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 Advances in Antigenic Peptide-Based Vaccine and Neutralizing Antibodies against Viruses Causing Hand, Foot, and Mouth Disease

2019 ◽  
Vol 20 (6) ◽  
pp. 1256 ◽  
Author(s):  
Mohd Anasir ◽  
Chit Poh
Keyword(s):  
Neutralizing Antibodies ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Antigenic Peptide ◽  
Effective Vaccine ◽  
Inactivated Vaccine ◽  
Antigenic Peptides ◽  
Foot And Mouth ◽  
Etiological Agents

Hand, foot, and mouth disease (HFMD) commonly produces herpangina, but fatal neurological complications have been observed in children. Enterovirus 71 (EV-A71) and Coxsackievirus 16 (CV-A16) are the predominant viruses causing HFMD worldwide. With rising concern about HFMD outbreaks, there is a need for an effective vaccine against EV-A71 and CV-A16. Although an inactivated vaccine has been developed against EV-A71 in China, the inability of the inactivated vaccine to confer protection against CV-A16 infection and other HFMD etiological agents, such as CV-A6 and CV-A10, necessitates the exploration of other vaccine platforms. Thus, the antigenic peptide-based vaccines are promising platforms to develop safe and efficacious multivalent vaccines, while the monoclonal antibodies are viable therapeutic and prophylactic agents against HFMD etiological agents. This article reviews the available information related to the antigenic peptides of the etiological agents of HFMD and their neutralizing antibodies that can provide a basis for the design of future therapies against HFMD etiological agents.

scholarly journals Early Evidence of Inactivated Enterovirus 71 Vaccine Impact Against Hand, Foot, and Mouth Disease in a Major Center of Ongoing Transmission in China, 2011–2018: A Longitudinal Surveillance Study

2019 ◽  
Author(s):  
Jennifer R Head ◽  
Philip A Collender ◽  
Joseph A Lewnard ◽  
Nicholas K Skaff ◽  
Ling Li ◽  
...  
Keyword(s):  
Time Series ◽  
Incidence Rate ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Asia Pacific ◽  
Full Time ◽  
Study Region ◽  
Foot And Mouth ◽  
Vaccine Impact

Abstract Background Enterovirus 71 (EV71) is a major causative agent of hand, foot, and mouth disease (HFMD), associated with severe manifestations of the disease. Pediatric immunization with inactivated EV71 vaccine was initiated in 2016 in the Asia-Pacific region, including China. We analyzed a time series of HFMD cases attributable to EV71, coxsackievirus A16 (CA16), and other enteroviruses in Chengdu, a major transmission center in China, to assess early impacts of immunization. Methods Reported HFMD cases were obtained from China’s notifiable disease surveillance system. We compared observed postvaccination incidence rates during 2017–2018 with counterfactual predictions made from a negative binomial regression and a random forest model fitted to prevaccine years (2011–2015). We fit a change point model to the full time series to evaluate whether the trend of EV71 HFMD changed following vaccination. Results Between 2011 and 2018, 279 352 HFMD cases were reported in the study region. The average incidence rate of EV71 HFMD in 2017–2018 was 60% (95% prediction interval [PI], 41%–72%) lower than predicted in the absence of immunization, corresponding to an estimated 6911 (95% PI, 3246–11 542) EV71 cases averted over 2 years. There were 52% (95% PI, 42%–60%) fewer severe HFMD cases than predicted. However, the incidence rate of non-CA16 and non-EV71 HFMD was elevated in 2018. We identified a significant decline in the trend of EV71 HFMD 4 months into the postvaccine period. Conclusions We provide the first real-world evidence that programmatic vaccination against EV71 is effective against childhood HFMD and present an approach to detect early vaccine impact or intended consequences from surveillance data.

scholarly journals Hand, Foot and Mouth Disease (HFMD): An Update

2017 ◽  
Vol 40 (2) ◽  
pp. 115-119 ◽  
Author(s):  
Probir Kumar Sarkar ◽  
Nital Kumar Sarker ◽  
Md Abu Tayab
Keyword(s):  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Coxsackie Virus ◽  
Asia Pacific ◽  
Human Enterovirus ◽  
Small Scale ◽  
Human Enterovirus 71 ◽  
Mild Disease ◽  
Foot And Mouth

Hand, foot, and mouth disease (HFMD) also known as vesicular stomatitis with exanthema, first reported in New Zealand in 1957 is caused by Coxsackie virus A16 (CVA16), human enterovirus 71 (HEV71) and occasionally by other HEV-A serotypes, such as Coxsackie virus A6 and Coxsackie virus A10, are also associated with HFMD and herpangina. While all these viruses can cause mild disease in children, EV71 has been associated with neurological disease and mortality in large outbreaks in the Asia Pacific region over the last decade. It is highly contagious and is spread through direct contact with the mucus, saliva, or feces of an infected person. This is characterized by erythrematous papulo vesicular eruptions over hand, feet, perioral area, knee, buttocks and also intra-orally mostly in children, typically occurs in small epidemics usually during the summer and autumn months. HFMD symptoms are usually mild and resolve on their own in 7 to 10 days. Treatment is symptomatic but good hygiene during and after infection is very important in preventing the spread of the disease. Though only small scale outbreaks have been reported from United States, Europe, Australia Japan and Brazil for the first few decade, since 1997 the disease has conspicuously changed its behavior as noted in different Southeast Asian countries. There was sharp rise in incidence, severity, complications and even fatal outcomes that were almost unseen before that period. There are reports of disease activity in different corners of India since 2004, and the largest outbreak of HFMD occurred in eastern part of India in and around Kolkata in 2007and Bhubaneswar, Odisha in 2009. In recent years there are cases of HFMD have been seen in Bangladesh also. Although of milder degree, continuous progress to affect larger parts of the neighboring may indicate vulnerability of Bangladesh from possible future outbreaks.Bangladesh J Child Health 2016; VOL 40 (2) :115-119

scholarly journals Human enterovirus 71 and hand, foot and mouth disease

2010 ◽  
Vol 138 (8) ◽  
pp. 1071-1089 ◽  
Author(s):  
S. S. Y. WONG ◽  
C. C. Y. YIP ◽  
S. K. P. LAU ◽  
K. Y. YUEN
Keyword(s):  
Vaccine Development ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Asia Pacific ◽  
Human Enterovirus ◽  
Human Enterovirus 71 ◽  
Asian Pacific Region ◽  
Route Of Transmission ◽  
Foot And Mouth

SUMMARYHand, foot and mouth disease (HFMD) is generally a benign febrile exanthematous childhood disease caused by human enteroviruses. The route of transmission is postulated to be faeco-oral in developing areas but attributed more to respiratory droplet in developed areas. Transmission is facilitated by the prolonged environmental survival of these viruses and their greater resistance to biocides. Serious outbreaks with neurological and cardiopulmonary complications caused by human enterovirus 71 (HEV-71) seem to be commoner in the Asian Pacific region than elsewhere in the world. This geographical predilection is unexplained but could be related to the frequency of intra- and inter-typic genetic recombinations of the virus, the host populations' genetic predisposition, environmental hygiene, and standard of healthcare. Vaccine development could be hampered by the general mildness of the illness and rapid genetic evolution of the virus. Antivirals are not readily available; the role of intravenous immunoglobulin in the treatment of serious complications should be investigated. Monitoring of this disease and its epidemiology in the densely populated Asia Pacific epicentre is important for the detection of emerging epidemics due to enteroviruses.

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 DNA methylation and SNP in IFITM3 are correlated with hand, foot and mouth disease caused by enterovirus 71

2021 ◽  
Vol 105 ◽  
pp. 199-208
Author(s):  
Mei Li ◽  
Ya-Ping Li ◽  
Hui-Ling Deng ◽  
Mu-Qi Wang ◽  
Yuan Chen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Foot And Mouth

scholarly journals Meteorological factors affect the hand, foot, and mouth disease epidemic in Qingdao, China, 2007–2014

2016 ◽  
Vol 144 (11) ◽  
pp. 2354-2362 ◽  
Author(s):  
F. C. JIANG ◽  
F. YANG ◽  
L. CHEN ◽  
J. JIA ◽  
Y. L. HAN ◽  
...  
Keyword(s):  
Meteorological Factors ◽  
Enterovirus 71 ◽  
Rank Correlation ◽  
Foot And Mouth Disease ◽  
Late Summer ◽  
Atmospheric Temperature ◽  
Early Spring ◽  
Mouth Disease ◽  
Foot And Mouth ◽  
Spearman Rank Correlation Analysis

SUMMARYHand, foot, and mouth disease (HFMD) has caused public health concerns worldwide. We aimed to investigate the effect of meteorological factors on the HFMD epidemic in Qingdao, a port city in China. A total of 78641 cases were reported in Qingdao between January 2007 and December 2014. Of those, 71084 (90·39%) occurred in children aged 0–5 years, with an incidence of 1691·2/100000. The incidence increased from early spring, peaked between spring and summer, and decreased in late summer. Aetiological agents in all severe cases and selected mild cases were characterized by examining throat swabs. Except for enterovirus 71 (EV71) and coxsackievirus A16 (CA16), other EVs caused >50% of the HFMD cases between 2011 and 2014. EV71 was more frequent in the off-peak months than in the peak months and prone to causing more severe cases compared to CA16 (χ2 = 46·3, P < 0·001). CA10 caused more severe HFMD than did CA6 (χ2 = 20·49, P < 0·001) and all non-CA10 EVs (χ2 = 41·01, P < 0·001). Community-derived HFMD cases accounted for 65·11%. Spearman rank correlation analysis showed that HFMD incidence in children aged 0–5 years was positively correlated with atmospheric temperature (rs = 0·77, P < 0·001), relative humidity (rs = 0·507, P < 0·001), and precipitation (rs = 0·328, P < 0·001). Climate changes and CA10 surveillance in communities should be integrated into the current prophylactic programme.

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