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1.  Rabies Risk: Difficulties Encountered during Management of Grouped Cases of Bat Bites in 2 Isolated Villages in French Guiana 
In French Guiana, from 1984 to 2011, 14 animal rabies cases and 1 human rabies case (2008) were diagnosed. In January 2011, vampire-bat attacks occurred in 2 isolated villages. In mid-January, a medical team from the Cayenne Centre for Anti-Rabies Treatment visited the sites to manage individuals potentially exposed to rabies and, in April, an anti-rabies vaccination campaign for dogs was conducted. Twenty individuals were bitten by bats in 1 month, most frequently on the feet. The median time to start management was 15 days. The complete Zagreb vaccination protocol (2 doses on day 0 and 1 dose on days 7 and 21) was administered to 16 patients, 12 also received specific immunoglobulins. The antibody titration was obtained for 12 patients (different from those who received immunoglobulins). The antibody titers were ≥0.5 EU/mL for all of them. The serology has not been implemented for the 12 patients who received immunoglobulins. Accidental destruction of a vampire-bat colony could be responsible for the attacks. The isolation and absence of sensitization of the populations were the main explanations for the management difficulties encountered. Sensitization programs should be conducted regularly.
Author Summary
Rabies is a disease almost invariably fatal in humans once the first clinical signs appear. In French Guiana bats represent the virus reservoir, especially vampire bats. From 1984 to 2011, 14 animal rabies cases and 1 human rabies case (2008) were diagnosed. In case of bat bite, anti-rabies immunoglobulins (RIG) and rabies vaccine must be rapidly administrated. The specific rabies management is exclusively performed by Centre for Anti-Rabies Treatment (CART), located at the Institut Pasteur in Cayenne, the prefecture of French Guiana, and 6 Anti-Rabies Treatment Outposts distributed along the coastal edge and along the two main rivers. Only a CART physician can administer RIG. In January 2011, vampire-bat attacks occurred in 2 isolated villages. In mid-January, a medical team from the CART visited the sites to manage individuals potentially exposed to rabies and, in April, an anti-rabies vaccination campaign for dogs was conducted. The most relevant contribution of this study is to underline difficulties to provide rabies post-exposure prophylaxis to remote populations exposed to bat rabies in the Amazonian region and to show the lack of awareness of these rural populations concerning rabies and the risk associated to vampire bats.
doi:10.1371/journal.pntd.0002258
PMCID: PMC3694830  PMID: 23826400
2.  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
3.  Evolutionary History and Phylogeography of Rabies Viruses Associated with Outbreaks in Trinidad 
Bat rabies is an emerging disease of public health significance in the Americas. The Caribbean island of Trinidad experiences periodic outbreaks within the livestock population. We performed molecular characterisation of Trinidad rabies virus (RABV) and used a Bayesian phylogeographic approach to investigate the extent to which outbreaks are a result of in situ evolution versus importation of virus from the nearby South American mainland. Trinidadian RABV sequences were confirmed as bat variant and clustered with Desmodus rotundus (vampire bat) related sequences. They fell into two largely temporally defined lineages designated Trinidad I and II. The Trinidad I lineage which included sequences from 1997–2000 (all but two of which were from the northeast of the island) was most closely related to RABV from Ecuador (2005, 2007), French Guiana (1990) and Venezuela (1993, 1994). Trinidad II comprised sequences from the southwest of the island, which clustered into two groups: Trinidad IIa, which included one sequence each from 2000 and 2007, and Trinidad IIb including all 2010 sequences. The Trinidad II sequences were most closely related to sequences from Brazil (1999, 2004) and Uruguay (2007, 2008). Phylogeographic analyses support three separate RABV introductions from the mainland from which each of the three Trinidadian lineages arose. The estimated dates for the introductions and subsequent lineage expansions suggest periods of in situ evolution within Trinidad following each introduction. These data also indicate co-circulation of Trinidad lineage I and IIa during 2000. In light of these findings and the likely vampire bat origin of Trinidadian RABV, further studies should be conducted to investigate the relationship between RABV spatiotemporal dynamics and vampire bat population ecology, in particular any movement between the mainland and Trinidad.
Author Summary
The Caribbean island of Trinidad experiences periodic rabies virus (RABV) outbreaks within the livestock population. In this study, we inferred the evolutionary history of RABV in the Americas and reconstructed past patterns of RABV geographic spread in order to address the question of whether Trinidadian outbreaks arise from locally maintained RABV or are the result of virus importation from the mainland (presumably via infected bats). Our results provide statistical support for three importation events that gave rise to each of three Trinidadian vampire bat-associated lineages identified in the study. They also indicate limited periods of in situ evolution within Trinidad following each of these introductions. The results also support Mexico and Brazil as major epicenters for the expansion of RABV associated with vampire bats throughout the Americas and consequently to Trinidad. The findings of our study are particularly relevant to local RABV monitoring and control. In addition to justifying vampire bats as the main target for active rabies surveillance and control activities in Trinidad, they suggest that more intense surveillance of regions that lie close to the mainland may be warranted. Finally, in light of these findings, further studies should be conducted to investigate the relationship between RABV spatiotemporal dynamics and vampire bat population ecology.
doi:10.1371/journal.pntd.0002365
PMCID: PMC3749974  PMID: 23991230
4.  High Diversity of Rabies Viruses Associated with Insectivorous Bats in Argentina: Presence of Several Independent Enzootics 
Background
Rabies is a fatal infection of the central nervous system primarily transmitted by rabid animal bites. Rabies virus (RABV) circulates through two different epidemiological cycles: terrestrial and aerial, where dogs, foxes or skunks and bats, respectively, act as the most relevant reservoirs and/or vectors. It is widely accepted that insectivorous bats are not important vectors of RABV in Argentina despite the great diversity of bat species and the extensive Argentinean territory.
Methods
We studied the positivity rate of RABV detection in different areas of the country, and the antigenic and genetic diversity of 99 rabies virus (RABV) strains obtained from 14 species of insectivorous bats collected in Argentina between 1991 and 2008.
Results
Based on the analysis of bats received for RABV analysis by the National Rabies system of surveillance, the positivity rate of RABV in insectivorous bats ranged from 3.1 to 5.4%, depending on the geographic location. The findings were distributed among an extensive area of the Argentinean territory. The 99 strains of insectivorous bat-related sequences were divided into six distinct lineages associated with Tadarida brasiliensis, Myotis spp, Eptesicus spp, Histiotus montanus, Lasiurus blosseviilli and Lasiurus cinereus. Comparison with RABV sequences obtained from insectivorous bats of the Americas revealed co-circulation of similar genetic variants in several countries. Finally, inter-species transmission, mostly related with Lasiurus species, was demonstrated in 11.8% of the samples.
Conclusions
This study demonstrates the presence of several independent enzootics of rabies in insectivorous bats of Argentina. This information is relevant to identify potential areas at risk for human and animal infection.
Author Summary
In Argentina, successful vaccination and control of terrestrial rabies in the 1980s revealed the importance of the aerial route in RABV transmission. Current distribution of cases shows a predominance of rabies by hematophagous bats in the Northern regions where rabies is a major public health concern; in contrast, in Central and Southern regions where rabies is not a major public health concern, little surveillance is performed. Based on the analysis of insectivorous bats received for RABV analysis by the National Rabies system of surveillance, the positivity rate of RABV in insectivorous bats in these regions ranged from 3.1 to 5.4%. This rate is comparable to other nations such as the United States (9–10%) where insectivorous bats are an important cause of concern for RABV surveillance systems. Antigenic and genetic analysis of a wide collection of rabies strains shows the presence of multiple endemic cycles associated with six bat insectivorous species distributed among an extensive area of the Argentinean territory and several countries of the Americas. Finally, inter-species transmission, mostly related with Lasiurus species, was demonstrated in 11.8% of the samples. Increased public education about the relationship between insectivorous bats and rabies are essential to avoid human cases and potential spread to terrestrial mammals.
doi:10.1371/journal.pntd.0001635
PMCID: PMC3348165  PMID: 22590657
5.  Enhanced Passive Bat Rabies Surveillance in Indigenous Bat Species from Germany - A Retrospective Study 
In Germany, rabies in bats is a notifiable zoonotic disease, which is caused by European bat lyssaviruses type 1 and 2 (EBLV-1 and 2), and the recently discovered new lyssavirus species Bokeloh bat lyssavirus (BBLV). As the understanding of bat rabies in insectivorous bat species is limited, in addition to routine bat rabies diagnosis, an enhanced passive surveillance study, i.e. the retrospective investigation of dead bats that had not been tested for rabies, was initiated in 1998 to study the distribution, abundance and epidemiology of lyssavirus infections in bats from Germany. A total number of 5478 individuals representing 21 bat species within two families were included in this study. The Noctule bat (Nyctalus noctula) and the Common pipistrelle (Pipistrellus pipistrellus) represented the most specimens submitted. Of all investigated bats, 1.17% tested positive for lyssaviruses using the fluorescent antibody test (FAT). The vast majority of positive cases was identified as EBLV-1, predominately associated with the Serotine bat (Eptesicus serotinus). However, rabies cases in other species, i.e. Nathusius' pipistrelle bat (Pipistrellus nathusii), P. pipistrellus and Brown long-eared bat (Plecotus auritus) were also characterized as EBLV-1. In contrast, EBLV-2 was isolated from three Daubenton's bats (Myotis daubentonii). These three cases contribute significantly to the understanding of EBLV-2 infections in Germany as only one case had been reported prior to this study. This enhanced passive surveillance indicated that besides known reservoir species, further bat species are affected by lyssavirus infections. Given the increasing diversity of lyssaviruses and bats as reservoir host species worldwide, lyssavirus positive specimens, i.e. both bat and virus need to be confirmed by molecular techniques.
Author Summary
According to the World Health Organization rabies is considered both a neglected zoonotic and a tropical disease. The causative agents are lyssaviruses which have their primary reservoir in bats. Although bat rabies is notifiable in Germany, the number of submitted bats during routine surveillance is rarely representative of the natural bat population. Therefore, the aim of this study was to include dead bats from various sources for enhanced bat rabies surveillance. The results show that a considerable number of additional bat rabies cases can be detected, thus improving the knowledge on the frequency, geographical distribution and reservoir-association of bat lyssavirus infections in Germany. The overall proportion of positives was lower than during routine surveillance in Germany. While the majority of cases were found in the Serotine bat and characterized as European bat lyssavirus type 1 (EBLV-1), three of the four EBLV-2 infections detected in Germany were found in Myotis daubentonii during this study.
doi:10.1371/journal.pntd.0002835
PMCID: PMC4006713  PMID: 24784117
6.  Rabies Exposures, Post-Exposure Prophylaxis and Deaths in a Region of Endemic Canine Rabies 
Background
Thousands of human deaths from rabies occur annually despite the availability of effective vaccines following exposure, and for disease control in the animal reservoir. Our aim was to assess risk factors associated with exposure and to determine why human deaths from endemic canine rabies still occur.
Methods and Findings
Contact tracing was used to gather data on rabies exposures, post-exposure prophylaxis (PEP) delivered and deaths in two rural districts in northwestern Tanzania from 2002 to 2006. Data on risk factors and the propensity to seek and complete courses of PEP was collected using questionnaires. Exposures varied from 6–141/100,000 per year. Risk of exposure to rabies was greater in an area with agropastoralist communities (and larger domestic dog populations) than an area with pastoralist communities. Children were at greater risk than adults of being exposed to rabies and of developing clinical signs. PEP dramatically reduced the risk of developing rabies (odds ratio [OR] 17.33, 95% confidence interval [CI] 6.39–60.83) and when PEP was not delivered the risks were higher in the pastoralist than the agro-pastoralist area (OR 6.12, 95% CI 2.60–14.58). Low socioeconomic class and distance to medical facilities lengthened delays before PEP delivery. Over 20% of rabies-exposed individuals did not seek medical treatment and were not documented in official records and <65% received PEP. Animal bite injury records were an accurate indicator of rabies exposure incidence.
Conclusions
Insufficient knowledge about rabies dangers and prevention, particularly prompt PEP, but also wound management, was the main cause of rabies deaths. Education, particularly in poor and marginalized communities, but also for medical and veterinary workers, would prevent future deaths.
Author Summary
Thousands of human deaths from rabies occur annually despite availability of effective vaccines for humans following exposure, and for disease control in domestic dog populations. We established a 5-year contact-tracing study in northwest Tanzania to investigate risk factors associated with rabies exposure and to determine why human deaths from canine rabies still occur. We found that children were at greater risk of being bitten and of developing rabies than adults and that incidence of bites by suspected rabid animals was higher in an area with larger domestic dog populations. A large proportion (>20%) of those bitten by rabid animals are not recorded in official records because they do not seek post-exposure prophylaxis (PEP), which is crucial for preventing the onset of rabies. Of those that seek medical attention, a significant proportion do not receive PEP because of the expense or because of hospital shortages; and victims who are poorer, and who live further from medical facilities, typically experience greater delays before obtaining PEP. Our work highlights the need to raise awareness about rabies dangers and prevention, particularly prompt PEP, but also wound management. We outline practical recommendations to prevent future deaths, stressing the importance of education, particularly in poor and marginalized communities, as well as for medical and veterinary workers.
doi:10.1371/journal.pntd.0000339
PMCID: PMC2582685  PMID: 19030223
7.  Surveillance and control of rabies in La Reunion, Mayotte, and Madagascar 
Veterinary Research  2013;44(1):77.
Mayotte and La Reunion islands are currently free of animal rabies and surveillance is performed by the French Human and Veterinary Public Health Services. However, dog rabies is still enzootic in Madagascar with 4 to 10 confirmed human cases each year. The number of antirabies medical centres in Madagascar is still scarce to provide easy access to the local population for post-exposure rabies prophylaxis. Furthermore, stray dog populations are considerable and attempts to control rabies by mass campaigns of dog vaccination have not received sufficient attention from the national health authorities. To address these challenges, an expanded program to control rabies needs to be initiated by the Malagasy authorities.
doi:10.1186/1297-9716-44-77
PMCID: PMC3848982  PMID: 24016204
8.  Sylvatic rabies epidemic in Italy: implementation of a data management system to assess the level of application of preventive dog vaccination 
Pathogens and Global Health  2013;107(7):354-360.
After 20 years of absence, rabies re-emerged in wild animals in north-eastern Italy in October 2008. Besides measures undertaken to fight the spread of infection in wildlife, vaccination against rabies was made compulsory for dogs living in the risk area. In the last 15 years, the veterinary authorities have focused on implementing computerized data collection systems in animal health, to serve as working tools for epidemiological surveillance activities and emergencies management. The prerequisite for implementing any data collection system is knowledge of the animal population. This also applies to the Canine Registry Data Bank, in which data on dogs and their movements, together with personal data on each owner and keeper, have been stored since 2003. The management information system has been updated and specific functions have been integrated in order to support the activity of both the veterinary services and the veterinary practitioners involved in the dog vaccination program. Vaccination became voluntary in February 2013. This paper describes implementation of the software and organization of data gathering, highlighting the benefits of computerized data compared to previously used paper-based data collection systems. The new functions, designed to centralize collection of uniform, updated vaccination data, have led to more efficient organization and better control of the vaccination plan. Automated information processing allowed vaccination operations to be supervised, incurred costs to be calculated, and vaccination coverage of the dog population to be monitored during the 3 years of compulsory vaccination.
doi:10.1179/2047772413Z.000000000176
PMCID: PMC4083155  PMID: 24392678
Rabies; Vaccination; Dog; Information system; Italy
9.  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
10.  Rabies Post-Exposure Prophylaxis in the Philippines: Health Status of Patients Having Received Purified Equine F(ab')2 Fragment Rabies Immunoglobulin (Favirab) 
Background
Recommended treatment for severe rabies exposure in unvaccinated individuals includes wound cleaning, administration of rabies immunoglobulins (RIG), and rabies vaccination. We conducted a survey of rabies treatment outcomes in the Philippines.
Methods
This was a case series involving 7,660 patients (4 months to 98 years of age) given purified equine RIG (pERIG) at the Research Institute for Tropical Medicine (Muntinlupa, Philippines) from July 2003 to August 2004 following Category II or III exposures. Data on local and systemic adverse reactions (AR) within 28 days and biting animal status were recorded; outcome data were obtained by telephone or home visit 6–29 months post-exposure.
Results
Follow-up data were collected for 6,464 patients. Of 151 patients with laboratory-confirmed rabies exposure, 143 were in good health 6–48 months later, seven could not be contacted, and one 4-year-old girl died. Of 16 deaths in total, 14 were unrelated to rabies exposure or treatment. Two deaths were considered PEP failures: the 4-year old girl, who had multiple deep lacerated wounds from a rabid dog of the nape, neck, and shoulders requiring suturing on the day of exposure, and an 8-year-old boy who only received rabies PEP on the day of exposure.
Conclusions
This extensive review of outcomes in persons with Category III exposure shows the recommended treatment schedule at RITM using pERIG is well tolerated, while survival of 143 laboratory-confirmed rabies exposures confirms the intervention efficacy. Two PEP intervention failures demonstrate that sustained education and training is essential in rabies management.
Author Summary
Infection from a bite by a rabid animal is fatal unless rapid treatment (thorough cleaning of the wound, administration of rabies immunoglobulins (RIG), and a full anti-rabies vaccination course) is provided. Ideally human RIG should be used, but cheaper, more readily available purified horse RIG (pERIG) are widely used in developing countries. Follow-up of over 7,600 patients previously given pERIG at the rabies treatment reference center in Manila (Philippines) provided updated health status for 6,458 patients 39 days to 29 months after treatment. A total of 151 patients had been bitten by animals with laboratory-confirmed rabies. Two rabies deaths were reported, one in a 4-year-old girl with bites on the back, shoulder, and neck so severe that stitching was required to prevent bleeding (against recommended practice), and another in an 8-year-old boy who only received rabies vaccination on the day of initial treatment. A 7-year-old cousin of this boy, bitten by the same animal, who did receive the full vaccination course was still healthy 10 months later. Fourteen other reported deaths had causes unrelated to rabies. These data illustrate the effectiveness of pERIG as part of the recommended treatment regimen, while highlighting the importance of adhering to current recommendations.
doi:10.1371/journal.pntd.0000243
PMCID: PMC2386244  PMID: 18509475
11.  Using Serology to Assist with Complicated Post-Exposure Prophylaxis for Rabies and Australian Bat Lyssavirus 
Background
Australia uses a protocol combining human rabies immunoglobulin (HRIG) and rabies vaccine for post-exposure prophylaxis (PEP) of rabies and Australian bat lyssavirus (ABLV), with the aim of achieving an antibody titre of ≥0.5 IU/ml, as per World Health Organization (WHO) guidelines, as soon as possible.
Methodology/Principal Findings
We present the course of PEP administration and serological testing for four men with complex requirements. Following dog bites in Thailand, two men (62 years old, 25 years old) received no HRIG and had delayed vaccine courses: 23 days between dose two and three, and 18 days between dose one and two, respectively. Both seroconverted following dose four. Another 62-year-old male, who was HIV-positive (normal CD4 count), also suffered a dog bite and had delayed care receiving IM rabies vaccine on days six and nine in Thailand. Back in Australia, he received three single and one double dose IM vaccines followed by another double dose of vaccine, delivered intradermally and subcutaneously, before seroconverting. A 23-year-old male with a history of allergies received simultaneous HRIG and vaccine following potential ABLV exposure, and developed rash, facial oedema and throat tingling, which was treated with a parenteral antihistamine and tapering dose of steroids. Serology showed he seroconverted following dose four.
Conclusions/Significance
These cases show that PEP can be complicated by exposures in tourist settings where reliable prophylaxis may not be available, where treatment is delayed or deviates from World Health Organization recommendations. Due to the potentially short incubation time of rabies/ABLV, timely prophylaxis after a potential exposure is needed to ensure a prompt and adequate immune response, particularly in patients who are immune-suppressed or who have not received HRIG. Serology should be used to confirm an adequate response to PEP when treatment is delayed or where a concurrent immunosuppressing medical condition or therapy exists.
Author Summary
In Australia, the administration of rabies post-exposure prophylaxis (PEP) occurs for potentially exposed returned travellers from endemic regions or for potential local exposure to Australian Bat Lyssavirus. For Australian tourists, delays in commencing PEP or not receiving HRIG or all recommended doses of vaccine are common. We report a case series where serology provided information in four patients with delayed, incomplete, or complicated PEP treatment. Three of these patients reported a dog bite in Thailand and the fourth was scratched by a bat and had bat urine enter his eye in Australia. Management was complicated by lack of HRIG administration, delays in the recommended timeframe for receipt of vaccine doses, and immunosuppression caused by co-administration of steroids and by HIV infection with a normal CD4 count. All patients seroconverted but this was delayed in some cases, and in the HIV-positive subject required a double dose of vaccine delivered intradermally and subcutaneously. In complex or non-standard PEP delivery, including delayed treatment and immunosuppression due to steroid treatment, HIV or another immunosuppressing medical condition, serology can be used to guide further treatment and should be used to confirm seroconversion.
doi:10.1371/journal.pntd.0002066
PMCID: PMC3584984  PMID: 23469301
12.  Moving from Rabies Research to Rabies Control: Lessons from India 
Background
Despite the availability of effective interventions and public recognition of the severity of the problem, rabies continues to suffer neglect by programme planners in India and other low and middle income countries. We investigate whether this state of ‘policy impasse’ is due to, at least in part, the research community not catering to the information needs of the policy makers.
Methods & Findings
Our objective was to review the research output on rabies from India and examine its alignment with national policy priorities. A systematic literature review of all rabies research articles published from India between 2001 and 2011 was conducted. The distribution of conducted research was compared to the findings of an earlier research prioritization exercise. It was found that a total of 93 research articles were published from India since 2001, out of which 61% consisted of laboratory based studies focussing on rabies virus. Animals were the least studied group, comprising only 8% of the research output. One third of the articles were published in three journals focussing on vaccines and infectious disease epidemiology and the top 4 institutions (2 each from the animal and human health sectors) collectively produced 49% of the national research output. Biomedical research related to development of new interventions dominated the total output as opposed to the identified priority domains of socio-politic-economic research, basic epidemiological research and research to improve existing interventions.
Conclusion
The paper highlights the gaps between rabies research and policy needs, and makes the case for developing a strategic research agenda that focusses on rabies control as an expected outcome.
Author Summary
Rabies is among the most widely spread zoonoses (diseases that are naturally transmitted between vertebrate animals and humans) in humans in most Asian, African and Latin American countries. Even though researchers have demonstrated effectiveness of strategies to control rabies at the population level, such as post exposure prophylaxis in humans and animal birth control and immunization among dogs, are well known, policy makers in most countries are hesitant to implement these strategies. This paper examines the disconnect that prevents the translation of scientific research outputs into effective policies. We contrasted the type of research papers published on rabies from India in the last eleven years with a previously identified set of priority research options. We found that most published research articles related to biomedical research focussing on development of new interventions. This was in contrast to policy and systems-related research and research to improve the performance of existing interventions that were identified as priority research options for India earlier. The findings of our study highlight the importance of moving beyond a purely researcher-driven agenda and suggest the need to promote research that has a vision of rabies control in the near future.
doi:10.1371/journal.pntd.0001748
PMCID: PMC3413711  PMID: 22880139
13.  Bat Rabies in Guatemala 
Rabies in bats is considered enzootic throughout the New World, but few comparative data are available for most countries in the region. As part of a larger pathogen detection program, enhanced bat rabies surveillance was conducted in Guatemala, between 2009 and 2011. A total of 672 bats of 31 species were sampled and tested for rabies. The prevalence of rabies virus (RABV) detection among all collected bats was low (0.3%). Viral antigens were detected and infectious virus was isolated from the brains of two common vampire bats (Desmodus rotundus). RABV was also isolated from oral swabs, lungs and kidneys of both bats, whereas viral RNA was detected in all of the tissues examined by hemi-nested RT-PCR except for the liver of one bat. Sequencing of the nucleoprotein gene showed that both viruses were 100% identical, whereas sequencing of the glycoprotein gene revealed one non-synonymous substitution (302T,S). The two vampire bat RABV isolates in this study were phylogenetically related to viruses associated with vampire bats in the eastern states of Mexico and El Salvador. Additionally, 7% of sera collected from 398 bats demonstrated RABV neutralizing antibody. The proportion of seropositive bats varied significantly across trophic guilds, suggestive of complex intraspecific compartmentalization of RABV perpetuation.
Author Summary
In this study we provide results of the first active and extensive surveillance effort for rabies virus (RABV) circulation among bats in Guatemala. The survey included multiple geographic areas and multiple species of bats, to assess the broader public and veterinary health risks associated with rabies in bats in Guatemala. RABV was isolated from vampire bats (Desmodus rotundus) collected in two different locations in Guatemala. Sequencing of the isolates revealed a closer relationship to Mexican and Central American vampire bat isolates than to South American isolates. The detection of RABV neutralizing antibodies in 11 species, including insectivorous, frugivorous, and sanguivorous bats, demonstrates viral circulation in both hematophagous and non-hematophagous bat species in Guatemala. The presence of bat RABV in rural communities requires new strategies for public health education regarding contact with bats, improved laboratory-based surveillance of animals associated with human exposures, and novel techniques for modern rabies prevention and control. Additionally, healthcare practitioners should emphasize the collection of a detailed medical history, including questions regarding bat exposure, for patients presenting with clinical syndromes compatible with rabies or any clinically diagnosed progressive encephalitis.
doi:10.1371/journal.pntd.0003070
PMCID: PMC4117473  PMID: 25080103
14.  Knowledge, Attitudes and Practices (KAP) about Rabies Prevention and Control: A Community Survey in Tanzania 
Background
Despite being entirely preventable, canine rabies still kills 55,000 people/year in developing countries. Information about local beliefs and practices can identify knowledge gaps that may affect prevention practices and lead to unnecessary deaths.
Methodology/Principal Findings
We investigated knowledge, attitudes and practices related to rabies and its prevention and control amongst a cross-section of households (n = 5,141) in urban and rural areas of central, southern and northern Tanzania. Over 17% of respondents owned domestic dogs (average of 2.3 dogs/household),>95% had heard about rabies, and>80% knew that rabies is transmitted through dog bites. People who (1) had greater education, (2) originated from areas with a history of rabies interventions, (3) had experienced exposure by a suspect rabid animal, (4) were male and (5) owned dogs were more likely to have greater knowledge about the disease. Around 80% of respondents would seek hospital treatment after a suspect bite, but only 5% were aware of the need for prompt wound cleansing after a bite. Although>65% of respondents knew of dog vaccination as a means to control rabies, only 51% vaccinated their dogs. Determinants of dog vaccination included (1) being a male-headed household, (2) presence of children, (3) low economic status, (4) residing in urban areas, (5) owning livestock, (6) originating from areas with rabies interventions and (7) having purchased a dog. The majority of dog-owning respondents were willing to contribute no more than US$0.31 towards veterinary services.
Conclusions/Significance
We identified important knowledge gaps related to, and factors influencing the prevention and control of rabies in Tanzania. Increasing knowledge regarding wound washing, seeking post-exposure prophylaxis and the need to vaccinate dogs are likely to result in more effective prevention of rabies; however, greater engagement of the veterinary and medical sectors is also needed to ensure the availability of preventative services.
Author Summary
Rabies remains a major public health problem in Africa and Asia, although means to control and prevent the disease are available through mass dog vaccination and provision of post-exposure prophylaxis to people exposed to bites by suspect rabid animals. Here we report the results of an extensive community survey on knowledge, attitudes and practices related to rabies control and prevention, covering rural and urban settings in central, northern and southern Tanzania. Our results showed that the majority of people across Tanzania had heard about rabies and knew that it is transmitted by dog bites, but most lacked comprehensive knowledge about key practices, such as the need for wound cleansing, which could prevent unnecessary deaths from the disease. In other circumstances, knowledge (for example, about the need to vaccinate dogs to control rabies) did not reflect good practice. In order to address the knowledge gaps identified by this study, there is a need for interventions aimed at increasing awareness, focusing on simple messages and targeting the community as a whole. This information could be channelled through media, community meetings and professionals including community leaders, health workers, teachers, livestock officers and clinicians.
doi:10.1371/journal.pntd.0003310
PMCID: PMC4256472  PMID: 25473834
15.  Epidemiological and clinical features of human rabies cases in Bali 2008-2010 
Background
Previously thought to be rabies free, Bali experienced an outbreak of animal and human rabies cases in November 2008. We describe the epidemiological and clinical data of human rabies cases occurring in the first two years of the outbreak.
Methods
We analysed the patient records of all rabies cases from the Sanglah General Hospital in Denpasar, and district hospitals in Buleleng and Tabanan. A conventional reverse transcriptase polymerase chain reaction was developed to detect the rabies virus genome in saliva, corneal swabs, and ante- and post-mortem cerebrospinal fluid (CSF).
Results
There were 104 human rabies cases in Bali during November 2008-November 2010. Patients' mean age was 36.6 years (range 3-84 years; SD 20.7), most were male (56.7%), and originated from rural districts. Almost all (92%) cases had a history of dog bite. Only 5.8% had their wounds treated and received an anti-rabies vaccine (ARV) after the bite incident. No patients received rabies immunoglobulin (RIG). The estimated time from dog bite to the onset of signs and symptoms was 110.4 days (range 12-720 days; SD 118.2). The mean length of medical care until death was 21.8 hours (range 1-220 hours; SD 32.6). Less than 50% of patients had prodromal symptoms. The most frequent prodromal symptom was pain or paraesthesia at the bite site (37.6%). The two most common central nervous system infection signs were agitation (89.2%) and confusion (83.3%). Signs of autonomic nervous system dysfunction included hydrophobia (93.1%), hypersalivation (88.2%), and dyspnea (74.4%). On admission, 22 of 102 patients (21.6%) showed paralytic manifestations, while the rest (78.4%) showed furious rabies manifestations. The case-fatality rate was 100%. The rabies virus genome was detected in 50 of 101 patients (49.5%) with the highest detection rate from post-mortem CSF samples.
Conclusions
Rabies is a major public health problem in Bali. Human fatalities occur because of a lack of knowledge regarding rabies risk, the poor management of dog bites, and the limited availability of RIG. Increasing public awareness of dog bite management, increasing the availability of ARV and RIG, and implementing an island-wide dog vaccination campaign will help prevent human rabies cases.
doi:10.1186/1471-2334-12-81
PMCID: PMC3353247  PMID: 22471410
Rabies virus; Bali; RT-PCR
16.  Rabies Diagnosis for Developing Countries 
Background
Canine rabies is a neglected disease causing 55,000 human deaths worldwide per year, and 99% of all cases are transmitted by dog bites. In N'Djaména, the capital of Chad, rabies is endemic with an incidence of 1.71/1,000 dogs (95% C.I. 1.45–1.98). The gold standard of rabies diagnosis is the direct immunofluorescent antibody (DFA) test, requiring a fluorescent microscope. The Centers for Disease Control and Prevention (CDC, Atlanta, United States of America) developed a histochemical test using low-cost light microscopy, the direct rapid immunohistochemical test (dRIT).
Methodology/Principal Findings
We evaluated the dRIT in the Chadian National Veterinary Laboratory in N'Djaména by testing 35 fresh samples parallel with both the DFA and dRIT. Additional retests (n = 68 in Chad, n = 74 at CDC) by DFA and dRIT of stored samples enhanced the power of the evaluation. All samples were from dogs, cats, and in one case from a bat. The dRIT performed very well compared to DFA. We found a 100% agreement of the dRIT and DFA in fresh samples (n = 35). Results of retesting at CDC and in Chad depended on the condition of samples. When the sample was in good condition (fresh brain tissue), we found simple Cohen's kappa coefficient related to the DFA diagnostic results in fresh tissue of 0.87 (95% C.I. 0.63–1) up to 1. For poor quality samples, the kappa values were between 0.13 (95% C.I. −0.15–0.40) and 0.48 (95% C.I. 0.14–0.82). For samples stored in glycerol, dRIT results were more likely to agree with DFA testing in fresh samples than the DFA retesting.
Conclusion/Significance
The dRIT is as reliable a diagnostic method as the gold standard (DFA) for fresh samples. It has an advantage of requiring only light microscopy, which is 10 times less expensive than a fluorescence microscope. Reduced cost suggests high potential for making rabies diagnosis available in other cities and rural areas of Africa for large populations for which a capacity for diagnosis will contribute to rabies control.
Author Summary
A new diagnostic test for rabies in animals was evaluated in N'Djaména, capital of Chad. The test is based on a direct immuno-histochemical detection of rabies virus in brain tissue (dRIT) visible by normal light microscopy. Rabies detection by dRIT light microscopy is 10 times less expensive than fluorescence microscopy required for the current gold standard of rabies diagnosis. The test showed ideal results in fresh samples with 100% agreement with the gold standard and confirms the results of a first study in Tanzania. Thus, it has a significant potential for diagnosing rabies in low-income countries, and under field conditions where rabies diagnosis is unavailable for the moment. This new test opens up a great potential to train technical staff and to establish rabies diagnosis without delay in low-income countries with urban rabies.
doi:10.1371/journal.pntd.0000206
PMCID: PMC2268742  PMID: 18365035
17.  The Activity of Rabies Vaccines against Genetic Clusters of Rabies Virus Circulating at the Territory of Ukraine 
Objective
To identify the presence of genetic clusters of rabies virus at the territory of Ukraine and to determine the degree of activity of rabies vaccines against these genetic clusters.
Introduction
To develop and implement an effective program of rabies eradication in Ukraine in 2008 was founded the unique collection of samples of pathological materials confirmed as positive in rabies at the regional veterinary laboratories of Ukraine. The collection is constantly updated and to present moment it includes 1389 samples from all regions of Ukraine, selected from 17 animal species and humans.
Methods
Identification of the rabies virus in samples of pathological material for their further selection was carried out using the test developed by us which based on RT-PCR with primers complementary to the conservative fragments of the 5’-end of nucleoprotein gene of rabies virus.
For the study of the street rabies virus isolates from the collection we use RT-PCR with the primers pair (509, 304) flanking the variable 3’-end part of nucleoprotein gene of the reference strain of rabies virus CVS (fragment in 377 bp).
Studies of rabies vaccines activity were carried out with modified method of U.S. National Institutes of Health using rabies virus street isolates of both genetic clusters instead of the Challenge Virus Standard (CVS). All isolates of street rabies virus were inoculated in a dose of 5–50 LD50. The criteria for evaluation of protective activity of rabies vaccine was effective dose (− lg ED50).
Results
In molecular genetic studies with variant-specific primers we established the presence in Ukraine of two clusters of rabies virus. Clusters I circulates on the right bank of the Dnipro river (the largest water barrier that divides the country into eastern and western side), and cluster II – on the left bank of the Dnieper.
The relationship of these variants with the epizootic situation was researched. For this purpose epizootological zoning of Ukraine according to the intensity of the epizootic situation in 2005–2009 was carried out. As a result of this analysis all the regions of Ukraine belong to three categories: high, medium and low epizootic situation intensity of rabies.
The projection of differentiated genetic clusters on the epizootic situation showed that cluster II circulating at Left Bank of the Dnieper in areas with high and medium intensity of the epizootic situation, and the cluster I – at the Right Bank of the Dnieper, mainly in the areas with low intensity of the epizootic situation.
That’s why our interest was in the degree of protection of rabies vaccines against street rabies virus isolates belonging to these two genetic clusters.
The commercial vaccines made with rabies virus vaccine strains SAD (Street-Alabama-Dufferin) and Wistar PM/WI were chosen to evaluate this parameter.
After the mathematical calculations of effective dose and the analysis of the data the less effective protection of rabies vaccines (at 29–30 %) against street rabies virus isolates belonging to cluster II in comparison with isolates belonging to cluster I irrespective to the strain vaccine is made was shown.
Conclusions
The data will be used for the effective planning of specific prophylaxis of rabies in Ukraine based on differentiated approach to distribution of rabies vaccines in according to region and their activity.
PMCID: PMC3692803
rabies vaccine; vaccine activity; street rabies virus isolates; genetic variants of rabies virus
18.  The Feasibility of Canine Rabies Elimination in Africa: Dispelling Doubts with Data 
Background
Canine rabies causes many thousands of human deaths every year in Africa, and continues to increase throughout much of the continent.
Methodology/Principal Findings
This paper identifies four common reasons given for the lack of effective canine rabies control in Africa: (a) a low priority given for disease control as a result of lack of awareness of the rabies burden; (b) epidemiological constraints such as uncertainties about the required levels of vaccination coverage and the possibility of sustained cycles of infection in wildlife; (c) operational constraints including accessibility of dogs for vaccination and insufficient knowledge of dog population sizes for planning of vaccination campaigns; and (d) limited resources for implementation of rabies surveillance and control. We address each of these issues in turn, presenting data from field studies and modelling approaches used in Tanzania, including burden of disease evaluations, detailed epidemiological studies, operational data from vaccination campaigns in different demographic and ecological settings, and economic analyses of the cost-effectiveness of dog vaccination for human rabies prevention.
Conclusions/Significance
We conclude that there are no insurmountable problems to canine rabies control in most of Africa; that elimination of canine rabies is epidemiologically and practically feasible through mass vaccination of domestic dogs; and that domestic dog vaccination provides a cost-effective approach to the prevention and elimination of human rabies deaths.
Author Summary
Elimination of canine rabies has been achieved in some parts of the world, but the disease still kills many thousands of people each year in Africa. Here we counter common arguments given for the lack of effective canine rabies control in Africa presenting detailed data from a range of settings. We conclude that (1) rabies substantially affects public and animal health sectors, hence regional and national priorities for control ought to be higher, (2) for practical purposes domestic dogs are the sole maintenance hosts and main source of infection for humans throughout most of Africa and Asia and sufficient levels of vaccination coverage in domestic dog populations should lead to elimination of canine rabies in most areas, (3) the vast majority of domestic dog populations across sub-Saharan Africa are accessible for vaccination with community sensitization being of paramount importance for the success of these programs, (4) improved local capacity in rabies surveillance and diagnostics will help evaluate the impact of control and elimination efforts, and (5) sustainable resources for effective dog vaccination campaigns are likely to be available through the development of intersectoral financing schemes involving both medical and veterinary sectors.
doi:10.1371/journal.pntd.0000626
PMCID: PMC2826407  PMID: 20186330
19.  Improvement Control System of Rabies in Ukraine 
Objective
The purpose of the research was to find out the reasons of rabies antropurgisation in Ukraine.
Introduction
In Ukraine in spite of considerable financial expenses on oral immunization of foxes and parenteral immunization of dogs and cats, it is not succeeded to reach considerable results in the fight with rabies. Unfortunately there was a negative tendency to increasing a part of dogs and cats in the structure of rabies disease which are the main source of rabies in people.
Methods
Analysis of 228 anamnesis data of rabies infected dogs during 2008–2012. Research of 234 samples of the blood serum from dogs on existence of antibodies to the rabies virus by the ELISA method.
Results
Analysis of animal morbidity on rabies in Ukraine in period of 2006–2011 found out the changes of structure of morbidity in animal species that means decreasing a part of wild animals (from 49,0 % in 2006 to 38,7 % in 2011) and increasing a part of dogs (from 18,3 % in 2006 to 23,2 % in 2011) and cats (from 19,8 % in 2006 to 25,0 % in 2011) in the general amount of animals which perished from rabies (Fig. 1).
A lot of Ukrainian scientists and doctors of veterinary medicine consider that the main reason of spreading the rabies is a great number of homeless animals which factually are the reservoirs of infection in towns and villages.
However, in our opinion spreading of rabies shows the insufficient level of measures of control of rabies among home animals. It was confirmed with conducted analysis that only 26 (12,9 %) dogs were stray, others 202 (87,1 %) had owners, but didn’t get necessary protective rabies vaccination.
According to Ukrainian instruction “Preventive measures against rabies of animals”, all the dogs must be vaccinated against rabies, but it actually appears it is quite not so.
At research of 234 samples of the blood serum of dogs on existence of antibodies to the rabies virus it was determined that the level of population immunity in dogs is 36,6 % in Ukrainian towns, but the protective level of antibodies was found in 9,1 % of village dogs. We consider that the main reason of this is imperfection of the Ukrainian legislation in the questions of responsibility of proprietors of animals.
For breaking of epizootic chain it is necessary the percent of vaccinated animals (in this case dogs) to be on a high level – more than 50%. Nowadays for reaching epidemic welfare in rabies it is important within the framework of the registered epidemic incidents dogs to be brought over to the ecocycles of infection sporadically without taking part in circulation of exciter, stay their biological deadlock and have low epidemic potential.
Conclusions
The conducted analysis expressly demonstrates that at present problems the eradication of rabies in Ukraine is impossible considering the low level of dogs’ protection from rabies. Obtained results were sent to the State committee of veterinary medicine of Ukraine and will be the argument for enhancement of control after conducting rabies vaccination of dogs.
Rabies cases in the years 2006–2011.
PMCID: PMC3692804
population rabies immunity; rabies vaccination; stray dogs
20.  Potential rabies exposures in a Virginia county. 
Public Health Reports  1998;113(3):258-262.
OBJECTIVE: Although records of animal bites and scratches are kept at most local health departments, little is known about the epidemiology and characteristics of these potential rabies exposures on a local level. Bite and scratch records for a four-and-a-half-year period from Montgomery County, Virginia, were examined in order to identify preventable trends. METHODS: The author retrospectively reviewed animal bite and scratch records from the Montgomery County Health Department dating from January 1992 through July 1996. RESULTS: Cat bites or scratches involved stray or feral animals more than eight times as often as dog bites or scratches. Cats were involved in the majority of incidents in which rabies postexposure prophylaxis (PEP) was recommended. Overall, PEP was recommended following 5.9% of reported incidents. The records also indicated that 65% of owned cats were unvaccinated at the time of the incident, while only 28% of owned dogs were unvaccinated. Children under the age of 18 were significantly more likely to be involved in a potential exposure than adults. CONCLUSIONS: Potential exposures should be analyzed periodically by local health departments. Suggestions for minimizing the number of potential rabies exposures in Montgomery County based on the results of the study reported here include: reducing the stray and feral cat population, targeting educational programs to children, and encouraging owners to vaccinate their pets.
PMCID: PMC1308679  PMID: 9633873
21.  Molecular Inferences Suggest Multiple Host Shifts of Rabies Viruses from Bats to Mesocarnivores in Arizona during 2001–2009 
PLoS Pathogens  2012;8(6):e1002786.
In nature, rabies virus (RABV; genus Lyssavirus, family Rhabdoviridae) represents an assemblage of phylogenetic lineages, associated with specific mammalian host species. Although it is generally accepted that RABV evolved originally in bats and further shifted to carnivores, mechanisms of such host shifts are poorly understood, and examples are rarely present in surveillance data. Outbreaks in carnivores caused by a RABV variant, associated with big brown bats, occurred repeatedly during 2001–2009 in the Flagstaff area of Arizona. After each outbreak, extensive control campaigns were undertaken, with no reports of further rabies cases in carnivores for the next several years. However, questions remained whether all outbreaks were caused by a single introduction and further perpetuation of bat RABV in carnivore populations, or each outbreak was caused by an independent introduction of a bat virus. Another question of concern was related to adaptive changes in the RABV genome associated with host shifts. To address these questions, we sequenced and analyzed 66 complete and 20 nearly complete RABV genomes, including those from the Flagstaff area and other similar outbreaks in carnivores, caused by bat RABVs, and representatives of the major RABV lineages circulating in North America and worldwide. Phylogenetic analysis demonstrated that each Flagstaff outbreak was caused by an independent introduction of bat RABV into populations of carnivores. Positive selection analysis confirmed the absence of post-shift changes in RABV genes. In contrast, convergent evolution analysis demonstrated several amino acids in the N, P, G and L proteins, which might be significant for pre-adaptation of bat viruses to cause effective infection in carnivores. The substitution S/T242 in the viral glycoprotein is of particular merit, as a similar substitution was suggested for pathogenicity of Nishigahara RABV strain. Roles of the amino acid changes, detected in our study, require additional investigations, using reverse genetics and other approaches.
Author Summary
Host shifts of the rabies virus (RABV) from bats to carnivores are important for our understanding of viral evolution and emergence, and have significant public health implications, particularly for the areas where “terrestrial” rabies has been eliminated. In this study we addressed several rabies outbreaks in carnivores that occurred in the Flagstaff area of Arizona during 2001–2009, and caused by the RABV variant associated with big brown bats (Eptesicus fuscus). Based on phylogenetic analysis we demonstrated that each outbreak resulted from a separate introduction of bat RABV into populations of carnivores. No post-shift changes in viral genomes were detected under the positive selection analysis. Trying to answer the question why certain bat RABV variants are capable for host shifts to carnivores and other variants are not, we developed a convergent evolution analysis, and implemented it for multiple RABV lineages circulating worldwide. This analysis identified several amino acids in RABV proteins which may facilitate host shifts from bats to carnivores. Precise roles of these amino acids require additional investigations, using reverse genetics and animal experimentation. In general, our approach and the results obtained can be used for prediction of host shifts and emergence of other zoonotic pathogens.
doi:10.1371/journal.ppat.1002786
PMCID: PMC3380930  PMID: 22737076
22.  Rabies Situation in Cambodia 
Background
Rabies, a fatal but preventable zoonosis, is a major public health problem in developing countries. In Cambodia the disease burden is largely underestimated because patients with encephalitis following dog bites are rarely hospitalized and die at home. Since 1998 Institut Pasteur in Cambodia (IPC), Phnom Penh has been the only source of free post-exposure prophylaxis (PEP) and post-mortem diagnosis.
Methods
The 1998–2007 data compiled by IPC was analyzed to describe all treated patients for PEP, results of human testing and confirmed rabies cases, and results of animal testing. From dog bites' characteristics, we defined a suspected rabid dog bite injury (SRDBI) in humans as a bite that was unprovoked, from a dog that died spontaneously, or from a dog that was reported sick. We applied a deterministic probability model to estimate 2007 rabies human mortality nationwide from the estimated incidence of rabid dog bites, the body distribution of bite wounds, and the probability of PEP access.
Results
During 1998–2007, 124,749 patients received PEP at IPC (average 12,470; range 8,907–14,475), and 63 fatal human cases presenting with encephalitis following a dog bite were reported, in which 73% were confirmed positive for rabies by direct immunofluorescence assay or by reverse-transcriptase polymerase chain reaction. During 1998–2007, IPC tested 1,255 animal brain samples; 1,214 (97%) were from dogs including 610 (49%) positive samples. In 2007, 14,475 patients received PEP (100 PEP/100,000 people in Cambodia) including 95% who resided in Phnom Penh (615 PEP/100,000) or five neighboring provinces. The predictive model estimated 810 human rabies deaths would occur in 2007 (95%confidence interval [CI] 394–1,607), an incidence of 5.8/100,000 (95% CI 2.8–11.5).
Conclusions
Access to PEP is only sufficient for Phnom Penh residents. In 2007, the estimated rabies related mortality exceeded that of malaria and that of dengue. A national rabies control program is needed to improve surveillance and access to PEP, and to initiate vaccination campaigns in dogs.
Author Summary
In Cambodia, rabies still elicits fear in the communities. Since 1998 the Institut Pasteur in Cambodia (IPC), Phnom Penh has been the only source of free post-exposure prophylaxis (PEP) and post mortem diagnosis. During 1998–2007, on average ∼12,400 patients received PEP annually at IPC (range 8,907–14,475) and 63 fatal human cases presenting with encephalitis following a dog bite were reported including 73% who tested positive by fluorescent-antibody test on brain samples or/and by reverse-transcriptase polymerase chain reaction on skin, cerebrospinal fluid, or urine. In 2007, 14,475 patients received PEP (100 PEP/100,000 people in Cambodia) including 95% who resided in Phnom Penh city (615 PEP/100,000) or five neighboring provinces. Using a step-by-step probability model, we estimated that 810 human rabies deaths would occur in 2007 (95% confidence interval [CI] 394–1,607); an incidence of 5.8/100,000 (95%CI 2.8–11.5). As a result, despite high attendance at the IPC's PEP center most Cambodians living in peripheral provinces in Cambodia may not have adequate access to PEP. Finally, the model generated one of the highest incidences of rabies worldwide. A national rabies control program is needed to improve surveillance and access to PEP, and to initiate vaccination campaigns in dogs.
doi:10.1371/journal.pntd.0000511
PMCID: PMC2731168  PMID: 19907631
23.  Intravenous Inoculation of a Bat-Associated Rabies Virus Causes Lethal Encephalopathy in Mice through Invasion of the Brain via Neurosecretory Hypothalamic Fibers 
PLoS Pathogens  2009;5(6):e1000485.
The majority of rabies virus (RV) infections are caused by bites or scratches from rabid carnivores or bats. Usually, RV utilizes the retrograde transport within the neuronal network to spread from the infection site to the central nervous system (CNS) where it replicates in neuronal somata and infects other neurons via trans-synaptic spread. We speculate that in addition to the neuronal transport of the virus, hematogenous spread from the site of infection directly to the brain after accidental spill over into the vascular system might represent an alternative way for RV to invade the CNS. So far, it is unknown whether hematogenous spread has any relevance in RV pathogenesis. To determine whether certain RV variants might have the capacity to invade the CNS from the periphery via hematogenous spread, we infected mice either intramuscularly (i.m.) or intravenously (i.v.) with the dog-associated RV DOG4 or the silver-haired bat-associated RV SB. In addition to monitoring the progression of clinical signs of rabies we used immunohistochemistry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to follow the spread of the virus from the infection site to the brain. In contrast to i.m. infection where both variants caused a lethal encephalopathy, only i.v. infection with SB resulted in the development of a lethal infection. While qRT-PCR did not reveal major differences in virus loads in spinal cord or brain at different times after i.m. or i.v. infection of SB, immunohistochemical analysis showed that only i.v. administered SB directly infected the forebrain. The earliest affected regions were those hypothalamic nuclei, which are connected by neurosecretory fibers to the circumventricular organs neurohypophysis and median eminence. Our data suggest that hematogenous spread of SB can lead to a fatal encephalopathy through direct retrograde invasion of the CNS at the neurovascular interface of the hypothalamus-hypophysis system. This alternative mode of virus spread has implications for the post exposure prophylaxis of rabies, particularly with silver-haired bat-associated RV.
Author Summary
Rabies virus (RV) infects mammalian neurons and cycles in regionally distinct animal populations such as the red fox in Europe, domestic canines in Asia, or raccoons, skunks and bats in Northern America. Although human rabies can be prevented by pre- and post-exposure prophylaxis, more than 50,000 people die annually from the severe encephalopathy caused by RV. Recently, two cases of RV transmission by organ transplantation were reported. In our study, using intravenous inoculation of mice, we evaluated the pathogenetic relevance of virions that reach the bloodstream. Mice inoculated intravenously with a canine-derived RV survived the infection in contrast to intramuscularly injected mice, while mice infected with a silver-haired bat-related RV succumbed to the disease regardless of the route of inoculation. We found that the silver-haired bat-related RV was able to transit from the blood to the brain by invading neurosecretory fibers of the hypothalamus, which form neurohemal synapses lacking a blood-brain-barrier. This newly described route of brain invasion might reflect how RV reached the central nervous system from transplanted organs, since it takes longer to establish the neural connections between host and grafted tissue necessary for classical RV migration than the time until the infection became symptomatic in the two reported cases.
doi:10.1371/journal.ppat.1000485
PMCID: PMC2691950  PMID: 19543379
24.  Transmission dynamics of rabies virus in Thailand: Implications for disease control 
Background
In Thailand, rabies remains a neglected disease with authorities continuing to rely on human death statistics while ignoring the financial burden resulting from an enormous increase in post-exposure prophylaxis. Past attempts to conduct a mass dog vaccination and sterilization program have been limited to Bangkok city and have not been successful. We have used molecular epidemiology to define geographic localization of rabies virus phylogroups and their pattern of spread in Thailand.
Methods
We analyzed 239 nucleoprotein gene sequences from animal and human brain samples collected from all over Thailand between 1998 and 2002. We then reconstructed a phylogenetic tree correlating these data with geographical information.
Results
All sequences formed a monophyletic tree of 2 distinct phylogroups, TH1 and TH2. Three subgroups were identified in the TH1 subgroup and were distributed in the middle region of the country. Eight subgroups of TH2 viruses were identified widely distributed throughout the country overlapping the TH1 territory. There was a correlation between human-dependent transportation routes and the distribution of virus.
Conclusion
Inter-regional migration paths of the viruses might be correlated with translocation of dogs associated with humans. Interconnecting factors between human socioeconomic and population density might determine the transmission dynamics of virus in a rural-to-urban polarity. The presence of 2 or more rabies virus groups in a location might be indicative of a gene flow, reflecting a translocation of dogs within such region and adjacent areas. Different approaches may be required for rabies control based on the homo- or heterogeneity of the virus. Areas containing homogeneous virus populations should be targeted first. Control of dog movement associated with humans is essential.
doi:10.1186/1471-2334-5-52
PMCID: PMC1184074  PMID: 15985183
25.  Imported Episodic Rabies Increases Patient Demand for and Physician Delivery of Antirabies Prophylaxis 
Background
Imported cases threaten rabies reemergence in rabies-free areas. During 2000–2005, five dog and one human rabies cases were imported into France, a rabies-free country since 2001. The Summer 2004 event led to unprecedented media warnings by the French Public Health Director. We investigated medical practice evolution following the official elimination of rabies in 2001; impact of subsequent episodic rabies importations and national newspaper coverage on demand for and delivery of antirabies prophylaxis; regular transmission of epidemiological developments within the French Antirabies Medical Center (ARMC) network; and ARMC discussions on indications of rabies post-exposure prophylaxis (RPEP).
Methodology/Principal Findings
Annual data collected by the National Reference Center for Rabies NRCR (1989–2006) and the exhaustive database (2000–2005) of 56 ARMC were analyzed. Weekly numbers of patients consulting at ARMC and their RPEP- and antirabies-immunoglobulin (ARIG) prescription rates were determined. Autoregressive integrated moving-average modeling and regression with autocorrelated errors were applied to examine how 2000–2005 episodic rabies events and their related national newspaper coverage affected demand for and delivery of RPEP. A slight, continuous decline of rabies-dedicated public health facility attendance was observed from 2000 to 2004. Then, during the Summer 2004 event, patient consultations and RPEP and ARIG prescriptions increased by 84%, 19.7% and 43.4%, respectively. Moreover, elevated medical resource use persisted in 2005, despite communication efforts, without any secondary human or animal case.
Conclusions
Our findings demonstrated appropriate responsiveness to reemerging rabies cases and effective newspaper reporting, as no secondary case occurred. However, the ensuing demand on medical resources had immediate and long-lasting effects on rabies-related public health resources and expenses. Henceforth, when facing such an event, decision-makers must anticipate the broad impact of their media communications to counter the emerging risk on maintaining an optimal public health organization and implement a post-crisis communication strategy.
Author Summary
Rabies has been eliminated from a large part of the European Union and, thus, any newly imported cases threaten its reemergence. The 2000–2005 data derived from the exhaustive surveillance system implemented in France was analyzed to evaluate the impact on demand for and delivery of antirabies prophylaxis following introduction of five rabies-infected dogs and one infected human into this rabies-free area. Using these events, we were able to illustrate the difficulties encountered in reducing the demand for and prescription of post-exposure rabies prophylaxis in this context of episodic importation. Moreover, we highlighted the need for public health decision-makers to anticipate the broad spectrum of consequences of their media communications and to prepare appropriate responses (in terms of health resources) to maintain an optimally effective public health organization after importation of an exotic infectious agent or its emergence. These responses are particularly relevant in the context of limited availability of rabies post-exposure prophylaxis, especially antirabies immunoglobulin.
doi:10.1371/journal.pntd.0000723
PMCID: PMC2889823  PMID: 20582307

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