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1.  Implementation of an Intersectoral Program to Eliminate Human and Canine Rabies: The Bohol Rabies Prevention and Elimination Project 
Background
The province of Bohol, located in the Visayas islands region in the Philippines has a human population of 1.13 million and was the 4th highest region for human rabies deaths in the country, averaging 10 per year, prior to the initiation of the Bohol Rabies Prevention and Elimination Project (BRPEP).
Aims
The BRPEP was initiated in 2007 with the goal of building a sustainable program that would prevent human rabies by eliminating rabies at its source, in dogs, by 2010. This goal was in line with the Philippine National Rabies Program whose objective is to eliminate rabies by 2020.
Methods
The intersectoral BRPEP was launched in 2007 and integrated the expertise and resources from the sectors of agriculture, public health and safety, education, environment, legal affairs, interior and local government. The program included: increasing local community involvement; implementing dog population control; conducting mass dog vaccination; improving dog bite management; instituting veterinary quarantine; and improving diagnostic capability, surveillance and monitoring. Funding was secured from the national government, provincial, municipal and village units, dog owners, NGOs, the regional office of the WHO, the UBS Optimus Foundation, and the Global Alliance for Rabies Control. The BRPEP was managed by the Bohol Rabies Prevention and Eradication Council (BRPEC) under the jurisdiction of the Governor of Bohol. Parallel organizations were created at the municipal level and village level. Community volunteers facilitated the institution of the program. Dog population surveys were conducted to plan for sufficient resources to vaccinate the required 70% of the dogs living in the province. Two island-wide mass vaccination campaigns were conducted followed by “catch up” vaccination campaigns. Registration of dogs was implemented including a small fee that was rolled back into the program to maintain sustainability. Children were educated by introducing rabies prevention modules into all elementary schools in Bohol. Existing public health legislation at the national, provincial, and municipal level strengthened the enforcement of activities. A Knowledge, Attitude and Practices (KAP) survey was conducted in 2009 to evaluate the educational knowledge of the population. Increased surveillance was instituted to ensure that dogs traveling into and out of the province were vaccinated against rabies. Human and animal cases of rabies were reported to provincial and national authorities.
Key Results
Within the first 18 months of the BRPEP, human rabies deaths had decreased annually from 0.77 to 0.37 to zero per 100,000 population from 2007–2009. Between October 2008 and November 2010 no human and animal cases were detected. Increased surveillance on the island detected one suspected human rabies case in November 2010 and one confirmed case of canine rabies in April 2011. Two mass vaccination campaigns conducted in 2007 and 2008 successfully registered and vaccinated 44% and 70% of the dogs on the island. The additional surveillance activities enabled a mobilization of mop up vaccination activities in the region where the human and canine case was located. Due to the increased effective and continuous surveillance activities, rabies was stopped before it could spread to other areas on the island. The program costs totaled USD 450,000. Registration fees collected to maintain the program amounted to USD 105,740 and were re-allocated back into the community to sustain the program.
Author Summary
The Province of Bohol, Philippines has eliminated dog and human rabies in less than three years by empowering the community and implementing an intersectoral strategy. In 2006, Bohol ranked 4th highest in the Philippines for human rabies, averaging 10 deaths per year. Launched in 2007, the program utilized a social awareness campaign, dog population control, mass dog vaccination campaigns, improved dog bite management and veterinary quarantine, a new diagnostic laboratory, expanded surveillance, and the inclusion of education modules into the school curriculum. Improving community compliance to existing national and provincial rabies laws and engaging volunteers to help conduct the project was a key to success. The program, led by the Governor of Bohol, was administered through a group of departments working together at a provincial and local level, and supervised through the Office of the Provincial Veterinarian. Financial support came through the Governor and several NGOs including the Global Alliance for Rabies Control. The program is self-sustaining, through a small dog registration fee fed back into the program, through the continuing education of children in their classrooms, and through the dedicated efforts of over 15,000 staff and volunteers throughout the island.
doi:10.1371/journal.pntd.0001891
PMCID: PMC3516573  PMID: 23236525
2.  Dog Bites in Humans and Estimating Human Rabies Mortality in Rabies Endemic Areas of Bhutan 
Background
Dog bites in humans are a public health problem worldwide. The issues of increasing stray dog populations, rabies outbreaks, and the risk of dogs biting humans have been frequently reported by the media in Bhutan. This study aimed to estimate the bite incidence and identify the risk factors for dog bites in humans, and to estimate human deaths from rabies in rabies endemic south Bhutan.
Methods
A hospital-based questionnaire survey was conducted during 2009–2010 among dog bites victims who visited three hospitals in Bhutan for anti-rabies vaccine injection. Decision tree modeling was used to estimate human deaths from rabies following dog bite injuries in two rabies endemic areas of south Bhutan.
Results
Three hundred and twenty four dog bite victims were interviewed. The annual incidence of dog bites differed between the hospital catchment areas: 869.8 (95% CI: 722.8–1022.5), 293.8 (240–358.2) and 284.8 (251.2–323) per 100,000 people in Gelephu, Phuentsholing and Thimphu, respectively. Males (62%) were more at risk than females (P<0.001). Children aged 5–9 years were bitten more than other age groups. The majority of victims (71%) were bitten by stray dogs. No direct fatal injury was reported. In two hospital areas (Gelephu and Phuentsholing) in south Bhutan the annual incidence of death from rabies was 3.14 (95% CI: 1.57–6.29) per 100,000 population. The decision tree model predicted an equivalent annual incidence of 4.67 (95% CI: 2.53–7.53) deaths/100,000 population at risk. In the absence of post exposure prophylaxis, the model predicted 19.24 (95% CI: 13.69–25.14) deaths/year in these two areas.
Conclusions
Increased educational awareness of people about the risk of dog bites and rabies is necessary, particularly for children in rabies endemic areas of Bhutan.
Author Summary
Dog bites in humans are a public health problem worldwide. We conducted a hospital based questionnaire survey and described the incidence and risk factors for human dog bites in Bhutan. We also estimated the human death rate attributable to rabies in two rabies endemic areas of south Bhutan. Our study shows that dog bites incidents in humans are common in the survey areas. There were significant gender and age differences in bite incidents; males and the children are affected the most. The majority of the victims were bitten by stray dogs, increasing the risk of rabies infection if not treated in time. Our decision tree model predicted 2.23 (95% CI: 1.20–3.59) human deaths from rabies/year, equivalent to an annual incidence of 4.67 (95% CI: 2.53–7.53) deaths/100,000 in the two rabies endemic areas of south Bhutan. In the absence of post exposure prophylaxis, the model predicted 19.24 (95% CI: 13.69–25.14) deaths/year in these two areas. The public should be encouraged to visit hospitals for post exposure prophylaxis following dog bite injury in south Bhutan.
doi:10.1371/journal.pntd.0001391
PMCID: PMC3222627  PMID: 22132247
3.  Evaluation of a Monoclonal Antibody–Based Rapid Immunochromatographic Test for Direct Detection of Rabies Virus in the Brain of Humans and Animals 
Rabies diagnosis uses a direct fluorescent antibody test (FAT) that is difficult, costly, and time-consuming, and requires trained personnel. We developed a rapid immunochromatographic test (RICT) for the diagnosis of rabies. The efficacy of the RICT was compared with that of the FAT. Brain samples were collected from humans, dogs, cats, and other animals in Sri Lanka (n = 248), Bhutan (n = 27), and Thailand (n = 228). The sensitivity (0.74–0.95), specificity (0.98–1.0), positive predictive value (0.98–1.0), negative predictive value (0.75–0.97), accuracy (0.91–0.98), and kappa measure of agreement (0.79–0.93) were all satisfactory for animal samples and samples preserved in 50% glycerol saline solution. Because the RICT showed high sensitivity but low specificity with human brain samples, it is unsuitable for confirming rabies in humans. No amino acid substitutions were found in the antibody attachment sites of the nucleoprotein gene with FAT-positive, RICT-negative samples. The RICT is reliable, user friendly, rapid, robust, and can be used in laboratories with a modest infrastructure.
doi:10.4269/ajtmh.2012.11-0332
PMCID: PMC3403755  PMID: 22492163
4.  Ferret badger rabies origin and its revisited importance as potential source of rabies transmission in Southeast China 
BMC Infectious Diseases  2010;10:234.
Background
The frequent occurrence of ferret badger-associated human rabies cases in southeast China highlights the lack of laboratory-based surveillance and urges revisiting the potential importance of this animal in rabies transmission. To determine if the ferret badgers actually contribute to human and dog rabies cases, and the possible origin of the ferret badger-associated rabies in the region, an active rabies survey was conducted to determine the frequency of rabies infection and seroprevalence in dogs and ferret badgers.
Methods
A retrospective survey on rabies epidemics was performed in Zhejiang, Jiangxi and Anhui provinces in southeast China. The brain tissues from ferret badgers and dogs were assayed by fluorescent antibody test. Rabies virus was isolated and sequenced for phylogenetic analysis. The sera from ferret badgers and dogs were titrated using rabies virus neutralizing antibodies (VNA) test.
Results
The ferret badgers presented a higher percentage of rabies seroconversion than dogs did in the endemic region, reaching a maximum of 95% in the collected samples. Nine ferret badger-associated rabies viruses were isolated, sequenced, and were phylogenetically clustered as a separate group. Nucleotide sequence revealed 99.4-99.8% homology within the ferret badger isolates, and 83-89% homology to the dog isolates in the nucleoprotein and glycoprotein genes in the same rabies endemic regions.
Conclusions
Our data suggest ferret badger-associated rabies has likely formed as an independent enzootic originating from dogs during the long-term rabies infestation in southeast China. The eventual role of FB rabies in public health remains unclear. However, management of ferret badger bites, rabies awareness and control in the related regions should be an immediate need.
doi:10.1186/1471-2334-10-234
PMCID: PMC2927599  PMID: 20691095
5.  Human rabies postexposure prophylaxis during a raccoon rabies epizootic in New York, 1993 and 1994. 
Emerging Infectious Diseases  1999;5(3):415-423.
We describe the epidemiology of human rabies postexposure prophylaxis (PEP) in four upstate New York counties during the 1st and 2nd year of a raccoon rabies epizootic. We obtained data from records of 1,173 persons whose rabies PEP was reported to local health departments in 1993 and 1994. Mean annual PEP incidence rates were highest in rural counties, in summer, and in patients 10 to 14 and 35 to 44 years of age. PEP given after bites was primarily associated with unvaccinated dogs and cats, but most (70%) was not attributable to bites. Although pet vaccination and stray animal control, which target direct exposure, remain the cornerstones of human rabies prevention, the risk for rabies by the nonbite route (e. g., raccoon saliva on pet dogs' and cats' fur) should also be considered.
PMCID: PMC2640781  PMID: 10341178
6.  Rabies in Iraq: Trends in Human Cases 2001–2010 and Characterisation of Animal Rabies Strains from Baghdad 
Control of rabies requires a consistent supply of dependable resources, constructive cooperation between veterinary and public health authorities, and systematic surveillance. These are challenging in any circumstances, but particularly during conflict. Here we describe available human rabies surveillance data from Iraq, results of renewed sampling for rabies in animals, and the first genetic characterisation of circulating rabies strains from Iraq. Human rabies is notifiable, with reported cases increasing since 2003, and a marked increase in Baghdad between 2009 and 2010. These changes coincide with increasing numbers of reported dog bites. There is no laboratory confirmation of disease or virus characterisation and no systematic surveillance for rabies in animals. To address these issues, brain samples were collected from domestic animals in the greater Baghdad region and tested for rabies. Three of 40 brain samples were positive using the fluorescent antibody test and hemi-nested RT-PCR for rabies virus (RABV). Bayesian phylogenetic analysis using partial nucleoprotein gene sequences derived from the samples demonstrated the viruses belong to a single virus variant and share a common ancestor with viruses from neighbouring countries, 22 (95% HPD 14–32) years ago. These include countries lying to the west, north and east of Iraq, some of which also have other virus variants circulating concurrently. These results suggest possible multiple introductions of rabies into the Middle East, and regular trans-boundary movement of disease. Although 4000 years have passed since the original description of disease consistent with rabies, animals and humans are still dying of this preventable and neglected zoonosis.
Author Summary
Control of rabies requires cooperation between government departments, consistent funding, and an understanding of the epidemiology of the disease obtained through surveillance. Here we describe human rabies surveillance data from Iraq and the results of renewed sampling for rabies in animals. In Iraq, it is obligatory by law to report cases of human rabies. These reports were collated and analysed. Reported cases have increased since 2003, with a marked increase in Baghdad 2009–2010. There is no system for detecting rabies in animals and the strains circulating in Iraq have not previously been characterized. To address this, samples were collected from domestic animals in Baghdad and tested for rabies. Three out of 40 were positive for rabies virus. Comparison of part of the viral genetic sequence with other viruses from the region demonstrated that the viruses from Iraq are more closely related to each other than those from surrounding countries, but diverged from viruses isolated in neighbouring countries approximately 22 (95% HPD 14–32) years ago. Although 4000 years have passed since the original description of disease consistent with rabies, animals and humans are still dying of this preventable and neglected zoonosis.
doi:10.1371/journal.pntd.0002075
PMCID: PMC3585036  PMID: 23469303
7.  Novel Vaccines to Human Rabies 
Rabies, the most fatal of all infectious diseases, remains a major public health problem in developing countries, claiming the lives of an estimated 55,000 people each year. Most fatal rabies cases, with more than half of them in children, result from dog bites and occur among low-income families in Southeast Asia and Africa. Safe and efficacious vaccines are available to prevent rabies. However, they have to be given repeatedly, three times for pre-exposure vaccination and four to five times for post-exposure prophylaxis (PEP). In cases of severe exposure, a regimen of vaccine combined with a rabies immunoglobulin (RIG) preparation is required. The high incidence of fatal rabies is linked to a lack of knowledge on the appropriate treatment of bite wounds, lack of access to costly PEP, and failure to follow up with repeat immunizations. New, more immunogenic but less costly rabies virus vaccines are needed to reduce the toll of rabies on human lives. A preventative vaccine used for the immunization of children, especially those in high incidence countries, would be expected to lower fatality rates. Such a vaccine would have to be inexpensive, safe, and provide sustained protection, preferably after a single dose. Novel regimens are also needed for PEP to reduce the need for the already scarce and costly RIG and to reduce the number of vaccine doses to one or two. In this review, the pipeline of new rabies vaccines that are in pre-clinical testing is provided and an opinion on those that might be best suited as potential replacements for the currently used vaccines is offered.
doi:10.1371/journal.pntd.0000515
PMCID: PMC2742899  PMID: 19787033
8.  Reemerging Rabies and Lack of Systemic Surveillance in People’s Republic of China 
Emerging Infectious Diseases  2009;15(8):1159-1164.
Standardized protocols and diagnostic-based surveillance are imperative for detection and elimination.
Rabies is a reemerging disease in China. The high incidence of rabies leads to numerous concerns: a potential carrier-dog phenomenon, undocumented transmission of rabies virus from wildlife to dogs, counterfeit vaccines, vaccine mismatching, and seroconversion testing in patients after their completion of postexposure prophylaxis (PEP). These concerns are all scientifically arguable given a modern understanding of rabies. Rabies reemerges periodically in China because of high dog population density and low vaccination coverage in dogs. Mass vaccination campaigns rather than depopulation of dogs should be a long-term goal for rabies control. Seroconversion testing after vaccination is not necessary in either humans or animals. Human PEP should be initiated on the basis of diagnosis of biting animals. Reliable national systemic surveillance of rabies-related human deaths and of animal rabies prevalence is urgently needed. A laboratory diagnosis–based epidemiologic surveillance system can provide substantial information about disease transmission and effective prevention strategies.
doi:10.3201/eid1508.081426
PMCID: PMC2815959  PMID: 19751575
Rabies; viruses; carrier-dog phenomenon; China; counterfeit vaccines; seroconversion testing; vaccination coverage; mass vaccination campaigns; postexposure prophylaxis; perspective
9.  Protection of dogs against death from experimental rabies by postexposure administration of rabies vaccine and hyperimmune globulin (human). 
Two experiments on simulated postexposure treatment were carried out in dogs using human rabies immunoglobulin (RIGH) and human diploid cell vaccine for human use. In one experiment, when animals were challenged by injecting street virus into the masseter muscle and treated with a combination of RIGH and vaccine, 50% of the animals were protected from rabies. In the other trial, in which animals were challenged by injecting the virus into the femoral muscle, treatment with RIGH and vaccine protected all the animals against rabies. To our knowledge this is the highest rate of postexposure survival in animals reported to date. In addition, five out of eight (62.5%) dogs that received RIGH alone after the virus challenge were protected, while none of the animals receiving vaccine alone were protected from rabies. These trials suggest that animals can be protected from rabies by postexposure treatment. The route of exposure and timing of the administration of vaccine and hyperimmune serum would seem to be important.
PMCID: PMC1255572  PMID: 2590870
10.  Factors Associated with Dog Rabies Vaccination in Bohol, Philippines: Results of a Cross-Sectional Cluster Survey Conducted Following the Island-Wide Rabies Elimination Campaign 
Zoonoses and public health  2012;60(7):494-503.
Summary
The Philippines has a long history of rabies control efforts in their dog populations; however, long-term success of such programmes and the goal of rabies elimination have not yet been realized. The Bohol Rabies Prevention and Elimination Program was developed as an innovative approach to canine rabies control in 2007. The objective of this study was to assess canine rabies vaccination coverage in the owned-dog population in Bohol and to describe factors associated with rabies vaccination two years after implementation of the programme. We utilized a cross-sectional cluster survey based on the World Health Organization’s Expanded Programme on Immunization coverage survey technique. We sampled 460 households and collected data on 539 dogs residing within these households. Seventy-seven percent of surveyed households reported owning at least one dog. The human to dog ratio was approximately 4 : 1, and the mean number of dogs owned per household was 1.6. Based on this ratio, we calculated an owned-dog population of almost 300 000. Overall, 71% of dogs were reported as having been vaccinated for rabies at some time in their lives; however, only 64% of dogs were reported as having been recently vaccinated. Dogs in our study were young (median age = 24 months). The odds of vaccination increased with increasing age. Dogs aged 12 – 23 months had 4.6 times the odds of vaccination compared to dogs aged 3 – 11 months (95% CI 1.8 – 12.0; P = 0.002). Confinement of the dog both day and night was also associated with increased odds of vaccination (OR = 2.1; 95% CI 0.9 – 4.9; P = 0.07), and this result approached statistical significance. While the programme is on track to meet its goal of 80% vaccination coverage, educational efforts should focus on the need to confine dogs and vaccinate young dogs.
doi:10.1111/zph.12026
PMCID: PMC3805987  PMID: 23280122
rabies; dog; cross-sectional; Philippines; cluster survey
11.  A Novel Rabies Vaccine Based on a Recombinant Parainfluenza Virus 5 Expressing Rabies Virus Glycoprotein 
Journal of Virology  2013;87(6):2986-2993.
Untreated rabies virus (RABV) infection leads to death. Vaccine and postexposure treatment have been effective in preventing RABV infection. However, due to cost, rabies vaccination and treatment have not been widely used in developing countries. There are 55,000 human death caused by rabies annually. An efficacious and cost-effective rabies vaccine is needed. Parainfluenza virus 5 (PIV5) is thought to contribute to kennel cough, and kennel cough vaccines containing live PIV5 have been used in dogs for many years. In this work, a PIV5-vectored rabies vaccine was tested in mice. A recombinant PIV5 encoding RABV glycoprotein (G) (rPIV5-RV-G) was administered to mice via intranasal (i.n.), intramuscular (i.m.), and oral inoculation. The vaccinated mice were challenged with a 50% lethal challenge dose (LD50) of RABV challenge virus standard 24 (CVS-24) intracerebrally. A single dose of 106 PFU of rPIV5-RV-G was sufficient for 100% protection when administered via the i.n. route. The mice vaccinated with a single dose of 108 PFU of rPIV5-RV-G via the i.m. route showed very robust protection (90% to 100%). Intriguingly, the mice vaccinated orally with a single dose of 108 PFU of rPIV5-RV-G showed a 50% survival rate, which is comparable to the 60% survival rate among mice inoculated with an attenuated rabies vaccine strain, recombinant LBNSE. This is first report of an orally effective rabies vaccine candidate in animals based on PIV5 as a vector. These results indicate that rPIV5-RV-G is an excellent candidate for a new generation of recombinant rabies vaccine for humans and animals and PIV5 is a potential vector for oral vaccines.
doi:10.1128/JVI.02886-12
PMCID: PMC3592160  PMID: 23269806
12.  Rabies in Sri Lanka: Splendid Isolation 
Emerging Infectious Diseases  2003;9(3):368-371.
Rabies virus exists in dogs on Sri Lanka as a single, minimally divergent lineage only distantly related to other rabies virus lineages in Asia. Stable, geographically isolated virus populations are susceptible to local extinction. A fully implemented rabies-control campaign could make Sri Lanka the first Asian country in >30 years to become free of rabies virus.
doi:10.3201/eid0903.020545
PMCID: PMC2958551  PMID: 12643834
rabies virus; Sri Lanka; dogs; communicable disease control; lyssavirus; virus typing; phylogenetic analysis; dispatch
13.  Challenges and needs for China to eliminate rabies 
In China, rabies is a significant public health concern where dogs remain the main reservoir of disease transmission to humans; rabies-related mortality ranks second in the world.
We compiled all published articles and official documents on rabies in mainland China to examine challenges and needs to eliminate rabies in the country. The Chinese authorities have identified rabies as a priority, recognized rabies control in dogs as key to control rabies in humans and required intersectoral collaborations. Efforts have been made to respond effectively to the latest re-emergence of rabies, which peaked in 2007 with >3,300 cases. Despite these outcomes and the increasing volume of publications and regulations in the recent years, our review points to some major information gaps to improve rabies control activities and envisage elimination program. An emphasis on laboratory or pathogen-associated and basic epidemiology research in the literature has contrasted with the absence of information to monitor various systems in humans and animals (e.g. quality of surveillance, response and post-exposure prophylaxis). Information is also lacking to appropriately inform policymakers (e.g. economic disease burden, impact of policies) and assist program managers (e.g. comprehensive and strategic guidance for cost-effective prevention and control activities, public education and dog population management).
In conclusion, strategic planning is needed to provide a sense of direction, demonstrate feasibility of elimination in China, and develop a research agenda, addressing country’s operational needs and constraints. The planning should be a multisectoral effort.
doi:10.1186/2049-9957-2-23
PMCID: PMC3851465  PMID: 24088366
Rabies; Elimination; China; Needs; Challenges; Review
14.  Transmission Dynamics and Prospects for the Elimination of Canine Rabies 
PLoS Biology  2009;7(3):e1000053.
Rabies has been eliminated from domestic dog populations in Western Europe and North America, but continues to kill many thousands of people throughout Africa and Asia every year. A quantitative understanding of transmission dynamics in domestic dog populations provides critical information to assess whether global elimination of canine rabies is possible. We report extensive observations of individual rabid animals in Tanzania and generate a uniquely detailed analysis of transmission biology, which explains important epidemiological features, including the level of variation in epidemic trajectories. We found that the basic reproductive number for rabies, R0, is very low in our study area in rural Africa (∼1.2) and throughout its historic global range (<2). This finding provides strong support for the feasibility of controlling endemic canine rabies by vaccination, even near wildlife areas with large wild carnivore populations. However, we show that rapid turnover of domestic dog populations has been a major obstacle to successful control in developing countries, thus regular pulse vaccinations will be required to maintain population-level immunity between campaigns. Nonetheless our analyses suggest that with sustained, international commitment, global elimination of rabies from domestic dog populations, the most dangerous vector to humans, is a realistic goal.
Author Summary
Canine rabies has been successfully eliminated from Western Europe and North America, but in the developing world, someone dies every ten minutes from this horrific disease, which is primarily spread by domestic dogs. A quantitative understanding of rabies transmission dynamics in domestic dog populations is crucial to determining whether global elimination can be achieved. The unique pathology of rabies allowed us to trace case-to-case transmission directly, during a rabies outbreak in northern Tanzania. From these unusual data, we generated a detailed analysis of rabies transmission biology and found evidence for surprisingly low levels of transmission. We also analysed outbreak data from around the world and found that the transmission of canine rabies has been inherently low throughout its global historic range, explaining the success of control efforts in developed countries. However, we show that when birth and death rates in domestic dog populations are high, such as in our study populations in Tanzania, it is more difficult to maintain population-level immunity in between vaccination campaigns. Nonetheless, we conclude that, although the level of vaccination coverage required is higher than would be predicted from naïve transmission models, global elimination of canine rabies can be achieved through appropriately designed, sustained domestic dog vaccination campaigns.
Low transmission rates in rural Africa and elsewhere suggest that sustained, appropriately designed domestic dog vaccination campaigns could lead to global elimination of canine rabies, which would save over 50,000 human lives per year.
doi:10.1371/journal.pbio.1000053
PMCID: PMC2653555  PMID: 19278295
15.  Detection of Rabies Virus Antigen in Dog Saliva Using a Latex Agglutination Test 
Journal of Clinical Microbiology  2000;38(8):3098-3099.
Dog bites are responsible for more than 90% of human rabies deaths in Asia. We developed a simple and inexpensive test based on latex agglutination (LA) for rabies virus antigen detection in dog saliva. Rabies virus antigen could be detected by agglutination on a glass slide using latex particles coated with gamma globulin. By evaluation of paired saliva-brain specimens from 238 dogs, the LA test using saliva was 99% specific and 95% sensitive compared to the fluorescent antibody test (FAT) on brain smears. The advantages of the LA test over the standard FAT are that it is comparatively simple and there is no need to kill the animal before examination.
PMCID: PMC87197  PMID: 10921987
16.  Rabies Postexposure Prophylaxis, New York, 1995–2000 
Emerging Infectious Diseases  2005;11(12):1921-1927.
Bats are now the leading source of rabies postexposure prophylaxis.
The epidemiology of human rabies postexposure prophylaxis (PEP) in 4 upstate New York counties was described from data obtained from 2,216 incidences of PEP recorded by local health departments from 1995 to 2000. Overall annual incidence for the study period was 27 cases per 100,000 persons. Mean annual PEP incidence rates were highest in rural counties and during the summer months. PEP incidence was highest among patients 5–9 and 30–34 years of age. Bites accounted for most PEP (51%) and were primarily associated with cats and dogs. Bats accounted for 30% of exposures, more than any other group of animals; consequently, bats have replaced raccoons as the leading rabies exposure source to humans in this area.
doi:10.3201/eid1112.041278
PMCID: PMC3367620  PMID: 16485480
Rabies; epidemiology; animal exposure; vaccination; zoonoses; research
17.  Costs of Rabies Control: An Economic Calculation Method Applied to Flores Island 
PLoS ONE  2013;8(12):e83654.
Background
Rabies is a zoonotic disease that, in most human cases, is fatal once clinical signs appear. The disease transmits to humans through an animal bite. Dogs are the main vector of rabies in humans on Flores Island, Indonesia, resulting in about 19 human deaths each year. Currently, rabies control measures on Flores Island include mass vaccination and culling of dogs, laboratory diagnostics of suspected rabid dogs, putting imported dogs in quarantine, and pre- and post-exposure treatment (PET) of humans. The objective of this study was to estimate the costs of the applied rabies control measures on Flores Island.
Methodology/principal findings
A deterministic economic model was developed to calculate the costs of the rabies control measures and their individual cost components from 2000 to 2011. The inputs for the economic model were obtained from (i) relevant literature, (ii) available data on Flores Island, and (iii) experts such as responsible policy makers and veterinarians involved in rabies control measures in the past. As a result, the total costs of rabies control measures were estimated to be US$1.12 million (range: US$0.60–1.47 million) per year. The costs of culling roaming dogs were the highest portion, about 39 percent of the total costs, followed by PET (35 percent), mass vaccination (24 percent), pre-exposure treatment (1.4 percent), and others (1.3 percent) (dog-bite investigation, diagnostic of suspected rabid dogs, trace-back investigation of human contact with rabid dogs, and quarantine of imported dogs).
Conclusions/significance
This study demonstrates that rabies has a large economic impact on the government and dog owners. Control of rabies by culling dogs is relatively costly for the dog owners in comparison with other measures. Providing PET for humans is an effective way to prevent rabies, but is costly for government and does not provide a permanent solution to rabies in the future.
doi:10.1371/journal.pone.0083654
PMCID: PMC3873960  PMID: 24386244
18.  Use of Rabies Postexposure Prophylaxis Supplied by the Alaska Section of Epidemiology, Alaska, 2002–2007 
Public Health Reports  2009;124(2):262-266.
SYNOPSIS
Objective
The aim of this study was to summarize the Alaska experience in centralizing distribution of rabies postexposure prophylaxis (PEP).
Methods
Data were collected from standard treatment sheets used to track doses and notes related to the exposure investigations.
Results
From 2002 to 2007, the annual PEP usage rate was 2.2 per 100,000. Dogs were involved in 79% (68/86) of exposures. More than 50% (49/87) of people were exposed to a confirmed rabid animal; 31 (63%) of those people experienced nonbite exposures. Conversely, of the remaining 38 people exposed to an animal for which rabies status could not be confirmed, 35 (92%) sustained a bite or puncture. Direct and indirect costs averaged more than $3,000 per person.
Conclusions
The Alaska PEP usage rate was lower and the proportion of people exposed to confirmed rabid animals was higher when compared with other states. Alaska public health personnel invested significant time to ensure that PEP was only given when indicated. Without this gatekeeper approach, PEP would likely be administered at a much higher rate because medical facility staff lacks the time or ability to investigate animal exposures to rule out rabies. In Alaska, centralizing rabies PEP not only serves the patient's best interest, but it also makes efficient use of a potentially scarce product and supports rabies surveillance efforts by guaranteeing animals for testing. Such a program might not be feasible for a more populous state or jurisdiction, or areas with different rabies epizootiology; however, that may change if the supply of rabies biologics changes in the future.
PMCID: PMC2646483  PMID: 19320368
19.  Response to a Rabies Epidemic, Bali, Indonesia, 2008–2011 
Emerging Infectious Diseases  2013;19(4):648-651.
Emergency vaccinations and culling failed to contain an outbreak of rabies in Bali, Indonesia, during 2008–2009. Subsequent island-wide mass vaccination (reaching 70% coverage, >200,000 dogs) led to substantial declines in rabies incidence and spread. However, the incidence of dog bites remains high, and repeat campaigns are necessary to eliminate rabies in Bali.
doi:10.3201/eid1904.120380
PMCID: PMC3647408  PMID: 23632033
rabies; epidemic; Indonesia; Bali; rabies vaccination; dogs; dog bites; zoonoses; viruses
20.  Designing Programs for Eliminating Canine Rabies from Islands: Bali, Indonesia as a Case Study 
Background
Canine rabies is one of the most important and feared zoonotic diseases in the world. In some regions rabies elimination is being successfully coordinated, whereas in others rabies is endemic and continues to spread to uninfected areas. As epidemics emerge, both accepted and contentious control methods are used, as questions remain over the most effective strategy to eliminate rabies. The Indonesian island of Bali was rabies-free until 2008 when an epidemic in domestic dogs began, resulting in the deaths of over 100 people. Here we analyze data from the epidemic and compare the effectiveness of control methods at eliminating rabies.
Methodology/Principal Findings
Using data from Bali, we estimated the basic reproductive number, R0, of rabies in dogs, to be ∼1·2, almost identical to that obtained in ten–fold less dense dog populations and suggesting rabies will not be effectively controlled by reducing dog density. We then developed a model to compare options for mass dog vaccination. Comprehensive high coverage was the single most important factor for achieving elimination, with omission of even small areas (<0.5% of the dog population) jeopardizing success. Parameterizing the model with data from the 2010 and 2011 vaccination campaigns, we show that a comprehensive high coverage campaign in 2012 would likely result in elimination, saving ∼550 human lives and ∼$15 million in prophylaxis costs over the next ten years.
Conclusions/Significance
The elimination of rabies from Bali will not be achieved through achievable reductions in dog density. To ensure elimination, concerted high coverage, repeated, mass dog vaccination campaigns are necessary and the cooperation of all regions of the island is critical. Momentum is building towards development of a strategy for the global elimination of canine rabies, and this study offers valuable new insights about the dynamics and control of this disease, with immediate practical relevance.
Author Summary
Canine rabies continues to cause tens of thousands of horrific deaths worldwide, primarily in Asia and Africa. Momentum is building towards development of a global elimination strategy for canine rabies, but questions remain over how best to eliminate rabies epidemics. This paper uses data generated from the recent high-profile rabies outbreak in Bali, Indonesia to evaluate different control options. We find that, despite high dog densities, the spread of rabies on the island was remarkably similar to canine rabies spread elsewhere, suggesting that the practice of dog culling is an ineffective control strategy. We then simulate rabies transmission and spread across the island and compare the effectiveness of mass dog vaccination strategies in terms of how many lives are saved and how long it will take for elimination to be achieved. We find that the effectiveness of campaigns is not improved by being more reactive or synchronized but depends almost entirely upon reaching sufficient coverage (70%) across the population in successive campaigns. Even small ‘gaps’ in vaccination coverage can significantly impede the prospects of elimination. The outputs of this study provide the kind of evidence needed by rabies program coordinators to help design effective national control programmes, and to build the evidence-base to drive forward the development and implementation of effective global rabies policy.
doi:10.1371/journal.pntd.0002372
PMCID: PMC3749988  PMID: 23991233
21.  Epidemiologic Features of Animal Bite Cases Occurring in Rabies-Endemic Areas of Korea, 2005 to 2009 
Objectives
Human rabies is a reemerging infectious disease in Korea. There was no human rabies case for 14 years until the disease had reoccurred in 1999. To prevent occurrence of human rabies, surveillance for animal bite patients in rabies endemic areas in Korea was conducted since 2005 as a part of a human rabies control program. The animal bite cases were analyzed to determine whether patients were treated according to the post-exposure prophylaxis (PEP) guideline of the Korea Centers for Disease Control and Prevention.
Methods
Information of animal bite cases that occurred from 2005 to 2009 in rabies high-risk regions were collected by cooperation with Regional Public Health Centers in 18 cities/districts of rabies endemic areas.
Results
A total of 2458 animal bite cases were reported. Dogs accounted for 86% of animal bites and 67% of the animals were not vaccinated against rabies virus. For PEP, among rabies-vaccinated animals, 92.7% were observed for clinical signs and 1.4% underwent necropsy. Among unvaccinated animals, 72.7% were observed for clinical signs and 4.1% underwent necropsy. The remaining animals were not available for examination. Of the animal bite patients, 32.5% received PEP and 51.6% were treated by first aid or by washing the wound.
Conclusions
Given that no human rabies cases were reported since 2005 and animal rabies was continuously reported in endemic areas of Korea, the human rabies control program implemented in 2005 appears to have a significant role in the prevention and control of human rabies.
doi:10.1016/j.phrp.2012.01.002
PMCID: PMC3738676  PMID: 24159481
animal bite; post-exposure prophylaxis; rabies; wild animal
22.  Molecular Epidemiology of Rabies in Southern People’s Republic of China 
Emerging Infectious Diseases  2009;15(8):1192-1198.
Migration and transport of dogs may have caused recent epidemics of human rabies.
In recent years, the number of human rabies cases in the People’s Republic of China has increased during severe epidemics in 3 southern provinces (Guizhou, Guangxi, and Hunan). To analyze the causes of the high incidence of human rabies in this region, during 2005–2007, we collected 2,887 brain specimens from apparently healthy domestic dogs used for meat consumption in restaurants, 4 specimens from suspected rabid dogs, and 3 from humans with rabies in the 3 provinces. Partial nucleoprotein gene sequences were obtained from rabies-positive specimens. Phylogenetic relationships and distribution of viruses were determined. We infer that the spread of rabies viruses from high-incidence regions, particularly by long-distance movement or transprovincial translocation of dogs caused by human-related activities, may be 1 cause of the recent massive human rabies epidemics in southern China.
doi:10.3201/eid1508.081551
PMCID: PMC2815963  PMID: 19751579
Molecular epidemiology; nucleoprotein; rabies; epidemic; China; viruses; research
23.  Evaluation of a new five-injection, two-site,intradermal schedule for purified chick embryo cell rabies vaccine: A randomized, open-label, active-controlled trial in healthy adult volunteers in India 
Background:
Human rabies is an ongoing significant public health problem inmany developing countries, with India reporting the highest incidence of rabies-related deaths (∼20,000 per year). Many people living in India cannot afford the standard IM postexposure prophylaxis (PEP) with cell-culture vaccines, which are administered using a 5-dose regimen developed in Essen, Germany. A potentially less expensive intradermal (ID) regimen, based on the Essen regimen, has been developed at the Kempegowda Institute of Medical Sciences (KIMS), Bangalore, India.
Objective:
The objective of this study was to compare the immunogenicity and local and systemic tolerability of the KIMS-1D regimen with those of the standard Essen IM regimen in healthy adult volunteers in India.
Methods:
This randomized, open-label, active-controlled trial was conductedat the Antirabies Clinic, Medical College, KIMS. Healthy adult volunteers were randomly assigned to receive purified chick embryo cell vaccine (PCECV) using the KIMS-1D regimen (0.1 mL injected ID at 2 body sites on days 0, 3, 7, 14, and 28 [“2-2-2-2-2”]) or the Essen IM regimen (1 mL injected IM at 1 body site on the same days Subjects were followed up for 365 days by the treating physician and encouraged to voluntarily report any adverse events (AEs). Serum rabies virus-neutralizing antibody (RVNA) concentrations were measured before the first injection on day 0 (baseline) and on days 14, 28, 90, 180, and 365, using the rapid fluorescent focus inhibition test.
Results:
Ninety-one subjects were enrolled and included in the tolerabilityand immunogenicity analyses. The ID group comprised 45 subjects (26 men, 19 women; mean [SD] age, 20.84 [1.48] years); the IM group, 46 subjects (28 men, 18 women; mean [SD] age, 21.02 [1.16] years). The most common local AEs were pain at the injection site (2/225 [0.9%] in the ID group and 10/230 [4.3%] in the IM group; P < 0.006) and itching at the injection site (5/225 [2.2%] in the ID group and none in the IM group; P = 0.026). All of the AEs were transient and resolved without the need for medication. All subjects had serum RVNA concentrations ≥0.5 IU/mL—considered protective by the World Health Organization—at all follow-up visits. However, the mean RVNA concentrations in the IM group were significantly higher compared with those in the ID group from days 14 to 365 (all, P < 0.001).
Conclusion:
In this study in healthy volunteers, PEP with PCECV administered using the KIMS-ID regimen was well tolerated and immunologically efficacious for 365 days. Adequate RVNA levels were maintained with the KIMS-ID regimen from days 14 to 365, although these levels were significantly lower than those achieved in the group receiving the Essen IM regimen (all, P < 0.001).
doi:10.1016/j.curtheres.2005.08.009
PMCID: PMC3964532
rabies; intradermal rabies vaccination; KIMS-ID regimen; randomizedcontrolled trial
24.  Rabies molecular virology, diagnosis, prevention and treatment 
Virology Journal  2012;9:50.
Rabies is an avertable viral disease caused by the rabid animal to the warm blooded animals (zoonotic) especially human. Rabies occurs in more than 150 countries and territories. According to an estimation by WHO, almost 55,000 people die because of rabies every year. The Dogs are the major reason behind this, approximately 99% human deaths caused by dog's bites. Developing and under developing countries, both are the victims of rabies. With the post-exposure preventive regimes, 327,000 people can prevent this disease annually.
The current article mainly covers the genome, virology, symptoms, epidemiology, diagnostic methods, and the high risk countries around the globe.
doi:10.1186/1743-422X-9-50
PMCID: PMC3307483  PMID: 22348291
Rabies; Zoonosis; Vaccine; Prevention
25.  Diagnosis, management and post-mortem findings of a human case of rabies imported into the United Kingdom from India: a case report 
Virology Journal  2014;11:63.
Background
Human rabies infection continues to be a significant public health burden globally, and is occasionally imported to high income settings where the Milwaukee Protocol for intensive care management has recently been employed, with limited success in improving survival. Access to molecular diagnostics, pre- and post-mortem, and documentation of pathophysiological responses while using the Milwaukee protocol, can add useful insights for the future of rabies management.
Case presentation
A 58-year-old British Asian woman was referred to a regional general hospital in the UK with hydrophobia, anxiety and confusion nine weeks after receiving a dog bite in North West India. Nuchal skin biopsy, saliva, and a skin biopsy from the site of the dog bite wound, taken on the day of admission, all demonstrated the presence of rabies virus RNA. Within 48 hours sequence analysis of viral RNA confirmed the diagnosis and demonstrated that the virus was a strain closely related to canine rabies viruses circulating in South Asia. Her condition deteriorated rapidly with increased agitation and autonomic dysfunction. She was heavily sedated and intubated on the day after admission, treated according to a modified Milwaukee protocol, and remained stable until she developed heart block and profound acidosis and died on the eighth day. Analysis of autopsy samples showed a complete absence of rabies neutralizing antibody in cerebrospinal fluid and serum, and corresponding high levels of virus antigen and nucleic acid in brain and cerebrospinal fluid. Quantitative PCR showed virus was also distributed widely in peripheral tissues despite mild or undetectable histopathological changes. Vagus nerve branches in the heart showed neuritis, a probable Negri body but no demonstrable rabies antigen.
Conclusion
Rapid molecular diagnosis and strain typing is helpful in the management of human rabies infection. Post-mortem findings such as vagal neuritis highlight clinically important effects on the cardiovascular system which are typical for the clinical course of rabies in humans. Management guided by the Milwaukee protocol is feasible within well-resourced intensive care units, but its role in improving outcome for canine-derived rabies remains theoretical.
doi:10.1186/1743-422X-11-63
PMCID: PMC3977668
Rabies; Milwaukee protocol; Diagnosis

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