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. 2020 Apr 14;15(4):e0231661. doi: 10.1371/journal.pone.0231661

The spatiotemporal distribution of Japanese Encephalitis cases in Yunnan Province, China, from 2007 to 2017

Xianghua Mao 1,2, Hongning Zhou 2,*
Editor: Tian Wang3
PMCID: PMC7156086  PMID: 32287313

Abstract

Background

Japanese encephalitis (JE) is a vector-borne disease with a high prevalence in Yunnan Province, China. However, there has been a lack of a JE epidemic systematic analysis, which is urgently needed to guide control and prevention efforts.

Methods

This study explored and described the spatiotemporal distribution of JE cases observed among two different age groups in Yunnan Province from 2007 to 2017. The epidemiological features and spatial features were analyzed according to basic statistics, ArcGIS software (version 9.3; ESRI, Redlands, CA) and SPSS software (version 20; IBM Corp., Armonk, New York).

Results

Overall, the whole province had a high incidence of JE. The annual incidence rates in 2007 and 2017 were 1.668/100,000 and 0.158/100,000, respectively. The annual mortality was under 0.095/100,000 for these years. Although the whole province was in danger of JE, the Diqing autonomous prefecture and the Lijiang autonomous prefecture had no JE cases recorded for over 10 years. The JE cases were reported by hospitals located in 60 counties of 14 municipalities. The top ten areas with the most JE cases were Kunming City, Zhaotong City, Jinghong City, Wenshan City, Mangshi City, Pu’er City, Baoshan City, Dali City, Chuxiong City, and Gejiu City. The incidence declined smoothly, with a peak occurring from June to September, which accounted for 96.1% of the total cases. Children whose age was equal or less than 10 years old (LEQ10) still maintained a high frequency of JEV infection, and a large number of cases were reported in August, despite the Expanded Program on Immunization (EPI), which was established in April 2008. There was no difference in the quantity of cases between the two groups (t = -0.411, P>0.05); additionally, the number of JE cases among patients LEQ10 were significantly greater than those among patients older than 10 years (GTR10). Further analysis using local indicators of spatial association (LISA) revealed that the distribution of JE exhibited a high-high cluster characteristic (Z = 2.06, P<0.05), which showed that Jinghong City, Guangnan County, Yanshan County, Funing County, and Mengzi City were hot spots for the JE epidemic.

Conclusions

Although the EPI was established in 2008 and the incidence of JE declined smoothly in Yunnan Province, there was no difference in the number of cases between the two age groups, which reveals that the EPI has been conducted with a low level success. In the context of limited vaccine supply capacity, we should strengthen the implementation of the children's immunization program before strengthening other immunization programs.

Introduction

Japanese encephalitis (JE) is a mosquito-borne disease caused by a virus that belongs to the family Flaviviridae, genus Flavivirus [1, 2], which causes approximately 30,000 to 50,000 cases and 10,000 to 15,000 deaths in Asian countries annually [3], with an overall incidence of 1.8 per 100,000 [4]. During an epidemic, approximately 0.1–4% of infected individuals develop clinically apparent encephalitis [5]. However, these figures are probably underestimated [6]. An estimated 3 billion persons live in countries where the JE virus (JEV) is endemic [7]. In these areas, the case fatality rate is 20–30%, and 30–40% of survivors suffer from permanent neurological sequelae [8]. Previous studies from India have ascertained that for every case of symptomatic JE, 200 patients suffer from asymptomatic or subclinical disease [9]. JE was first described in 1871, and the first recognized epidemic occurred in Japan in 1924 [10–12]. The prototype Nakayama JEV strain was isolated from a postmortem human brain in Tokyo, Japan, in 1935 [13, 14]. Phylogenetic analysis of JEV strains revealed that JEVs can be divided into four genotypes using the prM gene [15] and five genotypes according to the E gene or full-length genome [16, 17]. Genetic studies suggest that JEV originated from an ancestral virus in the area of the Malay Archipelago, after which the virus evolved into different genotypes (I–IV) and spread across Asia. Until recently, most of the strains of JEV at the origin of major epidemics in the South, East, and Southeast Asia regions belonged to genotype III [18]. However, a shift in prevalence from JEV genotype III to JEV genotype I has been observed in several Asian countries [19–21], although an evolutionary study has demonstrated that three genotypes (I, III, V) were confirmed to be co-circulating in China in both high and low prevalence areas [22]. All JEV strains belong to a single serotype, as evident from an epidemiological observation of the absence of secondary encephalitis [23]. The main vector of JEV transmission is Culex tritaeniorhynchus [24], although it can be transmitted with vector-free [5]. In Australia [25, 26], Culex annulirostris was identified as the main vector for JEV transmission. Domestic pigs are considered the major amplifying hosts, and humans are considered dead-end hosts [27, 28].

JE is one of the ongoing epidemics in Yunnan Province, China. Although many measures have been taken in recent years, both the accumulated experience and international cooperation for JE control, especially in the management of the program and the analysis of data, are either moving backward or closed. Therefore, we urgently need to analyze the data collected from a primary survey to inform a reliable and effective strategy for the termination of JE. Furthermore, we also expect to exchange views with the international community.

Materials and methods

Study region

Yunnan Province is located on the southwestern border of China between 21–29° north latitude and 97–106° east longitude. The borders are adjacent to Guizhou and Guangxi in the East, Sichuan in the North, Tibet in the Northwest, Myanmar in the West, and Laos and Vietnam in the South, and the province occupies a total area of 394,000 square kilometers. While the climate is largely subtropical and tropical monsoon, there is a plateau climate in the Northwest. By the end of 2017, Yunnan Province had jurisdiction over 129 counties or districts that belong to eight provincial municipalities or eight autonomous prefectures.

Data collection and management

China has a relevant reporting system of epidemics and strong support of the network for data collection. We obtained the database of JE cases from the China Information System for Diseases Control and Prevention (CISDCP). A list of study regions was created for data collection, and the inclusion and exclusion criteria were provided. The factors collected included sex, age, date of onset, occupational distribution, case classification, and reporting areas. Personal identifying factors, such as name, address and clinical information, were removed. Individuals were divided into two groups by age to analyze the differences between them; one group was LEQ10 and the other group was GTR10. Then, we collected demographic information from the national statistical bulletin. The data analyzed in this study included the total number of outbreaks, occupations of the patient, time of symptom onset, reporting area and reporting time. The use of clinical symptoms or medical information was forbidden in this study. All data were analyzed by the ArcGIS software (version 9.3; ESRI, Redlands, CA) and SPSS software (version 20; IBM Corp., Armonk, New York) automatically.

Analysis of the epidemiological characteristics

The annual incidence and annual mortality of JE were displayed by wave patterns, with a scale of 1 to 100,000. The seasonal pattern was displayed in a histogram based on the monthly cases from 2007 to 2017. The t-test was used to analyze differences among JE cases by age, which was divided into two groups: one group was LEQ10, and the other group was GTR10. A ratio was used to reveal the distribution of males and females. The distributions of the JE cases by epidemiological parameters, including sex, age and occupation, were calculated according to basic statistics.

Spatial cluster analysis

All data from the JE cases were plotted with ArcGIS software (version 9.3; ESRI, Redlands, CA). The geographical distribution of JE cases was divided into five levels: 0, 1–3, 4–10, 11–30 and above 30 cases. All data were displayed on GIS maps at the county level or municipal level. The local indicators of spatial association (LISA) were used to analyze the distribution of JE, and the Z-score, P-value and local Moran's I coefficient were calculated. A local Moran's I coefficient >0 indicates that the data have a positive spatial correlation. In contrast, a local Moran's I coefficient <0 indicates that the data have a negative spatial correlation, and a local Moran's I coefficient = 0 indicates that the data are random. In addition, the Z-score and P-value were utilized for data analysis. When the Z-score was > 1.96 (P<0.05), the distribution of JE cases was clustered, which indicated that the surrounding features had similar values (high-high or low-low), and when the Z-score was < -1.96 (P<0.05), the distribution of JE cases was dispersed, which indicates that the surrounding features had a significant spatial outlier (high-low or low-high). If the Z-score was between -1.96 and +1.96 and the P-value was > 0.05, the data were random.

Results

Epidemiological features of JE in Yunnan Province

Incidence and mortality

A total of 3038 cases were reported from 2007 to 2017, with an annual incidence between 0.158/100,000 and 1.668/100,000 and an annual mortality between 0.004/100,000 and 0.095/100,000. While the annual incidence and mortality in 2007 were 1.668/100,000 and 0.095/100,000, respectively, they decreased to 0.158/100,000 and 0.004/100,000 in 2017, respectively, which suggested a downward trend from 2007 to 2017 (Fig 1).

Fig 1. Annual incidence and mortality of JE in Yunnan Province, China, 2007–2017.

Fig 1

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Sex

Among the 3038 JE cases reported from 2007 to 2017, 1802 were male and 1236 were female, reflecting a male to female ratio of 1.46:1.

Seasonal pattern

The distribution of cases shows a clear seasonal pattern, which had the highest wave from June to September with a peak in August, whether the incidence for a given year was high (2007) or low (2017). A total of 96.1% of the total cases occurred from June to September, while 72.6% occurred in July and August (Fig 2).

Fig 2. Monthly cumulative cases in Yunnan Province, China, 2007–2017.

Fig 2

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Distribution by age

Among both age groups, the median age was 10 years old, with a minimum age of 0.1 years old and a maximum age of 86 years old. Of the cases that had been reported from 2007 to 2017, 1625 were LEQ10, and 1413 were GTR10, reflecting a ratio of 1.15:1. The proportion of JE patients whose age was GTR10 was 46.5%, while the proportion of JE patients whose age was LEQ10 was 53.5%. The highest number of cases was reported in 2007 in both age groups.

Occupational distribution

Children and students accounted for a large portion of cases (68.5% of the total). Additionally, the JE incidence was highest among children, accounting for 35.6% of the total. Among the other cases, medical staff, merchants, farmers and urban residents accounted for 31.5% of the total occupations.

Geographical distribution

The geographical distribution of JE changed every year. Since 2007, the cases exhibited a downward trend until 2011. In 2011, the region of Zhaoyang, which declined in 2010, increased notably. In 2007, there were 60 counties or districts with reported cases, which dropped to 20 counties by the end of 2017, reflecting a decline of 66.7%. From 2015, the number of cases decreased significantly, dropping to less than 100 cases in both age groups. In the past decade, the top ten areas according to case reporting were Kunming City, Zhaotong City, Jinghong City, Wenshan City, Mangshi City, Pu’er City, Baoshan City, Dali City, Chuxiong City, and Gejiu City. In 2017, the top five areas in terms of cases reported were Kunming City, Gejiu City, Pu’er City, Jinghong City, and Mengzi City (Fig 3).

Fig 3. Spatiotemporal distribution of JE in Yunnan Province, China, 2007–2017.

Fig 3

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The cases of JE plotted on the map were derived from the crude data at the county level.

From 2007 to 2017, 82 counties of 14 municipalities reported JE cases; however, the Diqing autonomous prefecture and the Lijiang autonomous prefecture were free of JE and had no reports of JE for over 10 years. The top five municipalities according to the number of reported cases were Kunming City, Zhaotong City, Wenshan City, Pu’er City, and the Xishuangbanna autonomous prefecture. In terms of the two age groups, the geographical distribution of JE was different between them. In the group aged GTR10, Kunming City, Zhaotong City, Pu’er City, the Xishuangbanna autonomous prefecture and the Dehong autonomous prefecture were ranked among the top five areas in case reporting, while the Wenshan autonomous prefecture, Zhaotong City, Kunming City, the Xishuangbanna autonomous prefecture and the Dehong autonomous prefecture were ranked among the top five in the group aged LEQ10 (Fig 4).

Fig 4. Geographical distribution of the two age groups in Yunnan Province, China, 2007–2017.

Fig 4

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The cases of JE plotted on the map were derived from the crude data at the municipal level.

Spatial features of JE in Yunnan Province

Dispersion and clustering

The cluster analysis showed that there was a significant agglomeration. In 2007, both Kunming City and Longyang District had high-low cluster characteristics, while Jinghong City, Guangnan County, Yanshan County, and Funing County had high-high cluster characteristics (Z = 2.06, P<0.05). In 2017, although Kunming City had high-low cluster characteristics and both Mengzi City and Jinghong City had high-high cluster characteristics, the clustering was not obvious, which suggested that the JE reporting was random (Fig 5).

Fig 5. Dispersion and clustering of JE reporting.

Fig 5

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Statistical analysis

Among the 3038 cases that were reported from 2007 to 2017, there were 1625 patients aged LEQ10 and 1413 patients aged GTR10. The statistical analysis showed that there was no significant difference between these two age groups (t = -0.411, P = 0.686). Furthermore, the number of patients aged LEQ10 was greater than the number of patients aged GTR10 (1.15:1).

Discussion

Recently, there has been a great amount of support for vaccinating adults against JE. Supporters believe that it is urgent to carry out vaccination for adults based on the number of adult patients and the age of onset. Their claim is unrealistic and unsustainable for all adults to be vaccinated, at least in Yunnan Province, which does not have ample facilities. In fact, the in-depth analysis of epidemiological JE data is limited and it has been erroneously concluded that adults need to be vaccinated immediately. Other provinces of China believe that the strategy of vaccination for adults would not respond to the actual situation in Yunnan Province.

Although the incidence and mortality of JE have shown a downtrend in Yunnan Province, China, the risk of an epidemic or an outbreak is still high. The incidence and mortality of JE in 2007 was 1.668/100,000 and 0.095/100,000, respectively, and they decreased to 0.158/100,000 and 0.004/100,000, respectively, in 2017. In recent years, we established a strong system for epidemic reporting, and the system has been running smoothly. However, most cases of JE are asymptomatic and go unreported, which makes the spatial distribution of the virus difficult to estimate [29]. For example, the reporting of cases depends on the quality of the health information systems and the ability to clinically and serologically diagnose the disease [10]. Meanwhile, these data were from a passive surveillance system, which means that there may have been underreporting of JE because some cases had subclinical symptoms [10, 30]. In a study that was reported in 2009, the infection rate of Culex tritaeniorhynchus was 13.2% [31], indicating a high level of virus activity. In Tibet, during a JE epidemic, the overall seroprevalence of JEV IgM in pigs was 5.1% [32]. Furthermore, JE epidemics have occurred along the border of Yunnan Province [33, 34]. In addition, geographic changes; agricultural changes; ecological factors; birds; climate changes; changing risks from rural exposures; changing profiles of international travelers; peri-urban risk; personal factors and JE risk; non-mosquito vector transmission in pigs; the incidence of JEV infections in febrile travelers; JEV infection without encephalitis; changes in trip duration for JE cases; and changes in JE vaccine utilization can also cause an outbreak or epidemic [35]. This study suggested that the risk of another JE epidemic occurring is still high and that prevention efforts in Yunnan Province should not be neglected.

JE is widely distributed in Yunnan Province except for in the Lijiang autonomous prefecture and the Diqing autonomous prefecture. For the years studied, the prevention of JE in Yunnan Province has been steadily carried out, and human cases have been found or reported in most areas. The Lijiang and Diqing autonomous prefectures, however, had no cases reported in over 10 years. The JE cases were not randomly distributed [36], they also show the same characteristics in Yunnan Province, especially in the areas of Jinghong City, Guangnan County, Yanshan County, Funing County, and Mengzi City, which are hot spots for the JE epidemic. Usually, cases in Yunnan Province are treated by nearby hospitals; however, some of the cases reported in an area were not acquired in that area; sometimes the number of cases only reflects the strong diagnostic testing capacity of the area [10]. The number of treatments by hospitals, however, is roughly equal to the actual number of cases because of the special expense reimbursement system and process in China. Therefore, the incidence of JE showed a downward trend, and the epidemic range is becoming increasingly smaller. In the Lijiang and Diqing autonomous prefectures, where there is no JE epidemic, we should carefully investigate whether this is due to their limited facilities [10].

Children should be given priority with regard to the JE vaccine. According to a study that monitored JE in Jinan, Yichang, Shijiazhuang, and Guigang, cases can be found in sentinel hospitals and non-sentinel hospitals [30]. People also have increased awareness of the prevention of JE [37]. These results provide a prerequisite for the implementation of immunization. The benefits of vaccination are also obvious from a study conducted by Guizhou Province in China, which showed that immunization of 100,000 persons was predicted to save 1.6 billion dollars for the health system and 11.6 billion dollars for society [38]. The EPI has been implemented in Yunnan Province for many years. The number of cases in the group aged LEQ10, however, was still at a high level. The results indicate that there was no difference in the number of cases between the two age groups. In addition, the proportion of JE cases among LEQ10 patients was still significantly greater than that among GTR10 patients, which indicates that the implementation of our EPI must be strengthened. In the current study, we found that the EPI has not been implemented very well in some regions, and in a few regions, there was also a shortage of vaccines. Because of the limited supply of vaccines and these constraints, the vaccination of all adults against JE is unrealistic and unsustainable in Yunnan Province. Further cluster analysis revealed that five areas were hot spots for JE cases, and these regions should draw up similar strategies for JE prevention. Furthermore, the whole province should strengthen the vaccination of children as the first option, before vaccinating adults, due to the low supply of the vaccine. For the prevention of JE among adults, more environmental modifications should be adopted, rather than an unrealistic promotion of vaccines with limited availability. The core mission is to provide high-quality and affordable vaccines. At the same time, monitoring and data analysis should be strengthened more than blind work and unrealistic slogans.

Supporting information

S1 Data. Spatiotemporal distribution and geographical distribution.

(XLS)

Click here for additional data file. (38KB, xls)
S2 Data. Annual incidence and mortality.

(XLSX)

Click here for additional data file. (8.5KB, xlsx)
S3 Data. Monthly cumulative cases.

(XLSX)

Click here for additional data file. (8.3KB, xlsx)

Data Availability

All relevant data are within the paper and its Supporting Information files. The JE data used in this study were obtained from the China Information System for Diseases Control and Prevention (available at http://www.phsciencedata.cn/).

Funding Statement

This work was supported by grants from National Natural Science Foundation of China(U1602223), and Major Science and Technology Projects in Yunnan Province (2017ZF007).The funders had no role in study design, data collection and analysis,decision to publish, or preparation of the manuscript.

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Decision Letter 0

Tian Wang

23 Jan 2020

PONE-D-19-35285

The Spatio-temporal Distribution of Japanese Encephalitis Cases in Yunnan Province, China from 2007 to 2017

PLOS ONE

Dear Mr. Mao,

Thank you very much for submitting your manuscript. While both reviewers appreciated the efforts on the revision, there is one remaining concern on the manuscript’s writing (see the comments from reviewer 2 below).   We therefore ask you to edit the manuscript according to reviewer 2’s recommendation before we can consider your manuscript for acceptance.

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We look forward to receiving your revised manuscript.

Kind regards,

Tian Wang, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: I Don't Know

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: All of my concerns have been adequately addressed .

Reviewer #2: Portions of the manuscript have improved compared to the first submission. Unfortunately, the manuscript still contains numerous grammatical errors throughout, which make it difficult to follow and understand the methods. Additional editing is needed.

**********

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Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Apr 14;15(4):e0231661. doi: 10.1371/journal.pone.0231661.r003

Author response to Decision Letter 0

6 Mar 2020

Response: Thank you for the helpful comment. In accordance with the comment, we have asked professionals (American Journal Experts, AJE) to carefully revise the manuscript. Additionally, to make sure the statistical analysis been performed appropriately and rigorously, we also added new supporting information to ensure the conclusions.

Attachment

Submitted filename: Response to Reviewers.rtf

Click here for additional data file. (49.8KB, rtf)

Decision Letter 1

Tian Wang

16 Mar 2020

PONE-D-19-35285R1

The spatiotemporal distribution of Japanese Encephalitis cases in Yunnan Province, China, from 2007 to 2017

PLOS ONE

Dear Mr. Mao,

Thank you for submitting your revised manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

We would appreciate receiving your revised manuscript by Apr 30 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Tian Wang, PhD

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors have addressed my concerns regarding grammatical errors from the previous draft. This revised draft is much improved and easier to follow. I only have a few minor editing suggestions listed below.

Line 41 a high-high cluster? Should this be “a high cluster characteristic?”

Line 74 Can you explain non-vector transmission or give an example here?

Line 90 Change provide to province.

Lines 105-106 This sentence seems redundant and should be removed, if I am understanding it correctly: “Private information had been completely erased from the original JE dataset; therefore, the data we used for this analyses no longer included names, addresses, etc.” Lines 100-101 already state that “Personal identifying factors, such as name, address and clinical information, were removed.”

Line 109 What software? ArcGIS?

Line 123 Change revealed to displayed.

Lines 125-126 Edit sentence to: A local Moran’s I coefficient >0 indicates that the data have a positive spatial correlation.

Line 128 Edit sentence to: In addition, the Z-score and P-value were utilized for data analysis.

Line 212 Edit sentence to: Recently, there has been a great amount of support…

Line 213 Change quantity to number.

Line 218 Change “respond to” to improve.

Line 219 Edit sentence to: Although the incidence and mortality of JE have shown a downward trend in Yunnan Province…

Line 222 Remove: …which seems to be a downward trend of incidence and mortality. This is redundant.

Line 229 Edit sentence to: In a study that was reported in 2009, the infection rate of Culex tritaeniorhynchus was 13.2% [31], indicating a high level of virus activity.

Line 231 Edit sentence to: In Tibet, during a JE epidemic, the overall seroprevalence…

Line 232 Edit sentence to: Furthermore, JE epidemics have occurred along the border…

Line 238 Edit sentence to: This study suggested that the risk of another JE epidemic occurring is still high and that prevention efforts in Yunnan Province should not be neglected.

Line 242 Change any to human.

Line 248 Change “caused or infected” to acquired.

Line 249 Change discovery to diagnostic testing.

Line 257 Change has to have.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Apr 14;15(4):e0231661. doi: 10.1371/journal.pone.0231661.r005

Author response to Decision Letter 1

25 Mar 2020

Dear Dr. Wang,

We have received the comments about the manuscript entitled “The spatiotemporal distribution of Japanese Encephalitis cases in Yunnan Province, China, from 2007 to 2017” (Manuscript Number: PONE-D-19-35285R1). We thank you very much for giving us an opportunity to revise the manuscript. We appreciate editors and reviewers very much for their positive and constructive comments and suggestions. In accordance with the format requirements of PLOS ONE, we have revised the manuscript. The main changes are as follows:

A. Corrected the manuscript again, including words and usage, to make it clear, correct, and unambiguous. We also unify the definition of age groups.

B. Revised the format of the manuscript again. The first page contains the title and authors information merely.

C. The differences among Japanese Encephalitis cases were analyzed again by SPSS software (version 20; IBM Corp., Armonk, New York). We also added SPSS software information to the manuscript. The statistical analysis results were submitted as other supporting information.

D. The uploaded figures were re-plotted in accordance with the publishing requirements, and the format of figures is TIFF, 600 DPI. All figures in the manuscript had been corrected by PACE.

#Response to reviewer 2

Reviewer #2: The authors have addressed my concerns regarding grammatical errors from the previous draft. This revised draft is much improved and easier to follow. I only have a few minor editing suggestions listed below.

Response: Thank you for the helpful comments, which have helped us a lot. In accordance with the comment, we have carefully revised the manuscript. In addition, to make sure the statistical analysis been performed appropriately and rigorously, the statistical analysis results were submitted as other supporting information. Thanks for your patient work again.

Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: I Don't Know

Response: The differences among Japanese Encephalitis cases were analyzed again by SPSS software (version 20; IBM Corp., Armonk, New York). The statistical analysis results were submitted as other supporting information.

Line 41 a high-high cluster? Should this be “a high cluster characteristic?”

Response: It is the definition of local indicators of spatial association (LISA), when the Z-score was > 1.96 (P�0.05), the distribution of JE cases was clustered, which indicated that the surrounding features had similar values (high-high or low-low).

Line 74 Can you explain non-vector transmission or give an example here?

Response: We are also concerned about the conclusion of vector-free transmission of JE virus, however, this reference entitled "Vector-free transmission and persistence of Japanese encephalitis virus in pigs" (doi: 10.1038/ncomms10832 PMID: 26902924) had described the possibility. They demonstrate that JEV can be transmitted between pigs in the absence of arthropod vectors. To keep the original meaning, we change "no vector" to "vector-free".

Line 90 Change provide to province.

Response: Change provide to province. We also recheck similar errors according to the full text.

Lines 105-106 This sentence seems redundant and should be removed, if I am understanding it correctly: “Private information had been completely erased from the original JE dataset; therefore, the data we used for this analyses no longer included names, addresses, etc.” Lines 100-101 already state that “Personal identifying factors, such as name, address and clinical information, were removed.”

Response: Lines 105-106 those sentences indeed redundant as pointed out, we deleted them. In addition, not only lines 105-106 seem redundant but also lines 107-108, however, to stress the protection of personal information, we remain lines 107-108.

Line 109 What software? ArcGIS?

Response: Add "ArcGIS" in line 109. The complete sentence is “All data were analyzed by the ArcGIS software (version 9.3; ESRI, Redlands, CA) and SPSS software (version 20; IBM Corp., Armonk, New York) automatically.”

Line 123 Change revealed to displayed.

Response: Change revealed to displayed.

Lines 125-126 Edit sentence to: A local Moran’s I coefficient >0 indicates that the data have a positive spatial correlation.

Response: Edit sentence to “A local Moran’s I coefficient >0 indicates that the data have a positive spatial correlation.”

Line 128 Edit sentence to: In addition, the Z-score and P-value were utilized for data analysis.

Response: Change Meanwhile to In addition.

Line 212 Edit sentence to: Recently, there has been a great amount of support…

Response: Edit the sentence to "Recently, there has been a great amount of support for vaccinating adults against JE."

Line 213 Change quantity to number.

Response: Change quantity to number.

Line 218 Change “respond to” to improve.

Response: We carefully analyzed these words, such as improve, reflect, and suitable for, however, we believe that the word "respond to" is clear to show the meaning we want to say.

Line 219 Edit sentence to: Although the incidence and mortality of JE have shown a downward trend in Yunnan Province…

Response: Change had to have shown.

Line 222 Remove: …which seems to be a downward trend of incidence and mortality. This is redundant.

Response: Delete this sentence.

Line 229 Edit sentence to: In a study that was reported in 2009, the infection rate of Culex tritaeniorhynchus was 13.2% [31], indicating a high level of virus activity.

Response: Edit sentence to “In a study that was reported in 2009, the infection rate of Culex tritaeniorhynchus was 13.2% [31], indicating a high level of virus activity.”

Line 231 Edit sentence to: In Tibet, during a JE epidemic, the overall seroprevalence…

Response: Edit sentence to “In Tibet, during a JE epidemic, the overall seroprevalence of JEV IgM in pigs was 5.1% [32].”

Line 232 Edit sentence to: Furthermore, JE epidemics have occurred along the border…

Response: Edit sentence to “Furthermore, JE epidemics have occurred along the border of Yunnan Province [33,34]. ”

Line 238 Edit sentence to: This study suggested that the risk of another JE epidemic occurring is still high and that prevention efforts in Yunnan Province should not be neglected.

Response: Edit sentence to “This study suggested that the risk of another JE epidemic occurring is still high and that prevention efforts in Yunnan Province should not be neglected.”

Line 242 Change any to human.

Response: Change any to human.

Line 248 Change “caused or infected” to acquired.

Response: Change “caused or infected” to acquired.

Line 249 Change discovery to diagnostic testing.

Response: Change discovery to diagnostic testing.

Line 257 Change has to have.

Response: Change has to have.

Other revisions：

A. We unify the definition of age groups. The similar various expression, such as less than 10 years old, younger 10 years old, under 10 years old, and≤ 10 years were unified with equal or less than 10 years old, abbreviated as LEQ10; in addition, these versions of age groups, such as older than 10 years, greater than 10 years, above 10 years, and>10 years were unified with greater than 10 years, abbreviated as GTR10. We re-plotted the figures based on the revisions.

B. Delete the line 244 word “Although”. Edit line 244 sentence to “The JE cases were not randomly distributed [36], they also show the same characteristics in Yunnan Province, especially in the areas of Jinghong City, Guangnan County, Yanshan County, Funing County, and Mengzi City, which are hot spots for the JE epidemic.”

C. Change pmid to PMID in references.

Attachment

Submitted filename: Response to Reviewers.rtf

Click here for additional data file. (97.3KB, rtf)

Decision Letter 2

Tian Wang

30 Mar 2020

The spatiotemporal distribution of Japanese Encephalitis cases in Yunnan Province, China, from 2007 to 2017

PONE-D-19-35285R2

Dear Dr. Mao,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Tian Wang, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Tian Wang

1 Apr 2020

PONE-D-19-35285R2

The spatiotemporal distribution of Japanese Encephalitis cases in Yunnan Province, China, from 2007 to 2017

Dear Dr. Mao:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Tian Wang

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Data. Spatiotemporal distribution and geographical distribution.

    (XLS)

    Click here for additional data file. (38KB, xls)
    S2 Data. Annual incidence and mortality.

    (XLSX)

    Click here for additional data file. (8.5KB, xlsx)
    S3 Data. Monthly cumulative cases.

    (XLSX)

    Click here for additional data file. (8.3KB, xlsx)
    Attachment

    Submitted filename: rebuttal letter.docx

    Click here for additional data file. (35.8KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.rtf

    Click here for additional data file. (49.8KB, rtf)
    Attachment

    Submitted filename: Response to Reviewers.rtf

    Click here for additional data file. (97.3KB, rtf)

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files. The JE data used in this study were obtained from the China Information System for Diseases Control and Prevention (available at http://www.phsciencedata.cn/).

    Articles from PLoS ONE are provided here courtesy of PLOS

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