other compounds were less effective against EV-71 than against RV-87 and EV-D68. The most promising compound inhibiting both virus infections at low concentrations was rupintrivir. Antiviral activity was confirmed for the ten compounds in virus yield reduction (VYR) assays in RD cells, and for enviroxime, guanidine HCl, and pirodavir by cytopathic effect (CPE) assays in A549, HeLa-Ohio-1, and RD cells. These studies may serve as a basis for further pre-clinical discovery of anti-enterovirus inhibitors. Furthermore, the antiviral profiles and growth characteristics observed herein support the assertion that EV-D68 should be classified together with RV-87.

Copyright © 2016. Published by Elsevier B.V.

KEYWORDS: Enterovirus D68; antiviral; enterovirus 71; picornavirus; rhinovirus 87

PMID: 27063860 [PubMed – as supplied by publisher]

Keywords: Research; Abstracts; EV D68; EV 71; Antivirals.

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#HFMD in #China: Modeling #Epidemic #Dynamics of #Enterovirus Serotypes and Implications for #Vaccination (PLoS Medicine, abstract)

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

Open Access / Peer-reviewed / Research Article

Hand, Foot, and Mouth Disease in China: Modeling Epidemic Dynamics of Enterovirus Serotypes and Implications for Vaccination [      ]

Saki Takahashi,  Qiaohong Liao,  Thomas P. Van Boeckel,  Weijia Xing,  Junling Sun,  Victor Y. Hsiao,  C. Jessica E. Metcalf,  Zhaorui Chang,  … Fengfeng Liu,  Jing Zhang

Published: February 16, 2016  / DOI: 10.1371/journal.pmed.1001958

 

Abstract

Background

Hand, foot, and mouth disease (HFMD) is a common childhood illness caused by serotypes of the Enterovirus A species in the genus Enterovirus of the Picornaviridae family. The disease has had a substantial burden throughout East and Southeast Asia over the past 15 y. China reported 9 million cases of HFMD between 2008 and 2013, with the two serotypes Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16) being responsible for the majority of these cases. Three recent phase 3 clinical trials showed that inactivated monovalent EV-A71 vaccines manufactured in China were highly efficacious against HFMD associated with EV-A71, but offered no protection against HFMD caused by CV-A16. To better inform vaccination policy, we used mathematical models to evaluate the effect of prospective vaccination against EV-A71-associated HFMD and the potential risk of serotype replacement by CV-A16. We also extended the model to address the co-circulation, and implications for vaccination, of additional non-EV-A71, non-CV-A16 serotypes of enterovirus.

Methods and Findings

Weekly reports of HFMD incidence from 31 provinces in Mainland China from 1 January 2009 to 31 December 2013 were used to fit multi-serotype time series susceptible–infected–recovered (TSIR) epidemic models. We obtained good model fit for the two-serotype TSIR with cross-protection, capturing the seasonality and geographic heterogeneity of province-level transmission, with strong correlation between the observed and simulated epidemic series. The national estimate of the basic reproduction number, R0, weighted by provincial population size, was 26.63 for EV-A71 (interquartile range [IQR]: 23.14, 30.40) and 27.13 for CV-A16 (IQR: 23.15, 31.34), with considerable variation between provinces (however, predictions about the overall impact of vaccination were robust to this variation). EV-A71 incidence was projected to decrease monotonically with higher coverage rates of EV-A71 vaccination. Across provinces, CV-A16 incidence in the post-EV-A71-vaccination period remained either comparable to or only slightly increased from levels prior to vaccination. The duration and strength of cross-protection following infection with EV-A71 or CV-A16 was estimated to be 9.95 wk (95% confidence interval [CI]: 3.31, 23.40) in 68% of the population (95% CI: 37%, 96%). Our predictions are limited by the necessarily short and under-sampled time series and the possible circulation of unidentified serotypes, but, nonetheless, sensitivity analyses indicate that our results are robust in predicting that the vaccine should drastically reduce incidence of EV-A71 without a substantial competitive release of CV-A16.

Conclusions

The ability of our models to capture the observed epidemic cycles suggests that herd immunity is driving the epidemic dynamics caused by the multiple serotypes of enterovirus. Our results predict that the EV-A71 and CV-A16 serotypes provide a temporary immunizing effect against each other. Achieving high coverage rates of EV-A71 vaccination would be necessary to eliminate the ongoing transmission of EV-A71, but serotype replacement by CV-A16 following EV-A71 vaccination is likely to be transient and minor compared to the corresponding reduction in the burden of EV-A71-associated HFMD. Therefore, a mass EV-A71 vaccination program of infants and young children should provide significant benefits in terms of a reduction in overall HFMD burden.

 

Editors’ Summary

Background

Hand, foot, and mouth disease (HFMD)—a common ailment that mainly affects young children—is caused by a group of enteroviruses (Enterovirus A species), which are close relatives of polioviruses (Enterovirus C species). Enteroviruses are divided into various viral serotypes (variants defined by molecules on their surface that are recognized by the immune system), and the most common serotypes that cause HFMD are Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16). Enteroviruses spread from person to person through contact with the mucus or saliva produced when an infected individual coughs or sneezes, with the feces or the fluid from vesicles of an infected individual, and through contact with contaminated surfaces. Frequent handwashing and good hygiene practices can reduce the spread of HFMD. Symptoms of HFMD include fever, sore throat, a non-itchy red rash with small blisters on the hands and feet, and painful mouth ulcers. HFMD is usually a self-limiting illness, and most children recover within 7–10 days. A small proportion of patients infected with EV-A71 develop severe complications such as meningitis (infection of the membranes around the brain and spinal cord) or encephalitis (infection of the brain). Currently, there is no specific treatment for HFMD, and vaccines are not yet available for routine use.

Why Was This Study Done?

HFMD is increasingly common in East and Southeast Asia. China, for example, reported 9 million cases of HFMD between 2008 and 2013. Vaccination is a specific and effective way to reduce the burden of HFMD in China. In three clinical trials, inactivated monovalent EV-A71 vaccines made in China were highly efficacious against EV-A71-associated HFMD but provided no protection against CV-A16-associated HFMD (an inactivated monovalent vaccine contains a single virus strain that is unable to replicate; exposure to the vaccine “primes” the immune system to respond quickly when challenged with live virus, thereby preventing infection with that virus). So, before these vaccines can be used for routine vaccination of infants, it is important to know whether vaccination with EV-A71 will alter the burden of HFMD caused by other enterovirus serotypes. In particular, it is important to know whether infection with EV-A71 provides cross-protection against CV-A16 and whether infections with CV-A16 or other serotypes might increase following vaccination against EV-A71 because of increased circulation of these viruses in the population (serotype replacement). Here, the researchers use mathematical models to assess the effect of vaccination against EV-A71-associated HFMD in China and the potential risk of serotype replacement by CV-A16.

What Did the Researchers Do and Find?

The researchers used weekly data on HFMD incidence collected in 31 Chinese provinces between 2009 and 2013 to develop a two-serotype time series susceptible–infected–recovered epidemic model (a model in which individuals are born, become susceptible to a disease, become infected and infectious with the disease, and recover). The model accurately simulated the epidemic cycles of EV-A71- and CV-A16-associated HFMD for the 31 provinces and the seasonal transmission patterns in both northern and southern Chinese provinces. It provided an estimate of cross-protection following infection with EV-A71 or CV-A16 of ten weeks in 68% of the population (an average duration of cross-protection of 6.77 weeks). The estimated basic reproduction number (the average number of additional cases one case of an infectious disease generates in an otherwise uninfected population) across China for both serotypes was 25, which means that vaccination coverage levels of above 96% are required to achieve population-level immunity. Finally, the model predicted a decrease in EV-A71-associated HFMD incidence with higher rates of EV-A71 vaccination and suggested that CV-A16 incidence following EV-A71 vaccination would be comparable to or only slightly higher than its incidence before vaccination.

What Do These Findings Mean?

These findings suggest that herd immunity (indirect protection from infectious disease that occurs when most of a population has become immune to an infection, thereby providing some protection for the rare individuals who are not immune) is driving the dynamics of the HFMD epidemic caused by multiple enterovirus serotypes in China. Moreover, they suggest that the infection with EV-A71 or CV-A16 serotype can provide temporary immunity against each the other serotype and that serotype replacement by CV-A16 following EV-A71 vaccination is likely to be transient and minor compared to the reduction in the burden of EV-A71-associated HFMD produced by vaccination. The accuracy of these findings depends on the assumptions included in the model and the quality and quantity of data used to run the models. However, the researchers suggest that a mass EV-A71 vaccination campaign targeted at infants and young children should greatly reduce the burden of HFMD in China, provided a high vaccination uptake level is achieved.

 

Additional Information

This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001958.

The US Centers for Disease Control and Prevention provide information on hand, foot, and mouth disease (in English and Spanish), including a podcast on the condition

The UK National Health Service Choices website provides detailed information on hand, foot, and mouth disease

Further information about hand, foot, and mouth disease is provided by the World Health Organization (including up-to-date HFMD surveillance reports from China), the Nemours Foundation (in English and Spanish), and MedlinePlus (in English and Spanish)

The Government of the Hong Kong Special Administrative Region Department of Health Centre for Health Protection provides information on hand, foot, and mouth disease

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Citation: Takahashi S, Liao Q, Van Boeckel TP, Xing W, Sun J, Hsiao VY, et al. (2016) Hand, Foot, and Mouth Disease in China: Modeling Epidemic Dynamics of Enterovirus Serotypes and Implications for Vaccination. PLoS Med 13(2): e1001958. doi:10.1371/journal.pmed.1001958

Academic Editor: Lone Simonsen, George Washington University, UNITED STATES

Received: April 21, 2015; Accepted: January 5, 2016; Published: February 16, 2016

Copyright: © 2016 Takahashi 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 work is supported by the National Science Fund for Distinguished Young Scholars (No. 81525023) (HY), the National Natural Science Foundation of China (No. 81473031) (HY), the Li Ka Shing Oxford Global Health Programme (No. B9RST00-B900.57) (HY), the Science and Technology Directorate, Department of Homeland Security contract HSHQDC-12-C-00058 (TPVB, CJEM, BTG), the Fulbright Program (TPVB), the Bill & Melinda Gates Foundation (OPP1094793) (CJEM, BTG), the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health (CJEM, BTG), the Harvard Center for Communicable Disease Dynamics from the National Institute of General Medical Sciences (grant no. U54 GM088558) (JTW, BJC, GML), a commissioned grant from the Health and Medical Research Fund from the Government of the Hong Kong Special Administrative Region (JTW, BJC, GML), the Wellcome Trust (JJF), the Li Ka Shing Oxford Global Health Programme (JJF), and the Wellcome Trust Programme Grant 089276/Z/09/Z (HRvD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: The views expressed in this study are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of General Medical Sciences, the National Institutes of Health, or the Chinese Center for Disease Control and Prevention. BJC has received research funding from MedImmune Inc. and Sanofi Pasteur, and consults for Crucell NV. MedImmune Inc, Sanofi Pasteur, and Crucell NV do not market HFMD vaccines. The other authors have declared that no competing interests exist.

Abbreviations: China CDC, Chinese Center for Disease Control and Prevention; CI, confidence interval; CV-A16, Coxsackievirus A16; EV-A71, Enterovirus A71; GLM, generalized linear model; HFMD, hand, foot, and mouth disease; IQR, interquartile range; OLS, ordinary least squares; PE, prediction error; SIR, susceptible–infected–recovered; SIRS, susceptible–infected–recovered–susceptible; TSIR, time series susceptible–infected–recovered.

Keywords: Research; Abstracts; HFMD; China; EV-71; Vaccines.

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#Clinical #Efficacy of #Therapy with Recombinant Human #Interferon a1b in #HFMD with #Enterovirus 71 #Infection [PLoS One, abstract)

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

Open Access / Peer-reviewed / Research Article

Clinical Efficacy of Therapy with Recombinant Human Interferon a1b in Hand, Foot, and Mouth Disease with Enterovirus 71 Infection [      ]

Xueyong Huang,  Xi Zhang,  Fang Wang,  Haiyan Wei,  Hong Ma,  Meili Sui,  Jie Lu,  Huaili Wang,  J. Stephen Dumler,  Guangyao Sheng

Published: February 16, 2016  / DOI: 10.1371/journal.pone.0148907

 

Abstract

A rapid expansion of HFMD with enterovirus 71 infection outbreaks has occurred and caused deaths in recent years in China, but no vaccine or antiviral drug is currently available for EV71 infection. This study aims to provide treatment programs for HFMD patients. We conducted a randomized, double-blind, controlled trial and evaluated clinical efficacy of therapy with rHuIFN-α1b in HFMD patients with EV71 infection. There were statistical differences in outcomes including the fever clearance time, healing time of typical skin or oral mucosa lesions, and EV71 viral load of the HFMD patients among ultrasonic aerosol inhalation group, intramuscular injection group and control group. rHuIFN-α1b therapy reduced the fever clearance time, healing time of typical skin or oral mucosa lesions, and EV71 viral load in children with HFMD.

Trial Registration: Chinese Clinical Trial Registry ChiCTR-TRC-14005153

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Citation: Huang X, Zhang X, Wang F, Wei H, Ma H, Sui M, et al. (2016) Clinical Efficacy of Therapy with Recombinant Human Interferon α1b in Hand, Foot, and Mouth Disease with Enterovirus 71 Infection. PLoS ONE 11(2): e0148907. doi:10.1371/journal.pone.0148907

Editor: Marc S. Horwitz, University of British Columbia, CANADA

Received: August 28, 2015; Accepted: January 20, 2016; Published: February 16, 2016

Copyright: © 2016 Huang 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 Henan Province Health Department and National Health and Family Planning Commission of the People’s Republic of China Co-build Project (201001015), and Science and Technology Bureau of Henan Province (122102310268).

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

Keywords: Research; Abstracts; HMFD; Ev-71; Interferons.

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#Seroepidemiology of #Human #Enterovirus 71 #Infection among #Children, #Cambodia (@CDC_EIDjournal, abstract)

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

Volume 22, Number 1—January 2016 / Dispatch

Seroepidemiology of Human Enterovirus 71 Infection among Children, Cambodia [      ]

Paul F. Horwood, Alessio Andronico, Arnaud Tarantola, Henrik Salje, Veasna Duong, Channa Mey, Sovann Ly, Philippe Dussart, Simon Cauchemez, and Philippe Buchy

Author affiliations: Institut Pasteur in Cambodia, Phnom Penh, Cambodia (P.F. Horwood, A. Tarantola, V. Duong, C. Mey, P. Dussart, P. Buchy); Institut Pasteur, Paris, France (A. Andronico, H. Salje, S. Cauchemez); Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA (H. Salje); Ministry of Health, Phnom Penh (S. Ly); GlaxoSmithKline Vaccines, Singapore (P. Buchy)

 

Abstract

Enterovirus 71 is reported to have emerged in Cambodia in 2012; at least 54 children with severe encephalitis died during that outbreak. We used serum samples collected during 2000–2011 to show that the virus had been widespread in the country for at least a decade before the 2012 outbreak.

Keywords: Research; Abstracts; EV-71; Cambodia; Serosurveys.

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