Assessing the modification impact of vaccination on the relationship of the Discomfort Index with hand, foot, and mouth disease in Guizhou: A multicounty study.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is a major public health issue in China while temperature and humidity are well-documented predictors. However, evidence on the combined effect of temperature and humidity is still limited. It also remains unclear whether such an effect could be modified by the enterovirus 71 (EV71) vaccination. METHODS: Based on 320,042 reported HFMD cases during the summer months between 2012 and 2019, we conducted a study utilizing Distributed Lag Non-Linear Models (DLNM) and time-varying DLNM to examine how China's HFMD EV71 vaccine strategy would affect the correlation between meteorological conditions and HFMD risk. RESULTS: The incidence of HFMD changed with the Discomfort Index in an arm-shaped form. The 14-day cumulative risk of HFMD exhibited a statistically significant increase during the period of 2017-2019 (following the implementation of the EV71 vaccine policy) compared to 2012-2016 (prior to the vaccine implementation). For the total population, the range of relative risk (RR) values for HFMD at the 75th, 90th, and 99th percentiles increased from 1.082-1.303 in 2012-2016 to 1.836-2.022 in 2017-2019. In the stratified analyses, Han Chinese areas show stronger relative growth, with RR values at the 75th, 90th, and 99th percentiles increased by 14.3%, 39.1%, and 134.4% post-vaccination, compared to increases of 22.7%, 41.6%, and 38.8% in minority areas. Similarly, boys showed greater increases (24.4%, 47.7%, 121.5%) compared to girls (8.1%, 28.1%, 58.3%). Additionally, the central Guizhou urban agglomeration displayed a tendency for stronger relative growth compared to other counties. CONCLUSIONS: Although the EV71 vaccine policy has been implemented, it hasn't effectively controlled the overall risk of HFMD. There's been a shift in the main viral subtypes, potentially altering population susceptibility and influencing HFMD occurrences. The modulating effects of vaccine intervention may also be influenced by factors such as race, sex, and economic level.

Immunogenicity and immunodominant linear B-cell epitopes of a new DNA-based tetravalent vaccine against four major enteroviruses causing hand, foot, and mouth disease.

Hand, foot, and mouth disease (HFMD) poses a significant public health threat primarily caused by four major enteroviruses: enterovirus 71 (EV71), coxsackieviruses A16, A10, and A6. Broadly protective immune responses are essential for complete protection against these major enteroviruses. In this study, we designed a new tetravalent immunogen for HFMD, validated it in silico, in vivo evaluated the immunogenicity of the DNA-based tetravalent vaccine in mice, and identified immunogenic B-cell and T-cell epitopes. A new tetravalent immunogen, VP1me, was designed based on the chimeric protein and epitope-based vaccine principles. It contains a complete EV71 VP1 protein and six reported neutralizing B-cell epitopes derived from the four major enteroviruses causing HFMD. In silico validation using multiple immunoinformatic tools indicated good attributes of the VP1me immunogen suitable for vaccine development. The VP1me-based DNA vaccine efficiently induced both humoral and cellular immune responses in BALB/cAJcl mice. A combination of in silico prediction and immunoassays enabled the identification of immunogenic linear B-cell and CD8 T-cell epitopes within the VP1me immunogen. Immunodominant linear B-cell epitopes were identified in six regions of VP1me, with one epitope located at the N-terminus of the VP1 protein (aa 9-23) regarded as a novel epitope. Interestingly, some B-cell epitopes could also induce the CD8 T-cell response, suggesting their dual functions in immune stimulation. These results lay the groundwork for further development of VP1me as a new vaccine candidate.

Quantitation of Enterovirus A71 Empty and Full Particles by Sedimentation Velocity Analytical Ultracentrifugation.

The enterovirus A71 (EV71) inactivated vaccine is an effective intervention to control the spread of the virus and prevent EV71-associated hand, foot, and mouth disease (HFMD). It is widely administered to infants and children in China. The empty particles (EPs) and full particles (FPs) generated during production have different antigenic and immunogenic properties. However, the antigen detection methods currently used were established without considering the differences in antigenicity between EPs and FPs. There is also a lack of other effective analytical methods for detecting the different particle forms, which hinders the consistency between batches of products. In this study, we analyzed the application of sedimentation velocity analytical ultracentrifugation (SV-AUC) in characterizing the EPs and FPs of EV71. Our results showed that the proportions of the two forms could be quantified simultaneously by SV-AUC. We also determined the repeatability and accuracy of this method and found that both parameters were satisfactory. We assessed SV-AUC for bulk vaccine quality control, and our findings indicated that SV-AUC can be used effectively to analyze the percentage of EPs and FPs and monitor the consistency of the process to ensure the quality of the vaccine.

Impact of the COVID-19 outbreak and interventions on hand, foot and mouth disease in Zhengzhou, China, 2014-2022: a retrospective study.

BACKGROUND: Since December 2019, COVID-19 has spread rapidly around the world, and studies have shown that measures to prevent COVID-19 can largely reduce the spread of other infectious diseases. This study explored the impact of the COVID-19 outbreak and interventions on the incidence of HFMD. METHODS: We gathered data on the prevalence of HFMD from the Children's Hospital Affiliated to Zhengzhou University. An autoregressive integrated moving average model was constructed using HFMD incidence data from 2014 to 2019, the number of cases predicted from 2020 to 2022 was predicted, and the predicted values were compared with the actual measurements. RESULTS: From January 2014 to October 2022, the Children's Hospital of Zhengzhou University admitted 103,995 children with HFMD. The average number of cases of HFMD from 2020 to 2022 was 4,946, a significant decrease from 14,859 cases from 2014 to 2019. We confirmed the best ARIMA (2,0,0) (1,1,0)12 model. From 2020 to 2022, the yearly number of cases decreased by 46.58%, 75.54%, and 66.16%, respectively, compared with the forecasted incidence. Trends in incidence across sexes and ages displayed patterns similar to those overall. CONCLUSIONS: The COVID-19 outbreak and interventions reduced the incidence of HFMD compared to that before the outbreak. Strengthening public health interventions remains a priority in the prevention of HFMD.

Modeling and analysis of the effect of optimal virus control on the spread of HFMD.

A within-host and between-host hand, foot and mouth disease (HFMD) mathematical model is established and the affect of optimal control in its within-host part on HFMD transmission is studied. Through define two basic reproduction numbers, by using the fast-slow system analysis method of time scale, the global stabilities of the between-host (slow) system and within-host (fast) system are researched, respectively. An optimal control problem with drug-treatment control on coupled within-host and between-host HFMD model is formulated and analysed theoretically. Finally, the purposed optimal control measures are applied to the actual HFMD epidemic analysis in Zhejiang Province, China from April 1, 2021 to June 30, 2021. The numerical results show that the drug control strategies can reduce the virus load per capita and can effectively prevent large-scale outbreaks of HFMD.

Effectiveness of enterovirus A71 vaccine against pediatric HFMD and disease profile of post-vaccination infection.

BACKGROUND: Vaccination has been proven effective against infection with enterovirus A71 (EV-A71) in clinical trials, but vaccine effectiveness in real-world situations remains incompletely understood. Furthermore, it is not clear whether previous vaccination will result in symptom attenuation among post-vaccinated cases. METHODS: Based on long-term data extracted from the only designed referral hospital for infectious diseases, we used a test-negative case-control design and multivariate logistic regression models to analyze the effectiveness of EV-A71 vaccine against hand, foot and mouth disease (HFMD). And then, generalized linear regression models were used to evaluate the associations between prior vaccination and disease profiles. RESULTS: We selected 4883 inpatients for vaccine efficacy estimations and 2188 inpatients for disease profile comparisons. Vaccine effectiveness against EV-A71-induced HFMD for complete vaccination was 63.4 % and 51.7 % for partial vaccination. The vaccine effectiveness was higher among cases received the first dose within 12 months. No protection was observed against coxsackievirus (CV) A6-, CV-A10- or CV-A16-associated HFMD among children regardless of vaccination status. Completely vaccinated cases had shorter hospital stay and disease course compared to unvaccinated cases (P < 0.05). CONCLUSIONS: These findings reiterate the need to continue the development of a multivalent vaccine or combined vaccines, and have implications for introducing optimized vaccination strategies.

Chinese parents' intention to vaccinate their 0-5-year-old children with the EV-71 vaccine against hand, foot, and mouth disease and willingness-to-pay.

Background: This study aimed to determine the intention and willingness-to-pay (WTP) of Chinese parents/guardians to vaccinate their children with the EV-71 vaccine. Knowledge levels about hand, foot, and mouth disease (HFMD) and the EV-71 vaccine were also investigated. Methods: A cross-sectional, self-administered online survey was conducted between November 2022 and March 2023. A stratified multi-stage random sampling method was used to recruit parents/guardians of children aged 0-5 years in southeastern China. Results: A total of 3,626 complete responses were received. The mean knowledge score of HFMD was 9.99 (±4.23) out of a total of 14 points. The majority of the participants reported a somewhat willing intent (58.8%), followed by an extremely willing intent (28.9%). Participants who did not consider the EV-71 vaccine expensive (OR = 2.94, 95%CI 2.45-3.53) perceived that the EV-71 vaccine is effective (OR = 2.73, 95%CI 1.52-4.90), and a high knowledge level of HFMD (OR = 1.90, 95%CI 1.57-2.29) had the highest significant odds of having an extremely willing intent to vaccinate their children with the EV-71 vaccine. The median (interquartile range [IQR]) of WTP for the EV-71 vaccine was CNY¥200/USD$28 (IQR CNY¥100-400/USD$14-56). The highest marginal WTP for the vaccine was mainly influenced by the perceived high cost of the vaccine. Those participants who did not consider the EV-71 vaccine expensive had more than 10 times higher odds of vaccinating their children (OR = 10.86, 95%CI 8.49-13.88). Perceived susceptibility, perceived benefits, and perceived barriers were also significant influencing factors in the highest marginal WTP. Conclusion: The findings demonstrate the importance of improving health promotion and reducing the barriers to EV-71 vaccination. Therefore, it is important to improve health promotion and reduce the barriers to EV-71 vaccination.

Effectiveness of Enterovirus 71 inactivated vaccines against hand, foot, and mouth disease: A test-negative case-control study.

The Enterovirus A71 (EV-A71) vaccine was introduced in China in December 2015 as a preventive measure against hand, foot, and mouth disease (HFMD) caused by EV-A71. However, the effectiveness of the vaccine (VE) in real-world settings needs to be evaluated. We conducted a test-negative case-control study to assess the effectiveness of EV-A71 vaccines in preventing EV-A71-associated HFMD. Children aged 6-71 months with HFMD were enrolled as participants. The case group comprised those who tested positive for EV-A71, while the control group comprised those who tested negative for EV-A71. To estimate VE, a logistic regression model was employed, adjusting for potential confounders including age, gender, and clinical severity. In total, 3223 children aged 6 to 71 months were included in the study, with 162 in the case group and 3061 in the control group. The proportion of children who received EV-A71 vaccination was significantly lower in the case group compared to the control group (p < .001). The overall VEadj was estimated to be 90.8%. The VEadj estimates for partially and fully vaccinated children were 90.1% and 90.9%, respectively. Stratified by age group, the VEadj estimates were 88.7% for 6 to 35-month-olds and 95.5% for 36 to 71-month-olds. Regarding disease severity, the VEadj estimates were 86.3% for mild cases and 100% for severe cases. Sensitivity analysis showed minimal changes in the VE point estimates, with most changing by no more than 1% point. Our study demonstrates a high level of vaccine effectiveness against EV-A71-HFMD, especially in severe cases. Active promotion of EV-A71 vaccination is an effective strategy in preventing EV-A71 infections.

Potential of a bivalent vaccine for broad protection against enterovirus 71 and coxsackie virus 16 infections causing hand, foot, and mouth disease.

Hand, foot, and mouth disease (HFMD) is a highly contagious viral infection that is mainly caused by enterovirus 71 (EV71) and coxsackievirus 16 (CVA16). As there are no specific therapeutics for HFMD, the development of a bivalent vaccine is required to cover a broad range of infections. In this study, the effectiveness of novel monovalent and bivalent vaccines targeting EV71 C4a and CVA16 was investigated for their ability to prevent viral infections in neonatal human scavenger receptor class B member 2 (hSCARB2) transgenic mice. As hSCARB2 serves as a key viral receptor for EV71, these transgenic mice are susceptible to EV71 strains and facilitate viral binding, internalization, and uncoating processes. Antisera prepared by vaccine immunization were transferred to 2-day-old hSCARB2 transgenic mice, which were then infected with EV71 C4a or CVA16 virus. The antisera generated by each monovalent or bivalent vaccine effectively protected against EV71 C4a and CVA16 infections. The examination of tissue damage and viral contents in various organs indicated that both monovalent and bivalent antisera reduced EV71 C4a viral load in the brainstem, and no significant tissue damage was observed. During CVA16 infection, the monovalent and bivalent antisera significantly reduced viral contents in both the brainstem and muscles. These results suggest that passive immunity by monovalent and bivalent antisera can effectively protect against EV71 C4a and CVA16 infections. Thus, the development of a bivalent vaccine that can provide broad protection against both CV and EV infections may be a promising strategy in preventing HFMD.

Hand, Foot, and Mouth Disease Outbreak What You Need to Know.

HFMD is an obvious disease in children mostly below the age of five constituting a public health challenge to Asian-Pacific and developing countries majorly. This disease is often caused by enterovirus 71 (EV71) and Coxsackievirus A16. HFMD is a mild degree fever and general illness which manifests for about 10 days. Young age, male gender, poor hygiene, and high social contacts are some risk factors. HFMD can be diagnosed clinically by isolating the virus from stool and pharynx and identifying it on Light microscopic examination. Polymerase Chain Reaction Assay is a gold standard for confirming the virus from swabbed lesions. Late confirmation could lead to severe complications. There are no specific treatments and vaccines licensed for general use in the treatment of various serotypes of HFMD. The major strategy to prevent and control this disease is to strictly follow the WHO 8 guidelines to curb the spread of the disease.

Preclinical safety evaluation of a bivalent inactivated EV71-CA16 vaccine in mice immunized intradermally.

Hand, foot and mouth disease is a common acute viral infectious disease that poses a serious threat to the life and health of young children. With the development of an effective inactivated EV71 vaccine, CA16 has become the main pathogen causing HFMD. Effective and safe vaccines against this disease are urgently needed. In our previous study, a bivalent inactivated vaccine was shown to have good immunogenicity and to induce neutralizing antibodies in mice and monkeys. Repeated administration toxicity is a critical safety test in the preclinical evaluation of vaccines. In this study, BALB/c mice were used to evaluate the toxicity of the bivalent vaccine after multiple intradermal administrations. Clinical observation was performed daily, and body weight, food intake, hematological characteristics, serum biochemical parameters, antinuclear antibodies, CD4+/CD8a+ T-cell proportions, bone marrow smear results and pathology results were recorded. The results showed that there was no significant change at the injection site and no adverse reactions related to the vaccine. The bivalent inactivated EV71-CA16 vaccine exhibits good safety in mice, and these results provide a sufficient basis for further clinical trials.

[Analysis of the vaccination status of enterovirus type 71 inactivated vaccine in China from 2017 to 2021].

Objective: To understand the vaccination status of enterovirus type 71 (EV71) inactivated vaccines in China from 2017 to 2021 and provide evidence for making policy on immunization strategy against hand, foot and mouth disease (HFMD). Methods: Using the reported dose number of EV71 vaccination and birth cohort population data collected by the China immunizaiton program information system to estimate the cumulative coverage of EV71 vaccine by the end of 2021 among the birth cohorts since 2012 at national, provincial, and prefecture levels, and analyze the correlation between the vaccination coverage and the potential influencing factors. Results: As of 2021, the estimated cumulative vaccination coverage of the EV71 vaccine was 24.96% in birth cohorts since 2012. The cumulative vaccination coverage was between 3.09% and 56.59% in different provinces, between 0 and 88.17% in different prefectures. There was a statistically significant correlation between vaccination coverage in different regions and the region's previous HFMD prevalence and disposable income per capita. Conclusions: Since 2017, the EV71 vaccines have been widely used nationwide, but the coverage of EV71 vaccination varies greatly among regions. Vaccination coverage is higher in relatively developed regions, and the intensity of previous epidemic of HFMD may have a certain impact on the acceptance of the vaccine and the pattern of immunization service. The impact of EV71 vaccination on the epidemic of HFMD requires further studies.

Propagation and immunological characterization of coxsackievirus A10 in a serum-free HEK293A cell culture system.

Coxsackievirus A10 (CVA10) is one of enteroviral pathogens that cause the hand, foot, and mouth disease (HFMD). Since CVA10 was reported to be not easily propagated in the Vero cell culture, a feasible manufacture process for producing formalin-inactivated CVA10 vaccine is urgently needed. Several cell lines that commonly used for viral vaccine production was tested for CVA10 (M2014 strain) culture in this study, and our result showed that CVA10 could be easily propagated in the HEK293A cells. A serum-free HEK293A cell culture system was developed for CVA10 production and the yields have reached over 108 TCID50/mL. The biochemical and immunogenic properties of CVA10 particles obtained from this serum-free HEK293A culture were identical to our previous study. Two major particles of CVA10 were separated by ultracentrifugation, and only the infectious mature particles were capable of inducing CVA10 neutralizing antibody responses in the mouse immunogenicity studies. Additionally, we found that coxsackievirus A6 and enterovirus A71 could also be easily propagated using this serum-free HEK293A cell culture system. Our results provide a solution to overcome the obstacle in the propagation of CVA10 and facilitate the development of multivalent vaccines for prevention of HFMD.

Humoral and cellular immunogenicity and efficacy of a coxsackievirus A10 vaccine in mice.

Coxsackievirus A10 (CV-A10) has become one of the major pathogens of hand, foot and mouth disease (HFMD), and studies on the vaccine and animal model of CV-A10 are still far from complete. Our study used a mouse-adapted CV-A10 strain, which was lethal for 14-day-old mice, to develop an infected mouse model. Then this model was employed to establish an actively immunized-challenged mouse model to evaluate the efficacy of a formaldehyde-inactivated CV-A10 vaccine, which was prepared from a Vero cell-adapted strain. CV-A10 vaccine at a dose of 0.5 or 2.0 µg was inoculated intraperitoneally in neonatal Kunming mice on the third and ninth day. Then the mice were challenged on day 14. The survival rate of mice immunized with 0.5 or 2.0 µg vaccine were 90% and 100%, respectively, while all Alum-inoculated mice died. Compared to those in the two vaccinated groups, the Alum-inoculated mice showed severe pathological damage, strong viral protein expression and high viral loads. The antisera from vaccinated mice showed high level of neutralizing antibodies against CV-A10. Meanwhile, three potential T cell epitopes located at the carboxyl-terminal regions of the VP1 and VP3 were identified and exhibited CV-A10 serotype-specific. The humoral and cellular immunogenicity analysis showed that immunization with two doses of the vaccine elicited CV-A10 specific neutralizing antibody and T cell response in BALB/c mice. Collectively, these findings indicated that this actively immunized-challenged mouse model will be invaluable in future studies on CV-A10 pathogenesis and evaluation of vaccine candidates.

Non-neutralizing monoclonal antibody targeting VP2 EF loop of Coxsackievirus A16 can protect mice from lethal attack via Fc-dependent effector mechanism.

Coxsackievirus A16 (CA16), a main causative agent of hand, foot, and mouth disease (HFMD), has become a serious public health concern in the Asia-Pacific region. Here, we generated an anti-CA16 monoclonal antibody, DMA2017, derived from an epidemic strain CA16. Surprisingly, although DMA2017 could not neutralize the original and circulating CA16 strains in vitro, the passive transfer of DMA2017 (10 µg/g) could protect suckling mice from a lethal challenge with CA16 in vivo. Then, we confirmed the protective effect of DMA2017 relies on the Fc-dependent effector functions, such as antibody-dependent cellular cytotoxicity (ADCC). The linear epitope of DMA2017 was mapped by phage display technique to a conserved patch spanning residues 143-148 (NSHPPY) of the VP2 EF-loop of CA16. DMA2017 could inhibit the binding of the antibodies present in the sera of naturally infected children to CA16, indicating that the epitope of DMA2017 is immunodominant for CA16. Our results confirm, for the first time, that a potential preventive and therapeutic effect could be mediated by a non-neutralizing antibody elicited against CA16. These findings bring a hitherto understudied protective role of non-neutralizing antibodies during viral infections into the spotlight and provide a new perspective on the design and evaluation of CA16 vaccines.

Assessing the impact of COVID-19 interventions on the hand, foot and mouth disease in Guangdong Province, China: a Bayesian modeling study.

Background: The non-pharmaceutical interventions (NPIs) against COVID-19 may have affected the transmission of hand, foot and mouth disease (HFMD). We aimed to assess the impact of the NPIs on HFMD in the high epidemic area of HFMD, Guangdong Province. Methods: The data of HFMD cases, etiological information, and meteorological factors in Guangdong from January 1, 2012, to December 31, 2021, were collected. Using a Bayesian structural time series (BSTS) model integrated counterfactual framework, we assessed the effect of NPIs on HFMD by different intervention periods, populations (gender, age, occupation), and cities. We further explored the correlation between the reduction of HFMD and socioeconomic factors in 21 cities. Results: A total of 351,217 HFMD cases were reported and 455,327 cases were averted in Guangdong Province during 2020-2021 with a reduction of 84.94% (95%CI: 81.63-87.22%) in 2020 and 29.49% (95%CI: 15.26-39.54%) in 2021. The impact of NPIs on HFMD differed by age and gender. The effects of NPIs were more remarkable for children aged 0-2 years and scattered children. We found that the relative reductions in 21 cities were related to the composition ratio of children and COVID-19 incidence. Conclusion: The reduction of HFMD incidence was significantly associated with COVID-19 NPIs, and school closure was an effective intervention to prevent HFMD outbreaks. Our findings will contribute to the development of HFMD prevention and control measures.

Analysis of the vaccination status of enterovirus type 71 inactivated vaccine in China from 2017 to 2021 / 中华流行病学杂志

Objective: To understand the vaccination status of enterovirus type 71 (EV71) inactivated vaccines in China from 2017 to 2021 and provide evidence for making policy on immunization strategy against hand, foot and mouth disease (HFMD). Methods: Using the reported dose number of EV71 vaccination and birth cohort population data collected by the China immunizaiton program information system to estimate the cumulative coverage of EV71 vaccine by the end of 2021 among the birth cohorts since 2012 at national, provincial, and prefecture levels, and analyze the correlation between the vaccination coverage and the potential influencing factors. Results: As of 2021, the estimated cumulative vaccination coverage of the EV71 vaccine was 24.96% in birth cohorts since 2012. The cumulative vaccination coverage was between 3.09% and 56.59% in different provinces, between 0 and 88.17% in different prefectures. There was a statistically significant correlation between vaccination coverage in different regions and the region's previous HFMD prevalence and disposable income per capita. Conclusions: Since 2017, the EV71 vaccines have been widely used nationwide, but the coverage of EV71 vaccination varies greatly among regions. Vaccination coverage is higher in relatively developed regions, and the intensity of previous epidemic of HFMD may have a certain impact on the acceptance of the vaccine and the pattern of immunization service. The impact of EV71 vaccination on the epidemic of HFMD requires further studies.

Effects of different levels of non-pharmaceutical interventions on hand, foot and mouth disease in Guangzhou, China.

BACKGROUND: Non-pharmaceutical interventions (NPIs) against coronavirus disease 2019 (COVID-19) may have suppressed the transmission of other infectious diseases. This study aimed to evaluate the impact of different degrees of NPIs during the COVID-19 pandemic on hand, foot and mouth disease (HFMD) in Guangzhou, China. METHODS: Weekly reported HFMD cases and pathogens information during 2015-2021 in Guangzhou were collected from the China National Notifiable Disease Reporting System. The observed number of HFMD cases in 2020 and 2021 was compared to the average level in the same period during 2015-2019. Then, an interrupted time-series segmented regression analysis was applied to estimate the impact of NPIs on HFMD, such as social distancing, suspension of schools, community management and mask wearing. The effects across different subgroups stratified by gender, children groups and enterovirus subtype of HFMD were also examined. RESULTS: A total of 13,224 and 36,353 HFMD cases were reported in 2020 and 2021, which decreased by 80.80% and 15.06% respectively compared with the average number of cases in the same period during 2015-2019. A significant drop in the number of HFMD cases during time when strict NPIs were applied (relative change: 69.07% [95% confidence interval (CI): 68.84%-69.30%]). The HFMD incidence rebounded to historical levels in 2021 as the lockdown eased. The slightest reduction of HFMD cases was found among children at kindergartens or childcare centres among the three children groups (children at kindergartens or childcare centres: 55.50% [95% CI: 54.96%-56.03%]; children living at home: 72.64% [95% CI: 72.38%-72.89%]; others: 74.06% [95% CI: 73.19%-74.91%]). CONCLUSIONS: The strong NPIs during the COVID-19 epidemic may have a significant beneficial effect on mitigating HFMD. However, the incidence of HFMD rebounded as the NPIs became less stringent. Authorities should consider applying these NPIs during HFMD outbreaks and strengthening personal hygiene in routine prevention.

The knowledge, attitudes and practices of hand, foot, and mouth disease prevention strategies amongst parents and educators of children under 5 years amidst COVID-19 pandemic: A cross-sectional study.

Background: Hand, foot, and mouth disease (HFMD) is endemic in Singapore. Prevention efforts have been ramped up since major outbreaks in the early 2000's. This study aims to assess the current knowledge, and attitudes towards and practise (KAP) levels of HFMD prevention strategies (HFMD-PS) amongst parents and teachers of children under 5 years amidst the COVID-19 pandemic. Methods and results: A convenience sample of 240 teachers and 404 parents responded to a self-administered standardised questionnaire between mid-October and December 2020. A scoring framework was used to assess responses in the 'knowledge', 'attitude', and 'practice' domains. A multivariable analysis was adjusted for ethnicity and attitudes towards getting children to follow proper handwashing steps and regularly disinfecting children's toys amongst parents, knowledge about HFMD's infectious period, and the responses to a child turning symptomatic in the childcare centre amongst teachers. Existing levels of knowledge and attitudes of parents and teachers were not high, and only a small proportion practised high levels of prevention measures (99 parents and 28 teachers). Key facilitators for a higher practise level in parents include the following: (1) awareness of regular liquid soap's efficacy as a disinfectant, (2) toy cleaning before and after playtime, and (3) the cleaning agent used for this practise. Teachers had no significant factors associated with higher practise levels. Conclusion: This study suggested potential gaps between positive knowledge and attitudes towards prevention strategies and their actual adoption levels in homes and childcare centres during COVID-19 pandemic. These evidences suggest the importance of continuous promotion of HFMD prevention practise in homes and childcare centres, even amidst pandemics.

The transfer of maternal antibodies and dynamics of maternal and natural infection-induced antibodies against coxsackievirus A16 in Chinese children 0-13 years of age: a longitudinal cohort study.

BACKGROUND: A major hand-foot-and-mouth disease (HFMD) pathogen, coxsackievirus A16 (CVA16), has predominated in several of the last 10 years and caused the largest number of HFMD outbreaks between 2011 and 2018 in China. We evaluated the efficacy of maternal anti-CVA16 antibody transfer via the placenta and explored the dynamics of maternal and natural infection-induced neutralizing antibodies in children. METHODS: Two population-based longitudinal cohorts in southern China were studied during 2013-2018. Participants were enrolled in autumn 2013, including 2475 children aged 1-9 years old and 1066 mother-neonate pairs, and followed for 3 years. Blood/cord samples were collected for CVA16-neutralizing antibody detection. The maternal antibody transfer efficacy, age-specific seroprevalence, geometric mean titre (GMT) and immune response kinetics were estimated. RESULTS: The average maternal antibody transfer ratio was 0.88 (95% CI 0.80-0.96). Transferred maternal antibody levels declined rapidly (half-life: 2.0 months, 95% CI 1.9-2.2 months). The GMT decayed below the positive threshold (8) by 1.5 months of age. Due to natural infections, it increased above 8 after 1.4 years and reached 32 by 5 years of age, thereafter dropping slightly. Although the average duration of maternal antibody-mediated protection was < 3 months, the duration extended to 6 months on average for mothers with titres ≥ 64. CONCLUSIONS: Anti-CVA16 maternal antibodies are efficiently transferred to neonates, but their levels decline quickly. Children aged 0-5 years are the main susceptible population and should be protected by CVA16 vaccination, with the optimal vaccination time between 1.5 months and 1 year of age.