Trends and spatial distribution of animal bites and vaccination status among victims and the animal population, Uganda: A veterinary surveillance system analysis, 2013–2017

Fred Monje; Daniel Kadobera; Deo Birungi Ndumu; Lilian Bulage; Alex Riolexus Ario

doi:10.1371/journal.pntd.0007944

. 2021 Apr 19;15(4):e0007944. doi: 10.1371/journal.pntd.0007944

Trends and spatial distribution of animal bites and vaccination status among victims and the animal population, Uganda: A veterinary surveillance system analysis, 2013–2017

Fred Monje ^1,^*, Daniel Kadobera ¹, Deo Birungi Ndumu ², Lilian Bulage ¹, Alex Riolexus Ario ¹

Editor: Daniel Leo Horton³

PMCID: PMC8084341 PMID: 33872314

Abstract

Rabies is a vaccine-preventable fatal zoonotic disease. Uganda, through the veterinary surveillance system at National Animal Disease Diagnostics and Epidemiology Centre (NADDEC), captures animal bites (a proxy for rabies) on a monthly basis from districts. We established trends of incidence of animal bites and corresponding post-exposure prophylactic anti-rabies vaccination in humans (PEP), associated mortality rates in humans, spatial distribution of animal bites, and pets vaccinated during 2013–2017. We reviewed rabies surveillance data at NADDEC from 2013–2017. The surveillance system captures persons reporting bites by a suspected rabid dog/cat/wild animal, human deaths due to suspected rabies, humans vaccinated against rabies, and pets vaccinated. Number of total pets was obtained from the Uganda Bureau of Statistics. We computed incidence of animal bites and corresponding PEP in humans, and analyzed overall trends, 2013–2017. We also examined human mortality rates and spatial distribution of animal bites/rabies and pets vaccinated against rabies. We identified 8,240 persons reporting animal bites in Uganda during 2013–2017; overall incidence of 25 bites/ 100,000population. The incidence significantly decreased from 9.2/100,000 in 2013 to 1.3/100,000 in 2017 (OR = 0.62, p = 0.0046). Of the 8,240 persons with animal bites, 6,799 (82.5%) received PEP, decreasing from 94% in 2013 to 71% in 2017 (OR = 0.65, p<0.001). Among 1441 victims, who reportedly never received PEP, 156 (11%) died. Western region had a higher incidence of animal bites (37/100,000) compared to other regions. Only 5.6% (124,555/2,240,000) of all pets in Uganda were vaccinated. There was a decline in the reporting rate (percentage of annual district veterinary surveillance reports submitted monthly to Commissioner Animal Health by districts) of animal bites. While reported animal bites by districts decreased in Uganda, so did PEP among humans. Very few pets received anti-rabies vaccine. Evaluation of barriers to complete reporting may facilitate interventions to enhance surveillance quality. We recommended improved vaccination of pets against rabies, and immediate administration of exposed humans with PEP.

Author summary

Rabies is a deadly viral disease, that is transmitted mainly by dog bites. Globally at least 59,000 deaths are reported to occur annually- mostly in Sub-Saharan Africa and Asia. However, rabies can be prevented through vaccination of pets (dogs and cats) and administration of rabies vaccine in humans exposed to rabies. In our study we reviewed secondary data of animal bites and rabies captured at the National Animal disease diagnostic epidemiology centre in Entebbe for the period 2013–2017. We found that of 1441 animal bite victims who never received rabies vaccine, only 156 (11%) died hence need for immediate administration of exposed humans with rabies and sensitization of the public about the consequences of animal bites and need for urgent health care. There was a decline in the reporting rate of animal bites during the study period suggesting that evaluation of the barriers to complete reporting may facilitate interventions to enhance surveillance quality. Less than 10% of the pets in the Uganda were vaccinated against rabies hence need for improved vaccination of pets against rabies through appropriated legislation.

Introduction

Rabies is a fatal viral vaccine-preventable zoonotic disease that can infect warm-blooded animals [1–3]. Worldwide, canine rabies causes an estimated 59,000 human deaths and 8.6 billion USD (95% CIs: 2.9–21.5 billion) in economic losses annually [3]. Rabies is transmitted primarily through bites from an infected rabid animal; however, it can also be transmitted from licks or scratches from an infected rabid animal or, rarely, through transplantation of tissues or organs from an infected individual [4–6]. Rabies occurs on all continents except Antarctica, with most cases reported in Africa and Asia [7, 8]. Nearly all cases of human rabies are due to bites from infected dogs [7]. In dogs, the incubation period of rabies is 10 days to 6 months, with most cases manifesting signs between 2 weeks to 3 months after exposure [9]. In humans, the average incubation period of rabies is 20–60 days, though it can last up to several years [6, 10].

Prevention of rabies in animals is primarily achieved through vaccination. Indeed, in developed countries, mass canine vaccination coupled with oral vaccination in wildlife have greatly contributed to the elimination of rabies in canines, and consequently a reduction in human rabies [7]. In humans, rabies prevention typically occurs through rabies Post-Exposure Prophylaxis (rPEP) in the form of a rabies vaccine. This vaccine should be administered to victims of bites from suspected rabid animals as soon as possible, and continued while the animal is being observed for 10–14 days or pending the results of laboratory tests [6]. However, rPEP requires multiple doses, is not always available, and must be administered in a timely manner to be effective. The most cost-effective method of controlling rabies is to prioritize canine vaccination, rather than using reactive rPEP in humans [7].

In Uganda, Ministry of Agriculture, Animal Industry and Fisheries (MAAIF) procures anti-rabies vaccine annually to control rabies in animals, though in limited doses [11]. This vaccine is provided to districts based on the magnitude of reported animal bites, the dog population in the district, and confirmed rabies cases in pets. Historically, MAAIF has allocated about 2,000 doses of anti-rabies vaccine for pets to each of the districts in Uganda affected by rabies. This is generally insufficient for the estimated pet populations in each of the districts. While people are able to obtain human rabies vaccine (rPEP) from private providers (such as pharmacies, private health centres) following exposure to a suspected rabid animal, the cost ($8–12 USD per dose) is prohibitive for most [12].

Among humans, an animal bite is treated as being from a rabid animal, until proved otherwise. Surveillance data of animal bites among humans provides vital information to guide resource allocation in the control and prevention of rabies [13]. An analysis of human rabies surveillance data from the Epidemiology and Surveillance Division (ESD) of the Ministry of Health in 2001–2015 in Uganda revealed 208,720 animal bites, with 486 suspected human rabies deaths [14]. However, Uganda also captures rabies-related data in a veterinary surveillance system, at National Animal Disease Diagnostic Epidemiology Centre (NADDEC) to aid in animal disease monitoring and surveillance. Beyond capturing animal bites and suspected human rabies deaths, NADDEC also captures the number of pets vaccinated against rabies (including by private providers) and conducts confirmatory tests of suspected rabid animals. We used data from NADDEC to describe trends in the incidence of animal bites and corresponding rPEP in humans, mortality associated with animal bites in humans, spatial distribution of animal bites, and pets vaccinated in Uganda from 2013–2017.

Methods

Ethics statement

We got verbal permission to conduct this investigation from the NADDEC, of the Ministry of Agriculture, Animal Industry and Fisheries. Additionally, CDC determined that this investigation was a public health emergency activity whose primary intent was to control rabies at the source (animals) such that exposure and transmission to humans is curtailed, and therefore it was classified as not research.

Study setting and design

We conducted the study using national surveillance data from National Animal Disease Diagnostics and Epidemiology Centre (NADDEC) of the Ministry of Agriculture, Animal Industry and Fisheries. When a bite from a suspected rabid animal is reported in the communities, Uganda guidelines require that it must be immediately reported as soon as possible to the nearest veterinary officer or animal husbandry officer at the sub-county headquarters. The officer visits the scene of the incident, assesses the circumstances under which the victim was bitten and the vaccination history of the dog/cat at the time of the incident, and advises whether or not the suspected rabid animal (usually dog/cat) should be killed and its head packaged for shipment to NADDEC for laboratory testing. Meanwhile, the veterinary officer/animal husbandry officer writes a referral letter for the victim to receive rPEP at the nearest health facility (usually Health centre IV, Hospital, or Referral Hospital). At the health facility, there are usually limited doses of human rabies vaccine and rabies immunoglobin. The standard rPEP regimen against rabies in Uganda is administered on days 0, 3, 7, 14, and 28 into the deltoid muscle. However, there is no data on the total number of doses received. If the veterinary/AH officer issues a referral letter for rPEP to the bite victim, who fails to attend the health facility, or there is no vaccine/RIG available on arrival at the facility, then this is recorded as “did not receive rPEP”. A monthly sub-county report with all the animal bites is compiled by the officer and shared with the District Veterinary Officer (DVO), for compilation and entry into a standard veterinary surveillance form. The DVO then submits a district monthly veterinary surveillance report to the Commissioner for Animal Health (CAH), and NADDEC for compilation. In case any human death occurs weeks or months after the bite, this data is gathered and reported through the health facility system (health management information system). Additionally, there is a system of reporting suspect human rabies cases by health facility back to the veterinary or AH officer who also reports it through the DVO to CAH and NADDEC. The human rabies data for suspect human cases are based solely on clinical presentation. The findings from veterinary disease data are intended to be shared with the districts through annual DVO meetings [15].

We carried out a retrospective descriptive study involving review of rabies data captured in standard veterinary surveillance forms at NADDEC during 2013–2017 from all districts in Uganda. We extracted rabies-specific variables from standard veterinary surveillance forms at NADDEC. For example: date (month and year), district name, number of suspected cases in animals, number of bites by suspected animals, number of cases in humans (deaths and emergency vaccinations), vaccinations in dogs and cats, and number of pets destroyed. We excluded all records that had had missing variables such as district name and date. To understand more about the completeness of reporting, we also captured information about the number of monthly surveillance reports expected in a year at NADDEC, and number of reports actually received.

To get information about confirmed rabies cases in animals during 2013–2017, we reviewed NADDEC laboratory records for rabies testing for suspected animals. Rabies diagnosis was conducted on animal brain tissue using the direct fluorescent antibody test (dFAT, Onderstepoort Veterinary Institute, Pretoria, South Africa) at NADDEC [16].

Data management and analysis

We extracted monthly epidemiological rabies data from standard veterinary surveillance forms at NADDEC into Microsoft Excel and cleaned it before analysis. During, analysis we computed proportions, percentages and rates. We calculated annual and overall incidence of animal bites by using number of new cases as a numerator and total human population at risk as a denominator during 2013–2017. We drew maps using Quantum Geographic information system (QGIS) to demonstrate geographical distribution of animal bites by district. From the NADDEC data, we computed the annual trends in rPEP and mortality rates in humans associated with animal bites in the period 2013–2017. We also computed the proportion of pets vaccinated against rabies during the period 2013–2017, using pet population data obtained from the Uganda Bureau of Statistics from a 2008 census [17]. To do a trends analysis, we used logistic regression in Epiifo version 7.2.2.6.

Results

We identified 8,240 reports of animal bites in Uganda during the study period, with an overall incidence of 25 animal bites per 100,000 population. The annual incidence significantly decreased from 9.2/100,000 in 2013 to 1.3/100,000 in 2017 (OR = 0.62, p = 0.0046) (Fig 1). Animal bites were reported in almost all districts during 2013-2017in Uganda (Fig 2). Western region had the highest incidence of animal bites (37/100,000), followed by Northern region (22/100,000), Central region (17/100,000), and Eastern region (17/100,000) (Fig 3). These differences were largely driven by differences in reported bites during 2013 and 2014; reported incidences were much lower among all regions during 2015–2017 (Fig 3). Laboratory data indicated that 36% (28/77) of the brain samples from suspected rabid animals tested positive for rabies during the study period.

Fig 1 — The Long Dash Dot line represents the incidence of animal bites (/100,000) in humans. The Solid line represents the anti-rabies vaccinations in humans. The Long Dash line represents the mortality rates in humans following a bite from a suspected rabid animal. The Square Dot line represents the reporting rates per year.

Fig 2 — The variation in incidence of animal bites (/100,000) per district from 0.21–183.

Fig 3 — The Solid line represents incidence of animal bites (/100,000) in Western region. The Long Dash Dot line represents incidence of animal bites (/100,000) in Northern region. The Square Dot line represents incidence of animal bites (/100,000) in Central region. The Long Dash line represents incidence of animal bites (/100,000) in Eastern region.

Of the 8,240 human animal bite victims, 6,799 (82.5%) reportedly obtained rPEP. The number of doses of rPEP initiated was not recorded- instead what was captured was whether rPEP was initiated or not. The percentage obtaining rPEP after the bite decreased from 94% in 2013 to 71% in 2017 (OR = 0.65; p<0.001) (Fig 1). Among all human animal bite victims, 156 (1.9%) died. The annual reported mortality rates among bitten humans decreased from 3.0% in 2013 to 0.21% in 2017 (OR = 0.58, p = 0.08) (Fig 1). Of the 2,221,620 pets, 6,997 (0.31%) were reported destroyed by the communities following infliction of bite injuries to humans; the proportion reported destroyed by the communities rose from 62% in 2013 to 69% in 2017 (OR = 1.2; p = 0.095) (Fig 4). During the study period, 124,555 rabies vaccines were provided for the estimated 2,221,620 pets (1,580, 930 dogs and 640,690 cats) in Uganda, resulting in a maximum of 5.6% of pets vaccinated. Of the 6,576 monthly veterinary reports expected from the districts, only 2,517 (38%) overall were received during the study period. The percentage of expected reports received decreased from 73% in 2013 to 19% in 2017 (OR = 0.67, P<0.001) (Fig 1).

Fig 4 — The Solid line represents biting animals. The Long Dash Dot line represents pets destroyed.

Discussion

We describe veterinary surveillance data for suspected rabies in Uganda, which shows changes in the regularity of district-level reporting of data and bite-associated human mortality in Uganda during 2013–2017. In addition, the proportion of bitten persons receiving rPEP decreased over time. Most of the animal samples tested did not test positive for rabies.

Although the data in this report appear promising for rabies reduction in Uganda, reporting rates (percentage of annual district veterinary surveillance reports submitted monthly to Commissioner Animal Health by districts) over the study period decreased greatly. During 2013 and 2014 in Uganda, active animal disease surveillance was being supported by donors, including the Pan African Control of Epizootics (PACE) and others [18]. This enabled district veterinary officers to physically bring hard-copy monthly reports to CAH, and hence to NADDEC, which improved the completeness of reporting and likely provided a more accurate picture of each of the metrics included in NADDEC rabies reporting. This support ended in 2015, which drastically affected not only rabies surveillance and reporting, but also other district-level animal disease reporting in Uganda. Other studies have also shown that passive surveillance for rabies results in underreporting [19], particularly in developing countries [3, 20]. Analysis of ESD rabies surveillance data from 2001–2015 found that animal bites were increasing in Uganda [14], and it is reasonable to assume that complete reporting in NADDEC might have shown a similar trend. Perhaps the use of eHealth and mobile technology could improve the efficiency and timeliness of case reporting as has been demonstrated elsewhere without increasing cost [21, 22]. A full evaluation of both rabies surveillance systems and the challenges to complete reporting is important to enable the system to contribute to its fullest extent in Uganda.

Regardless, findings from this study provide important information for Uganda. Vaccinating pets is one of the most important ways to prevent rabies infections among both animals and humans [7, 23]. However, there are clear gaps in pet vaccination in Uganda; fewer than one in ten pets were vaccinated in our analysis. This may be due in part to the limited quantities of anti-rabies vaccine procured by MAAIF for the districts [11]. However, a review of other studies highlights that most dogs are accessible for vaccination [24]. Furthermore, a sufficient proportion of dogs in most African communities are amenable to handling for parenteral vaccination [24]. One study indicated that the total dog population in Uganda may be less than previously estimated, although their findings were based on modelling using a small fraction of the entire population [25]. Though a relatively small fraction of regions were sampled in this study, the methods appear statistically sound and the power of the sample size adequate, which would have enabled valid estimation of the national population. A detailed Livestock census conducted by the Uganda bureau of Statistics in collaboration with the Ministry of Agriculture Animal industry and Fisheries estimated that the dog population was 1,580, 930 and cat population was 640, 690[17]. The initial estimate of the study at 1.3 million dogs is not hugely dissimilar to that of the livestock census at 1.6 million dogs. In view of the differences from these two estimates, we shall consider the Livestock census the more valid option for purposes of this study. Ultimately whether the total dog population is estimated at 0.7 million, 1.3 million or 1.6 million, the conclusion remains the same; dog vaccination in Uganda is inadequate and a systematic national dog vaccination campaign is needed.

A study in rural Uganda indicated that over 80% of dogs could be vaccinated in a pilot campaign through Static Point vaccination [26]. Another study pointed out that rabies control can be achieved with sufficient vaccination rates: a study modelling the minimum dog vaccination coverage required for interruption of transmission of rabies in humans in Ndjamena, Chad showed that only 71% of dogs would require vaccination [27]. Mass oral rabies vaccination for free-ranging dogs (OVD), which has been researched and promoted by WHO since 1988, should also be a part of the rabies control strategy [28].

While the total numbers of biting animals reported declined, the proportion of biting animals destroyed appeared to increase slightly throughout the study period. However, not all biting pets were destroyed. The accuracy of these data is unclear. Some biting pets might have escaped before the community had an opportunity to kill them; this is a common occurrence [29, 30]. The community might also have destroyed the pet but not reported it to the DVO, as has been reported to occur elsewhere [12]. A follow up evaluation of knowledge, attitudes and practices around animal bites in the communities may be necessary to understand this issue more fully.

Most persons bitten by pets in our study received rPEP. In Uganda, rPEP is provided by government and can easily be found at high-level health centers and hospitals. However, the proportion of persons receiving rPEP in Uganda after a bite declined over the study period. The reasons for this are unclear but may relate to changes in availability at government health centers. In some areas, although rPEP is supposed to be provided free of charge, patients may be charged regardless, which can impact uptake. At least one study has shown that the costs of rPEP are typically underestimated [12]. Alternately, changes in healthcare-seeking behaviors may have occurred that resulted in the decline; however, further qualitative investigation would be needed to identify these. In Haiti, methods of Integrated Bite Case Management (IBCM) have shown considerable benefits in improving the investigation of suspect rabies cases [31, 32]. Probably methods of IBCM could also be of benefit in Uganda to increase compliance with rPEP in cases of highest risk.

Furthermore, our findings indicated that approximately 1/3 of animals tested had rabies. The heads that were sent for testing likely reflect animals that had a higher pre-test probability of having rabies, thus this proportion is likely to be an overestimate of overall rabies infection among animals biting humans. In addition, among persons who did not receive rPEP, few died, suggesting that most of the animals biting might not have rabies. This is consistent with other studies that have shown that most biting animals do not have rabies [32]. However, it is also possible that some animal bite victims accessed rPEP from private health facilities and were not captured in the rabies surveillance system in the veterinary sector. It is also possible that deaths due to suspected rabies could have been missed in surveillance, as rabies has a varied incubation period (three weeks to several years) and may not have been properly recognized and reported [6, 10]. A more detailed investigation and follow-up of persons bitten by animals, as well as active surveillance to track rPEP, could inform this issue.

Although animal bites were reported throughout Uganda, Western region had the highest incidence of animal bites during the study period. This may be due to its proximity to the Democratic Republic of Congo (DRC), which reported alarming numbers of people bitten by rabid dogs in 2013 [33, 34]. The thick forests of eastern DRC that border Uganda may shelter reservoirs of rabies such as jackals, and serve as sources of cross-border infections [34]. In rabies elimination efforts in Uganda, this area may need special attention.

Limitations

We were unable to link individual rPEP results to outcomes, preventing us from knowing if persons who died did or did not receive rPEP. We also did not have data about their causes of death, making it uncertain if they died from rabies. Beyond this, we did not have recent data about the number of pets in Uganda, nor about changes over time, and could only access a single value for pet numbers from the year 2008. The increase in human population in Uganda almost certainly indicates an increase in pets as well, which would have led to overestimations of vaccination rates. In addition, there was substantial underreporting, which almost certainly led to an underestimation of the magnitude of the animal bites and hence rabies in our study.

Conclusions and recommendations

Animal bites decreased in Uganda, with western Uganda having the highest bite rate. Rabies PEP receipt among bite victims decreased over time, and overall, very few pets received anti-rabies vaccine nationwide. There was a decline in the reporting rate (percentage of annual district veterinary surveillance reports submitted monthly to Commissioner Animal Health by districts) during 2013–2017. Evaluation of barriers to complete reporting may facilitate interventions to enhance surveillance quality. We recommended improved vaccination of pets against rabies through legislation, immediate administration of exposed humans to post-exposure anti-rabies vaccine, and sensitization of the public about the consequences of animal bites and need for urgent health care.

Acknowledgments

The authors are indebted to the Uganda’s National Animal Disease Diagnostic Epidemiology Centre (NADDEC) of the Ministry of Agriculture, Animal Industry and Fisheries (MAAIF), for providing access to the rabies surveillance data and laboratory results of animal samples. We also appreciate Uganda Public Health Fellowship for the technical support during the design, analysis, and interpretation of this study. We thank PHFP cohort 2018 Fellows for the technical support during the execution of this study. The views and opinions expressed in this article are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention, the Department of Health and Human Services, Makerere University School of Public Health, or the MoH.

Data Availability

The datasets upon which our findings are based are owned by the government of Uganda. To access this dataset, we can contact the rabies focal person, Dr. Moses Mwanja, Email: drmwanja@gmail.com.

Funding Statement

This project was supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) through the US Centers for Disease Control and Prevention Cooperative Agreement number GH001353–01 and through Makerere University School of Public Health to the Uganda Public Health Fellowship Program, MoH. The staff of the funding body provided technical guidance in the design of the study, ethical clearance and collection, analysis, and interpretation of data and in writing the manuscript.

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PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0007944.r001

Decision Letter 0

Sergio Recuenco, Amy T Gilbert

5 Feb 2020

Dear Dr Monje,

Thank you very much for submitting your manuscript "Trends and spatial distribution of animal bites and vaccination status among victims and the animal population, Uganda: A veterinary surveillance system analysis, 2013 – 2017" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

The authors report on a timely and important topic that will be of interest to all authorities and others involved in neglected tropical diseases and in particular the global tri-partite agenda to end human rabies deaths mediated by dogs by 2030. Reports such as this one are important to call attention to the diagnostic, infrastructure and/or reporting gaps which could compromise efforts towards the global goal. Nevertheless, the methods of the current study are incompletely described and referenced, which call the validity of the results and conclusions into question. Please provide the necessary level of detail in the methods so that the study may be reproducible by others. The Discussion should also address the limitations of the data analysis more clearly and acknowledge how this study advances knowledge in the context of other recent and relevant background literature highlighted by the reviewers.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the 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.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Amy T. Gilbert

Guest Editor

PLOS Neglected Tropical Diseases

Sergio Recuenco

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Line 122 – please include some brief information about the services available at the health facilities – was rabies immunoglobulin available in any regions during the study period? Were human rabies vaccines widely available throughout the study period or were there shortages? Please describe the standard PEP regimen used in Uganda during the study period. Is there any data available for the total number of doses received?

Line 122 - If the veterinary/ AH officer issues a referral letter for PEP, but then that bite victim does not attend the health facility, or there is no vaccine/RIG available when they arrive there, how is this recorded in the data? If this still gets recorded as ‘received PEP’, then rates of rPEP uptake may be overestimated. This should be clearly stated in the methods, but also as a limitation when interpreting the results around PEP compliance.

Line 124 – Is it possible to include the standard surveillance form as Supplementary Materials?

Line 128 – It is not clear how the ‘survival status of the bitten human’ is reported. The data for the study is described as being gathered by the veterinary officer/animal husbandry officer at the time of the bite and then reported through the DVO and CAH to NADDEC. As any human death would occur weeks or months after the bite, how is this data gathered and reported? Although some information is provided in the Limitations (Line 255 – 256), please state in the methods whether the human rabies data is for suspect human cases based solely on clinical presentation or confirmed by laboratory diagnosis. Is there a system of reporting suspect human rabies cases by hospitals back to the veterinary or AH officer who then reported it through the DVO to CAH to NADDEC or was this data reported to NADDEC by the Department of Health? Please clarify the methods around this data.

Line 134 – Please state what the key variables were. For example I assume if the vaccination status of the animal were missing, the record was not excluded.

Reviewer #2: The objectives and population of the study are clearly written in the methods section with plain language. The authors present a simple analysis of national level surveillance data from a veterinary public health reporting system. Some specific areas for revision include the following:

Line 134: What are the key variables? Indicate completeness of data in the results in addition to overall reporting rates

Line 136: How are the number of expected reports calculated?

Line147: How does total human population at risk differ from total population?

Reviewer #3: My main concern regarding the present manuscript is in the methods section, which is poorly described and I missing a lot of information. The authors need to provide details on how the study was designed, and the statistical methods used.

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: 164 – 165 – Please include how the incidence of rabies in animals change during the study period. It would also be beneficial to plot the geographic animal rabies incidence by year on Figure 2, perhaps as a bubble plot on top of the choropleth map of bite incidence.

Line 167 – Was the number of doses of rPEP recorded, or only that they received the first dose?

Line 169 – 170 – Is there correlation between the geographic and temporal distribution of animal rabies cases and that of human rabies? Again some information about the geographic incidence of human rabies cases, like for animals, would be important to include.

Line 169 – 171 – Please also include the number of human deaths with the percentages.

Line 175 – The estimate of 2.2 million owned dogs should be compared with the analysis published by Wallace et al (2017), which estimated 730,000 owned dogs in Uganda.

Line 175 - The use of population estimates is not recommended as a basis for estimating vaccination coverage (Sambo et al 2017), however the point that insufficient dog vaccinations are taking place in Uganda is valid. A national vaccination coverage is also very misleading as it gives no indication of the heterogeneity of vaccination effort across the country. Intensive regions of vaccination are most important in the early stages to develop experience and methods before expanding nationally, however this would not be clear from only reporting a nationally low vaccination coverage. A recent paper (Evans et al 2019) reported high vaccination coverage through a static point vaccination approach in Nwoya District.

Figure 1 – This figure is generally cumbersome for the reader to interpret, moving between two axis, the colour legend and the line graphs, as well as percentages with different denominators. It is also difficult to make any interpretation of mortality rate which is too small on the scale and has no reference to what this proportion is relating to (i.e. percentage mortality in bite victims). I think this graph would therefore be more effective and impactful if split into at least two graphs. Perhaps a staked bar graph with total number of animal bite cases (y-axis) by year (x-axis), with bars coloured to show the number of cases within these that received rPEP. Human mortality rate could also be shown on this graph as a line graph on a second y-axis of total human deaths by year. I think reporting rate should be displayed on a second figure with additional explanation about what this relates to e.g. Percentage of reports received from district as compared to the expected number of reports.

REFERENCES

Wallace, R.; Mehal, J.; Y, N.; S, R.; B, B.; M, O.; V, T.; JD, B.; A, G.; J, W. The impact of poverty on dog ownership and access to canine rabies vaccination: Results from a knowledge, attitudes and practices survey, Uganda 2013. 2017, 1–22.

Sambo, M.; Johnson, P.C.D.; Hotopp, K.; Changalucha, J. Comparing Methods of Assessing Dog Rabies Vaccination Coverage in Rural and Urban Communities in Tanzania. 2017, 4.

Evans, M.J.; Burdon Bailey, J.L.; Lohr, F.E.; Opira, W.; Migadde, M.; Gibson, A.D.; Handel, I.G.; Bronsvoort, B.M. d. C.; Mellanby, R.J.; Gamble, L.; et al. Implementation of high coverage mass rabies vaccination in rural Uganda using predominantly static point methodology. Vet. J. 2019, 249, 60–66.

Reviewer #2: Results from the analysis are presented clearly. Figures and legends could use some additional information for clarity. There are some concerns for the completeness (only 38% of jurisdictions reported, bite events might not be linked to fatal rabies outcomes) and correctness (incidence was calculated from unverified dog population and outdated census information). Many of the trends reported in the results are likely influenced by a change in reporting over the five year period. Specific areas for revision include:

Would suggest breaking down the number of pets into dogs and cats specifically

Figure 2: Do these administrative divisions represent districts or regions? I suggest the legend be updated to include this information. Since regions are mentioned in the text it would be helpful to the reader if the regional borders are shown here. May be helpful to include a layer for water (lake Victoria) and large cities

Line 167: Clarify if receiving rPEP mean the individual completed the entire 4/5 dose series?

Line 171-173: Where does the 2.24M pets number come from? Is that the entire pet population of Uganda? Please clarify how the 62% of dogs destroyed but communities was calculated

Conclusions:

Line 237-238: Stating that because only a few of he persons bitten by animals died could be misinterpreted by readers that rPEP should not we a concern after a bite

Line 247-250: given the low levels of dog vaccination presented here there are likely numerous endemic factors that could lead to higher rabies rates in addition to only importation

Reviewer #3: My main concerns in the results section is how the statistical analysis was performed. I do not know if the authors used appropriated statistical tests.

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Line 181 – 183 – I think these headline conclusions need to be given more context from the outset as it seems the decline in bite cases could be explained by the decline in reporting during the study period as opposed to a true decline in incidence. It would be important to also give the human mortality data more context; perhaps that there was a decline in the proportion of bite victims which were reported to have died of rabies (depending on how the human rabies death data was gathered).

Line 183 – 184 – The fact that most of the animal samples did not test positive for rabies does not give us any information about the rabies situation. Higher rates of negative results are expected as mentioned in the discussion. It would be more relevant to report any change in animal rabies incidence over time.

Line 198 – 200 – Perhaps the use of eHealth and mobile technology could improve the efficiency and timeliness of case reporting as has been demonstrated elsewhere without increasing cost? (Mtema et al 2016, Gibson et al 2018)

Line 206 – 208 – The reference cited here (Lembo et al 2010) is a review which highlights that most dogs are accessible for vaccination as opposed to this being a major limitation. Several studies show that a sufficient proportion of dogs in most African communities are amenable to handling for parenteral vaccination. The Wallace et al (2017) study indicates that the total dog population in Uganda may be less than previously estimated and Evans et al (2019) indicate that over 80% of dogs could be vaccinated in a pilot campaign through Static Point vaccination. These studies should be included in the discussion of the results of this paper and help to consider the prospects for rabies control in Uganda.

Line 224 – 232 – Methods for Integrated Bite Case Management (IBCM) have shown considerable benefits in improving the investigation of suspect rabies cases (Etheart 2017, Medley 2017). It would be worth considering in the discussion if these could also be of benefit in Uganda to increase compliance with PEP in cases of highest risk.

Line 254 – 256 – Here it states that it was not possible to know if the person who died did or did not receive rPEP, however in Line 237 – 238 it states that few people of those who did not receive PEP, few died. This seems contradictory if it is known who of the people who did not receive PEP died. This stems from the lack of clarity around how the human rabies incidence data was obtained. Please clarify.

REFERENCES

Mtema, Z.; Changalucha, J.; Cleaveland, S.; Elias, M.; Ferguson, M.; Halliday, J.E.B.; Haydon, D.T.; Jaswant, G. Mobile Phones As Surveillance Tools : Implementing and Evaluating a Large-Scale Intersectoral Surveillance System for Rabies in Tanzania. PLoS Negl. Trop. Dis. 2016, 1–12.

Gibson, A.D.; Mazeri, S.; Lohr, F.; Mayer, D.; Burdon, J.L.; Wallace, R.M.; Handel, I.G.; Shervell, K.; Bronsvoort, B.M.; Mellanby, R.J.; et al. One million dog vaccinations recorded on mHealth innovation used to direct teams in numerous rabies control campaigns. PLoS One 2018, 13.

Etheart, M.D.; Kligerman, M.; Augustin, P.D.; Blanton, J.D.; Monroe, B.; Fleurinord, L.; Millien, M.; Crowdis, K.; Fenelon, N.; Wallace, R.M. Effect of counselling on health-care-seeking behaviours and rabies vaccination adherence after dog bites in Haiti , 2014 – 15 : a retrospective follow-up survey. Lancet Glob. Heal. 2017, 5, e1017–e1025.

Medley, A.; Millien, M.; Blanton, J.; Ma, X.; Augustin, P.; Crowdis, K.; Wallace, R. Retrospective Cohort Study to Assess the Risk of Rabies in Biting Dogs, 2013-2015, Republic of Haiti. Trop. Med. Infect. Dis. 2017, 2, 14.

Reviewer #2: The conclusions presented by the author are not fully supported by the data. While they do note several limitations, they are understated and could lead to the results of the manuscript being taken out of context. The authors do present reasons why this type of analysis is important in Uganda and for others working in public health in low resource settings. Specific comments include:

Line 237-238: Stating that because only a few of he persons bitten by animals died could be misinterpreted by readers that rPEP should not we a concern after a bite

Line 247-250: given the low levels of dog vaccination presented here there are likely numerous endemic factors that could lead to higher rabies rates in addition to only importation

Reviewer #3: (No Response)

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: Line 59 – amend to ‘rabies causes an estimated 59,000 deaths’ as opposed to ‘at least’.

Line 68 – 73 – Long sentence, suggest splitting in two for readability.

Reference formatting needs to be reviewed throughout the References section. Some examples include References 9, 11, 12, 17, 18, 26, 29, 30.

Punctuation should be reviewed throughout. E.g. Line 148, Line 153.

Reviewer #2: Minor revisions. Suggest the authors review the text and change some terms to be more in line with the scientific literature (e.g. destroying dogs to euthanasia). Some references are not peer-reviewed

Reviewer #3: Major revision

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: Congratulations to the authors on this relevant study which describes the current rabies surveillance activities in Uganda. The manuscript is well written and the results are of relevance to continuing to develop comprehensive rabies surveillance systems in Uganda and other East African countries. Inclusion of the temporal and geographic distribution of both human and canine rabies incidence is crucial to the study and to planning a national dog vaccination initiative. This data would be of benefit as it would be logical and cost-effective to first scale intensive dog vaccination efforts in districts with the greatest human burden, generating effective methods and demonstrating examples of success to apply elsewhere in the country.

The source of human rabies incidence data is not clear in the current manuscript which makes interpretation of these results difficult. The lack of information around whether bite victims received a single dose or full course of rPEP and the potential for over-reporting rPEP uptake as described in comments is a concern for interpreting the results. It would be of great concen if a high proportion of bite victims who have been exposed to a rabid dog only take a single dose of rPEP, whereas compliance in victims who were bitten by vaccinated, healthy pet dogs would be of less concern. The use of basic IBCM protocols could help to generate a more complete picture of rabies exposures and PEP compliance in different risk groups. This appears to be the top priority for reducing risk to rabies through existing health care resources.

Reviewer #2: The authors present a summary of veterinary surveillance data for animal bites and rabies prevention efforts in Uganda for a 5-year time period. The data includes both periods of active and passive surveillance in the national system that is marked by a significant decrease in reporting. Data for incidence and proportion used national census data for both humans and animals. The data, which are largely incomplete, show a related downward trend in both animal bite incidence and reporting. The authors also summarize animal specimens tested for rabies, persons receiving post exposure prophylaxis, and community culling of aggressive dogs.

The manuscript was well-written using plain language. It provides new information from systematically collected data from an area of the world where it is difficult to come by. The content will be useful to public health officials and researchers who work on rabies in Africa and other low-resource setting.

The limitations of the data used in this study are presented in the results and discussion sections but may not be properly emphasized. This could lead to the publication being improperly cited. I would suggest the authors provide more detail.

Reviewer #3: In the manuscript entitled “Trends and spatial of animal bites and vaccination status among victims and the animal population, Uganda: A veterinary surveillance system analysis, 2013–2017”, the authors describe important results regarding incidence and spatial distribution of animal bites, PEP use, and mortality rates due to rabies disease in Uganda. However, the manuscript is missing important and precise information on the methods and a weak discussion and conclusion. Please, see my specific comments below.

Introduction

Line 58: All mammals? Is it not too much?

Line 64: I recommend changing the word “Almost” for something like…

Lines 65-73: I don’t think is necessary to describe the clinical course of the disease in dogs and humans. I recommend suggest deleting the entire paragraph.

Line 75: “Prevention of rabies in animals is primarily achieved through vaccination”. This is the focus of your manuscript.

Lines 92-93: Please clarify why the cost of rabies vaccine is “prohibitive”.

Lines 95-96: This first sentence looks confuse. Please rewrite to have a better flow, or I recommend deleting this sentence.

Lines 101-102: “However, Uganda also captures rabies-related data in a veterinary surveillance system, at National Animal Disease Diagnostic Epidemiology Centre (NADDEC)”. I think this sentence seems disconnected. However, Uganda also captures rabies-related data, and…? I recommend merging with the next sentence to have a better flow.

Line 103: Please clarify “mandated”.

Major: The introduction section is too long and makes it lose the main focus of the manuscript. My suggestion is to delete some excessive information and focus on what your study brings of most important.

Methods

Lines 117-118: “The officer visits the scene of the incident to ensure that the animal (usually dog/cat) is killed and its head packaged for shipment to NADDEC for analysis”. The office always kills the SUSPECTED animals? Is there any observation at the first moment? Please clarify.

Lines 126-131: I recommend creating another topic to explain the variables were capture for further analysis, giving more details and adding information about inclusion and exclusion criteria.

Lines 139-141: Same here, please provide further details about using laboratory records.

Lines 145-146: “Regional and national human population data were obtained from the Uganda National Census 2014” and? What other information did the authors collect? Please provide details.

Major: The methods section is poorly described and I missed a lot of information. The authors need to provide details on how the study was designed, how the data was collected specifically for each group they want to show results (dogs, humans, distribution maps, PEP data, mortality data, etc). The data analysis section is confused. The authors should separate acquiring data from analyzing data. What statistical methods were used and why? I also recommend a general map of Uganda to show the readers the features of the country and how it looks like in terms of geography and how population (dogs and humans) are distributed

Results

Lines 156-159: Great, but how did the authors calculate this?

Lines 160-163: Please provide statistical data to support the differences among regions (although it’s clear in the figure).

Lines 171-174: What does it mean “6,997 pets were reported destroyed by the communities”? Please clarify.

Discussion

Lines 187-192: I think authors should also include here a discussion about the increase of animal bites in 2014.

Lines 202-204: “Vaccinating pets…” Only pets? Please clarify.

Other comments:

Did the authors separate bite rates from dogs, cats, or wild animals?

8420 persons reported animal bites. How many from dogs, cats, or wild?

Western region had a higher incidence. Can you add risk ratio or any other statistics?

Any recommendations regarding education of the population?

--------------------

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Reviewer #1: No

Reviewer #2: Yes: Benjamin P Monroe

Reviewer #3: Yes: Galileu Barbosa Costa

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PLoS Negl Trop Dis. 2021 Apr 19;15(4):e0007944. doi: 10.1371/journal.pntd.0007944.r002

Author response to Decision Letter 0

8 Jun 2020

Attachment

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PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0007944.r003

Decision Letter 1

Sergio Recuenco, Daniel Leo Horton

10 Aug 2020

Dear Dr Monje,

Thank you very much for submitting your manuscript "Trends and spatial distribution of animal bites and vaccination status among victims and the animal population, Uganda: A veterinary surveillance system analysis, 2013 – 2017" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Reviewers agree that the manuscript is much improved, but there are still some minor suggestions that need to be addressed below

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the 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

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Daniel Leo Horton, PhD

Associate Editor

PLOS Neglected Tropical Diseases

Sergio Recuenco

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Reviewers agree that the manuscript is much improved, but there are still some minor suggestions that need to be addressed below

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: (No Response)

Reviewer #2: The objectives of the study are clear and the methods used are standard for this type of analysis. The manuscript is evaluating a public health surveillance system and no ethical or regulatory concerns are apparent.

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: (No Response)

Reviewer #2: The results match the proposed analysis and have been clarified over the previous version. Figures are adequate for this type of information

What is the total population of Uganda that was used to calculate incidence?

How many records were removed for unknown district or date?

line 179: suggest authors replace 'received' with 'initiated'

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: (No Response)

Reviewer #2: The public health relevance of this topic is important and the authors provide some generalizations from their analysis that highlight the issues with rabies surveillance in Afria. They highlight how changing from active to passive surveillance can influence reporting rates and by extension incidence. While the limitations of the analysis are presented, I would caution that some of their conclusions about overall rabies risk in Uganda could be more nuanced.

--------------------

Editorial and Data Presentation Modifications?

Reviewer #1: (No Response)

Reviewer #2: The current version clarifies many of the issues of the original version. Some minor editing of language and punctuation my improve the overall readability of the manuscript.

--------------------

Summary and General Comments

Reviewer #1: Thank you to the authors for addressing the reviewer comments, which has improved the clarity of the study, particularly in the methods. I feel the discussion and conclusions have been given additional context and the limitations of the study have been more clearly stated. The study still presents data which will be useful in planning rabies control activities and identifies challenges in progressing disease control efforts in the region. I have a few minor comments which would need to be addressed before the manuscript would be suitable for publication.

In the abstract and elsewhere in the manuscript, greater clarity around what ‘reporting’ refers to is needed. Specifically the distinction between ‘decreased reporting’ of dog bites, i.e. a reduction in people reporting to healthcare facilities with dog bites, as compared to decreased reporting of bite data through district-level human or veterinary government reporting channels (Line 34, Line 35, Line 198 – 199, Line 290).

Line 193-195 - The first paragraph in the discussion remains misleading; “…shows an overall decline in animal bites in Uganda during 2013 – 2017”. This does not appear to be the case from the data in this study, but rather the overall animal bite rate in Uganda cannot be determined due to changes in the regularity of district-level reporting of data.

Line 222 – 224 - The reason for dismissal of the previously published peer-reviewed study of dog population enumeration in Uganda is not valid from a sample size perspective. Although a relatively small fraction of regions were sampled in this study, the methods appear statistically sound and the power of the sample size adequate, which would have enabled valid estimation of the national population. The initial estimate of the study at 1.3 million dogs is not hugely dissimilar to that of the livestock census at 1.6 million dogs. It is fair to comment on the differences between these estimates and perhaps to consider the Livestock census the more valid for purposes of this study, but the comment of sample size is not be valid from a statistical sense. Ultimately whether the total dog population is estimated at 0.7 million, 1.3 million or 1.6 million, the conclusion remains the same; dog vaccination in Uganda is inadequate and a systematic national dog vaccination campaign is needed.

Figure 1 – This figure still lacks clarity and is difficult to interpret. It is not immediately clear which axis refers to which line graph and the ‘Mortality rate in bite victims’ is not clear in the current scale. This may be more clearly displayed in stacked graphs aligned by year on the x-axis, but with distinct y-axes scales and labels. This could be presented as a single figure.

Reviewer #2: The manuscript provides important information for persons interested in canine rabies elimination. It highlights many of the issues faced by government institutions in low resource settings including incomplete reporting, unreliable population data, laboratory testing capacity, and inability to follow patient outcomes.

--------------------

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Reviewer #1: No

Reviewer #2: No

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PLoS Negl Trop Dis. 2021 Apr 19;15(4):e0007944. doi: 10.1371/journal.pntd.0007944.r004

Author response to Decision Letter 1

28 Oct 2020

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PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0007944.r005

Decision Letter 2

Sergio Recuenco, Daniel Leo Horton

8 Dec 2020

Dear Dr Monje,

Thank you very much for submitting your manuscript "Trends and spatial distribution of animal bites and vaccination status among victims and the animal population, Uganda: A veterinary surveillance system analysis, 2013 – 2017" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Thank you for responding to the reviewers comments. Reviewer 1 has made further suggestions just to Figure 1, which I agree would enhance the manuscript further. If you decide not to make these changes please provide justification.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Sincerely,

Daniel Leo Horton, PhD

Associate Editor

PLOS Neglected Tropical Diseases

Sergio Recuenco

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: (No Response)

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: (No Response)

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: (No Response)

--------------------

Editorial and Data Presentation Modifications?

Reviewer #1: (No Response)

--------------------

Summary and General Comments

Reviewer #1: Thank you to the authors for their thorough revisions in response to previous comments, which have improved the clarity of conclusions drawn from the results. All concerns in the text have been addressed, however some final adjustment to Figure 1 would considerably benefit the clarity of communicating key points in the data.

I'm sorry for poorly communicating the suggestion of a stacked graph in previous comments. As opposed to stacked bar graphs, I was trying to suggest stacked line graphs with each plotted on an independent y-axis. This avoids the need for additional labelling / colour which can hamper interpretation. Each axis has it's own scale and label as opposed to grouping multiple variables into one axis, allowing the reader to immediately understand what data is being shown in each line. An example of this approach can be seen here: http://www.performance-ideas.com/2012/03/27/stacked-line-charts/

Other than this concern the manuscript appears suitable for publication and would be of interest to the readership of PLOS NTD.

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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 #1: No

Figure Files:

Data Requirements:

Reproducibility:

To enhance the reproducibility of your results, PLOS recommends that you deposit 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/plosntds/s/submission-guidelines#loc-materials-and-methods

PLoS Negl Trop Dis. 2021 Apr 19;15(4):e0007944. doi: 10.1371/journal.pntd.0007944.r006

Author response to Decision Letter 2

26 Dec 2020

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PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0007944.r007

Decision Letter 3

Sergio Recuenco, Daniel Leo Horton

6 Jan 2021

Dear Dr Monje,

We are pleased to inform you that your manuscript 'Trends and spatial distribution of animal bites and vaccination status among victims and the animal population, Uganda: A veterinary surveillance system analysis, 2013 – 2017' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Daniel Leo Horton, PhD

Associate Editor

PLOS Neglected Tropical Diseases

Sergio Recuenco

Deputy Editor

PLOS Neglected Tropical Diseases

***********************************************************

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0007944.r008

Acceptance letter

Sergio Recuenco, Daniel Leo Horton

7 Apr 2021

Dear Dr Monje,

We are delighted to inform you that your manuscript, "Trends and spatial distribution of animal bites and vaccination status among victims and the animal population, Uganda: A veterinary surveillance system analysis, 2013 – 2017," has been formally accepted for publication in PLOS Neglected Tropical Diseases.

We have now passed your article onto the PLOS Production Department who will complete the rest of the publication process. All authors will receive a confirmation email upon publication.

The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Editorial, Viewpoint, Symposium, Review, etc...) are generated on a different schedule and may not be made available as quickly.

Soon after your final files are uploaded, the early version of your manuscript will be published online unless you opted out of this process. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers.

Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Associated Data

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

Supplementary Materials

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Submitted filename: Responses to reviewer 3.docx

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Attachment

Submitted filename: Responses to reviewer 2_V19Oct2020.docx

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Attachment

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Data Availability Statement

The datasets upon which our findings are based are owned by the government of Uganda. To access this dataset, we can contact the rabies focal person, Dr. Moses Mwanja, Email: drmwanja@gmail.com.

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PERMALINK

Trends and spatial distribution of animal bites and vaccination status among victims and the animal population, Uganda: A veterinary surveillance system analysis, 2013–2017

Fred Monje

Daniel Kadobera

Deo Birungi Ndumu

Lilian Bulage

Alex Riolexus Ario

Roles

Abstract

Author summary

Introduction

Methods

Ethics statement

Study setting and design

Data management and analysis

Results

Fig 1. Trends of incidence of animal bites, anti-rabies vaccinations in humans, corresponding mortality rates and reporting rates in Uganda: 2013–2017.

Fig 2. Reported incidence (/100,000 population) of animal bites by district in Uganda, 2013–2017.

Fig 3. Reported incidence of animal bites (/100,000) by region in Uganda: 2013–2017.

Fig 4. Reported trends of pets destroyed (%) among biting animals in Uganda: 2013–2017.

Discussion

Limitations

Conclusions and recommendations

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Sergio Recuenco

Amy T Gilbert

Roles

Author response to Decision Letter 0

Decision Letter 1

Sergio Recuenco

Daniel Leo Horton

Roles

Author response to Decision Letter 1

Decision Letter 2

Sergio Recuenco

Daniel Leo Horton

Roles

Author response to Decision Letter 2

Decision Letter 3

Sergio Recuenco

Daniel Leo Horton

Roles

Acceptance letter

Sergio Recuenco

Daniel Leo Horton

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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