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1.  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
2.  Experimental rabies vaccines for humans 
Expert review of vaccines  2010;9(10):1177-1186.
Rabies remains a global public health threat that kills more than 55,000 people per year. Rabies disproportionately affects children and, therefore, is ranked the seventh most important infectious disease due to years lost. Prevention of human rabies is accomplished by controlling rabies in domestic and wild animals, including the use of vaccination programs. The usefulness of human rabies vaccines is hampered by high cost, complicated vaccination regimens and lack of compliance, especially in areas of Africa and Asia where human rabies infections are endemic. A single-dose vaccine would greatly benefit efforts to combat this global health threat. However, a single-dose vaccine based on current inactivated vaccines does not appear feasible and other approaches are needed. Technology has advanced since modern human rabies vaccines were developed over 40 years ago. In addition, our understanding of immunological principles that influence the outcome of vaccination has increased. This article describes the current status of inactivated rabies virus vaccines and recent developments arising from the use of reverse genetics technologies designed to develop replication-deficient or single-cycle live rabies virus-based vectors for use as a single-dose rabies vaccine for humans.
doi:10.1586/erv.10.105
PMCID: PMC3072237  PMID: 20923268
attenuated rabies vaccines; post-exposure vaccines; pre-exposure vaccines; rabies vaccines; replication-deficient vectors; reverse genetics; single-cycle vectors
3.  Ecoepidemiological and Social Factors Related to Rabies Incidence in Venezuela during 2002-2004 
Rabies in Venezuela has been important in last years, affecting dogs, cats, and human, among other animals, being a reportable disease. In Zulia state, it is considered a major public health concern. Recently, a considerable increase in the incidence of rabies has been occurring, involving many epidemiological but also ecoepidemiological and social factors. These factors are analyzed in this report. During 2002-2004, 416 rabies cases were recorded. Incidence has been increasingly significantly, affecting mainly dogs (88.94%). Given this epidemiology we associated ecoepidemiological and social factors with rabies incidence in the most affected state, Zulia. In this period 411 rabies cases were recorded. Zulia has varied environmental conditions. It is composed mostly of lowlands bordered in the west by mountain system and in the south by the Andes. The mean is temperature 27.8°C, and mean yearly rainfall is 750 mm. Climatologically, 2002 corresponded with El Niño (drought), middle 2003 evolved to a Neutral period, and 2004 corresponded to La Niña (rainy); this change may have affected many diseases, including rabies. Ecological analysis showed that most cases occurred in lowland area of the state and during rainy season (p<0.05). Additionally, there is an important social problem due to educational deficiencies in the native population. Many ethnic groups live un Zulia, many myths about rabies are in circulation, and the importance of the disease is not widely realized. The full scale of the rabies burden is unknown, owing to inadequate disease surveillance. Although there have been important advances in our knowledge and ability to diagnose and prevent it, enormous challenges remain in animal rabies control and provision of accessible-appropriate human prophylaxis worldwide. Human and animal surveillance including ecological and social factors is needed.
PMCID: PMC3614572  PMID: 23674960
Rabies virus; ecoepidemiology; climate variability; social factors
4.  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
5.  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
6.  Oral Rabies Vaccination in North America: Opportunities, Complexities, and Challenges 
Steps to facilitate inter-jurisdictional collaboration nationally and continentally have been critical for implementing and conducting coordinated wildlife rabies management programs that rely heavily on oral rabies vaccination (ORV). Formation of a national rabies management team has been pivotal for coordinated ORV programs in the United States of America. The signing of the North American Rabies Management Plan extended a collaborative framework for coordination of surveillance, control, and research in border areas among Canada, Mexico, and the US. Advances in enhanced surveillance have facilitated sampling of greater scope and intensity near ORV zones for improved rabies management decision-making in real time. The value of enhanced surveillance as a complement to public health surveillance was best illustrated in Ohio during 2007, where 19 rabies cases were detected that were critical for the formulation of focused contingency actions for controlling rabies in this strategically key area. Diverse complexities and challenges are commonplace when applying ORV to control rabies in wild meso-carnivores. Nevertheless, intervention has resulted in notable successes, including the elimination of an arctic fox (Vulpes lagopus) rabies virus variant in most of southern Ontario, Canada, with ancillary benefits of elimination extending into Quebec and the northeastern US. Progress continues with ORV toward preventing the spread and working toward elimination of a unique variant of gray fox (Urocyon cinereoargenteus) rabies in west central Texas. Elimination of rabies in coyotes (Canis latrans) through ORV contributed to the US being declared free of canine rabies in 2007. Raccoon (Procyon lotor) rabies control continues to present the greatest challenges among meso-carnivore rabies reservoirs, yet to date intervention has prevented this variant from gaining a broad geographic foothold beyond ORV zones designed to prevent its spread from the eastern US. Progress continues toward the development and testing of new bait-vaccine combinations that increase the chance for improved delivery and performance in the diverse meso-carnivore rabies reservoir complex in the US.
doi:10.1371/journal.pntd.0000549
PMCID: PMC2791170  PMID: 20027214
7.  Intracerebral Administration of Recombinant Rabies Virus Expressing GM-CSF Prevents the Development of Rabies after Infection with Street Virus 
PLoS ONE  2011;6(9):e25414.
Recently it was found that prior immunization with recombinant rabies virus (RABV) expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) (LBNSE-GM-CSF) resulted in high innate/adaptive immune responses and protection against challenge with virulent RABV (Wen et al., JVI, 2011). In this study, the ability of LBNSE-GM-CSF to prevent animals from developing rabies was investigated in mice after infection with lethal doses of street RABV. It was found that intracerebral administration of LBNSE-GM-CSF protected more mice from developing rabies than sham-treated mice as late as day 5 after infection with street RABV. Intracerebral administration of LBNSE-GM-CSF resulted in significantly higher levels of chemokine/cytokine expression and more infiltration of inflammatory and immune cells into the central nervous system (CNS) than sham-administration or administration with UV-inactivated LBNSE-GM-CSF. Enhancement of blood-brain barrier (BBB) permeability and increases in virus neutralizing antibodies (VNA) were also observed in mice treated with LBNSE-GM-CSF. On the other hand, intracerebral administration with UV-inactivated LBNSE-GM-CSF did not increase protection despite the fact that VNA were induced in the periphery. However, intracerebral administration with chemoattractant protein-1 (MCP-1, also termed CCL2) increased significantly the protective efficacy of UV-inactivated LBNSE-GM-CSF. Together these studies confirm that direct administration of LBNSE-GM-CSF can enhance the innate and adaptive immunity as well as the BBB permeability, thus allowing infiltration of inflammatory cells and other immune effectors enter into the CNS to clear the virus and prevent the development of rabies.
doi:10.1371/journal.pone.0025414
PMCID: PMC3182207  PMID: 21980450
8.  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
9.  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
10.  National Borders Effectively Halt the Spread of Rabies: The Current Rabies Epidemic in China Is Dislocated from Cases in Neighboring Countries 
China has seen a massive resurgence of rabies cases in the last 15 years with more than 25,000 human fatalities. Initial cases were reported in the southwest but are now reported in almost every province. There have been several phylogenetic investigations into the origin and spread of the virus within China but few reports investigating the impact of the epidemic on neighboring countries. We therefore collected nucleoprotein sequences from China and South East Asia and investigated their phylogenetic and phylogeographic relationship. Our results indicate that within South East Asia, isolates mainly cluster according to their geographic origin. We found evidence of sporadic exchange of strains between neighboring countries, but it appears that the major strain responsible for the current Chinese epidemic has not been exported. This suggests that national geographical boundaries and border controls are effective at halting the spread of rabies from China into adjacent regions. We further investigated the geographic structure of Chinese sequences and found that the current epidemic is dominated by variant strains that were likely present at low levels in previous domestic epidemics. We also identified epidemiological linkages between high incidence provinces consistent with observations based on surveillance data from human rabies cases.
Author Summary
Rabies as a fatal zoonotic disease continues to be a public threat to global public health. After India, China reports the second highest number of human cases, with more than 117,500 deaths and three major epidemics since 1950. China remains in the middle of the third epidemic. In this work we investigate the impact of China on rabies in South East (SE) Asia. We collected nucleoprotein sequences from samples isolated throughout SE Asia and investigated their phylogenetic and geographic relationships. Our results indicate that clear geographic patterns exist within rabies virus in SE Asia, with isolates mainly clustered according to their geographic origin. While we found evidence of the sporadic exchange of strains between neighboring countries, the major strain responsible for the current Chinese epidemic does not appear to spread to neighboring countries. Our findings suggest that national geographical boundaries and border controls act as effective barriers to halt the spread of rabies from China into adjacent regions. We further investigated the geographic structure of Chinese sequences and found the current epidemic is dominated by variant strains that likely evolved from previous domestic epidemics. Our study provides valuable insight for rabies control and prevention in China and SE Asia.
doi:10.1371/journal.pntd.0002039
PMCID: PMC3561166  PMID: 23383359
11.  Chimeric Rabies Virus-Like Particles Containing Membrane-Anchored GM-CSF Enhances the Immune Response against Rabies Virus 
Viruses  2015;7(3):1134-1152.
Rabies remains an important public health threat in most developing countries. To develop a more effective and safe vaccine against rabies, we have constructed a chimeric rabies virus-like particle (VLP), which containing glycoprotein (G) and matrix protein (M) of rabies virus (RABV) Evelyn-Rokitnicki-Abelseth (ERA) strain, and membrane-anchored granulocyte-macrophage colony-stimulating factor (GM-CSF), and it was named of EVLP-G. The immunogenicity and protective efficacy of EVLP-G against RABV were evaluated by intramuscular administration in a mouse model. The EVLP-G was successfully produced in insect cells by coinfection with three recombinant baculoviruses expressing G, M, and GM-CSF, respectively. The membrane-anchored GM-CSF possesses a strong adjuvant activity. More B cells and dendritic cells (DCs) were recruited and/or activated in inguinal lymph nodes in mice immunized with EVLP-G. EVLP-G was found to induce a significantly increased RABV-specific virus-neutralizing antibody and elicit a larger and broader antibody subclass responses compared with the standard rabies VLP (sRVLP, consisting of G and M). The EVLP-G also elicited significantly more IFN-γ- or IL-4-secreting CD4+ and CD8+ T cells than the sRVLP. Moreover, the immune responses induced by EVLP-G protect all vaccinated mice from lethal challenge with RABV. These results suggest that EVLP-G has the potential to be developed as a novel vaccine candidate for the prevention and control of animal rabies.
doi:10.3390/v7031134
PMCID: PMC4379564  PMID: 25768031
rabies virus; virus-like particles; GM-CSF; rabies vaccine
12.  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
13.  Right Place, Wrong Species: A 20-Year Review of Rabies Virus Cross Species Transmission among Terrestrial Mammals in the United States 
PLoS ONE  2014;9(10):e107539.
Introduction
In the continental US, four terrestrial mammalian species are reservoirs for seven antigenic rabies virus variants. Cross species transmission (CST) occurs when a rabies virus variant causes disease in non-reservoir species.
Methods
This study analyzed national surveillance data for rabies in terrestrial mammals. The CST rate was defined as: number of rabid non-reservoir animals/number of rabid reservoir animals. CST rates were analyzed for trend. Clusters of high CST rate counties were evaluated using space-time scanning statistics.
Results
The number of counties reporting a raccoon variant CST rate >1.0 increased from 75 in 1992 to 187 in 2011; counties with skunk variant CST rates >1.0 remained unchanged during the same period. As of 2011, for every rabid raccoon reported within the raccoon variant region, there were 0.73 cases of this variant reported in non-reservoir animals. Skunks were the most common non-reservoir animal reported with the raccoon rabies variant. Domestic animals were the most common non-reservoir animal diagnosed with a skunk rabies virus variant (n = 1,601). Cross species transmission rates increased fastest among domestic animals.
Conclusions
Cross species transmission of rabies virus variants into non-reservoir animals increases the risk of human exposures and threatens current advances toward rabies control. Cross species transmission in raccoon rabies enzootic regions increased dramatically during the study period. Pet owners should vaccinate their dogs and cats to ensure against CST, particularly in regions with active foci of rabies circulation. Clusters of high CST activity represent areas for further study to better understand interspecies disease transmission dynamics. Each CST event has the potential to result in a rabies virus adapted for sustained transmission in a new species; therefore further understanding of the dynamics of CST may help in early detection or prevention of the emergence of new terrestrial rabies virus variants.
doi:10.1371/journal.pone.0107539
PMCID: PMC4189788  PMID: 25295750
14.  Epidemiological investigations of human rabies in China 
Background
The epidemic of rabies showed a rising trend in China in recent years. To identify the potential factors involved in the emergence, we investigated and analyzed the status and characteristics of human rabies between 1996 and 2008. Moreover, the status of rabies infection and vaccination in dogs, and prophylaxis of humans after rabies exposure were analyzed.
Methods
Human rabies data in China between 1996 and 2008 collected from the annual reports of Chinese Center for Disease Control and Prevention (China CDC) were analyzed. To investigate the status of dogs and postexposure prophylaxis (PEP) of humans, brain specimens of domestic dogs were collected and detected, and the demographic details, exposure status and PEP of rabies patients were obtained in 2005 and 2006 in Guangxi, Hunan and Guizhou provinces.
Results
The results showed 19,806 human rabies cases were reported in China from 1996 to 2008, with an average of 1,524 cases each year, and the incidence almost was rising rapidly, with the peak in 2007 (3,300 cases). It was notable that nearly 50% of the total rabies cases nationwide were reported in Guangxi, Hunan and Guizhou provinces. In these three provinces, the rabies infection rate in dogs was 2.3%, and 60% investigated cities had a dog vaccination rate of below 70%; among the 315 recorded human cases, 66.3% did not receive any PEP at all, 27.6% received inadequate PEP, and only 6.0% received a full regime of PEP.
Conclusions
In recent years, rabies is reemerging and becoming a major public-health problem in China. Our analysis showed that unsuccessful control of dog rabies and inadequate PEP of patients were the main factors leading to the high incidence of human rabies in China, then there are following suggestions: (1) Strict control of free-ranging dogs and mandatory rabies vaccination should be enforced. (2)Establishing national animal rabies surveillance network is imperative. (3) PEP should be decided to initiate or withhold according to postmortem diagnosis of the biting animal. (4) The cost of PEP should be decreased or free, especially in rural areas. (5)Education of the public and health care staff should be enhanced.
doi:10.1186/1471-2334-9-210
PMCID: PMC2803182  PMID: 20025742
15.  Laboratory Diagnosis of Human Rabies: Recent Advances 
The Scientific World Journal  2013;2013:569712.
Rabies, an acute progressive, fatal encephalomyelitis, transmitted most commonly through the bite of a rabid animal, is responsible for an estimated 61,000 human deaths worldwide. The true disease burden and public health impact due to rabies remain underestimated due to lack of sensitive laboratory diagnostic methods. Rapid diagnosis of rabies can help initiate prompt infection control and public health measures, obviate the need for unnecessary treatment/medical tests, and assist in timely administration of pre- or postexposure prophylactic vaccination to family members and medical staff. Antemortem diagnosis of human rabies provides an impetus for clinicians to attempt experimental therapeutic approaches in some patients, especially after the reported survival of a few cases of human rabies. Traditional methods for antemortem and postmortem rabies diagnosis have several limitations. Recent advances in technology have led to the improvement or development of several diagnostic assays which include methods for rabies viral antigen and antibody detection and assays for viral nucleic acid detection and identification of specific biomarkers. These assays which complement traditional methods have the potential to revolutionize rabies diagnosis in future.
doi:10.1155/2013/569712
PMCID: PMC3848253  PMID: 24348170
16.  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
17.  Bats, emerging infectious diseases, and the rabies paradigm revisited 
Emerging Health Threats Journal  2011;4:10.3402/ehtj.v4i0.7159.
The significance of bats as sources of emerging infectious diseases has been increasingly appreciated, and new data have been accumulated rapidly during recent years. For some emerging pathogens the bat origin has been confirmed (such as lyssaviruses, henipaviruses, coronaviruses), for other it has been suggested (filoviruses). Several recently identified viruses remain to be ‘orphan’ but have a potential for further emergence (such as Tioman, Menangle, and Pulau viruses). In the present review we summarize information on major bat-associated emerging infections and discuss specific characteristics of bats as carriers of pathogens (from evolutionary, ecological, and immunological positions). We also discuss drivers and forces of an infectious disease emergence and describe various existing and potential approaches for control and prevention of such infections at individual, populational, and societal levels.
doi:10.3402/ehtj.v4i0.7159
PMCID: PMC3168224  PMID: 24149032
bats; Chiroptera; emerging infectious disease; rabies; lyssavirus; coronavirus; filovirus; henipavirus; prevention; control
18.  Human Rabies in the WHO Southeast Asia Region: Forward Steps for Elimination 
There are eleven Member States in the WHO southeast Asia region (Bangladesh, Bhutan, Democratic People's Republic of Korea, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand, Timor-Leste) of which eight are endemic for rabies. More than 1.4 billion people in the Region are at risk of rabies infection, and approximately 45% of worldwide rabies deaths occur in Asia. Dog bites account for 96% of human rabies cases. Progress in preventing human rabies through control of the disease in dogs has been slow due to various factors. Innovative control tools and techniques have been developed and standardized in recent years. The introduction of cost-effective intradermal rabies vaccination regimens in Asian countries has increased the availability and affordability of postexposure prophylaxis. Elimination of rabies is not possible without regional and intersectoral cooperation. Considering the importance of consolidating achievements in rabies control in Member countries, the WHO Regional Office for southeast Asia has developed a regional strategy for elimination of human rabies transmitted by dogs in the Region. They have committed to provide technical leadership, to advocate national health authorities to develop major stakeholder consensus for a comprehensive rabies elimination programme, and to implement national strategies for elimination of human rabies.
doi:10.4061/2011/383870
PMCID: PMC3178116  PMID: 21991437
19.  The Spatiotemporal Expansion of Human Rabies and Its Probable Explanation in Mainland China, 2004-2013 
PLoS Neglected Tropical Diseases  2015;9(2):e0003502.
Background
Human rabies is a significant public health concern in mainland China. However, the neglect of rabies expansion and scarce analyses of the dynamics have made the spatiotemporal spread pattern of human rabies and its determinants being poorly understood.
Methods
We collected geographic locations and timeline of reported human rabies cases, rabies sequences and socioeconomic variables for the years 2004-2013, and integrated multidisciplinary approaches, including epidemiological characterization, hotspots identification, risk factors analysis and phylogeographic inference, to explore the spread pattern of human rabies in mainland China during the last decade.
Results
The results show that human rabies distribution and hotspots were expanding from southeastern regions to north or west regions, which could be associated with the evolution of the virus, especially the clade I-G. A Panel Poisson Regression analysis reveals that human rabies incidences had significant correlation with the education level, GDP per capita, temperature at one-month lag and canine rabies outbreak at two-month lag.
Conclusions
The reduction in the overall human rabies incidence was accompanied by a westward and northward expansion of the circulating region in mainland China. Higher risk of human rabies was associated with lower level of education and economic status. New clades of rabies, especial Clade I-G, played an important role in recent spread. Our findings provide valuable information for rabies control and prevention in the future.
Author Summary
Although the number of human rabies cases has slightly decreased since 2008 in mainland China, the rabies seemed to be gradually expanding to the low-incidence or non-epidemic areas. The neglect of rabies expansion and scarce analyses of the dynamics have made the spatiotemporal spread pattern of human rabies and its determinants poorly understood. Here, we integrate multidisciplinary approaches to explore and describe the spread pattern and evolution dynamic of human rabies in mainland China during the last decade. The results indicated that the reduction in the overall human rabies incidence was accompanied by a westward and northward expansion of the circulating region, which could be associated with the evolution of the virus, especially the clade I-G. And the education level, GDP per capita, temperature at one-month lag and canine rabies outbreak at two-month lag were firstly found to be significant correlation human rabies incidences according to the Panel Poisson Regression analysis. Our findings give a relatively complete picture about the human rabies spatiotemporal dynamics and spread pattern, thus provide new insights on risk factors and control strategies for the disease spread.
doi:10.1371/journal.pntd.0003502
PMCID: PMC4334667  PMID: 25692883
20.  Public Health Responses to Reemergence of Animal Rabies, Taiwan, July 16–December 28, 2013 
PLoS ONE  2015;10(7):e0132160.
Taiwan had been free of indigenous human and animal rabies case since canine rabies was eliminated in 1961. In July 2013, rabies was confirmed among three wild ferret-badgers, prompting public health response to prevent human rabies cases. This descriptive study reports the immediate response to the reemergence of rabies in Taiwan. Response included enhanced surveillance for human rabies cases by testing stored cerebrospinal fluids (CSF) from patients with encephalitides of unknown cause by RT-PCR, prioritizing vaccine use for postexposure prophylaxis (PEP) during periods of vaccine shortage and subsequent expansion of PEP, surveillance of animal bites using information obtained from vaccine application, roll out of preexposure prophylaxis (PrEP) with vaccine stock restoration, surveillance for adverse events following immunization (AEFI), and ensuring surge capacity to respond to general public inquiries by phone and training for healthcare professionals. Enhanced surveillance for human rabies found no cases after testing 205 stored CSF specimens collected during January 2010–July 2013. During July 16 to December 28, 2013, we received 8,241 rabies PEP application; 6,634 (80.5%) were consistent with recommendations. Among the 6,501persons who received at least one dose of rabies vaccine postexposure, 4,953 (76.2%) persons who were bitten by dogs; only 59 (0.9%) persons were bitten by ferret-badgers. During the study period, 6,247 persons received preexposure prophylaxis. There were 23 reports of AEFI; but no anaphylaxis, Guillain-Barré syndrome, or acute disseminated encephalomyelitis were found. During the study period, there were 40,312 calls to the Taiwan Centers for Disease Control hotline, of which, 8,692 (22%) were related to rabies. Recent identification of rabies among ferret-badgers in a previously rabies-free country prompted rapid response. To date, no human rabies has been identified. Continued multifaceted surveillance and interministerial collaboration are crucial to achieve the goal of rabies-free status in Taiwan.
doi:10.1371/journal.pone.0132160
PMCID: PMC4498755  PMID: 26162074
21.  Rabies virus antinucleoprotein antibody protects against rabies virus challenge in vivo and inhibits rabies virus replication in vitro. 
Journal of Virology  1993;67(10):6080-6086.
We previously reported that A/WySnJ mice vaccinated via a tail scratch with a recombinant raccoon poxvirus (RCN) expressing the rabies virus internal structural nucleoprotein (N) (RCN-N) were protected against a street rabies virus (D. L. Lodmell, J. W. Sumner, J.J. Esposito, W.J. Bellini, and L. C. Ewalt, J. Virol. 65:3400-3405, 1991). To improve our understanding of the mechanism(s) of this protection, we investigated whether sera of A/WySnJ mice that had been vaccinated with RCN-N but not challenged with street rabies virus had anti-rabies virus activity. In vivo studies illustrated that mice inoculated in the footpad with preincubated mixtures of anti-N sera and virus were protected. In addition, anti-N sera inoculated into the site of virus challenge protected mice. The antiviral activity of anti-N sera was also demonstrated in vitro. Infectious virus was not detected in cultures 24 h following infection with virus that had been preincubated with anti-N sera. At later time points, infectious virus was detected, but inhibition of viral production was consistently > or = 99% compared with control cultures. The protective and antiviral inhibitory activity of the anti-N sera was identified as anti-N antibody by several methods. First, absorption of anti-N sera with goat anti-mouse immunoglobulin serum, but not normal goat serum, removed the activity. Second, radioimmuno-precipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of sucrose density gradient-fractionated anti-N sera showed that antiviral activity was present only in the fraction containing anti-N antibody. Finally, absorption of anti-N sera with insect cells infected with a baculovirus expressing the N protein removed the protective activity. These data indicate that anti-N antibody is a component of the resistance to rabies virus infections.
Images
PMCID: PMC238029  PMID: 8371354
22.  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
23.  Estimating the Global Burden of Endemic Canine Rabies 
PLoS Neglected Tropical Diseases  2015;9(4):e0003709.
Background
Rabies is a notoriously underreported and neglected disease of low-income countries. This study aims to estimate the public health and economic burden of rabies circulating in domestic dog populations, globally and on a country-by-country basis, allowing an objective assessment of how much this preventable disease costs endemic countries.
Methodology/Principal Findings
We established relationships between rabies mortality and rabies prevention and control measures, which we incorporated into a model framework. We used data derived from extensive literature searches and questionnaires on disease incidence, control interventions and preventative measures within this framework to estimate the disease burden. The burden of rabies impacts on public health sector budgets, local communities and livestock economies, with the highest risk of rabies in the poorest regions of the world. This study estimates that globally canine rabies causes approximately 59,000 (95% Confidence Intervals: 25-159,000) human deaths, over 3.7 million (95% CIs: 1.6-10.4 million) disability-adjusted life years (DALYs) and 8.6 billion USD (95% CIs: 2.9-21.5 billion) economic losses annually. The largest component of the economic burden is due to premature death (55%), followed by direct costs of post-exposure prophylaxis (PEP, 20%) and lost income whilst seeking PEP (15.5%), with only limited costs to the veterinary sector due to dog vaccination (1.5%), and additional costs to communities from livestock losses (6%).
Conclusions/Significance
This study demonstrates that investment in dog vaccination, the single most effective way of reducing the disease burden, has been inadequate and that the availability and affordability of PEP needs improving. Collaborative investments by medical and veterinary sectors could dramatically reduce the current large, and unnecessary, burden of rabies on affected communities. Improved surveillance is needed to reduce uncertainty in burden estimates and to monitor the impacts of control efforts.
Author Summary
Rabies is a fatal viral disease largely transmitted to humans from bites by infected animals—predominantly from domestic dogs. The disease is entirely preventable through prompt administration of post-exposure prophylaxis (PEP) to bite victims and can be controlled through mass vaccination of domestic dogs. Yet, rabies is still very prevalent in developing countries, affecting populations with limited access to health care. The disease is also grossly underreported in these areas because most victims die at home. This leads to insufficient prioritization of rabies prevention in public health agendas. To address this lack of information on the impacts of rabies, in this study, we compiled available data to provide a robust estimate of the health and economic implications of dog rabies globally. The most important impacts included: loss of human lives (approximately 59,000 annually) and productivity due to premature death from rabies, and costs of obtaining PEP once an exposure has occurred. The greatest risk of developing rabies fell upon the poorest regions of the world, where domestic dog vaccination is not widely implemented and access to PEP is most limited. A greater focus on mass dog vaccination could eliminate the disease at source, reducing the need for costly PEP and preventing the large and unnecessary burden of mortality on at-risk communities.
doi:10.1371/journal.pntd.0003709
PMCID: PMC4400070  PMID: 25881058
24.  Renewed Global Partnerships and Redesigned Roadmaps for Rabies Prevention and Control 
Canine rabies, responsible for most human rabies deaths, is a serious global public health concern. This zoonosis is entirely preventable, but by focusing solely upon rabies prevention in humans, this “incurable wound” persists at high costs. Although preventing human deaths through canine rabies elimination is feasible, dog rabies control is often neglected, because dogs are not considered typical economic commodities by the animal health sector. Here, we demonstrate that the responsibility of managing rabies falls upon multiple sectors, that a truly integrated approach is the key to rabies elimination, and that considerable progress has been made to this effect. Achievements include the construction of global rabies networks and organizational partnerships; development of road maps, operational toolkits, and a blueprint for rabies prevention and control; and opportunities for scaling up and replication of successful programs. Progress must continue towards overcoming the remaining challenges preventing the ultimate goal of rabies elimination.
doi:10.4061/2011/923149
PMCID: PMC3135331  PMID: 21776359
25.  Strategic model of national rabies control in Korea 
Rabies is an important zoonosis in the public and veterinary healthy arenas. This article provides information on the situation of current rabies outbreak, analyzes the current national rabies control system, reviews the weaknesses of the national rabies control strategy, and identifies an appropriate solution to manage the current situation. Current rabies outbreak was shown to be present from rural areas to urban regions. Moreover, the situation worldwide demonstrates that each nation struggles to prevent or control rabies. Proper application and execution of the rabies control program require the overcoming of existing weaknesses. Bait vaccines and other complex programs are suggested to prevent rabies transmission or infection. Acceleration of the rabies control strategy also requires supplementation of current policy and of public information. In addition, these prevention strategies should be executed over a mid- to long-term period to control rabies.
doi:10.7774/cevr.2014.3.1.78
PMCID: PMC3890453  PMID: 24427765
Rabies; Raccoon dogs; Oral vaccine; Prevention and Control

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