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enterovirus a71 antivirals:Past,present,and future

Acta Pharmaceutica Sinica B 2022年第4期12卷 1542-1566页

作者： Jun Wang Yanmei Hu Madeleine Zheng Department of Pharmacology and Toxicology College of Pharmacythe University of ArizonaTucsonAZ 85721USA

enterovirus a71(EV-a71)is a significant human pathogen,especially in children.EV-a71 infection is one of the leading causes of hand,foot,and mouth diseases(HFMD),and can lead to neurological complications such as acute flaccid myelitis(AFM)in severe cases.Although three EV-a71 vaccines are available in China,they are not broadly protective and have reduced efficacy against emerging strains.There is currently no approved antiviral for EV-a71.Significant progress has been made in developing antivirals against EV-a71 by targeting both viral proteins and host factors.However,viral capsid inhibitors and protease inhibitors failed in clinical trials of human rhinovirus infection due to limited efficacy or side effects.This review discusses major discoveries in EV-a71 antiviral development,analyzes the advantages and limitations of each drug target,and highlights the knowledge gaps that need to be addressed to advance the field forward.

关键词： enterovirus a71 EV-a71 AntiviralsAcute flaccid myelitis Hand Foot and mouth disease(HFMD) Picornavirus 2C protein

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Structural and functional analysis of a potent human neutralizing antibody against enterovirus a71

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Science China(Life Sciences) 2022年第12期65卷 2517-2526页

作者： Zhe Chen Linlin Bao Bin Zhu Hua Fu Shuangli Zhu Tianjiao Ji Ying Xue Chuan Liu Xurong Wang Fengdi Li Qi Lv Feifei Qi Pin Yu Wei Deng Wenbo Xu Chuan Qin Hongrong Liu Qi Jin MOH Key Laboratory of Systems Biology of Pathogens Institute of Pathogen BiologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases NHC Key Laboratory of Human Disease Comparative MedicineInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciences and Comparative Medicine CenterPeking Union Medical CollegeBeijing 100021China School of Computer Science and Engineering Hunan University of Science and TechnologyXiangtan 411201China National Institute for Viral Disease Control and Prevention China CDCBeijing 102206China Ministry of Education Key Laboratory of Protein Sciences Beijing Advanced Innovation Center for Structural BiologyTsinghua UniversityBeijing 100084China Key Laboratory for Matter Microstructure and Function of Hunan Province Key Laboratory of Low-dimensional Quantum Structures and Quantum ControlSchool of Physics and ElectronicsHunan Normal UniversityChangsha 410081China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases Hangzhou 310058China

enterovirus a71(EV-a71) causes major outbreaks of hand,foot,and mouth disease(HFMD) in many countries,most frequently affecting children,and a small proportion of cases may lead to death.Currently,no vaccine is available in most endemic regions,and no licenced treatments for EV-a71 infection are available.Here,we characterize a human monoclonal antibody(Hu MAb),E1,by screening a Fab antibody phage library derived from patients who recovered from EV-a71 infection.E1 exhibits strong neutralizing activity against EV-a71 virus in cells.The cryo-electron microscopy(cryo-EM) structures of the EV-a71 virion in complex with E1 Fab fragments demonstrated that E1 recognized an epitope formed by residues in the BC and HI loops of VP1.In a mouse model,E1 effectively protected against lethal EV-a71 challenge in both prophylactic and therapeutic treatment.In particular,E1 significantly reduces virus titers and muscle damage.E1 might represent a potential adjunct to EV-a71 treatment.

关键词： enterovirus a71 antibody mouse models cryo-electron microscopy

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Seroprevalence of human enterovirus a71 in Guangzhou,China,2019-2021

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生物安全与健康(英文) 2023年第3期5卷 168-173页

作者： Huimin Lian Huimin Jianng Lina Yi Jing Sun Huaping Xie Ming Qiu Limei Sun Huifang Lin Mingda Yang Lin Qu Haiyi Yang Jing Lu Hanri Zeng School of Public Health Southern Medical UniversityGuangzhou 510515China Guangdong Provincial Institution of Public Health Guangdong Provincial Center for Disease Control and PreventionGuangzhou 511430China Guangdong Workstation for Emerging Infectious Disease Control and Prevention Guangdong Provincial Key Laboratory of Pathogen Detection for Emerging Infectious Disease ResponseGuangdong Provincial Center for Disease Control and PreventionGuangzhou 511430China Health Commission of Heping District Shenyang CityLiaoning 110003China Guangzhou Center for Disease Control and Prevention Guangzhou 510440China School of Public Health Sun Yat-Sen UniversityGuangzhou 510080China School of Public Health Jinan UniversityGuangzhou 510632China

enterovirus a71 (EV-a71) is a significant hand-foot-mouth disease (HFMD) etiology. The inactivated EV-a71 vaccines were approved in China in 2016. However, the seroprevalence of EV-a71 after the vaccine application and its potential association with the EV-a71 epidemic in the population are rarely studied. In this study, we analyzed the incidence of EV-a71 infection and seroepidemiology in Guangzhou City, China. From 2019 to 2021, 167,920 clinically confirmed HFMD cases were reported in Guangzhou. In 6,868 enterovirus-positive samples, Coxsackievirus A6 and Coxsackievirus A16 were dominant genotypes, and only 3 EV-a71-positive samples were detected, highlighting the deficient epidemic activity of EV-a71. Microneutralization assay was performed on 1,000 representative serum samples. Notably, the seroprevalence and geometric mean titer (GMT) decreased significantly in 2020, and that in the a71 vaccine was adopted in 2016 in Guangzhou. It may be one of the reasons for the lower epidemic activity of EV-a71 in Guangzhou from 2019 to 2021.

关键词： enterovirus a71 Vaccine Seroepidemiology

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Molecular Epidemiology of an Outbreak of Hand,Foot,and Mouth Disease Associated with Subgenotype C4a of enterovirus a71 in Nanchang,China in 2014

Molecular Epidemiology of an Outbreak of Hand,Foot,and Mouth...

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第十九次全国儿科中西医结合学术会议

作者： Xianfeng Zhou Qingxiong Zhu Wen Xia Fenglan He Maohong Hu Xiansheng Ni Meiling Gao Haiying Chen Shengen Chen Nanchang Center for Disease Cntrol and Pevention Department of Infectious Diseases Children's Hospital of Jiangxi Province Nanchang University Medical College

Background:From May 1 to June 25,2014,an outbreak of hand,foot,and mouth disease(HFMD)occurred in Nanchang City,capital of Jiangxi Province,China.Methods:A total of 244 throat swabs were collected from each patient,including 14patients with severe neurological involvement with HFMD.Etiological identification using direct reverse transcription-polymerase chain reaction(RT-PCR)and phylogenetic analysis were performed to characterize the pathogens causing this outbreak and to analyze their genetic features.Besides,epidemiological investigation was conducted on the basis of patients’symptoms,age,gender and geographical distribution.Results:enterovirus a71(EV-a71)was the predominant pathogen that caused this outbreak,accounting for 84.1%of the positive HFMD cases based on laboratory results.Epidemiological analyses indicated that children aged younger than 5 years old represented more than 94%of the positive cases,with the highest incidence rate among the age group of 1-2 years old.The ratio of male to female cases was 2.6 to 1(Pa71 strains belonged to subgenotype C4a,and 8 amino acid substitutions in VPl region were found among these strains compared with EV-a71 strains isolated in Nanchang from 2011 to 2012.Conclusions:This HFMD outbreak in Nanchang was mainly caused by EV-a71subgenotype C4a that has been continuously circulating in China.And the EV-a71strains circulating in Nanchang are undergoing continuously evolutionary changes.

关键词： hand,foot,and mouth disease enterovirus a71 molecular epidemiology subgenotype C4a

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