Search

Hand, foot, and mouth disease (HFMD), which is mainly caused by coxsackievirus A16 (CVA16) or enterovirus A71 (EV-A71), poses a serious threat to children’s health. However, the long-term dynamics of the neutralizing Ab (NAb) response and ideal paired-serum sampling time for serological diagnosis of CVA16-infected HFMD patients were unclear. In this study, 336 CVA16 and 253 EV-A71 PCR-positive HFMD inpatients were enrolled and provided 452 and 495 sera, respectively, for NAb detection. Random-intercept modeling with B-spline was conducted to characterize NAb response kinetics. The NAb titer of CVA16 infection patients was estimated to increase from negative (2.1, 95% confidence interval [CI]: 1.4–3.3) on the day of onset to a peak of 304.8 (95% CI: 233.4–398.3) on day 21 and then remained >64 until 26 mo after onset. However, the NAb response level of EV-A71–infected HFMD patients was much higher than that of CVA16-infected HFMD patients throughout. The geometric mean titer was significantly higher in severe EV-A71–infected patients than in mild patients, with a 2.0-fold (95% CI: 1.4–3.2) increase. When a 4-fold rise in titer was used as the criterion for serological diagnosis of CVA16 and EV-A71 infection, acute-phase serum needs to be collected at 0–5 d, and the corresponding convalescent serum should be respectively collected at 17.4 (95% CI: 9.6–27.4) and 24.4 d (95% CI: 15.3–38.3) after onset, respectively. In conclusion, both CVA16 and EV-A71 infection induce a persistent humoral immune response but have different NAb response levels and paired-serum sampling times for serological diagnosis. Clinical severity can affect the anti–EV-A71 NAb response.

Osteosarcoma is characterized by diverse genetic mutations, including single-nucleotide variants (SNVs), which can complicate clinical outcomes of the treatment. This study identified key mutations or polymorphisms in genes that correlate with osteosarcoma prognoses. A total of 110 patients with osteosarcoma were assigned to "good" or "poor" cohorts depending on their 5-year disease-free survival (DFS) after surgery and chemotherapeutic treatment. We performed next-generation sequencing analysis of tumor tissues for prognosis-associated SNVs in 315 tumorigenesis-related genes, followed by modeling of clinical outcomes for these patients using random forest classification via a support vector machine (SVM). Data from the Chinese Millionome Database were used to compare SNV frequency in osteosarcoma patients and healthy people. SVM screening identified 17 nonsynonymous SNVs located in 15 genes, of which rs17224367 and rs3733406 (located in MSH2 and FAT1, respectively) were strongly correlated with osteosarcoma prognosis. These results were verified in a 26-patient validation cohort, confirming that these SNVs could be used to predict prognosis. These results demonstrated that two SNVs located in MSH2 and FAT1 are associated with prognosis of osteosarcoma patients. © 2022 American Society for Bone and Mineral Research (ASBMR).

Dynamically adapting the allocation of COVID-19 vaccines to the evolving epidemiological situation could be key to reduce COVID-19 burden. Here we developed a data-driven mechanistic model of SARS-CoV-2 transmission to explore optimal vaccine prioritization strategies in China. We found that a time-varying vaccination program (i.e., allocating vaccines to different target groups as the epidemic evolves) can be highly beneficial as it is capable of simultaneously achieving different objectives (e.g., minimizing the number of deaths and of infections). Our findings suggest that boosting the vaccination capacity up to 2.5 million first doses per day (0.17% rollout speed) or higher could greatly reduce COVID-19 burden, should a new wave start to unfold in China with reproduction number ≤1.5. The highest priority categories are consistent under a broad range of assumptions. Finally, a high vaccination capacity in the early phase of the vaccination campaign is key to achieve large gains of strategic prioritizations., In the context of limited supply, strategies for optimising allocation of COVID-19 vaccines are needed. Here, the authors explore time-varying strategies that adapt to the epidemiological situation and simultaneously optimise for multiple objectives including reducing numbers of infections, hospitalisations, and deaths.

COVID-19 vaccination is being conducted in over 200 countries and regions to control SARS-CoV-2 transmission and return to a pre-pandemic lifestyle. However, understanding when non-pharmaceutical interventions (NPIs) can be lifted as immunity builds up remains a key question for policy makers. To address this, we built a data-driven model of SARS-CoV-2 transmission for China. We estimated that, to prevent the escalation of local outbreaks to widespread epidemics, stringent NPIs need to remain in place at least one year after the start of vaccination. Should NPIs alone be capable of keeping the reproduction number (Rt) around 1.3, the synergetic effect of NPIs and vaccination could reduce the COVID-19 burden by up to 99% and bring Rt below the epidemic threshold in about 9 months. Maintaining strict NPIs throughout 2021 is of paramount importance to reduce COVID-19 burden while vaccines are distributed to the population, especially in large populations with little natural immunity., Using data-driven epidemiological modelling, Yu et al. estimate that, even with increasing vaccine availability, China will have to maintain stringent non-pharmaceutical interventions for at least a year to prevent new widespread outbreaks of COVID-19.

SummaryBackgroundAn outbreak of COVID-19 caused by the SARS-CoV-2 Omicron BA.2 sublineage occurred in Shanghai, China from February to June 2022. The government organized multiple rounds of molecular test screenings for the entire population, providing a unique opportunity to capture the majority of subclinical infections and better characterize disease burden and the full spectrum of Omicron BA.2 clinical severity.MethodsUsing daily reports from the websites of the Shanghai Municipal Health Commission, we estimated the incidence of infections, severe/critical infections, and deaths to assess the disease burden. By adjusting for right censoring and Reverse Transcription-Polymerase Chain Reaction (RT□PCR) sensitivity, we provide estimates of clinical severity, including the infection fatality risk, symptomatic case fatality risk, and risk of developing severe/critical disease upon infection.FindingsFrom February 26 to June 30, 2022, the overall infection rate, severe/critical infection rate, and mortality rate were 2.74 (95% CI: 2.73-2.74) per 100 individuals, 6.34 (95% CI: 6.02-6.66) per 100,000 individuals and 2.42 (95% CI: 2.23-2.62) per 100,000 individuals, respectively. The severe/critical infection rate and mortality rate increased with age with the highest rates of 125.29 (95% CI: 117.05-133.44) per 100,000 and 57.17 (95% CI: 51.63-62.71) per 100,000 individuals, respectively, noted in individuals aged 80 years or older. The overall fatality risk and risk of developing severe/critical disease upon infection were 0.09% (95% CI: 0.08-0.10%) and 0.23% (95% CI: 0.20-0.25%), respectively. Having received at least one vaccine dose led to a 10-fold reduction in the risk of death for infected individuals aged 80 years or older.InterpretationUnder the repeated population-based screenings and strict intervention policies implemented in Shanghai, our results found a lower disease burden and mortality of the outbreak compared to other settings and countries, showing the impact of the successful outbreak containment in Shanghai. The estimated low clinical severity of this Omicron BA.2 epidemic in Shanghai highlight the key contribution of vaccination and availability of hospital beds to reduce the risk of death.FundingKey Program of the National Natural Science Foundation of China (82130093).Research in contextEvidence before this studyWe searched PubMed and Europe PMC for manuscripts published or posted on preprint servers after January 1, 2022 using the following query: (“SARS-CoV-2 Omicron”) AND (“burden” OR “severity”). No studies that characterized the whole profile of disease burden and clinical severity during the Shanghai Omicron outbreak were found. One study estimated confirmed case fatality risk between different COVID-19 waves in Hong Kong; other outcomes, such as fatality risk and risk of developing severe/critical illness upon infection, were not estimated. One study based on 21 hospitals across the United States focused on Omicron-specific in-hospital mortality based on a limited sample of inpatients (565). In southern California, United States, a study recruited more than 200 thousand Omicron-infected individuals and estimated the 30-day risk of hospital admission, intensive care unit admission, mechanical ventilation, and death. None of these studies estimated infection and mortality rates or other indictors associated with disease burden. Overall, the disease burden and clinical severity of the Omicron BA.2 variant have not been fully characterized, especially in populations predominantly immunized with inactivated vaccines.Added value of this studyThe large-scale and multiround molecular test screenings conducted on the entire population during the Omicron BA.2 outbreak in Shanghai, leading to a high infection ascertainment ratio, provide a unique opportunity to capture the majority of subclinical infections. As such, our study provides a comprehensive assessment of both the disease burden and clinical severity of the SARS-CoV-2 Omicron BA.2 sublineage, which are especially lacking for populations predominantly immunized with inactivated vaccines.Implications of all the available evidenceWe estimated the disease burden and clinical severity of the Omicron BA.2 outbreak in Shanghai in February-June 2022. These estimates are key to properly interpreting field evidence and assessing the actual spread of Omicron in other settings. Our results also provide support for the importance of strategies to prevent overwhelming the health care system and increasing vaccine coverage to reduce mortality.

Several mechanisms driving SARS-CoV-2 transmission remain unclear. Based on individual records of 1178 potential SARS-CoV-2 infectors and their 15,648 contacts in Hunan, China, we estimated key transmission parameters. The mean generation time was estimated to be 5.7 (median: 5.5, IQR: 4.5, 6.8) days, with infectiousness peaking 1.8 days before symptom onset, with 95% of transmission events occurring between 8.8 days before and 9.5 days after symptom onset. Most transmission events occurred during the pre-symptomatic phase (59.2%). SARS-CoV-2 susceptibility to infection increases with age, while transmissibility is not significantly different between age groups and between symptomatic and asymptomatic individuals. Contacts in households and exposure to first-generation cases are associated with higher odds of transmission. Our findings support the hypothesis that children can effectively transmit SARS-CoV-2 and highlight how pre-symptomatic and asymptomatic transmission can hinder control efforts., Detailed knowledge of COVID-19 epidemiology is needed to inform public health responses. Here, the authors use large-scale contact tracing data to provide empirical estimates of key parameters, and show that susceptibility increases with age but transmissibility does not vary significantly.

Summary Background Since 1997, epidemics of hand, foot, and mouth disease associated with enterovirus A71 (EV-A71) have affected children younger than 5 years in the Asia-Pacific region, including mainland China. EV-A71 vaccines have been licensed for use in children aged 6–71 months in China, but not for infants younger than 6 months. We aimed to assess the dynamics of maternal EV-A71 antibodies to inform choice of potential vaccination strategies to protect infants younger than 6 months, because they have a substantial burden of disease. Methods We did a longitudinal cohort study with mother–neonate pairs in local hospitals in southern China during 2013–18. We collected cord blood from neonates and venous blood from mothers at delivery. We followed up and collected blood samples from the children at ages 2, 4, 6, 12, 24, and 36 months and tested for the presence of neutralising antibodies against EV-A71 with virus neutralisation assays. Seropositivity, or protective titre, was defined as a neutralisation antibody titre of 16 or higher. We estimated the seroprevalence, geometric mean titre (GMT), and transfer ratio of maternal antibodies. We used a binomial distribution to derive the 95% CIs of seroprevalence. Seropositivity between mothers and neonates was compared by use of an agreement (κ), while GMTs were compared by use of paired Student's t tests. Findings Between Sept 20, 2013, and Oct 14, 2015, 1054 mothers with 1066 neonates were enrolled. The EV-A71 GMT was similar among pairs of neonates (22·7, 95% CI 20·8–24·9) and mothers (22·1, 95% CI 20·2–24·1; p=0·20). The mean transfer ratio of maternal antibodies was 1·03 (95% CI 0·98–1·08). Although 705 (66%) of 1066 neonates acquired protective concentrations of EV-A71 antibodies from mothers, these declined rapidly, with a half-life of 42 days (95% CI 40–44). The time to loss of protective immunity was extended to 5 months in neonates with mothers who had titres of 128 or higher. By age 30 months, 28% of children had become seropositive because of natural infection. Interpretation EV-A71 maternal antibodies were efficiently transferred to neonates, but declined quickly to below the protective threshold, particularly among those whose mothers had low antibody titres. Our findings suggest that maternal vaccination could be explored to provide neonatal protection against EV-A71 through maternal antibodies. Catch-up vaccination between ages 6 months to 5 years could provide protection to the approximately 30–90% of children that have not had natural EV-A71 infection by that age. Funding National Science Fund for Distinguished Young Scholars, National Natural Science Foundation of China.

Background The SARS-CoV-2 containment strategy has been successful in mainland China prior to the emergence of Omicron. However, in the era of highly transmissible variants, whether it is possible for China to sustain a local containment policy and under what conditions China could transition away from it are of paramount importance at the current stage of the pandemic. Methods We developed a spatially structured, fully stochastic, individual-based SARS-CoV-2 transmission model to evaluate the feasibility of sustaining SARS-CoV-2 local containment in mainland China considering the Omicron variants, China’s current immunization level, and nonpharmaceutical interventions (NPIs). We also built a statistical model to estimate the overall disease burden under various hypothetical mitigation scenarios. Results We found that due to high transmissibility, neither Omicron BA.1 nor BA.2 could be contained by China’s pre-Omicron NPI strategies which were successful prior to the emergence of the Omicron variants. However, increased intervention intensity, such as enhanced population mobility restrictions and multi-round mass testing, could lead to containment success. We estimated that an acute Omicron epidemic wave in mainland China would result in significant number of deaths if China were to reopen under current vaccine coverage with no antiviral uptake, while increasing vaccination coverage and antiviral uptake could substantially reduce the disease burden. Conclusions As China’s current vaccination has yet to reach high coverage in older populations, NPIs remain essential tools to maintain low levels of infection while building up protective population immunity, ensuring a smooth transition out of the pandemic phase while minimizing the overall disease burden.

Enteroviruses (EVs) species A are a major public health issue in the Asia–Pacific region and cause frequent epidemics of hand, foot and mouth disease (HFMD) in China. Mild infections are common in children; however, HFMD can also cause severe illness that affects the central nervous system. To molecularly characterize EVs, a prospective HFMD virological surveillance program was performed in China between 2013 and 2016. Throat swabs, rectal swabs and stool samples were collected from suspected HFMD patients at participating hospitals. EVs were detected using generic real-time and nested reverse transcription-polymerase chain reactions (RT-PCRs). Then, the complete VP1 regions of enterovirus A71 (EV-A71), coxsackievirus A16 (CVA16) and CVA6 were sequenced to analyze amino acid changes and construct a viral molecular phylogeny. Of the 2836 enrolled HFMD patients, 2,517 (89%) were EV positive. The most frequently detected EVs were CVA16 (32.5%, 819), CVA6 (31.2%, 785), and EV-A71 (20.4%, 514). The subgenogroups CVA16_B1b, CVA6_D3a and EV-A71_C4a were predominant in China and recombination was not observed in the VP1 region. Sequence analysis revealed amino acid variations at the 30, 29 and 44 positions in the VP1 region of EV-A71, CVA16 and CVA6 (compared to the respective prototype strains BrCr, G10 and Gdula), respectively. Furthermore, in 21 of 24 (87.5%) identified EV-A71 samples, a known amino acid substitution (D31N) that may enhance neurovirulence was detected. Our study provides insights about the genetic characteristics of common HFMD-associated EVs. However, the emergence and virulence of the described mutations require further investigation. Electronic supplementary material The online version of this article (10.1007/s12250-020-00266-7) contains supplementary material, which is available to authorized users.

Background China is facing substantial risks of imported coronavirus disease 2019 (COVID-19) cases and a domestic resurgence in the long run, and COVID-19 vaccination is expected to be the long-lasting solution to end the pandemic. We aim to estimate the size of the target population for COVID-19 vaccination at the provincial level in the mainland of China, and summarize the current progress of vaccination programs, which could support local governments in the timely determination and adjustment of vaccination policies and promotional measures. Methods We conducted a descriptive study of the entire population in the mainland of China, between December 2020 and August 2021. By extracting provincial-stratified data from publicly available sources, we estimated the size of priority target groups for vaccination programs, and further characterized the ongoing vaccination program at the provincial level, including the total doses administered, the coverage rate, and the vaccination capacity needed to achieve the target coverage of 80% by the end of 2021. We used R (version 4.1.0) to complete the descriptive statistics. Results The size of the target population shows large differences among provinces, ranging from 3.4 million to 108.4 million. As of 31 August, 2021, the speed of vaccine roll-out differs considerably as well, with the highest coverage occurring in Beijing and Shanghai, where 88.5% and 79.1% of the population has been fully vaccinated, respectively. In 22 of 31 provincial-level administrative divisions (PLADs), more than 70% of the population was administered at least one dose by August. With the current vaccination capacity, the target of 80% coverage could be achieved by 2021 in 28 PLADs. Conclusions Disparities exist in the target population size and vaccination progress across provinces in the mainland of China. China has made great strides in the vaccination speed since roll-out, and could basically achieve the targeted vaccine coverage. Graphic Abstract

Background China experiences large variations in influenza seasonal activity. We aim to update and improve the current understanding of regional-based within-year variations of influenza activity across mainland China to provide evidence for the planning and optimisation of healthcare strategies. Methods We conducted a systematic review and spatio-temporal meta-analysis to assess regional-based within-year variations of ILI outpatient consultation rates, influenza test positivity rates amongst both ILI outpatients and SARI inpatients, and influenza-associated excess mortality rates. We searched English and Chinese databases for articles reporting time-series data on the four influenza-related outcomes at the sub-national and sub-annual level. After synthesising the data, we reported on the mean monthly rate, epidemic onset, duration, peak and intensity. Results We included 247 (7.7%) eligible studies in the analysis. We found within-year influenza patterns to vary across mainland China in relation to latitude and geographic location. High-latitude provinces were characterised by having short and intense annual winter epidemics, whilst most mid-latitude and low-latitude provinces experience semi-annual epidemics or year-round activity. Subtype activity varied across the country, with A/H1N1pdm09 and influenza B occurring predominantly in the winter, whereas A/H3N2 activity exhibited a latitudinal divide with high-latitude regions experiencing a winter peak, whilst mid and low-latitude regions experienced a summer epidemic. Epidemic onsets and peaks also varied, occurring first in the north and later in the southeast. We found positive associations between all influenza health outcomes. In addition, seasonal patterns at the prefecture and county-level broadly resembled their wider province. Conclusions This is the first systematic review to simultaneously examine the seasonal variation of multiple influenza-related health outcomes at multiple spatial scales across mainland China. The seasonality information provided here has important implications for the planning and optimisation of immunisation programmes and healthcare provision, supporting the need for regional-based approaches to address variations in local epidemiology.

Understanding the spatial interactions of human mobility is crucial for urban planning, traffic engineering, as well as for the prevention and control of infectious diseases. Although many models have been developed to model human mobility, it is not clear whether such models could also capture the traveling mechanisms across different time periods (e.g. workdays, weekends or holidays). With one-year long nationwide location-based service (LBS) data in China, we investigate the spatiotemporal characteristics of population movements during different time periods, and make thorough comparisons for the applicability of five state-of-the-art human mobility models. We find that population flows show significant periodicity and strong inequality across temporal and spatial distribution. A strong “backflow” effect is found for cross-city movements before and after holidays. Parameter fitting of gravity models reveals that travels in different type of days consider the attractiveness of destinations and cost of distance differently. Surprisingly, the comparison indicates that the parameter-free opportunity priority selection (OPS) model outperforms other models and is the best to characterize human mobility in China across all six different types of days. However, there is still an urgent need for development of more dedicated models for human mobility on weekends and different types of holidays.

BackgroundTo allow a return to a pre-COVID-19 lifestyle, virtually every country has initiated a vaccination program to mitigate severe disease burden and control transmission. However, it remains to be seen whether herd immunity will be within reach of these programs.MethodsWe developed a data-driven model of SARS-CoV-2 transmission for China, a population with low prior immunity from natural infection. The model is calibrated considering COVID-19 natural history and the estimated transmissibility of the Delta variant. Three vaccination programs are tested, including the one currently enacted in China and model-based estimates of the herd immunity level are provided.ResultsWe found that it is unlike to reach herd immunity for the Delta variant given the relatively low efficacy of the vaccines used in China throughout 2021, the exclusion of underage individuals from the targeted population, and the lack of prior natural immunity. We estimate that, assuming a vaccine efficacy of 90% against the infection, vaccine-induced herd immunity would require a coverage of 93% or higher of the Chinese population. However, even when vaccine-induced herd immunity is not reached, we estimated that vaccination programs can reduce SARS-CoV-2 infections by 53-58% in case of an epidemic starts to unfold in the fall of 2021.ConclusionsEfforts should be taken to increase population’s confidence and willingness to be vaccinated and to guarantee highly efficacious vaccines for a wider age range.

Introduction: China is facing substantial risks of imported COVID-19 cases and a domestic resurgence in the long run, and COVID-19 vaccination is expected to be the long-lasting solution to end the pandemic. We aim to estimate the size of the target population for COVID-19 vaccination at the provincial level and summarize the current progress of vaccination programs, which could support local governments in the timely determination and adjustment of vaccination policies and promotional measures.Methods: By extracting provincial-stratified data from publicly available sources, we estimated the size of priority target groups for vaccination programs and further characterized the ongoing COVID-19 vaccination program at the provincial level, including the total doses administered, the coverage rate, and the vaccination capacity needed to achieve the target coverage of 70%.Results: The size of the target population shows large differences among provinces, ranging from 3.5 million to 115.2 million. As of June 10, the speed of vaccine roll-out differs remarkably as well, with the highest coverage occurring in Beijing and Shanghai, where 69.8% and 62.3% of the population is fully vaccinated, respectively. However, in 19 of 31 provinces, less than 40% of the population was administered at least one dose, in 9 of which the proportion was even less than 30%. Compared to the routine vaccination capacity before the COVID-19 pandemic, the COVID-19 vaccination capacity has greatly improved. Nevertheless, the current vaccination capacity is far lower than the target of 70% coverage by the end of 2021 or by mid-2022 in approximately 5%-20% of provinces, particularly the Guizhou, Yunnan, Xinjiang, Fujian and Hebei provinces.Conclusions: Large disparities exist in the target population size and vaccination progress across provinces in China. Vaccine coverage is far from meeting the herd immunity threshold, and the vaccination service capacity needs to be further improved.

Summary Background Inactivated monovalent enterovirus A71 (EV-A71) vaccines are now available in China to reduce the substantial public health burden of hand, foot, and mouth disease. However, post-licensure monitoring of vaccine effectiveness is important. We did an observational test-negative study of EV-A71 vaccine effectiveness. Methods Children with hand, foot, and mouth disease who were admitted to Henan Children's Hospital (Zhengzhou, China) within 7 days of illness onset were invited to participate in this test-negative case-control study. Participant vaccination history with EV-A71, including the number of doses received and the date of each dose of vaccination, was elicited from parents or legal guardians of participants with a standardised questionnaire. Children must have received two doses before hospitalisation to be counted as fully vaccinated. Patients who had received a single dose before hospitalisation were classified as partly vaccinated. Children who had received no EV-A71 vaccine before hospitalisation were classified as unvaccinated. Throat swabs and stool samples collected from patients were tested by RT-PCR to identify EV-A71 and other enteroviruses. The primary outcome of the study was paediatric hand, foot, and mouth disease associated with EV-A71 requiring hospitalisation. We estimated vaccine effectiveness with conditional logistic regression models adjusted for potential confounders. Findings Between Feb 15, 2017, and Feb 15, 2018, we enrolled 1803 children aged 6–71 months with hand, foot, and mouth disease. 234 (13%) children tested positive for EV-A71, 1529 (85%) tested positive for other enteroviruses—528 (29%) were positive for Coxsackievirus (CV)-A6 and 342 (19%) were positive for CV-A16—and 29 (2%) tested negative for all enteroviruses. 11 (1%) children with neither throat swab nor stool testing results were excluded from further analyses. Overall vaccine effectiveness was estimated to be 85·4% (95% CI 53·2 to 95·4) for fully vaccinated children and 63·1% (13·1 to 84·3) for partly vaccinated children. The vaccine effectiveness for full vaccination was estimated to be 91·1% (35·1 to 98·8) among non-severe cases compared with 73·3% (−32·6 to 94·6) in severe cases. The vaccine effectiveness for partial vaccination was 77·9% (4·3 to 94·9) in children aged 24–71 months and 40·8% (−71·1 to 79·5) in children aged 6–23 months. We found no significant association between full or partial vaccination and CV-A6 or CV-A16-related hand, foot, and mouth disease. Interpretation EV-A71 vaccination was effective in preventing non-severe hand, foot, and mouth disease associated with EV-A71 virus infection in children aged 6–71 months, and we found evidence that one dose of vaccination provided partial protection for children aged 24–71 months. Introduction of multivalent vaccines could further reduce the burden of hand, foot, and mouth disease. Funding The National Science Fund for Distinguished Young Scholars.

Objectives Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) were responsible for 43.3% (235 123/543 243) and 24.8% (134 607/543 243) of all laboratory-confirmed hand, foot and mouth disease (HFMD) cases during 2010–2015 in China. Three monovalent EV71 vaccines have been licensed in China while bivalent EV71/CA16 vaccines are under development. A comparative cost-effectiveness analysis of bivalent EV71/CA16 versus monovalent EV71 vaccination would be useful for informing the additional value of bivalent HFMD vaccines in China. Methods We used a static model parameterized with the national HFMD surveillance data during 2010–2013, virological HFMD surveillance records from all 31 provinces in mainland China during 2010–2013 and caregiver survey data of costs and health quality of life during 2012–2013. We estimated the threshold vaccine cost (TVC), defined as the maximum additional cost that could be paid for a cost-effective bivalent EV71/CA16 vaccine over a monovalent EV71 vaccine, as the outcome. The base case analysis was performed from a societal perspective. Several sensitivity analyses were conducted by varying assumptions governing HFMD risk, costs, discounting and vaccine efficacy. Results In the base case, choosing the bivalent EV71/CA16 over monovalent EV71 vaccination would be cost-effective only if the additional cost of the bivalent EV71/CA16 compared with the monovalent EV71 vaccine is less than €4.7 (95% CI 4.2–5.2). Compared with the TVC in the base case, TVC increased by up to €8.9 if all the test-negative cases were CA16-HFMD; decreased by €1.1 with an annual discount rate of 6% and exclusion of the productivity loss; and increased by €0.14 and €0.3 with every 1% increase in bivalent vaccine efficacy against CA16-HFMD and differential vaccine efficacy against EV71-HFMD, respectively. Conclusions Bivalent EV71/CA16 vaccines can be cost-effective compared with monovalent EV71 vaccines, if suitably priced. Our study provides further evidence for determining the optimal use of HFMD vaccines in routine paediatric vaccination programme in China.

Objective This study aimed to explore distance to highway and factory density related to lung cancer (LC) death and their spatial heterogeneity in effect. Methods We conducted a retrospective cohort study by using the data of registered LC patients in Jiading District from 2002 to 2012. Standard parametric model with weibull distribution was used to explore factors related to LC death and the spatial effect of environmental factors were detected by using spatial survival analysis. Results Shorter distance to highway (aOR = 1.15, 95% CI:1.03–1.30) and higher factory density (aOR = 1.20, 95% CI:1.05–1.37) were significantly associated with increased risks of LC death, and the associations showed spatial differences in northern and southern areas of Jiading District, respectively. High-risk areas were mainly distributed in the suburbs with a low population density, while low-risk areas were primarily located in the urban areas. Conclusion Traffic and factory-related pollution was significantly associated with increased risk of LC death with an obvious spatial heterogeneity.

Hand, foot and mouth disease (HFMD) is a common infectious disease in western Asia area and the full range of the long-term sequelae of HFMD remains poorly described. We conducted a retrospective hospital-based cohort study of HFMD patients with central nervous system (CNS) complications caused by EV-A71 or CV-A16 between 2010 and 2016. Patients were classified into three groups, including CNS only, autonomic nervous system (ANS) dysregulation, and cardiorespiratory failure. Neurologic examination, neurodevelopmental assessments, Magnetic Resonance Imaging (MRI) and lung function, were performed at follow up. Of the 176 patients followed up, 24 suffered CNS only, 133 ANS dysregulation, and 19 cardiorespiratory failure. Median follow-up period was 4.3 years (range [1.4-8.3]). The rate of neurological abnormalities was 25% (43 of 171) at discharge and 10% (17 of 171) at follow-up. The rates of poor outcome were significantly different between the three groups of complications in motor (28%, 38%, 71%) domain (p=0.020), but not for cognitive (20%, 24%, 35%), language (25%, 36%, 41%) and adaptive (24%, 16%, 26%) domains (p = 0.537, p = 0.551, p = 0.403). For children with ventilated during hospitalization, 41% patients (14 of 34) had an obstructive ventilatory defect, and one patient with scoliosis had mixed ventilatory dysfunction. Persistent abnormalities on brain MRI were 0% (0 of 7), 9% (2 of 23) and 57% (4 of 7) in CNS, ANS and cardiorespiratory failure group separately. Patients with HFMD may have abnormalities in neurological, motor, language, cognition, adaptive behaviour and respiratory function. Long-term follow-up programmes for children's neurodevelopmental and respiratory function may be warranted.

Access to vaccination information could influence public attitudes towards vaccination. This study investigated the number and types of vaccination-related information sources, and estimated their associations with vaccine confidence and hesitancy in China. In January 2019, we conducted a cross-sectional survey in China, and 2122 caregivers with children &lt, 6 years completed self-administered questionnaires. Logistic regressions were used to assess associations between caregivers’ primary information sources and vaccine confidence/hesitancy. A majority (72%) of caregivers had multiple sources of vaccination-related information. The proportions of caregivers reporting professional sources, media, and peers as primary information sources were 81%, 63%, and 26%. Internal migrants were less likely to get information from professional sources, more educated and wealthier caregivers reported more information sources and were more likely to get information from media and peers. Caregivers who reported professional information sources had significantly higher odds of being confident about the safety of vaccines and lower odds of being hesitant toward vaccination than those who did not. Caregivers who reported the media as a primary information source had significantly higher odds of being hesitant toward vaccination than those who did not. To address vaccine hesitancy, it is essential to promote universal access to professional vaccination-related information sources, and to use the media to disseminate evidence-based information and clarify misinformation. Health communication should target internal migrants, and more educated and wealthier caregivers.

Influenza causes substantial morbidity and mortality. Many original studies have been carried out to estimate disease burden of influenza in mainland China, while the full disease burden has not yet been systematically reviewed. We did a systematic review and meta-analysis to assess the burden of influenza-associated mortality, hospitalization, and outpatient visit in mainland China. We searched 3 English and 4 Chinese databases with studies published from 2005 to 2019. Studies reporting population-based rates of mortality, hospitalization, or outpatient visit attributed to seasonal influenza were included in the analysis. Fixed-effects or random-effects model was used to calculate pooled estimates of influenza-associated mortality depending on the degree of heterogeneity. Meta-regression was applied to explore the sources of heterogeneity. Publication bias was assessed by funnel plots and Egger’s test. We identified 30 studies eligible for inclusion with 17, 8, 5 studies reporting mortality, hospitalization, and outpatient visit associated with influenza, respectively. The pooled influenza-associated all-cause mortality rates were 14.33 and 122.79 per 100,000 persons for all ages and ≥ 65 years age groups, respectively. Studies were highly heterogeneous in aspects of age group, cause of death, statistical model, geographic location, and study period, and these factors could explain 60.14% of the heterogeneity in influenza-associated mortality. No significant publication bias existed in estimates of influenza-associated all-cause mortality. Children aged

Background Improvements of population health in China have been unevenly distributed among different sexes and regions. Mortality Registration System provides an opportunity for timely assessments of mortality trend and inequalities. Methods Causes of death were reclassified following the method of Global Burden of Disease Study (GBD). Age-standardized mortality rate (ASMR) and ring-map of the rate by town were used to describe inequalities in changing mortality. Life expectancy (LE) and cause-deleted LE were calculated on the basis of life table technique. Results The burden of death from 2002 to 2018 was dominated by cardiovascular diseases (CVD), neoplasms, chronic respiratory diseases and injuries in Jiading district, accounting for almost 80% of total deaths. The overall ASMR dropped from 407.6/100000 to 227.1/100000, and LE increased from 77.86 years to 82.31 years. Women lived about 3.0–3.5 years longer than men. Besides, a cluster of lower LE was found for CVD in the southeast corner and one cluster for neoplasms in the southern corner of the district. The largest individual contributor to increment in LE was neoplasms, ranged from 2.41 to 3.63 years for males, and from 1.60 to 2.36 years for females. Conclusions Improvement in health was mainly attributed to the decline of deaths caused by CVD and neoplasms, but was distributed with sex and town. This study served as a reflection of health inequality, is conducive to formulate localized health policies and measures.

Background: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in China. Although numerous studies have been conducted to determine the risk factors for COPD mortality such as ambient air pollution, the results are not fully consistent.Methods: This study included mortality analysis and a case-control design by using the data extracted from the Mortality Registration System in Jiading District, Shanghai. Traditional logistic regression, geographically weighted logistic regression (GWLR), and spatial scan statistical analysis were performed to explore the geographic variation of COPD mortality and the possible influencing factors.Results: Traditional logistic regression showed that extreme lower temperature in the month prior to death, shorter distance to highway, lower GDP level were associated with increased COPD mortality. GWRL model further demonstrated obvious geographical discrepancies for the above associations. We additionally identified a significant cluster of low COPD mortality (OR = 0.36, P = 0.002) in the southwest region of Jiading District with a radius of 3.55 km by using the Bernoulli model. The geographical variation in age-standardized mortality rate for COPD in Jiading District was explained to a certain degree by these factors.Conclusion: The risk of COPD mortality in Jiading District showed obvious geographical variation, which were partially explained by the geographical variations in effects of the extreme low temperature in the month prior to death, residential proximity to highway, and GDP level.

Background Diseases caused by human enteroviruses (EVs) are a major global public health problem. Thus, the effective diagnosis of all human EVs infections and the monitoring of epidemiological and ecological dynamic changes are urgently needed. Methods Based on two comprehensive virological surveillance systems of hand, foot and mouth disease (HFMD), real-time PCR and nested RT-PCR (RT-snPCR) methods based on the enteroviral VP1, VP4-VP2 and VP4 regions were designed to directly detect all human EVs serotypes in clinical specimens. Results The results showed that the proposed serotyping strategy exhibit very high diagnostic efficiency (Study 1: 99.9%; Study 2: 89.5%), and the variance between the study was due to inclusion of the specific Coxsackie virus A6 (CVA6) real-time RT-PCR and VP4 RT-snPCR in Study 1 but not Study 2. Furthermore, only throat swabs were collected and analyzed in Study 2, whereas in Study 1, if a specific EV serotype was not identified in the primary stool sample, other sample types (rectal swab and throat swab) were further tested where available. During the study period from 2013 to 2018, CVA6 became one of the main HFMD causative agents, whereas the level of enterovirus A71 (EV-A71) declined in 2017. Conclusion The findings of this study demonstrate the appropriate application of PCR methods and the combination of biological sample types that are useful for etiological studies and propose a molecular strategy for the direct detection of human EVs in clinical specimens associated with HFMD.

To investigate parenting and children’s emotional and lifestyle responses to the COVID-19 epidemic, we conducted an online survey of random, representative sample of residents with children aged 3–17 years in mid-March, 2020 in China. 1655 parents were surveyed with 80.1% response rate. During the epidemic, half (49%) of children had stress symptoms and 10% had emotional problems; children had higher screen time, less exercise and worse sleep than before. Socially disadvantaged children were more vulnerable to the epidemic. Children whose parents communicated about the epidemic more frequently, who had irritable parents and experienced worse parent-child closeness had higher probabilities of emotional problems, stress symptoms and worse lifestyles. Improve parenting skills and communication quality is necessary during the epidemic.

Background: Coronavirus disease 2019 (COVID-19) vaccines have been administered in priority populations in China since December 15, 2020. This study aims to assess the safety of the COVID-19 vaccination programme in Dalian, China. Methods: Passive surveillance for adverse events following immunization (AEFIs) with COVID-19 vaccines was performed by the Dalian Center for Disease Control and Prevention (CDC). Data were collected through June 8, 2021, from the Chinese National Adverse Events Following Immunization System (CNAEFIS) and were verified by local and upper-level CDCs. Findings: A total of 7.12 million doses of vaccine were administered from November 27, 2020, through June 8, 2021, and 623 vaccinees reported adverse events, resulting in a rate of 87.5 events per one million doses. The age-specific rates of AEFIs ranged from 74.0 per one million doses among persons aged 45 to 59 years to 102.0 per one million doses among persons aged 18 to 44 years; the manufacturer-specific rates ranged from 81.1 to 125.2 per one million doses. Among the 623 AEFIs, 544 (87.3%; rate, 76.4 per one million doses) were confirmed as common minor vaccine reactions. Very rare cases of anaphylaxis after vaccination were reported (5 cases; 0.7 per one million doses). Seven cases of AEFIs were classified as serious; however, available information indicated that there was no causal relationship with COVID-19 vaccination. Interpretation: No major safety concerns were identified during the COVID-19 vaccination campaign. There was no evidence of an increased risk of serious adverse events (SAEs). Funding Information: The study was supported by grants from the National Science Fund for Distinguished Young Scholars (No. 81525023), Key Emergency Project of Shanghai Science and Technology Committee (No. 20411950100). Declaration of Interests: H.Y. has received research funding from Sanofi Pasteur GlaxoSmithKline, Yichang HEC Changjiang Pharmaceutical Company, and Shanghai Roche Pharmaceutical Company. None of those research funding is related to development of COVID-19 vaccines. All other authors report no competing interests.

Time and intimacy drive transmission A minority of people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmit most infections. How does this happen? Sun et al. reconstructed transmission in Hunan, China, up to April 2020. Such detailed data can be used to separate out the relative contribution of transmission control measures aimed at isolating individuals relative to population-level distancing measures. The authors found that most of the secondary transmissions could be traced back to a minority of infected individuals, and well over half of transmission occurred in the presymptomatic phase. Furthermore, the duration of exposure to an infected person combined with closeness and number of household contacts constituted the greatest risks for transmission, particularly when lockdown conditions prevailed. These findings could help in the design of infection control policies that have the potential to minimize both virus transmission and economic strain. Science, this issue p. eabe2424, Modeling results indicate that SARS-CoV-2 control requires case isolation, contact quarantine, and population-level interventions., INTRODUCTION The role of transmission heterogeneities in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dynamics remains unclear, particularly those heterogeneities driven by demography, behavior, and interventions. To understand individual heterogeneities and their effect on disease control, we analyze detailed contact-tracing data from Hunan, a province in China adjacent to Hubei and one of the first regions to experience a SARS-CoV-2 outbreak in January to March 2020. The Hunan outbreak was swiftly brought under control by March 2020 through a combination of nonpharmaceutical interventions including population-level mobility restriction (i.e., lockdown), traveler screening, case isolation, contact tracing, and quarantine. In parallel, highly detailed epidemiological information on SARS-CoV-2–infected individuals and their close contacts was collected by the Hunan Provincial Center for Disease Control and Prevention. RATIONALE Contact-tracing data provide information to reconstruct transmission chains and understand outbreak dynamics. These data can in turn generate valuable intelligence on key epidemiological parameters and risk factors for transmission, which paves the way for more-targeted and cost-effective interventions. RESULTS On the basis of epidemiological information and exposure diaries on 1178 SARS-CoV-2–infected individuals and their 15,648 close contacts, we developed a series of statistical and computational models to stochastically reconstruct transmission chains, identify risk factors for transmission, and infer the infectiousness profile over the course of a typical infection. We observe overdispersion in the distribution of secondary infections, with 80% of secondary cases traced back to 15% of infections, which indicates substantial transmission heterogeneities. We find that SARS-CoV-2 transmission risk scales positively with the duration of exposure and the closeness of social interactions, with the highest per-contact risk estimated in the household. Lockdown interventions increase transmission risk in families and households, whereas the timely isolation of infected individuals reduces risk across all types of contacts. There is a gradient of increasing susceptibility with age but no significant difference in infectivity by age or clinical severity. Early isolation of SARS-CoV-2–infected individuals drastically alters transmission kinetics, leading to shorter generation and serial intervals and a higher fraction of presymptomatic transmission. After adjusting for the censoring effects of isolation, we find that the infectiousness profile of a typical SARS-CoV-2 patient peaks just before symptom onset, with 53% of transmission occurring in the presymptomatic phase in an uncontrolled setting. We then use these results to evaluate the effectiveness of individual-based strategies (case isolation and contact quarantine) both alone and in combination with population-level contact reductions. We find that a plausible parameter space for SARS-CoV-2 control is restricted to scenarios where interventions are synergistically combined, owing to the particular transmission kinetics of this virus. CONCLUSION There is considerable heterogeneity in SARS-CoV-2 transmission owing to individual differences in biology and contacts that is modulated by the effects of interventions. We estimate that about half of secondary transmission events occur in the presymptomatic phase of a primary case in uncontrolled outbreaks. Achieving epidemic control requires that isolation and contact-tracing interventions are layered with population-level approaches, such as mask wearing, increased teleworking, and restrictions on large gatherings. Our study also demonstrates the value of conducting high-quality contact-tracing investigations to advance our understanding of the transmission dynamics of an emerging pathogen. Transmission chains, contact patterns, and transmission kinetics of SARS-CoV-2 in Hunan, China, based on case and contact-tracing data from Hunan, China. (Top left) One realization of the reconstructed transmission chains, with a histogram representing overdispersion in the distribution of secondary infections. (Top right) Contact matrices of community, social, extended family, and household contacts reveal distinct age profiles. (Bottom) Earlier isolation of primary infections shortens the generation and serial intervals while increasing the relative contribution of transmission in the presymptomatic phase., A long-standing question in infectious disease dynamics concerns the role of transmission heterogeneities, which are driven by demography, behavior, and interventions. On the basis of detailed patient and contact-tracing data in Hunan, China, we find that 80% of secondary infections traced back to 15% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primary infections, which indicates substantial transmission heterogeneities. Transmission risk scales positively with the duration of exposure and the closeness of social interactions and is modulated by demographic and clinical factors. The lockdown period increases transmission risk in the family and households, whereas isolation and quarantine reduce risks across all types of contacts. The reconstructed infectiousness profile of a typical SARS-CoV-2 patient peaks just before symptom presentation. Modeling indicates that SARS-CoV-2 control requires the synergistic efforts of case isolation, contact quarantine, and population-level interventions because of the specific transmission kinetics of this virus.

ObjectiveTo investigate psychological and behavioural responses to COVID-19 among the Chinese general population.Design, setting and participantsWe conducted a population-based mobile phone survey between 1 February and 10 February 2020 via random digit dialling. A total of 1011 adult residents in Wuhan (n=510), the epicentre and quarantined city, and Shanghai (n=501) were interviewed. Proportional quota sampling and poststratification weighting were used. Multivariable logistic regression models were used to investigate perception factors associated with the public responses.Primary outcome measuresWe measured anxiety levels using the 7-item Generalised Anxiety Disorder Scale (GAD-7) and asked respondents to report their precautionary behaviours before and during the outbreak.ResultsThe prevalence of moderate or severe anxiety was significantly higher (pConclusionsPrevalence of moderate or severe anxiety and strict personal precautionary behaviours was generally high, regardless of the quarantine status. Our results support efforts for handwashing education programmes with a focus on hygiene procedures in China and timely dissemination of reliable information.

Background All countries are facing decisions about which population groups to prioritize for access to COVID-19 vaccination after the first vaccine products have been licensed, at which time supply shortages are inevitable. Our objective is to define the key target populations, their size, and priority for a COVID-19 vaccination program in the context of China. Methods On the basis of utilitarian and egalitarian principles, we define and estimate the size of tiered target population groups for a phased introduction of COVID-19 vaccination, considering evolving goals as vaccine supplies increase, detailed information on the risk of illness and transmission, and past experience with vaccination during the 2009 influenza pandemic. Using publicly available data, we estimated the size of target population groups, and the number of days needed to vaccinate 70% of the target population. Sensitivity analyses considered higher vaccine coverages and scaled up vaccine delivery relative to the 2009 pandemic. Results Essential workers, including staff in the healthcare, law enforcement, security, nursing homes, social welfare institutes, community services, energy, food and transportation sectors, and overseas workers/students (49.7 million) could be prioritized for vaccination to maintain essential services in the early phase of a vaccination program. Subsequently, older adults, individuals with underlying health conditions and pregnant women (563.6 million) could be targeted for vaccination to reduce the number of individuals with severe COVID-19 outcomes, including hospitalizations, critical care admissions, and deaths. In later stages, the vaccination program could be further extended to target adults without underlying health conditions and children (784.8 million), in order to reduce symptomatic infections and/or to stop virus transmission. Given 10 million doses administered per day, and a two-dose vaccination schedule, it would take 1 week to vaccinate essential workers but likely up to 7 months to vaccinate 70% of the overall population. Conclusions The proposed framework is general but could assist Chinese policy-makers in the design of a vaccination program. Additionally, this exercise could be generalized to inform other national and regional strategies for use of COVID-19 vaccines, especially in low- and middle-income countries.

We conducted two surveys to evaluate the health‐seeking behaviors of individuals with acute respiratory infections (ARI) during the COVID‐19 outbreak in Wuhan, China. Among 351 participants reporting ARI (10.3%, 351/3,411), 36.5% sought medical assistance. Children were more likely to seek medical assistance than other age‐groups (66.1% vs. 28.0%‐35.1%). This population‐based study demonstrates that the majority of patients with ARI symptoms did not seek medical assistance during the COVID‐19 outbreak in Wuhan. These findings may be used to refine the estimates of disease burden and clinical severity of COVID‐19 and to plan for health resources allocation.

The novel coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, where the initial wave of intense community transmissions was cut short by interventions. Using multiple data sources, here we estimate the disease burden and clinical severity by age of COVID-19 in Wuhan from December 1, 2019 to March 31, 2020. Our estimates account for the sensitivity of the laboratory assays, prospective community screenings, and healthcare seeking behaviors. Rates of symptomatic cases, medical consultations, hospitalizations and deaths were estimated at 796 (95% CI: 703–977), 489 (472–509), 370 (358–384), and 36.2 (35.0–37.3) per 100,000 persons, respectively. The COVID-19 outbreak in Wuhan had a higher burden than the 2009 influenza pandemic or seasonal influenza in terms of hospitalization and mortality rates, and clinical severity was similar to that of the 1918 influenza pandemic. Our comparison puts the COVID-19 pandemic into context and could be helpful to guide intervention strategies and preparedness for the potential resurgence of COVID-19., Here the authors analyze disease burden and clinical severity of COVID-19 during the first wave in Wuhan, China in comparison to past influenza virus pandemics and COVID-19 in the US and Canada. These estimates of symptomatic cases, medical consultations, hospitalizations and deaths should guide preparedness for this disease.

Highlights • Around 85% caregivers and 94% providers agreed vaccines were safe and effective. • An immediate decline in vaccine confidence were reported after vaccine incident. • Vaccine confidence regained following government and public health responses. • Providers overwhelmed by workload and psychological pressure after vaccine incident., Introduction The Changchun Changsheng Vaccine Incident (CCVI) occurred mid-2018 and involved irregularities in the manufacture and quality control of diphtheria-tetanus-acellular-pertussis and rabies vaccines. This study investigates vaccine confidence amongst Chinese caregivers and vaccination-service providers (VSPs) six months after the CCVI. Methods Quantitative surveys were conducted in January 2019 with 2124 caregivers of children and 555 VSPs in three areas in China. The proportions of respondents who agreed to the four statements from the Vaccine Confidence Index™ were used to measure vaccine confidence. Descriptive and univariate analyses were performed to study the level of vaccine confidence. Semi-structured interviews were conducted with 48 caregivers, 43 VSPs and 9 immunization program managers. Interviews were analyzed thematically using a combination of deductive and inductive coding. Media surveillance was conducted to monitor public responses to the CCVI. Results Media surveillance indicated that public attention to vaccine-related issues increased sharply immediately post-CCVI but declined rapidly thereafter. Six months post-CCVI, 96.0% of caregivers and the same proportion of VSPs reported that vaccination was important and compatible with their religious beliefs. 82.7% and 88.2% of caregivers agreed that vaccines were safe and effective. 92.8% and 94.6% of VSPs agreed that vaccines were safe and effective. Both caregivers and VSPs reported an immediate decline in vaccine confidence post-CCVI. In most cases this trust was regained over time following government and public health responses, however some people remained hesitant about vaccinating their children. Many VSPs were overwhelmed by consultations, workload and psychological pressure after the CCVI. Conclusion After an initial decline, vaccine confidence recovered to pre-incident levels six months after the CCVI. However, some caregivers moved from the higher to the lower end of the vaccine confidence spectrum, pointing to the need to promote the acceptance of vaccination especially given the need for new vaccines to control the coronavirus epidemic.