#Development of an #EV71 #vaccine efficacy #test using human scavenger receptor B2 transgenic mice (J Virol., abstract)

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

Development of an enterovirus 71 vaccine efficacy test using human scavenger receptor B2 transgenic mice

Ayumi Imura, Yui Sudaka, Ayako Takashino, Kanami Tamura, Kyousuke Kobayashi, Noriyo Nagata, Hidekazu Nishimura, Katsumi Mizuta, Satoshi Koike

DOI: 10.1128/JVI.01921-19

 

ABSTRACT

Enterovirus 71 (EV71) is a causative agent of hand-foot-mouth disease, and it sometimes causes severe neurological disease. Development of effective vaccines and animal models to evaluate vaccine candidates are needed. However, the animal models currently used for vaccine efficacy testing, monkeys and neonatal mice, have economic, ethical, and practical drawbacks. In addition, EV71 strains prepared for lethal challenge often develop decreased virulence during propagation in cell culture. To overcome these problems, we used a mouse model expressing human scavenger receptor B2 (hSCARB2) that showed life-long susceptibility to EV71. We selected virulent EV71 strains belonging to the subgenogroups B4, B5, C1, C2, and C4 and propagated them using a culture method for EV71 without an apparent reduction in virulence. Here, we describe a novel EV71 vaccine efficacy test based on these hSCARB2 transgenic (Tg) mice and these virulent viruses. Adult Tg mice were immunized subcutaneously with formalin-inactivated EV71. The vaccine elicited sufficient levels of neutralizing antibodies in the immunized mice. The mice were subjected to lethal challenge with virulent viruses via intravenous injection. Survival, clinical signs, and body weight changes were observed for 2 weeks. Most immunized mice survived without clinical signs or histopathological lesions. The viral replication in immunized mice was much lower than that in nonimmunized mice. Mice immunized with the EV71 vaccine were only partially protected against lethal challenge with coxsackievirus A16. These results indicate that this new model is useful for in vivo EV71 vaccine efficacy testing.

 

Importance

The development of new vaccines for EV71 relies on the availability of small animal models suitable for in vivo efficacy testing. Monkeys and neonatal mice have been used, but the use of these animals has several drawbacks, including high costs, limited susceptibility, and poor experimental reproducibility. In addition, the related ethical issues are considerable. The new efficacy test based on hSCARB2 Tg mice and virulent EV71 strains propagated in genetically modified cell lines presented here can overcome these disadvantages and is expected to accelerate the development of new EV71 vaccines.

Copyright © 2020 American Society for Microbiology. All Rights Reserved.

Keywords: EV-71; Vaccines; Coxsackievirus A16; Animal models.

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Next generation #sequencing of #human #enterovirus strains from an #outbreak of #EVA71 shows applicability to outbreak investigations (J Clin Invest., abstract)

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

Journal of Clinical Virology / Available online 17 November 2019, 104216 / In Press, Journal Pre-proof

Next generation sequencing of human enterovirus strains from an outbreak of enterovirus A71 shows applicability to outbreak investigations

Sacha Stelzer-Braid a,b, Matthew Wynn a, Richard Chatoor a, Matthew Scotchc d,e, Vidiya Ramachandran f, Hooi-Ling Teoh g, h, Michelle A.Farrarg h, Hugo Sampaio g,h, Peter Ian Andrews g,h, Maria E.Craig a,h, C. Raina Mac Intyre c,i,j, Hemalatha Varadhan k, Alison Kesson l, Philip N.Britton l,m, James Newcomb e,n, William D.Rawlinson a,b,h

{a} Virology Research Laboratory, Serology and Virology Division (SAViD), NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia; {b} School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia; {c} College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA; {d} Center for Environmental Health Engineering, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA; {e} School of Public Health and Community Medicine, University of New South Wales, Sydney, NSW 2033, Australia; {f} Serology and Virology Division (SAViD), NSW Health Pathology East, Department of Microbiology, Prince of Wales Hospital, Sydney, NSW 2031, Australia; {g} Department of Neurology, Sydney Children’s Hospital, Sydney, Australia; {h} School of Women’s and Children’s Health, University of New South Wales Medicine, Sydney, NSW 2052, Australia; {i} Biosecurity Program, Kirby Institute, University of New South Wales, Sydney, NSW 2052, Australia; {j} Watts College of Public Service and Community Solutions, Arizona State University, Phoenix, AZ 85004, USA; {k} NSW Health Pathology, John Hunter Hospital, Newcastle, United Kingdom; {l} Department of Infectious Diseases and Microbiology, The Children’s Hospital at Westmead, Australia; {m} Marie Bashir Institute, University of Sydney, Australia; {n} Pathology North, Royal North Shore Hospital, St Leonards, Australia

Received 24 April 2019, Revised 8 October 2019, Accepted 11 November 2019, Available online 17 November 2019.

DOI: https://doi.org/10.1016/j.jcv.2019.104216

 

Highlights

  • Near full-length genome analysis using next generation sequencing identified EV-A71 and other enterovirus A and B subtypes circulating.
  • The Sydney EV-A71 2013 strain was very similar to EV-A71 circulating in China and Vietnam during the previous year.
  • Strains causing more severe clinical manifestations grouped together phylogenetically.

 

Abstract

Background

The most recent documented Australian outbreak of enterovirus A71 (EV-A71) occurred in Sydney from 2012 to 2013. Over a four-month period more than 100 children presented to four paediatric hospitals with encephalitic presentations including fever and myoclonic jerks. The heterogeneous presentations included typical encephalomyelitis, and cardiopulmonary complications.

Objectives

To characterise the genomes of enterovirus strains circulating during the 2013 Sydney EV-A71 outbreak and determine their phylogeny, phylogeography and association between genome and clinical phenotype.

Study design

We performed an analysis of enterovirus (EV) positive specimens from children presenting to hospitals in the greater Sydney region of Australia during the 2013 outbreak. We amplified near full-length genomes of EV, and used next generation sequencing technology to sequence the virus. We used phylogenetic/phylogeographic analysis to characterize the outbreak viruses.

Results

We amplified and sequenced 23/63 (37 %) genomes, and identified the majority (61 %) as EV-A71. The EV-A71 sequences showed high level sequence homology to C4a genogroups of EV-A71 circulating in China and Vietnam during 2012-13. Phylogenetic analysis showed EV-A71 strains associated with more severe symptoms, including encephalitis or cardiopulmonary failure, grouped together more closely than those from patients with hand, foot and mouth disease. Amongst the non-EV-A71 sequences were five other EV subtypes (representing enterovirus subtypes A and B), reflecting the diversity of EV co-circulation within the community.

Conclusions

This is the first Australian study investigating the near full-length genome of EV strains identified during a known outbreak of EV-A71. EV-A71 sequences were very similar to strains circulating in Asia during the same time period. Whole genome sequencing offers additional information over routine diagnostic testing such as characterisation of emerging recombinant strains and inform vaccine design.

Keywords: Enterovirus – EV-A71 – Phylogeny – Hand, foot and mouth disease – Whole genome sequencing – Australia

© 2019 Published by Elsevier B.V.

Keywords: HFMD; Enterovirus; EV-A71; Australia.

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National #Epidemiology and #Evolutionary #History of Four #HFMD -Related #Enteroviruses in #China from 2008 to 2016 (Virol Sin., abstract)

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

National Epidemiology and Evolutionary History of Four Hand, Foot and Mouth Disease-Related Enteroviruses in China from 2008 to 2016

Authors: Xuemin Fu, Zhenzhou Wan, Yanpeng Li, Yihong Hu, Xia Jin, Chiyu Zhang

Research Article / First Online: 29 October 2019

 

Abstract

Hand, foot and mouth disease (HFMD) is a major public health concern in China. The most predominant enteroviruses that cause HFMD have traditionally been attributed to enterovirus A71 (EVA71) and coxsackievirus A16 (CVA16). Since its first large outbreak in 2008, the dominant HFMD pathogens are constantly changing. In 2013 and 2015, CVA6 exceeded both EVA71 and CVA16 to become the leading cause of HFMD in some provinces. However, there still lacks a comprehensive overview on the molecular epidemiology and evolution of HFMD-related enteroviruses at the national level. In this study, we performed systematic epidemiological analyses of HFMD-related enteroviruses using the data of 64 published papers that met the inclusion criteria, and conducted phylogenetic analyses based on 12,080 partial VP1 sequences identified in China before 31st June 2018. We found that EVA71 prevalence has decreased sharply but other enteroviruses have increased rapidly from 2008 to 2016 and that one subtype of each enterovirus is represented during the epidemic. In addition, four genotypes EVA71_C4, CVA16_B1, CVA6_D and CVA10_C are the most predominant enterovirus strains and collectively they cause over 90% of all HFMD cases in China according to the phylogenetic trees using representative partial VP1 sequences. These four major enterovirus genotypes have different geographical distributions, and they may co-circulate with other genotypes and serotypes. These results suggest that more molecular epidemiological studies should be performed on several enteroviruses simultaneously, and such information should have implications for virological surveillance, disease management, vaccine development and policy-making on the prevention and control of HFMD.

Keywords: Enterovirus – Hand, foot and mouth disease (HFMD) – Molecular epidemiology – Evolution – Genotype

 

Electronic supplementary material

The online version of this article ( https://doi.org/10.1007/s12250-019-00169-2) contains supplementary material, which is available to authorized users.

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Notes

Acknowledgements

We thank Zhihang Zheng and Rong Xu at Institut Pasteur of Shanghai, CAS for their technique help in this study. This work was supported by the TOTAL foundation, and the Grants from the National Science and Technology Major Project of China (2017ZX10103009-002), the “One Belt One Road” Project (153831KYSB20170043) of the Chinese Academy of Sciences, the 133 Project of Institut Pasteur of Shanghai, CAS.

Author Contributions

CZ conceived and designed the study. XF, ZW, XJ and YH collected the data. XF, ZW, and YL performed the analyses. CZ, XF and ZW analyzed and interpreted the data. XF and CZ drafted the manuscript, and XJ contributed to critical revision of the manuscript. All authors have read and approved the contents of the final manuscript.

 

Compliance with Ethical Standards

Animal and Human Rights Statement

This article does not contain any studies with human or animal subjects performed by any of the authors.

Keywords: HFMD; Enterovirus; EV-A71; Coxsackievirus A16; China.

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Emerging #HFMD in #Bangladeshi #Children- First Report of Rapid Appraisal on Pocket #Outbreak: Clinico-epidemiological Perspective Implicating Public Health Emergency (F1000Res., abstract)

[Source: F1000 Research, full page: (LINK). Abstract, edited.]

Emerging Hand Foot Mouth Disease in Bangladeshi Children- First Report of Rapid Appraisal on Pocket Outbreak: Clinico-epidemiological Perspective Implicating Public Health Emergency [version 3; peer review: 2 approved]

Md. Azraf Hossain Khan1, Kazi Selim Anwar 2, A. K. M. Muraduzzaman3, Md. Abid Hossain Mollah4, S. M. Akhter-ul-Alam1, Kazi Munisul Islam5, Sheikh Ariful Hoque6, Md. Nazrul Islam1, Md. Ahasan Ali7

Author details: 1 Department of Dermatology and Venereology, Pabna Medical College and General Hospital, Pabna, 6600, Bangladesh; 2 US-CDC’s GHSA Project, Institute of Epidemiology, Disease Control and Research (IEDCR), Dhaka, 1212, Bangladesh; 3 Department of Virology, Institute of Epidemiology, Disease Control and Research (IEDCR), Dhaka, 1212, Bangladesh; 4 Department of Pediatrics, Ibrahim Medical College & Hospital, Institute of Research & Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Dhaka, 1200, Bangladesh; 5 Infectious Disease Division, International Center for Diarrheal Diseases Research, Bangladesh (icddr,b), Dhaka, 1212, Bangladesh; 6 Tissue Culture Laboratory, Centre for Advanced Research in Sciences (CARS), University of Dhaka, Dhaka, 1000, Bangladesh; 7 Microbiology Section, Institute of Public Health (IPH), Mohakhali, Dhaka, 1212, Bangladesh

 

Abstract

Background:

Hand, foot and mouth disease (HFMD) is a common contagious disease among children under 5 years, particularly in the Asia-Pacific-region. We report a localized outbreak of childhood HFMD for the first time from Bangladesh, diagnosed only based on clinical features due to lack in laboratory-diagnostic facilities.

Methods:

Following the World Health Organization’s case-definition, we conducted a rapid-appraisal of HFMD among all of the 143 children attending Pabna Medical College and General Hospital with fever, mouth ulcers and extremity rash. Data were collected between September and November 2017 using a preset syndromic approach and stringent differential diagnostic-protocols.

Results:

The mean age of children was 2.9±2.3 years. There was a significant difference among the age and sex of children (P=0.98), first sibling being more belonging to middle-income families (62%). Younger children (<5 years) were more likely to suffer with moderate-to-high (38.5°C) fever (P<0.04), painful oral ulcers (P<0.03) and painful/itchy rash (P<0.01). Sex did not differ with other symptoms, but boys had less painful oral ulcers than girls (P<0.04). Fever (63%) and chicken-pox-like-rash (62%) was observed more in mid-October to mid-November than September to mid-October (P<0.01 and P<0.03, respectively). No differences in symptoms (fever, oral ulcers and extremity rash) were observed with precipitation, nor with ambient temperature. Children <5 years (85%) had quicker recovery (within 5 days) than those ≥5 years (69%), (P<0.04), with marginal differences in sex (P<0.05).

Conclusions:

Our findings highlight potential usefulness in diagnosing HFMD based on clinical parameters, although stringent differential diagnosis remains indispensable, which is particularly applicable for resource-constrained countries lacking appropriate virology/essential laboratories. Since no specific treatment or effective vaccination is available for HFMD, supportive therapy and preventive measures remain the primary methods to circumvent disease-transmission augmented by climate-related factors. Standardized virology laboratory warrants appropriate diagnosis and globally representative multivalent-vaccine deem essential towards preventing HFMD.

Keywords: Emerging Childhood-HFMD, Bangladesh, Rapid-Appraisal, Pocket-Outbreak

Corresponding author: Kazi Selim Anwar

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright:  © 2019 Hossain Khan MA et al. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).

How to cite: Hossain Khan MA, Anwar KS, Muraduzzaman AKM et al. Emerging Hand Foot Mouth Disease in Bangladeshi Children- First Report of Rapid Appraisal on Pocket Outbreak: Clinico-epidemiological Perspective Implicating Public Health Emergency [version 3; peer review: 2 approved]. F1000Research 2019, 7:1156 (https://doi.org/10.12688/f1000research.15170.3)

First published: 30 Jul 2018, 7:1156 (https://doi.org/10.12688/f1000research.15170.1)

Latest published: 28 Jun 2019, 7:1156 (https://doi.org/10.12688/f1000research.15170.3)

Keywords: HFMD; Bangladesh.

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Immunogenicity and safety of an inactivated #EV71 #vaccine administered simultaneously with recombinant #hepatitis B vaccine and group A #meningococcal polysaccharide vaccine… (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Immunogenicity and safety of an inactivated enterovirus 71 vaccine administered simultaneously with recombinant hepatitis B vaccine and group A meningococcal polysaccharide vaccine:  a phase IV, open-label, single-center, randomized, non-inferiority trial

Zewu Zhang, MS, Zhenglun Liang, PhD, Ji Zeng, MS, Jikai Zhang, MS, Peng He, MS, Jiali Su, MS, Yaoming Zeng, BS, Renfeng Fan, MS, Dan Zhao, BS, Wenjun Ma, MS, Gang Zeng, PhD, Qiaoli Zhang, MS, Huizhen Zheng, BS

The Journal of Infectious Diseases, jiz129, https://doi.org/10.1093/infdis/jiz129

Published: 19 March 2019

 

Abstract

Background

This study tested the hypothesis that the immunogenicity and safety of the simultaneous administration of the combined EV71 vaccine with recombinant hepatitis B vaccine (HepB) and group A meningococcal polysaccharide vaccine (MenA) is not inferior to separate administration of each vaccine.

Methods

The study was designed as a randomized, open-label, and non-inferiority trial, and was registered at ClinicalTrials.gov (NCT03274102). A total of 775 healthy infants aged 6 months were randomized 1:1:1 to simultaneous administration (SI) or separate administration (SE1:EV71 and SE2: HepB followed by MenA).

Results

According to per protocol set, antibody response against EV71, hepatitis B virus and group A meningococcal polysaccharide was similar regardless of administration schedule. With the non-inferiority margin set at 10%, the seroconversion of the three pathogens in the SI group (100% [98.25, 100], 44.84% [38.20, 51.63] and 27.83% [21.91, 34.38]) was not inferior to that of SE1 or SE2 group (100% [98.31, 100], 44.35% [37.82, 51.02] and 29.17% [23.20, 35.72]). The occurrences of adverse reactions of each vaccination regimen were comparable (60.62% vs 52.33% and 56.98%, P = 0.16).

Conclusions

Simultaneous administration of combined EV71 vaccine with HepB and MenA shows non inferiority in immunogenicity and safety compared with separate administration.

Clinical Trial Registration NCT03274102

simultaneous administration, EV71 vaccine, phase-IV trial

Issue Section: Major Article

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© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Enterovirus; EV-71; Vaccines.

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#Enterovirus A71 Phenotypes Causing #HFMD, #Vietnam (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 4—April 2019 / Dispatch

Enterovirus A71 Phenotypes Causing Hand, Foot and Mouth Disease, Vietnam

Hoang Minh Tu Van  , Nguyen To Anh, Nguyen Thi Thu Hong, Le Nguyen Truc Nhu, Lam Anh Nguyet, Tran Tan Thanh, Nguyen Thi Han Ny, Vu Thi Ty Hang, Truong Huu Khanh, Ho Lu Viet, Do Chau Viet, Ha Manh Tuan, Nguyen Thanh Hung, Du Tuan Quy, Do Quang Ha, Phan Tu Qui, Le Nguyen Thanh Nhan, Guy Thwaites, Nguyen Van Vinh Chau, Louise Thwaites, H. Rogier van Doorn, and Le Van Tan

Author affiliations: Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam (H.M.T. Van, N.T. Anh, N.T.T. Hong, L.N.T. Nhu, L.A. Nguyet, T.T. Thanh, N.T.H. Ny, V.T.T. Hang, D.Q. Ha, G. Thwaites, L. Thwaites, H.R. van Doorn, L.V. Tan); Children’s Hospital 2, Ho Chi Minh City (H.M.T. Van, H.L. Viet, D.C. Viet, H.M. Tuan); Children’s Hospital 1, Ho Chi Minh City (T.H. Khanh, N.T. Hung, D.T. Quy, L.N.T. Nhan); University of Oxford, Oxford, UK (P.T. Qui, G. Thwaites, L. Thwaites, H.R. van Doorn); Hospital for Tropical Diseases, Ho Chi Minh City (N.V.V. Chau)

 

Abstract

We investigated enterovirus A71–associated hand, foot and mouth disease in Vietnam and found that, after replacing subgenogroup C4 in 2013, B5 remained the leading cause of this disease. In contrast with previous observations, this switch did not result in an explosive outbreak, and B5 evolution was driven by negative selection.

Keywords: Enterovirus; EV-A71; HFMD; Vietnam.

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Hsp27 responds to and facilitates #enterovirus A71 #replication through enhancing viral IRES-mediated translation (J Virol., abstract)

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

Hsp27 responds to and facilitates enterovirus A71 replication through enhancing viral IRES-mediated translation

Xuelian Dan, Qianya Wan, Lina Yi, Jing Lu, Yang Jiao, Huangcan Li, Dan Song, Ying Chen, Hongxi Xu, Ming-Liang He

DOI: 10.1128/JVI.02322-18

 

ABSTRACT

Enterovirus 71 (EV-A71) is a human pathogen that causes hand, foot and mouth disease (HFMD) and fatal neurological diseases without effective treatment. Characterization of key host factors is important for understanding pathogenesis and developing antiviral drugs. Revealed by two-dimensional gel electrophoresis-based proteomics studies, here we report that Hsp27 is one of the most upregulated proteins responding to EV-A71 infection. Depletion of Hsp27 by siRNA or CRISPR-Cas9 mediated knockout significantly inhibits viral replication, protein expression and reproduction; while restoration of Hsp27 rescores such virus activities. Furthermore, we show that Hsp27 plays crucial role in regulating the viral internal ribosome entry site (IRES) activities by two different mechanisms. Hsp27 markedly promotes 2Apro-mediated eIF4G cleavage, an important process for selecting and initiating IRES-mediated translation. hnRNP A1 is a key IRES trans-acting factor (ITAF) for enhancing IRES-mediated translation. Surprisingly, knockout of Hsp27 differentially blocks hnRNP A1 but not FBP1 translocation from nucleus to cytoplasm, and therefore abolishes hnRNP A1 interaction with IRES. Most importantly, Hsp27 inhibitor TDP, a compound was isolated from a traditional Chinese herb, significantly protects cytopathic effects and inhibits EV-A71 infection. Collectively, our results demonstrate new functions of Hsp27 in facilitating virus infection and provides novel options for combating EV-A71 infection by targeting Hsp27.

 

IMPORTANCE

EV-A71 outbreak, repeatedly reported worldwide in the last decades, is a great public health problem for causing hand, foot and mouth disease and severe neurological disorders even deaths without approved treatments available. We show Hsp27, a heat shock protein, supports EV-A71 infection through two distinct ways to promote viral IRES dependent translation. A small molecule Hsp27 inhibitor isolated from traditional Chinese medical herb effectively reduced the virus yields. Together, we demonstrate that Hsp27 plays important role in EV-A71 infection and may serve as antiviral target.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: EV-A71; Enterovirus; Antivirals.

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