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

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.

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

Journal of Virology ◽

10.1128/jvi.01330-17 ◽

2017 ◽

Vol 92 (1) ◽

Cited By ~ 3

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.

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

Bangladesh Journal of Child Health ◽

10.3329/bjch.v40i2.31567 ◽

2017 ◽

Vol 40 (2) ◽

pp. 115-119 ◽

Cited By ~ 4

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

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

Eurosurveillance ◽

10.2807/1560-7917.es.2017.22.50.16-00824 ◽

2017 ◽

Vol 22 (50) ◽

Cited By ~ 37

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.

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Human enterovirus 71 and hand, foot and mouth disease

Epidemiology and Infection ◽

10.1017/s0950268809991555 ◽

2010 ◽

Vol 138 (8) ◽

pp. 1071-1089 ◽

Cited By ~ 178

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.

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Epidemic dynamics, interactions and predictability of enteroviruses associated with hand, foot and mouth disease in Japan

Journal of The Royal Society Interface ◽

10.1098/rsif.2018.0507 ◽

2018 ◽

Vol 15 (146) ◽

pp. 20180507 ◽

Cited By ~ 14

Author(s):

Saki Takahashi ◽

C. Jessica E. Metcalf ◽

Yuzo Arima ◽

Tsuguto Fujimoto ◽

Hiroyuki Shimizu ◽

...

Keyword(s):

Time Series ◽

Time Series Data ◽

Vaccine Development ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Asia Pacific ◽

Series Data ◽

Inhibitory Interaction ◽

Epidemic Dynamics ◽

Foot And Mouth

Outbreaks of hand, foot and mouth disease have been documented in Japan since 1963. This disease is primarily caused by the two closely related serotypes of Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16). Here, we analyse Japanese virologic and syndromic surveillance time-series data from 1982 to 2015. As in some other countries in the Asia Pacific region, EV-A71 in Japan has a 3 year cyclical component, whereas CV-A16 is predominantly annual. We observe empirical signatures of an inhibitory interaction between the serotypes; virologic lines of evidence suggest they may indeed interact immunologically. We fit the time series to mechanistic epidemiological models: as a first-order effect, we find the data consistent with single-serotype susceptible–infected–recovered dynamics. We then extend the modelling to incorporate an inhibitory interaction between serotypes. Our results suggest the existence of a transient cross-protection and possible asymmetry in its strength such that CV-A16 serves as a stronger forcing on EV-A71. Allowing for asymmetry yields accurate out-of-sample predictions and the directionality of this effect is consistent with the virologic literature. Confirmation of these hypothesized interactions would have important implications for understanding enterovirus epidemiology and informing vaccine development. Our results highlight the general implication that even subtle interactions could have qualitative impacts on epidemic dynamics and predictability.

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Transmissibility of hand, foot, and mouth disease in 97 counties of China.

10.21203/rs.3.rs-735005/v1 ◽

2021 ◽

Author(s):

Wei Zhang ◽

Jia Rui ◽

Xiaoqing Cheng ◽

Bin Deng ◽

Hesong Zhang ◽

...

Keyword(s):

Incidence Rate ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Jiangsu Province ◽

Asia Pacific ◽

Seasonal Characteristics ◽

High Incidence ◽

Foot And Mouth ◽

Low Incidence ◽

Serious Disease

Abstract Background Hand, foot, and mouth disease (HFMD) has been a serious disease burden in the Asia Pacific region represented by China, and the transmission characteristics of HFMD in regions haven’t been clear. This study calculated the transmissibility of HFMD at county levels in Jiangsu Province, China, analyzed the differences of transmissibility and explored the reasons. Methods We built susceptible-exposed-infectious-asymptomatic-removed (SEIAR) model for seasonal characteristics of HFMD, estimated effective reproduction number (Reff) by fitting the incidence of HFMD in 97 counties of Jiangsu Province from 2015 to 2020, compared incidence rate and transmissibility in different counties by non -parametric test, rapid cluster analysis and rank-sum ratio. Results The average daily incidence rate was between 0 and 4 per 100,000 in Jiangsu province from 2015–2020. The 97 counties could be divided into three levels: low incidence, medium incidence and high incidence, and occurred that the average daily incidence rate dropped sharply in 2016–2017, and increased sharply in 2017–2018 years. The Quartile of Reff in Jiangsu Province from 2015 to 2020 was 1.54 (0.49, 2.50), Rugao district in Central Jiangsu and Jianhu district in Northern Jiangsu had the highest transmissibility by rank-sum ratio. Reff generally decreased in 2017 and increased in 2018 in most counties, and the median level of Reff was lowest in 2017 (P < 0.05). Conclusion Transmissibility was different in 97 counties of Jiangsu Province, and the reasons for the differences may be related to the climate, demographic characteristics, virus subtypes, vaccination and other infectious diseases.

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Transmissibility of Hand, Foot, and Mouth Disease in 97 Counties of Jiangsu Province, China, 2015- 2020

10.21203/rs.3.rs-752604/v1 ◽

2021 ◽

Author(s):

Wei Zhang ◽

Jia Rui ◽

Xiaoqing Cheng ◽

Bin Deng ◽

Hesong Zhang ◽

...

Keyword(s):

Incidence Rate ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Jiangsu Province ◽

Asia Pacific ◽

Seasonal Characteristics ◽

High Incidence ◽

Foot And Mouth ◽

Low Incidence ◽

Serious Disease

Abstract Background: Hand, foot, and mouth disease (HFMD) has been a serious disease burden in the Asia Pacific region represented by China, and the transmission characteristics of HFMD in regions haven’t been clear. This study calculated the transmissibility of HFMD at county levels in Jiangsu Province, China, analyzed the differences of transmissibility and explored the reasons.Methods: We built susceptible-exposed-infectious-asymptomatic-removed (SEIAR) model for seasonal characteristics of HFMD, estimated effective reproduction number (Reff) by fitting the incidence of HFMD in 97 counties of Jiangsu Province from 2015 to 2020, compared incidence rate and transmissibility in different counties by non -parametric test, rapid cluster analysis and rank-sum ratio.Results: The average daily incidence rate was between 0 and 4 per 100,000 in Jiangsu province from 2015-2020. The 97 counties could be divided into three levels: low incidence, medium incidence and high incidence, and occurred that the average daily incidence rate dropped sharply in 2016-2017, and increased sharply in 2017-2018 years. The Quartile of Reff in Jiangsu Province from 2015 to 2020 was 1.54 (0.49, 2.50), Rugao district in Central Jiangsu and Jianhu district in Northern Jiangsu had the highest transmissibility by rank-sum ratio. Reff generally decreased in 2017 and increased in 2018 in most counties, and the median level of Reff was lowest in 2017 (P<0.05).Conclusion: Transmissibility was different in 97 counties of Jiangsu Province, and the reasons for the differences may be related to the climate, demographic characteristics, virus subtypes, vaccination and other infectious diseases.

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