scholarly journals Crystal Structures of Yeast-Produced Enterovirus 71 and Enterovirus 71/Coxsackievirus A16 Chimeric Virus-Like Particles Provide the Structural Basis for Novel Vaccine Design against Hand-Foot-and-Mouth Disease

2015 ◽  
Vol 89 (12) ◽  
pp. 6196-6208 ◽  
Author(s):  
Ke Lyu ◽  
Ya-Ling He ◽  
Hao-Yang Li ◽  
Rong Chen
Keyword(s):  
Crystal Structures ◽  
Vaccine Candidate ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Structural Basis ◽  
Coxsackievirus A16 ◽  
Virus Like Particle ◽  
Charge Potential ◽  
Foot And Mouth

ABSTRACTHuman enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the two major causative agents for hand-foot-and-mouth disease (HFMD). Previously, we demonstrated that a virus-like particle (VLP) for EV71 produced fromSaccharomyces cerevisiaeis a potential vaccine candidate against EV71 infection, and an EV71/CVA16 chimeric VLP can elicit protective immune responses against both virus infections. Here, we presented the crystal structures of both VLPs, showing that both the linear and conformational neutralization epitopes identified in EV71 are mostly preserved on both VLPs. The replacement of only 4 residues in the VP1 GH loop converted strongly negatively charged surface patches formed by portions of the SP70 epitope in EV71 VLP into a relatively neutral surface in the chimeric VLP, which likely accounted for the additional neutralization capability of the chimeric VLP against CVA16 infection. Such local variations in the amino acid sequences and the surface charge potential are also present in different types of polioviruses. In comparison to EV71 VLP, the chimeric VLP exhibits structural changes at the local site of amino acid replacement and the surface loops of all capsid proteins. This is consistent with the observation that the VP1 GH loop located near the pseudo-3-fold junction is involved in extensive interactions with other capsid regions. Furthermore, portions of VP0 and VP1 in EV71 VLP are at least transiently exposed, revealing the structural flexibility of the VLP. Together, our structural analysis provided insights into the structural basis of enterovirus neutralization and novel vaccine design against HFMD and other enterovirus-associated diseases.IMPORTANCEOur previous studies demonstrated that the enterovirus 71 (EV71) virus-like particle (VLP) produced from yeast is a vaccine candidate against EV71 infection and that a chimeric EV71/coxsackievirus A16 (CVA16) VLP with the replacement of 4 amino acids in the VP1 GH loop can confer protection against both EV71 and CVA16 infections. This study reported the crystal structures of both the EV71 VLP and the chimeric EV71/CVA16 VLP and revealed that the major neutralization epitopes of EV71 are mostly preserved in both VLPs. In addition, the mutated VP1 GH loop in the chimeric VLP is well exposed on the particle surface and exhibits a surface charge potential different from that contributed by the original VP1 GH loop in EV71 VLP. Together, this study provided insights into the structural basis of enterovirus neutralization and evidence that the yeast-produced VLPs can be developed into novel vaccines against hand-foot-and-mouth disease (HFMD) and other enterovirus-associated diseases.

scholarly journals Structure, Immunogenicity, and Protective Mechanism of an Engineered Enterovirus 71-Like Particle Vaccine Mimicking 80S Empty Capsid

2017 ◽  
Vol 92 (1) ◽  
Author(s):  
Xiaoli Wang ◽  
Zhiqiang Ku ◽  
Xiang Zhang ◽  
Xiaohua Ye ◽  
Jinhuan Chen ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Asia Pacific ◽  
Protective Mechanism ◽  
Particle Assembly ◽  
Virus Like Particle ◽  
Empty Capsid ◽  
Foot And Mouth

ABSTRACTEnterovirus 71 (EV71) is the major causative agent of severe hand, foot, and mouth disease, which affects millions of young children in the Asia-Pacific region annually. In this study, we engineered a novel EV71 virus-like particle (VLP) that lacks VP4 (therefore designated VLPΔVP4) and investigated its structure, antigenicity, and vaccine potential. The cryo-electron microscopy (cryo-EM) structure of VLPΔVP4was reconstructed to 3.71-Å resolution. Results from structural and biochemical analyses revealed that VLPΔVP4resembles the end product of the viral uncoating process, the 80S empty capsid. VLPΔVP4is able to elicit high-titer neutralizing antibodies and to fully protect mice against lethal viral challenge. Mechanistic studies showed that, at the cellular level, the anti-VLPΔVP4sera exert neutralization effects at both pre- and postattachment stages by inhibiting both virus attachment and internalization, and at the molecular level, the antisera can block multiple interactions between EV71 and its key receptors. Our study gives a better understanding of EV71 capsid assembly and provides important information for the design and development of new-generation vaccines for EV71, and perhaps for other enteroviruses, as well.IMPORTANCEEnterovirus 71 (EV71) infection may lead to severe hand, foot, and mouth disease, with significant morbidity and mortality. Knowledge regarding EV71 particle assembly remains limited. Here, we report the generation and characterization of a novel EV71 virus-like particle that lacks the VP4 capsid subunit protein. This particle, termed VLPΔVP4, structurally mimics the 80S empty capsid, which is the end stage of EV71 uncoating. We further show that VLPΔVP4exhibits desirable immunogenicity and protective efficacy in proof-of-concept studies. In addition, the inhibitory mechanisms of the VLPΔVP4-induced antibodies are unraveled at both the cellular and molecular levels. Our work provides the first evidence of picornaviral particle assembly in the complete absence of VP4 and identifies VLPΔVP4as an improved EV71 vaccine candidate with desirable traits. These findings not only enhance our understanding of particle assembly and uncoating of picornaviruses, but also provide important information for structure-guided vaccine design for EV71 and other enteroviruses.

scholarly journals Epidemiology of hand, foot and mouth disease in China, 2008 to 2015 prior to the introduction of EV-A71 vaccine

2017 ◽  
Vol 22 (50) ◽  
Author(s):  
Bingyi Yang ◽  
Fengfeng Liu ◽  
Qiaohong Liao ◽  
Peng Wu ◽  
Zhaorui Chang ◽  
...  
Keyword(s):  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Incidence Rates ◽  
Mouth Disease ◽  
Human Enterovirus ◽  
Coxsackievirus A16 ◽  
Serotype Replacement ◽  
Foot And Mouth ◽  
Vaccine Impact ◽  
National Surveillance System

Introduction Hand, foot and mouth disease (HFMD) is usually caused by several serotypes from human enterovirus A species, including enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16). Two inactivated monovalent EV-A71 vaccines have been recently licensed in China and monovalent CV-A16 vaccine and bivalent EV-A71 and CV-A16 vaccine are under development. Methods: Using notifications from the national surveillance system, we describe the epidemiology and dynamics of HFMD in the country, before the introduction of EV-A71 vaccination, from 2008 through 2015. Results: Laboratory-identified serotype categories, i.e. CV-A16, EV-A71 and other enteroviruses, circulated annually. EV-A71 remained the most virulent serotype and was the major serotype for fatal cases (range: 88.5–95.4%) and severe cases (range: 50.7–82.3%) across years. Except for 2013 and 2015, when other enteroviruses were more frequently found in mild HFMD (48.8% and 52.5%), EV-A71 was more frequently detected from mild cases in the rest of the years covered by the study (range: 39.4–52.6%). The incidence rates and severity risks of HFMD associated with all serotype categories were the highest for children aged 1 year and younger, and decreased with increasing age. Discussion/conclusion: This study provides baseline epidemiology for evaluation of vaccine impact and potential serotype replacement.

scholarly journals Clinical and Etiological Characteristics of Atypical Hand-Foot-and-Mouth Disease in Children from Chongqing, China: A Retrospective Study

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Xiang Yan ◽  
Zhen-Zhen Zhang ◽  
Zhen-Hua Yang ◽  
Chao-Min Zhu ◽  
Yun-Ge Hu ◽  
...  
Keyword(s):  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Good Prognosis ◽  
Mouth Disease ◽  
Coxsackievirus A16 ◽  
Neurologic Involvement ◽  
Coxsackievirus A6 ◽  
Foot And Mouth ◽  
Two Peaks ◽  
Epidemiological Characteristics

Background. Hand-foot-and-mouth disease (HFMD) is a disease that had similar manifestations to chickenpox, impetigo, and measles, which is easy to misdiagnose and subsequently causes delayed therapy and subsequent epidemic. To date, no study has been conducted to report the clinical and epidemiological characteristics of atypical HFMD.Methods. 64 children with atypical HFMD out of 887 HFMD children were recruited, stool was collected, and viral VP1 was detected.Results. The atypical HFMD accounted for 7.2% of total HFMD in the same period (64/887) and there were two peaks in its prevalence in nonepidemic seasons. Ten children (15.6%) had manifestations of neurologic involvement, of whom 4 (6.3%) were diagnosed with severe HFMD and 1 with critically severe HFMD, but all recovered smoothly. Onychomadesis and desquamation were found in 14 patients (21.9%) and 15 patients (23.4%), respectively. The most common pathogen was coxsackievirus A6 (CV-A6) which accounted for 67.2%, followed by nontypable enterovirus (26.6%), enterovirus 71 (EV-A71) (4.7%), and coxsackievirus A16 (A16) (1.5%).Conclusions. Atypical HFMD has seasonal prevalence. The manifestations of neurologic involvement in atypical HFMD are mild and usually have a good prognosis. CV-A6 is a major pathogen causing atypical HFMD, but not a major pathogen in Chongqing, China.

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