Basic Reproduction Number of Enterovirus 71 and Coxsackievirus A16 and A6: Evidence From Outbreaks of Hand, Foot, and Mouth Disease in China Between 2011 and 2018.

BACKGROUND: Enterovirus 71 (EV-A71), coxsackievirus A16 (CV-A16), and coxsackievirus A6 (CV-A6) are common serotypes causing hand, foot, and mouth disease (HFMD). Analyses on the basic reproduction number (R0) of common pathogens causing HFMD are limited and there are no related studies using field data from outbreaks in mainland China. METHODS: We estimated the pathogen-specific basic reproduction number based on laboratory-confirmed HFMD outbreaks (clusters of ≥10 HFMD cases) reported to the national surveillance system between 2011 and 2018. The reproduction numbers were calculated using a mathematical model and the cumulative cases during the initial growth periods. RESULTS: This study included 539 outbreaks, of which 198 were caused by EV-A71, 316 by CV-A16, and 25 by CV-A6. All 10 417 cases involved were children. Assuming the outbreaks occurred in closed systems and the incubation period is 5 days, the median (interquartile range [IQR]) R0 estimates of EV-A71, CV-A16, and CV-A6 were 5.06 (2.81, 10.20), 4.84 (3.00, 9.00), and 5.94 (3.27, 10.00). After adjusting for seroprevalences, the R0 (IQR) estimates for EV-A71, CV-A16 (optimistic and conservative scenarios), and CV-A6 were 12.60 (7.35, 25.40), 9.29 (6.01, 19.20), 15.50 (9.77, 30.40), and 25.80 (14.20, 43.50), respectively. We did not observe changes in the R0 of EV-A71 after vaccine licensure (P = .67). CONCLUSIONS: HFMD is highly transmissible when caused by the 3 most common serotypes. In mainland China, it primarily affects young children. Although a vaccine became available in 2016, we have not yet observed any related changes in the disease dynamics.

Assessing Asymptomatic, Presymptomatic, and Symptomatic Transmission Risk of Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: The relative contributions of asymptomatic, presymptomatic, and symptomatic transmission of severe acute respiratory syndrome coronavirus 2 have not been clearly measured, although control measures may differ in response to the risk of spread posed by different types of cases. METHODS: We collected detailed information on transmission events and symptom status based on laboratory-confirmed patient data and contact tracing data from 4 provinces and 1 municipality in China. We estimated the variation in risk of transmission over time and the severity of secondary infections by symptomatic status of the infector. RESULTS: There were 393 symptomatic index cases with 3136 close contacts and 185 asymptomatic index cases with 1078 close contacts included in the study. The secondary attack rates among close contacts of symptomatic and asymptomatic index cases were 4.1% (128 of 3136) and 1.1% (12 of 1078), respectively, corresponding to a higher transmission risk from symptomatic cases than from asymptomatic cases (odds ratio, 3.79; 95% confidence interval, 2.06-6.95). Approximately 25% (32 of 128) and 50% (6 of 12) of the infected close contacts were asymptomatic from symptomatic and asymptomatic index cases, respectively, while more than one third (38%) of the infections in the close contacts of symptomatic cases were attributable to exposure to the index cases before symptom onset. CONCLUSIONS: Asymptomatic and presymptomatic transmissions play an important role in spreading infection, although asymptomatic cases pose a lower risk of transmission than symptomatic cases. Early case detection and effective test-and-trace measures are important to reduce transmission.

Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 to Close Contacts, China, January-February 2020.

We estimated the symptomatic, PCR-confirmed secondary attack rate (SAR) for 2,382 close contacts of 476 symptomatic persons with coronavirus disease in Yichang, Hubei Province, China, identified during January 23-February 25, 2020. The SAR among all close contacts was 6.5%; among close contacts who lived with an index case-patient, the SAR was 10.8%; among close-contact spouses of index case-patients, the SAR was 15.9%. The SAR varied by close contact age, from 3.0% for those <18 years of age to 12.5% for those >60 years of age. Multilevel logistic regression showed that factors significantly associated with increased SAR were living together, being a spouse, and being >60 years of age. Multilevel regression did not support SAR differing significantly by whether the most recent contact occurred before or after the index case-patient's onset of illness (p = 0.66). The relatively high SAR for coronavirus disease suggests relatively high virus transmissibility.

Development of orthogonal T7 expression system in Klebsiella pneumoniae.

Most expression systems are tailored for model organisms rather than nonmodel organisms. However, heterologous gene expression in model organisms constrains the innate advantages of original strain carrying gene of interest. In this study, T7 expression system was developed in nonmodel bacterium Klebsiella pneumoniae for production of chemicals. First, we engineered a recombinant K. pneumoniae strain harboring two vectors. One vector was used to express T7 RNA polymerase (T7 RNAP) which would drive the expression of egfp in the other vector. This recombinant strain demonstrated 15.73-fold of fluorescence relative to wild-type K. pneumoniae and showed similar level of fluorescence to recombinant Escherichia coli overexpressing egfp. When egfp was replaced by puuC, an endogenous aldehyde dehydrogenase catalyzing 3-hydroxypropionic acid (3-HP) biosynthesis in K. pneumoniae, the recombinant strain coexpressing T7 RNAP and PuuC showed high-level PuuC expression. In shake-flask cultivation, this recombinant strain produced 1.72 g/L 3-HP in 24 hr, which was 3.24 times that of wild-type K. pneumoniae (0.53 g/L). To mitigate plasmid burden, the vector expressing T7 RNAP was eliminated, but the T7 RNAP expression cassette was integrated into K. pneumoniae genome. The resulting strain harboring only PuuC expression vector produced 2.44 g/L 3-HP in 24 hr under shake-flask conditions, which was 1.46 times that of the strain harboring both T7 RNAP and PuuC expression vectors. In bioreactor cultivation, this strain generated 67.59 g/L 3-HP and did not show significantly halted growth. Overall, these results indicate that the engineered T7 expression system functioned efficiently in K. pneumoniae. This study provides a paradigm for the development of T7 expression system in prokaryotes.

Impact of the coronavirus disease 2019 interventions on the incidence of hand, foot, and mouth disease in mainland China.

BACKGROUND: In early 2020, non-pharmaceutical interventions (NPIs) were implemented in China to reduce and contain the coronavirus disease 2019 (COVID-19) transmission. These NPIs might have also reduced the incidence of hand, foot, and mouth disease (HFMD). METHODS: The weekly numbers of HFMD cases and meteorological factors in 31 provincial capital cities and municipalities in mainland China were obtained from Chinese Center for Disease Control and Prevention (CCDC) and National Meteorological Information Center of China from 2016 to 2020. The NPI data were collected from local CDCs. The incidence rate ratios (IRRs) were calculated for the entire year of 2020, and for January-July 2020 and August-December 2020. The expected case numbers were estimated using seasonal autoregressive integrated moving average models. The relationships between kindergarten closures and incidence of HFMD were quantified using a generalized additive model. The estimated associations from all cities were pooled using a multivariate meta-regression model. FINDINGS: Stringent NPIs were widely implemented for COVID-19 control from January to July 2020, and the IRRs for HFMD were less than 1 in all 31 cities, and less than 0·1 for 23 cities. Overall, the proportion of HFMD cases reduced by 52·9% (95% CI: 49·3-55·5%) after the implementation of kindergarten closures in 2020, and this effect was generally consistent across subgroups. INTERPRETATION: The decrease in HFMD incidence was strongly associated with the NPIs for COVID-19. HFMD epidemic peaks were either absent or delayed, and the final epidemic size was reduced. Kindergarten closure is an intervention to prevent HFMD outbreaks. FUNDING: This research was supported by the National Natural Science Foundation of China (81973102 & 81773487), Public Health Talents Training Program of Shanghai Municipality (GWV-10.2-XD21), the Shanghai New Three-year Action Plan for Public Health (GWV-10.1-XK16), the Major Project of Scientific and Technical Winter Olympics from National Key Research and Development Program of China (2021YFF0306000), 13th Five-Year National Science and Technology Major Project for Infectious Diseases (2018ZX10725-509) and Key projects of the PLA logistics Scientific research Program (BHJ17J013).

Changing epidemiology of hand, foot, and mouth disease in China, 2013-2019: a population-based study.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is an important public health problem. A monovalent EV-A71 vaccine was launched in China in 2016. Previous studies showed that inactivated monovalent EV-A71 vaccines were highly efficient against HFMD associated with EV-A71 but not against HFMD with other etiologies, leading to a hypothesis that the introduction of EV-A71 vaccines might change the pathogen spectrum and epidemiological trend of HFMD. In this study, we described for the first time the changing epidemiological characteristics of HFMD after the launch of the EV-A71 vaccine. METHODS: We extracted individual-based epidemiological data on HFMD cases reported to the Chinese Center for Disease Control and Prevention between January 2013 and December 2019. We described the changing epidemiological characteristics of HFMD before and after vaccine launch according to the distribution of diseases characteristics (demographic, temporal, and geographical) and evaluated the potential changes in risk factors of severe patients. All analyses were stratified by the phase before and after vaccine launch, and by enterovirus serotype. FINDINGS: During 2013-2019, 15,316,710 probable cases of HFMD were reported. Of these, 787,197 (5·1%) were laboratory confirmed and 76,982 (0·5%) were severe. After the launch of the EV-A71 vaccine, the median age of HFMD patients infected with EV-A71 increased from 2·24 years (IQR:1·43, 3·56) to 2·81 years (IQR:1·58, 4·01). The proportion of patients less than 3 years of age decreased while the proportion of patients 3-5 years of age increased. There was a large decrease (60·7%) in the proportion of severe cases as well as a decline (28·3%) in HFMD patients infected with EV-A71. After the launch of the EV-A71 vaccine, the severe illness rate and mortality rate of HFMD patients in all age groups has decreased sharply, 62·20% and 83·78% respectively. The timing of the HFMD epidemic peak was delayed (1-2 months) . After the launch of EV-A71 vaccine, the risk of becoming a severe case for EV-A71 serotype was decreased, whereas that risk was instead increased for CV-A16 (from 0·17 (95% CI:0·16, 0·18) to 0·23 (95% CI:0·21, 0·25)) and other enterovirus compared to EV-A71 (from 0·38 (95% CI:0·37, 0·39) to 0·58 (95% CI:0·56, 0·61)). The longer the time from onset to diagnosis, the higher was the risk of being a severe case, but the effect size was decreased. INTERPRETATION: The introduction of the EV-A71 vaccine has effectively reduced the proportion of severe HFMD cases and mortality, but changes to the dominant serotypes should be closely monitored. Development of multivalent vaccines to avoid an increased case burden due to other enteroviruses is greatly needed. FUNDING: This research was supported by the National Natural Science Foundation of China (81973102, 81773487), Public Health Talents Training Program of Shanghai Municipality (GWV-10.2-XD21), the 5th Three-year Action Program of Shanghai Municipality for Strengthening the Construction of Public Health System (GWV-10.1-XK05), the Major Project of Scientific and Technical Winter Olympics from National Key Research and Development Program of China (2021YFF0306000), 13th Five-Year National Science and Technology Major Project for Infectious Diseases (2018ZX10725-509) and Key projects of the PLA logistics Scientific research Program (BHJ17J013).

Influenza Vaccine Effectiveness in Mainland China: A Systematic Review and Meta-Analysis.

Influenza endangers human health but can be prevented in part by vaccination. Assessing influenza vaccine effectiveness (VE) provides scientific evidence for developing influenza vaccination policy. We conducted a systematic review and meta-analysis of studies that evaluated influenza VE in mainland China. We searched six relevant databases as of 30 August 2019 to identify studies and used Review Manager 5.3 software to analyze the included studies. The Newcastle-Ottawa scale was used to assess the risk of publication bias. We identified 1408 publications, and after removing duplicates and screening full texts, we included 21 studies in the analyses. Studies were conducted in Beijing, Guangzhou, Suzhou, and Zhejiang province from the 2010/11 influenza season through the 2017/18 influenza season. Overall influenza VE for laboratory confirmed influenza was 36% (95% CI: 25-46%). In the subgroup analysis, VE was 45% (95% CI: 18-64%) for children 6-35 months who received one dose of influenza vaccine, and 57% (95% CI: 50-64%) who received two doses. VE was 47% (95% CI: 39-54%) for children 6 months to 8 years, and 18% (95% CI: 0-33%) for adults ≥60 years. For inpatients, VE was 21% (95% CI: -11-44%). We conclude that influenza vaccines that were used in mainland China had a moderate effectiveness, with VE being higher among children than the elderly. Influenza VE should be continuously monitored in mainland China to provide evidence for policy making and improving uptake of the influenza vaccine.

Evidence for pre-symptomatic transmission of coronavirus disease 2019 (COVID-19) in China.

BACKGROUND: Between mid-January and early February, provinces of mainland China outside the epicentre in Hubei province were on high alert for importations and transmission of COVID-19. Many properties of COVID-19 infection and transmission were still not yet established. METHODS: We collated and analysed data on 449 of the earliest COVID-19 cases detected outside Hubei province to make inferences about transmission dynamics and severity of infection. We analysed 64 clusters to make inferences on serial interval and potential role of pre-symptomatic transmission. RESULTS: We estimated an epidemic doubling time of 5.3 days (95% confidence interval (CI): 4.3, 6.7) and a median incubation period of 4.6 days (95% CI: 4.0, 5.2). We estimated a serial interval distribution with mean 5.7 days (95% CI: 4.7, 6.8) and standard deviation 3.5 days, and effective reproductive number was 1.98 (95% CI: 1.68, 2.35). We estimated that 32/80 (40%) of transmission events were likely to have occurred prior to symptoms onset in primary cases. Secondary cases in clusters had less severe illness on average than cluster primary cases. CONCLUSIONS: The majority of transmissions are occurring around illness onset in an infected person, and pre-symptomatic transmission does play a role. Detection of milder infections among the secondary cases may be more reflective of true disease severity.

Pathogen Spectrum of Hand, Foot, and Mouth Disease Based on Laboratory Surveillance - China, 2018.

WHAT IS ALREADY KNOWN ABOUT THIS TOPIC?: Enterovirus 71 (EV-A71) is the main causative pathogen for severe and fatal patients with Hand, Foot, and Mouth Disease (HFMD) in mainland China from 2008 to 2017. Non-EV-A71 and non-CV-A16 (other enterovirus) serotypes were the major causative-serotypes for mild HFMD in years of 2013, 2015, and 2017. WHAT IS ADDED BY THIS REPORT?: In 2018, other enterovirus serotypes replaced EV-A71 for the first time as the major cause of severe HFMD with a proportion of 70.7%. However, at the national level, only a small proportion of the other enterovirus serotypes were further identified as CV-A6 and CV-A10. WHAT ARE THE LIMITATIONS FOR PUBLIC HEALTH PRACTICE?: Further identification of other enterovirus serotypes is highly recommended for provincial CDCs, especially for severe HFMD. Studies contributing to a multivalent vaccine for HFMD should be prioritized.