| Summary: In recent decades, the primary biological population has been destroyed due to the human production activities and the shifts of ecological environment, which generally changes the ecological system of infectious disease and evolution pathway of pathogen, thus has greatly influenced the emergence and prevalence of infectious disease, presented with the emergence of emerging infectious disease and resurgence, expansion, migration of infectious diseases which had been under control. And it would even brought a serious disease outbreak, making it become a great threat to human health. For example, the recent resurgences and prevalences of Ebola virus disease, Rabies, human infections with Avain influenza, Dengue and so on, not only expanded the affected regions and victims, but also brought a serious economic loss. As the development of spatial information technology and phylogeography analysis technology, their advanced theories and unique superiorities had been got extensive concerns and applications in the recent studies on the transmission of infectious disease, and they had contributed to some important performance of these studies. However, due to the difficult of multidisciplinary approaches integration, combining these two technologies is infrequent. The emergence, spatiotemporal expansion, epidemic characteristic of infectious diseases are influenced not only by the environment and host, but also by the evolution of pathogen, and the shifts of ecological environment and the prevalence of infectious disease might also play a role in the evolutionary history of pathogen, so combining these two technologies will help us identify epidemic characteristics and transmission dynamics of diseases, and understand the evolutionary histories of pathogens. Meanwhile, it may explore the relationship among host, pathogen and environment, which may figure out the public health problem of global concern and promote the work of disease prevention and control.According to the key scientific issues of epidemiology study on Rabies and Ebola virus disease with global concern, especial their risk in developing countries, we had innovatively combined the spatial information technology and phylogeography analysis technology to conduct a study about the spatiotemporal distributions, expansion dynamics, influential factors, intervention effectiveness of two savage infectious diseases and genetic diversify, migration pathways, epidemic tracks, evolutionary histroies of their pathogens, which help us better understand their transmission and provided a decision-making basis for the targeted prevention and the constitution of control meausres.Background: Rabies is a global severe public health problem and a viral zoonotic infection of the central nervous system caused by Rabies virus(RABV), mortality rate of which is nearly 100%. Towards the end of the last century, China encountered the third wave of human rabies since 1949, and the reemerging disease was among the top three causes of human death due to infectious diseases in China. Although the number of human rabies cases slightly decreased since year 2007, the rabies seemed to be gradually expanding its epidemic areas, which would hinder the goal to eliminate rabies by year 2020. The previous studies including epidemiology investigation, distribution characterisitic, molecular evolution and others, were limited and incomprehensive, given the transmission dynamic and evolution characteristic of rabies and RABV remain unclear. To carry out a study about the transmission of rabies in China, which focus on identifying the expansion dynamics, exploring the possible influential factors related to the rabies expansion, understanding the genetic diversity and phylogeography of RABV, is a helpful scientific guidance and support for rabies prevention, control and elimination.Ebola virus disease(EVD), also known as Ebola hemorrhagic fever, is an acute hemorrhagic disease caused by the Ebola virus(EBOV), which is transmitted mainly through direct and indirect contacts with infectious patients or animal blood and secretions. An unprecedented outbreak of Ebola virus disease in West Africa during 2013-2015 had led to the highest cases and deaths since 1976, when the disease was first identified. Sierra Leone was the most severely affected country in West Africa, although Sierra Leone began to take different prevention measures soon after the outbreak, it was not under control in a short period, leading the overall epidemic had last for one and a half years. To help Sierra Leone fight against EVD, the Chinese government dispatched the China Mobile Laboratory Testing Team(CMLTT) in September upon request of the Sierra Leone government. The CMLTT, equipped with medical experts who specialize in laboratory testing and epidemiology. Based on the communication and cooperation with the Sierra Leone Ministry of Health and Sanitation, we had generally collected the data about the sample records of EVD cases and the EBOV genome sequences overlapping the whole outbreak. If we could integrate the data above effectively and conduct a study about the transmission of EVD in a finer scale, which focus on comprehensively identifying the epidemiology characteristic, expansion dynamic, influential factors, intervention effectiveness, household transmissibility of EVD and understanding the genetic diversity, migration pathway of EBOV, it will be of great significance to prevent and control the EVD outbreak in the future and improve the comprehensive ability on intervention formulation.Objectives and Contents: Our study included three sections.(1) We aimed at constructing comprehensive databases about the rabies and RABV in our country: to describe the spatiotemporal distribution characteristic of rabies, to understand the movement dynamic of rabies hotspots for identifying its expansion pattern; to explore the socioeconomic factors which may contribute to the transmission of rabies for programming key regions of rabies control and improving appropriate allotment of health resources; to characterize the genetic diversity, spatiotemporal dynamic of RABV and recognize the migration pathway, evolutionary history of major lineages for providing a direction for disease surveillance or other laboratory researches.(2) We aimed at constructing a comprehensive database including all sample records of EVD cases in Sierra Leone: to describe the spatiotemporal distribution of EVD in chiefdom level, and to classify the epidemic pattern of each chiefdom and summarize their epidemic features, and to evaluate the real-time effective reproductive number of different districts, so we could comprehensively understand the EVD epidemiology characteristic; to simulate the expansion dynamic of EVD and identify the expansion pattern, and to find out and assess the socioeconomic factors which may contribute to the expansion of EVD, so we could provide suggestions for controlling EVD expansion; to develop a spatiatemporal transmission model about the inter-chiefdom and intra-chiefdom transmission, and evaluate the interventions effectiveness and influential factors effects contributing to the EVD transmission, so we could provide a scientific guidance for constitution and implement of EVD interventions in the future; to build a household transmission model and assess the household transmissibility and susceptibility among different groups, and to compare the household transmissibility before and after the starting time of interventions, so we could understand the role of household transmission in the outbreak and explore the intervention importance for reducing the household transmissibility.(3) We aimed at constructing a comprehensive database including all EBOV genome sequences in Sierra Leone: to characterize the genetic diversity of EBOV and compare their temporal distribution and epidemic areas for completely understanding the evolutionary history of EBOV and exploring the transmissibility of each lineages; to find out the major lineages and recognize their migration pathways and epidemic tracks for providing a direction for disease surveillance; to construct the mutation pathway of EBOV and visually display the mutation dynamics of substitutions for exploring the possible key mutations and provide suggestions in the development of EBOV vaccine or other laboratory researches.Methods:(1)The reported data for human rabies from 2004 to 2013 and all sequences of N gene of RABV in China were collected and set up as database after linking animal rabies, climate and socioeconomic data; We started to characterize their spatial and temporal dynamic after combining spatial statistics and mapping technologies through Arc GIS; We evaluated the presence of space-time hotspots to identify the movement dynamic of hotspots using spatiotemporal scan statistic implemented in Sa TScan; To explore potential factors related to spatiotemporal heterogeneity of human rabies, a panel Poisson regression was fitted using STATA; Using BEAST, a phylogenetic analysis and phylogeography reconstruction were performed to understand genetic diversity of RABV and the migration pathways of major lineages.(2)We collected all EVD cases samples records from 2014-2015 during the whole EVD outbreak in Sierra Leone, which were established as database after linking the data about environment, socioeconomic, hospital distribution and so on; We started to characterize their spatial and temporal dynamic after combining spatial statistics and mapping technologies through Arc GIS, and used a weighted-average linkage method to classify the epidemic patterns; Real-time effective reproductive number of different districts were assessed based on their epidemic curves; A spatial trend contour plot of the EVD expansion was developed using a trend surface analysis after identifying the time of first case in each chiefdom, then survival analysis was performed to explore the factors associated with the spatial diffusion of EVD; A Poisson transmission model was developed to evaluate the factors effects and intervention effectiveness; A household transmission model was built to assess household transmissibility.(3) We collected all EBOV genome sequences from Sierra Leone and set up a database after linking the cases database for complementing the missing information; Using BEAST, a phylogenetic analysis was conducted to understand the genetic diversity and evolution history of EBOV; Furthermore, we identified the migration pathways and epidemic tracks of major lineages of EBOV using BEAST to perform a phylogeography reconstruction; Based on the phylogenetic tree, we manually constructed the mutation pathway of EBOV using Illustrator. The software used in the study including Microsoft office 2010, Uedit32, Arc GIS v9.3, STATA v10.0, Sa TScan v8.0, Illustrator v5.0, Python v2.7, R language, MEGA v5.0, BEAST v1.8.0, Fig Tree v1.4.2, SPREAD v1.0.6, Tracer v1.5 and so on.Results:(1)Transmission dynamic and phylogeography of Rabies and RABV in mainland China:(1)From 2004 to 2013, there were 22,684 cases reported in mainland China. The 40+, 0-10 age groups had the highest incidence in both males and females, most of which were peasant, herdsman, student and pre-school children, and males had a significantly higher incidence than females in all age groups, and the total risk ratio was 2.18. The annual incidence curve showed that the human rabies rapidly increased since 2004, reached its peak in 2006 and 2007, and kept declining slowly afterwards. During 2004-2013, 30 of the 31 provinces in China(except Tibet) reported human rabies cases.The high-incidence provinces were mainly in the south, such as Guizhou, Guangxi, Guangdong and Hunan provinces, and low-incidence provinces were Shanxi, Shaanxi, Inner Mongolia, Yunnan and so on. Overall, a decreasing annual incidence was found in the high-incidence provinces, while the low-incidence provinces had an increasing incidence(i.e. Shaanxi, Shanxi) after comparing their epidemic characteristc.(2)There were 23 hotspots in whole country over the 10 years based on the spatiotemporal scan statistic, most of them were mainly distributed in the southern, southeastern and central regions, which had covered a larger area,longer duration and higher incidence than other regions. Starting from 2006, new hotspots covering few counties were identified in the northern, western, northwestern regions, especially after 2010. The spatiotemporal dynamics of hotspots clearly showed that the rabies was moving from southern, eastern regions towards northern, western regions.(3)The panel Poisson regression result showed the transmission of rabies had positive correlations with temperature at a one-month lag, canine rabies outbreaks at a 2-month lag and negative correlations with GDP per capita and average education years, which could be explained that more canine rabies outbreaks, higher temperature, less GDP per capita and lower average education years the regions had, higer transmission risk of rabies the regions had.(4)Based on the phylogenetic analysis, there were a total of five lineages(Clade I to V) in mainland China, while only two main lineages, Clade I and Clade II, had a wide spatial distribution and contributed to rabies epidemic in mainland China from 2004 to 2013, and the sequences from 2009 to 2012 were all clustered in Clade I, most of which belonged to Clade I-G, indicating the dominant role of Clade I and Clade II in recent rabies epidemics, especial Clade I-G. The high-incidence provinces, such as Hunan and Guangxi, had more genetic diversities than the low-incidence provinces, such as Beijing, Hebei, Shaanxi and Anhui, which were only associated with Clade I-G or Clade II-B.(5)Interestingly, the further phylogeography analysis revealed more migration events of Clade I than that of Clade II, indicating that the Clade I-G was key lineages that related to the epidemic and expansion of human rabies in recent years.(2)Transmission dynamic and intervention effectiveness of EVD in Sierra Leone:(1)Essential data of 8,358 confirmed and 3,545 suspected EVD cases were extracted from database reported to the SLMHS from May 2014 to September 2015, which had overlapped the whole outbreak.(2)Based on symptom onset dates, after three months of the epidemic persisting at a relatively low level, the number of confirmed cases soared beginning in mid-August, peaked in early November, and then declined gradually but consistently in spite of some fluctuation. A total of 307 healthcare workers were confirmed to be infected, and the proportion of healthcare workers among confirmed cases was quite high from June to August 2014. One hundred and fourteen of 150 chiefdoms in Sierra Leone were affected during the outbreak. The spatial distribution of EVD in each month varied greatly, and the cumulative incidence rates among chiefdoms were notably heterogeneous across the country. The more densely populated and developed chiefdoms seemed to have more confirmed cases.(3)Using a weighted-average linkage clustering method, we grouped the epidemic patterns of 114 affected chiefdoms into six categories, which had different epidemic intensities and periods.(4)A trend surface analysis revealed two spatial diffusion corridors of EVD. One originated on 18 May 2014 from the border area of Kailahun District in the east adjacent to the EVD epicenter in Guinea. The other began on 25 June 2014 from Western Urban and Rural districts in the west. Both rapidly spread towards Tonkolili and Bo districts of central Sierra Leone and subsequently diffused northeast and southwest with a reduced velocity. The further survival analysis revealed the spatial diffusion was associated with intersection with main roads and hospital distributions. Chiefdoms intersected by main roads and close to hospitals had a high hazard of invasion.(5)We developed a Poisson model that simultaneously accounts for three transmission routes, and found the transmission rate of intra-chiefdoms was higher than that of inter-chiefdoms. Population density, cropland coverage, and atmospheric temperature were nonlinearly associated with EVD transmission. Furthermore, Interventions, such as nationwide strategic plan including cases isolation, beds adding and safe burials, had a strong effectiveness on controlling the disease. Compared to the reference phase, person-to-person transmissibility, estimated as the average number of secondary infections caused by a patient per week, was reduced by 43%(95% CI: 30%, 52%) during the intervention phase I and by 65%(95% CI: 57%, 71%) in the intervention phase II.(6)According to the household transmission analysis, the estimates of household transmissibility, defines as household secondary attack rate, ranged from 0.056 to 0.062. Females and children tended to be more prone to household infection than males and adults. The household SAR was reduced by 82% based on the comparison of household transmissibility between before and after the starting time of interventions, indicating the role of intervention(nationwide strategic plan) in reducing the household transmissibility.(3)Genetic diversity and major lineages’ phylogeography of EBOV in Sierra Leone:(1)We curated a comprehensive dataset with 514 EVD patients, of which have residence information, isolated time and so on(including 60 novel virus sequences).(2)A phylogenetic analysis of 514 viral genome sequences showed that there were three lineages named SL1, SL2, SL3 during the epidemic, and SL3 could be divided into nine lineages.(3)SL1 and SL2 emerged in the early stages of the outbreak in Sierra Leone, and were soon replaced by SL3 after June 2014. From the genetic diversified lineages of SL3, three lineages(SL3.1.2, SL3.2.4 and SL3.2.5) were shown to be more prevalent, and possibly infected more patients and had a longer duration. These three lineages would be the dominant viruses in the latter months of the outbreak in Sierra Leone during 2014.(4)Further discrete phylogeography analysis revealed that there major lineages had distinct migration pathways although they were original from Eastern Province. The SL3.1.2 emerged in capital of Sierra Leone, Freetown, in late August. Owing to the high population density in Freetown and a lack of competition from other EBOV lineages, SL3.1.2 rapidly expanded during September and continued to be a major lineage thereafter in Western Province, and spread to other regions nearby. The SL3.2.4 lineage first appeared in Eastern Province as a minor lineage in August. In September, the virus spread to the adjacent chiefdoms in the Eastern and Southern provinces, the dominant lineage at the time. Some SL3.2.4 viruses were also found in Western Rural during September. Since then, like SL3.1.2, SL3.2.4 became one of the major lineages in the Western Rural and Urban areas, and spread to the Northern and Southern provinces. Viruses from the SL3.2.5 lineage were sporadically distributed in the Eastern and Northern provinces in August, becoming more prevalent in some chiefdoms of Northern Province in September, and the chiefdom Buya Romende Chiefdom acted as the main transmission node in September. The SL3.2.5 lineage did not become prevalent in Western Province until early October. Since then, SL3.2.5 viruses became another major lineage in Western Province. The comparison among the migration pathways and epidemic tracks among SL3.1.2, SL3.2.4, SL3.2.5, revealed that SL3.2.5 lineage possibly possessed superior viral fitness compared to SL3.1.2 and SL3.2.4, and SL3.2.4 had higher transmissibility than SL3.1.2.(5)After mapping the mutation pathway of EBOV, we identified some possible key mutations associated with the lineages features or fitness, such as T3008 C,T3011C, T5849 C, T10479 A, C16895 T and so on.Conclusion: This study had effectively combined spatial information technology and phylogeography analysis to achieve the management and integration analysis of multidimensional information of infectious disease, which might provide a new direction and an advanced approach in the future study about the transmission of infectious disease. The above results implied:(1)The control work of rabies in mainland China during these years had achieved a great performance, but the reduction in the overall human rabies incidence was accompanied by expansion of the circulating region. Control efforts should focus on not only the high-incidence areas of rabies but also the low-incidence areas, emerging areas and poor areas. The control work should also strictly regulate interprovincial animal and strengthen animal rabies surveillance. The Clade I of RABV should been paied attention to the futher surveillance or other laboratory researches.(2)The traffic facility, develop level of each chiefdom in Sierra Leone were related to the epidemic of EVD, and the expansion of EVD was influenced by the traffic and hospital distributions. Inter-region surveillance, human movement and hospital infection control were important to control the expansion of EVD. The intervention including cases isolation, beds adding and safe burials were effective in reducing the transmission risk of EVD. The SL3.1.2, SL3.2.4, SL3.2.5 of EBOV and T3008, T3011 C or other key muations should been paied attention to the futher surveillance or other laboratory researches of EBOV. Overall, this study had comprehensively understand the spatiotemporal structure the rabies and EVD as well as their pathogen, and identified their transmission characteristics, which would provide data and scientific support for the accurate constitution of intervention, effective and rapid response of emergency and predictive epidemic of disease. |
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