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Global Perspective of Rabies and Rabies Related Viruses: A Comprehensive Review
Abstract
Rabies, a fatal neurological disease of warm blooded animals, is not only a national but also a global problem. It is caused by a RNA virus under the genus Lyssavirus and family Rhabdoviridae. The disease is of paramount importance because of its global distribution, wide host range including a number of wild animals and extremely high case fatality rate. In spite of development of anti-rabies vaccine by Pasteur in 1885, the disease is still endemic in about 100 countries in the world where 2.5 thousand million people live. The dog is the main perpetuator of rabies in developing country including India, it is to be emphasized to bring all the dogs under immunization umbrella or to control the unauthorized stray dogs. Over the time, there is lot of development in the field of immunology, vaccinology and diagnostic arena, the disease is still endemic particularly in developing countries. Few countries viz., USA, Canada, France have employed the recombinant vaccinia virus based bait and succeeded in controlling the wildlife rabies to a great extent. However, cooperation and collaboration of people from the different field should work in a coordinated manner to control the rabies in animals particularly the stray dogs, main source of infection to animals and human beings.
... Blood and blood products do not have a participating role in disease transmission as the disease is not accompanied by viremia [23]. The other non-bite exposures like aerosol transmission, organ transplantation [68,4] and gastro-intestinal tract transmission after ingestion of infected tissues or milk have been documented for the transmission of rabies [56,67]. The most common way of rabies transmission is presented in Fig. 2. ...
... The virus enters into the body via abrasions or by direct in touch with mucosal membranes. A bite from a rabid animal can result in inoculation infective saliva into subcutaneous tissues and muscles [37, 4] and starts replication into the bitten muscle tissue, where rabies virus binds to nicotinic acetylcholine receptors at the neuromuscular junction [47,56] and then it achieves entry towards the central nervous system [78] by centripetal spread within the motor and sensory axons by retrograde fast axonal transport at a rate of about 50 -100 nm per day [37]. The virus then spreads away from the CNS centrifugally along neuronal pathways, involving the parasympathetic nervous system, which is responsible for infection of the salivary glands, skin, heart, and a variety of other organs [39]. ...
... Rabies has no cure, once the clinical signs appear, it is invariably fatal. The symptoms in humans and animals can be similar but maybe highly variable and numerous [56]. The disease is characterized by the development of severe fatal nervous symptoms that lead to paralysis and death (Abera, 2015). ...
... Blood and blood products do not have a participating role in disease transmission as the disease is not accompanied by viremia [23]. The other non-bite exposures like aerosol transmission, organ transplantation [68,4] and gastro-intestinal tract transmission after ingestion of infected tissues or milk have been documented for the transmission of rabies [56,67]. The most common way of rabies transmission is presented in Fig. 2. ...
... The virus enters into the body via abrasions or by direct in touch with mucosal membranes. A bite from a rabid animal can result in inoculation infective saliva into subcutaneous tissues and muscles [37, 4] and starts replication into the bitten muscle tissue, where rabies virus binds to nicotinic acetylcholine receptors at the neuromuscular junction [47,56] and then it achieves entry towards the central nervous system [78] by centripetal spread within the motor and sensory axons by retrograde fast axonal transport at a rate of about 50 -100 nm per day [37]. The virus then spreads away from the CNS centrifugally along neuronal pathways, involving the parasympathetic nervous system, which is responsible for infection of the salivary glands, skin, heart, and a variety of other organs [39]. ...
... Rabies has no cure, once the clinical signs appear, it is invariably fatal. The symptoms in humans and animals can be similar but maybe highly variable and numerous [56]. The disease is characterized by the development of severe fatal nervous symptoms that lead to paralysis and death (Abera, 2015). ...
Rabies is a zoonotic disease caused by rabies virus of the genus Lyssa virus and family Rhabdoviridae. It affects all mammals and is prevalent throughout the world and endemic in many countries except in Islands like Australia and Antarctica. It is highly fatal, but preventable. Disease causes threat to public health because rabid dogs bite humans, resulting in thousands of deaths every year. Around 59,000 people die every year from rabies in the world. Dogs play a vital role in most of the human exposure in rabies endemic areas. Transmission of virus occurs through the bite of an infected dog. Disease is manifested by fatal nervous symptoms leading to paralysis and death. Direct fluorescent antibody technique is the gold standard for the diagnosis of the disease in animals and humans. Prevention of rabies involves the vaccination of dogs and humans before or after an exposure. This review describes the etiology, pathogenesis, diagnosis, its prevention and control strategies.
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Background and Objectives: The purpose of this study was to present a summary of the rabies surveillance program in humans in the country, its achievements and its strengths and weaknesses.
Methods: This study was a review of the country's plan for surveillance and control of rabies in humans. The sources of information included the data, reports, documents, and published guidelines. The viewpoints of stakeholders and experts were also reviewed in this study.
Results: Since rabies is a zoonotic disease, its effective management requires a good collaboration between several organizations. Moreover, because Iran is located in an endemic region, there is a need for the development of regional and international cooperation for the success of disease prevention, control and management. Animal services for biting and rabies control are provided free of charge in more than 700 centers in the country. Major achievements of the program include timely preventive treatment for animal bite cases, knowledge of the geographical distribution of the disease, identification of high-risk provinces, and decreasing the percentage of human deaths.
Conclusion: The program has performed well for rabies secondary prevention. Some aspects of the program, however, still need to be improved, including improvement of educational programs targeting general population and high-risk groups, animal bite prevention, vaccination of domestic dogs, controlling the population of stray dogs, rabies control in wild animals, and proper waste collection and disposal.
... The highly neurotropic rabies virus causes a rapidly progressive encephalomyelitis or meningoencephalitis (Tekki et al., 2014). Rabies affects all mammals but primarily domestic and wild dogs; other hosts include foxes, jackals, skunks, mongooses, raccoons and bats (Nandi and Kumar, 2011;Noah et al., 1998). However, there are reports of rabies in livestock like cattle, sheep and goats in Nigeria (Ojo and Adeoye, 1967;Okoh, 1981;Bello et al., 2007;Promed, 2012;Tekki et al., 2014). ...
Background
Rabies is endemic in Nigeria with clinical cases reported mainly in dogs and occasionally in livestock from all the geo-ecological zones of the country. Detection of rabies virus antigen in puppies at the age of five to ten weeks and in apparently healthy dogs shedding the virus in their saliva have been reported in some parts of Nigeria.
Material and Method
This report describes a clinical rabies in a set of eight weeks old puppies confirmed by antigen detection using the direct fluorescent antibody test (DFAT), the direct rapid immunohistochemical test (DRIT), and RT-PCR.
Results
it was positive for all test used including the RT-PCR which amplified at 750 bp from the gel electrophoresis.
Conclusion
Occurrence of rabies in puppies of this age, within which they are acquired and owned by other unsuspecting members of the public, is of grave public health consequences. People that love puppies, especially children, who are fond of carrying and playing with them, are also faced with the risk of exposure to rabies. Consequently, review of the existing dog antirabies vaccination schedule at twelve weeks of age in Nigeria, is recommended to ensure effective immunization of this age group of dogs and for the overall safety of the vulnerable members of the public.
... Bats do harbor a diversity of viruses including several known zoonotic diseases (those that jump from animals to humans), but so do all other wildlife species, including primates, rodents, ungulates, carnivores, other mammals, and birds (Olival et al. 2015). These diseases include the age-old scourge rabies; however, at least >1000 times more cases of rabies arise each year from domestic dogs than bats (De Serres et al. 2008;Nandi and Kumar 2011). New zoonotic diseases such as Nipah, Hendra, Marburg, and Ebola viruses have been linked to bats as 'natural reservoir hosts', and should be taken seriously, but the solution is not in destroying bat populations. ...
Rabies virus is a kind of virus having strict neurotropic property. Intracerebral inoculation method was commonly used to RV-related research. SRV9 is an attenuated RV vaccine strain. In the present study, we inoculated intracerebrally on suckling mouse with SRV9 strain. The results showed that SRV9 could cause a mortality rate of 100% on suckling mice below 13 day old. The mortality rates of 14-17 day old mice were 68, 33, 33 and 17%, respectively without incidence above 18 day old. Meanwhile, the results showed that the growth of survival suckling mice was inhibited remarkably after intracerebral inoculation SRV9. The 16 day old survival suckling mice were chosen to perform body weight test and the result showed that the weight growth was very slow with 14% less than normal growth rate. However, 2 weeks latter the weight of the mice began to recover gradually but slowly. It was suggested that the intracerebral RV reproduction could take a significant effect on the growth and development of the mice and with RV being eliminated by antibody, the weight of the mice which were inoculated with SRV9 could gradually recover.
Canine parvovirus (CPV) is a widespread pathogen among canine in China. It has made great veterinary public health burden and economic loss. Three CPV-2 variations, CPV-2a, CPV-2b and CPV-2c, have emerged, however, the CPV-2 variations distribution and the dominant epidemic strain in China are still undetermined. To better understand the epidemiology of CPV in China, the CPV-VP2 gene sequences which had been submitted to GenBank from 1983 to 2011 in China were analyzed and were compared with the representative references from other countries. Phylogenetic trees based on the VP2 sequences were constructed and they showed that the Chinese CPV-2a and CPV-2b strains were close to the Korean and Vietnam strains respectively. It was found that CPV-2a had been the prevalent strain in China and most CPV isolates existed in northeast China. The VP2 protein in CPV-2a and CPV-2b isolated from China had three mutations compared to the American standard strain: 297Ser-Ala, 324Tyr-Ile and 555Ile-Val.
Present study was undertaken to compare various routine laboratory diagnostic tests for rabies detection.
Seller’s staining, mouse inoculation test (MIT), Dot- ELISA, Agar gel precipitation test (AGPT) and counter
immunoelectrophoresis test (CIET) were the main basic tests performed in the laboratory for the rabies diagnosis. Out of 200 brain specimens, Negri bodies were observed in 52 brain samples by Seller’s staining. Rabies virus was isolated in 56 samples by intra-cerebral inoculation in newborn Swiss-albino mice. Dot-ELISA and AGPT could detect rabies antigen in 55 and 57 samples respectively. Comparative analysis revealed that the CIET is the most sensitive and rapid test among performed diagnostic tests.
To achieve higher titer of rabies virus higher density of host cells will need. In this study, capability of FibraCel disks packed in 500 mL spinner basket versus Cytodex-1 in 500 mL spinner flask was investigated for propagation of Vero cells and PV rabies virus proliferation. Minimal Essential Medium (MEM) + 10% Foetal Calf Serum (FCS) and Virus Production- Serum Free Medium (VP-SFM) +4 mM L-glutamine were used in growth phase and MEM+ 0.2% Bovine Serum Albumin (BSA) and VP-SFM were used in virus production phase. Adapted Vero cells grown in VP-SFM were used in all SFM experiments while batch and stepwise perfusion modes were applied and compared in growth stage. The highest Vero cell density were achieved in the trials with 10 g FibraCel disk in stepwise perfusion mode equal to 6.12 x 10(6) and 5.87 x 10(6) cells mL(-1) in MEM and VP-SFM, respectively while with 2.73 g Cytodex-1 lower density equal to 4.2 x 10(6) and 4.0 x 10(6) cells mL(-1) were achieved. The highest titer of rabies virus and overall virus production rate were resulted in VP-SFM and on 10 g disks equal to 2.9 x 10(7) Fluorescent Focus Unit (FFU) mL(-1) and 0.14 FFU/Cell/h, respectively versus 1.7 x 10(7) FFU mL(-1) and 0.08 FFU/cell/h on cytodex-1 in similar conditions. The second harvest of virus was also satisfactory in experiment with 10 g disks (1.7 x 10(7) FFU mL(-1)) in compare to Cytodex-1 (0.51 x 10(7) FFU mL(-1)). An equal surface area at 6600 and 12000 cm(-2) were provided in all comparable trials with seeding density of 12.5 x 10(3) cells cm(-2). Adapted Vero cells grown in VP-SFM were used in all SFM experiments while batch and stepwise perfusion modes were applied and compared in growth stage.
A 5-year study was conducted to investigate epidemiological aspects of rabies in different species of animals. The study was conducted on brain tissues collected from 384 animals comprising 231 dogs, 79 buffaloes, 46 cows and 28 wild species. Out of the 384 suspected cases, 55.98% were positive for rabies. Among the various species of animals, the maximum rabies cases were in dogs (59.53% -128/215) followed by buffaloes (20.46%-44/215), cows (13.48%29/215) and wild animals (6.51%-14/215). Higher incidence of rabies was reported during certain months of the year in different species of animals. Old male dogs (39%) and older female bovines (57%) were found more affected with rabies. As compared to the paralytic signs in 30% rabid dogs, 61% rabid dogs revealed aggressive clinical signs. The majority (61%) of the rabid dogs had bitten ahuman or another animals. In buffaloes and cows, anorexia, salivation and bellowing were most consistent features. Direct fluorescent antibody test (FAT) could detect rabies antigen in all the domestic and wild animals. FAT was closely followed by histopathological demonstration of Negri bodies. Rabid buffaloes could recognize their owners better (27%) than cows could (24%) while rabid dogs could recognize their owners the most (47%). The accumulated history records revealed that 78% of owned rabid dogs were not vaccinated prophylactically.
The sensitivities of BHK-21 (C-13) and murine neuroblastoma (C-1300; clone NA) cells for the isolation of small quantities of a street strain rabies virus were compared. Suspensions of brain from mice sacrificed prior to the onset of clinical signs of rabies were used to stimulate weakly positive diagnostic specimens. The results of cell culture isolation were compared with those of the direct fluorescent-antibody test and virus isolation in weanling mice. Neuroblastoma cells were more sensitive to the street strain rabies virus than were BHK-21 cells. Neuroblastoma cell virus isolation, the mouse inoculation test, and the fluorescent-antibody test all showed comparable sensitivity.
Rabies is one of the oldest diseases know to man, but its successful control has remained elusive. Although effective vaccines of tissue culture origin against rabies do exist, such preparations are expensive. Live vaccinia virus (VV) recombinants expressing influenza or hepatitis B antigens have recently been used to immunize against these diseases. We have now used this approach to produce a novel rabies vaccine. We first altered the rabies glycoprotein cDNA by site-directed mutagenesis and removed the poly(dG) tail. We then aligned the modified cDNA with an early VV promoter sequence inserted within a cloned copy of the vaccinia thymidine kinase gene and transfected this plasmid into VV-infected cells. Recombination between the virus and the plasmid resulted in a recombinant virus harbouring the rabies glycoprotein cDNA. Inoculation of rabbits with the live recombinant virus induced high titres of rabies virus-neutralizing antibodies, and scarification with the recombinant VV protected mice against challenge with street rabies virus.
The genetic diversity of representative members of the Lyssavirus genus (rabies and rabies-related viruses) was evaluated using the gene encoding the transmembrane glycoprotein involved in the virus-host interaction, immunogenicity, and pathogenicity. Phylogenetic analysis distinguished seven genotypes, which could be divided into two major phylogroups having the highest bootstrap values. Phylogroup I comprises the worldwide genotype 1 (classic Rabies virus), the European bat lyssavirus (EBL) genotypes 5 (EBL1) and 6 (EBL2), the African genotype 4 (Duvenhage virus), and the Australian bat lyssavirus genotype 7. Phylogroup II comprises the divergent African genotypes 2 (Lagos bat virus) and 3 (Mokola virus). We studied immunogenic and pathogenic properties to investigate the biological significance of this phylogenetic grouping. Viruses from phylogroup I (Rabies virus and EBL1) were found to be pathogenic for mice when injected by the intracerebral or the intramuscular route, whereas viruses from phylogroup II (Mokola and Lagos bat viruses) were only pathogenic by the intracerebral route. We showed that the glycoprotein R333 residue essential for virulence was naturally replaced by a D333 in the phylogroup II viruses, likely resulting in their attenuated pathogenicity. Moreover, cross-neutralization distinguished the same phylogroups. Within each phylogroup, the amino acid sequence of the glycoprotein ectodomain was at least 74% identical, and antiglycoprotein virus-neutralizing antibodies displayed cross-neutralization. Between phylogroups, the identity was less than 64.5% and the cross-neutralization was absent, explaining why the classical rabies vaccines (phylogroup I) cannot protect against lyssaviruses from phylogroup II. Our tree-axial analysis divided lyssaviruses into two phylogroups that more closely reflect their biological characteristics than previous serotypes and genotypes.
In Europe, two bat lyssaviruses referred to as European bat lyssaviruses (EBLVs) types 1 and 2 (genotypes 5 and 6 respectively) which are closely related to classical rabies virus are responsible for an emerging zoonosis. EBLVs are host restricted to bats, and have been known to infect not only their primary hosts but also in rare circumstances, induce spillover infections to terrestrial mammals including domestic livestock, wildlife and man. Although spillover infections have occurred, there has been no evidence that the virus adapted to a new host. Since 1977, four human deaths from EBLVs have been reported. None of them had a record of prophylactic rabies immunization. Only fragmentary data exist about the effectiveness of current vaccines in cross-protection against EBLVs. It is clear that EBLV in bats cannot be eliminated using conventional strategies similar to the control programmes based on vaccine baits used for fox rabies in Europe during the 1980s. Due to the protected status of bats in Europe, our knowledge of EBLV prevalence and epidemiology is limited. It is possible that EBLV is under-reported and that the recorded cases of EBLV represent only a small proportion of the actual number of infected bats. For this reason, any interaction between man and bats in Europe must be considered as a possible exposure. Human exposure through biting incidents, especially unprovoked attacks, should be treated immediately with rabies post-exposure treatment and the bat, where possible, retained for laboratory analysis. Preventative measures include educating all bat handlers of the risks posed by rabies-infected animals and advising them to be immunized. This review provides a brief history of EBLVs, their distribution in host species and the public health risks.
A six-month- old girl presents for a "well-baby" appointment in New Jersey. The mother is concerned about a dead bat she found in the child's bedroom. A Virginia businessman relaxing on his patio after work pulls a toy from his puppy's mouth. He notices a dead raccoon within his fenced yard, where his puppy has been playing, and telephones you for advice. You receive e-mail from a South American colleague, who has been bitten by a stray dog while jogging. She solicits your medical opinion. How would you manage these situations?
We have the knowledge and tools to eliminate the threat of canine rabies but this disease, nevertheless, remains a public health threat in many parts of the world. Lack of motivation by governments, cultural issues and inadequate funding remain barriers. This is amazing since the number of human rabies deaths worldwide is greater than that from polio, meningococcal meningitis, Japanese encephalitis, yellow fever, SARS, bird flue and other scourges that attract more attention. Safe and effective vaccines are now widely available. Reduced dose effective and less expensive post-exposure vaccination regimens have helped eliminate nerve tissue vaccines in Thailand, Philippines and Sri Lanka. India and Pakistan, the major users of dangerous nerve tissue derived Semple type vaccine, are now considering following suite. Immediate wound care and prompt use of a potent vaccine will save a majority of infected persons. Rabies immunoglobulin, injected into and around bite wounds, provides added safety for the severely exposed. The high cost of rabies immunoglobulin and tissue culture vaccines are remaining barriers, but new manufacturers and the use of intradermal vaccination schedules can reduce costs. Ultimately, it is the need to control rabies in dogs that must occupy most of our attention. The tools are available, but attitudes must change before they can be applied. There have been many new developments since publication of the last WHO rabies expert committee report in 1992 (new version in print)] and we will address those that have practical applicability.
European bat lyssaviruses types 1 and 2 (EBLV-1 and EBLV-2) are widespread in Europe, although little is known of their evolutionary history. We undertook a comprehensive sequence analysis to infer the selection pressures, rates of nucleotide substitution, age of genetic diversity, geographical origin, and population growth rates of EBLV-1. Our study encompassed data from 12 countries collected over a time span of 35 years and focused on the glycoprotein (G) and nucleoprotein (N) genes. We show that although the two subtypes of EBLV-1--EBLV-1a and EBLV-1b--have both grown at a low exponential rate since their introduction into Europe, they have differing population structures and dispersal patterns. Furthermore, there were strong constraints against amino acid change in both EBLV-1 and EBLV-2, as reflected in a low ratio of nonsynonymous to synonymous substitutions per site, particularly in EBLV-1b. Our inferred rate of nucleotide substitution in EBLV-1, approximately 5 x 10(-5) substitutions per site per year, was also one of the lowest recorded for RNA viruses and implied that the current genetic diversity in the virus arose 500 to 750 years ago. We propose that the slow evolution of EBLVs reflects their distinctive epidemiology in bats, where they occupy a relatively stable fitness peak.
In tropical and subtropical climates, the shipment of animal brains for rabies diagnosis may be a problem because brain specimens sometimes arrive decomposed at the diagnostic laboratory. In this situation, reverse transcription-polymerase chain reaction (RT-PCR) may serve as a potential solution because of its high sensitivity. However, little is known about the stability of rabies viral RNA in decomposed brain tissue. To determine the stability of rabies virus genomic RNA in brain samples, 72 mice were inoculated with the challenge virus strain-11 of rabies virus. After incubation period, mice were euthanized to obtain their brains. These were categorized in 2 different groups. In the first group, 36 brains were kept at room temperature (25-27 degrees C) immediately after euthanasia. In the second group, the other 36 inoculated brains were frozen at -70 degrees C and later maintained at room temperature. In both groups, RT-PCR was performed at days 0, 1, 2, 3, 4, 7, 10, 12, 16, 18, 23, and 26 by using primers previously described in the literature and a primer set specifically designed for a Mexican variant of vampire-bat rabies. Reverse-transcriptase PCR experiments were performed in 3 different inoculated brains, in which the direct fluorescent antibody (DFA) test was previously conducted to detect rabies viral antigen in the brains kept at room temperature and in the frozen brains. The DFA test resulted positive in both groups up to day 7. In brain samples stored at ambient temperature (25-27 degrees C), the intensity of the RT-PCR band started to diminish by day 12; however, rabies virus genome could be successfully amplified by RT-PCR up to 23 days. These results indicate that brain samples kept at ambient temperature (up to 27 degrees C) may reach a reference laboratory in an adequate state for rabies diagnosis by RT-PCR.
In India, rabies is enzootic and is a serious public health and economic problem. India has a large population of stray dogs which, together with a lack of effective control strategies, might have led to the persistence of rabies virus (RV) in the canine population. Our objective was to study the molecular epidemiology of RV isolates in India based on nucleotide sequence analysis of 29 RV isolates originating from different species of animals in four states. Here we have analyzed two sets of sequence data based upon a 132-nucleotide region of the cytoplasmic domain (CD) of the G gene (G-CD) and a 549-nucleotide region (Psi-L) that combines the noncoding G-L intergenic region (Psi) and a fragment of the polymerase gene (L). Phylogenetic analysis revealed that the RV isolates belong to genotype 1 and that they were related geographically but were not related according to host species. Five different genetic clusters distributed among three geographical regions were identified. Comparison of the deduced amino acid sequences of G-CD between RV isolates revealed three amino acid changes (amino acid 462G [aa462G], aa465H, and aa468K) that distinguished the Indian RVs from RV isolates in other parts of the world. Analysis of the data indicated that the dog rabies virus variants are the major circulating viruses in India that transmit the disease to other domestic animals and humans as well.
—During 2006, 49 states and Puerto Rico reported 6,940 cases of rabies in animals and 3 cases in humans to the CDC, representing an 8.2% increase from the 6,417 cases in animals and 1 case in a human reported in 2005. Approximately 92% of the cases were in wildlife, and 8% were in domestic animals. Relative contributions by the major animal groups were as follows: 2,615 raccoons (37.7%), 1,692 bats (24.4%), 1,494 skunks (21.5%), 427 foxes (6.2%), 318 cats (4.6%), 82 cattle (1.2%), and 79 dogs (1.1%). Compared with numbers of reported cases in 2005, cases in 2006 increased among all groups except cattle. Increases in numbers of rabid raccoons during 2006 were reported by 11 of the 20 eastern states where raccoon rabies was enzootic, and reported cases increased by 3.2% overall, compared with 2005.
On a national level, the number of rabies cases in skunks during 2006 increased by 6.1% from the number reported in 2005. Once again, Texas reported the greatest number (n = 351) of rabid skunks and the greatest overall state total of animal rabies cases (889). No cases of rabies associated with the dog/coyote rabies virus variant were reported. The last identified case of this canine rabies virus variant was identified in March 2004, along the US/Mexi-co border. With 2006 marking the second year of no apparent transmission of the dog/coyote variant, these findings from surveillance data support the contention that the canine rabies virus variant is no longer in circulation in the United States. Total number of cases of rabies reported nationally in foxes increased 13.6%, compared with 2005. Increases in the number of reported rabid foxes were attributable to greater numbers of foxes reported with the Arctic fox rabies virus variant in Alaska, the Texas gray fox rabies virus variant in Texas, and the raccoon rabies virus variant in Virginia. The 1,692 cases of rabies reported in bats represented a 14.5% increase, compared with numbers reported in 2005, making bats the second most reported rabid animal behind raccoons. Cases of rabies in cats, dogs, horses and mules, and sheep and goats increased 18.2%, 3.9%, 12.8%, and 22.2%, respectively, whereas cases reported in cattle decreased 11.8%. In Puerto Rico, reported cases of rabies in mongooses increased 9.2%, and rabies in domestic animals, presumably attributable to spillover infection from mongooses, increased 20%.
Three cases of human rabies were reported from Texas, Indiana, and California during 2006. The cases in Indiana and Texas were attributed to bat rabies virus variants, whereas the case in California was attributed to an exposure to a dog in the Philippines.
Latin American countries made the political decision to eliminate human rabies transmitted by dogs by the year 2005. The purpose of the current study is to evaluate to what extent this goal has been reached. The epidemiological situation and control measures were analyzed and broken down within the countries by georeferencing. The 27 human cases reported in 2003 occurred in some 0.2% of the second-level geopolitical units (municipalities or counties) in the region, suggesting that the disease is a local problem. Several areas within the countries reported no more transmission of rabies in dogs. Nearly 1 million people potentially exposed to rabies received treatment. On average, 34,383 inhabitants per health post receive anti-rabies treatment (range: 4,300-148,043). Nearly 42 million dogs are vaccinated annually. Surveillance is considered fair according to the epidemiological criteria adopted by the study. Samples sent for rabies testing represent 0.05% of the estimated canine population (range: 0.001 to 0.2%). The countries are quite close to achieving the goal.
Changes in demographics, land use, recreation and hunting practices in the last 50 years dramatically increased the public health importance of reservoirs for rabies in wild species in the United States. This article focuses on attributes of host natural history to interpret the molecular phylogenies of the rabies variant transmitted within a particular animal population and the threat to human health presented by this reservoir.
The current epizootic of rabies in Europe has as its main host the fox. Oral vaccination of the fox population has proven to be particularly effective. It is clear that the major components for a successful vaccination programme are a potent and stable vaccine, and an effective baiting system; the latter should attract the target animal but no non-target species. Recently, vaccines of increased stability have been generated; amongst these is a vaccinia recombinant virus which expresses rabies virus glycoprotein. Consequently, both attenuated live virus vaccines and a recombinant vaccine are available for routine field vaccination of the fox population.
The rabies tissue culture infection test (RTCIT) and rapid rabies enzyme immunodiagnosis (RREID) were compared to the fluorescent-antibody test (FAT) with field specimens. At the French National Reference Center for Rabies, 15,248 specimens were analyzed by FAT and RTCIT, and 2,290 of those specimens were also tested by RREID; 818 other specimens were tested by FAT and RREID in 12 laboratories located in Africa, Asia, and Latin America. The sensitivities and specificities of RREID and RTCIT were comparable. This study showed that both tests can be used as backup procedures to confirm FAT. RREID is also strongly recommended for epidemiological studies and for laboratories which are not equipped for performing FAT.
Isolates of rabies from separate enzootics can be distinguished by their reactions with panels of monoclonal antibodies (mAbs) directed to different sites on the nucleocapsid and glycoproteins of the virus. Estimates of antigenic relatedness can be made by comparing similarities among groups. In this manner it can be shown that while classic strains of rabies react with most of the mAbs, the rabies related Lyssaviruses (Mokola, Lagos and Duvenhage) react with only a few of the mAbs and isolates of rabies from Eptesicus serotinus bats in Europe are intermediate between the two groups. Mice immunized intraperitoneally with human diploid vaccine (HDCV) or animal vaccines (Rabisin and Rabiffa) were protected against a challenge with DBV, DUV-1 and most classic rabies strains. HDCV gave only partial protection against human virus isolates from Finland and Saudi Arabia. The HDCV did not protect mice against challenges with Lagos bat or Mokola virus (rabies-like viruses). The animal vaccines, however, did protect mice against Lagos bat virus, but not against Mokola. Dogs immunized with Rabisin were protected against an intracerebral challenge with DBV. Dogs developed rabies-neutralizing antibody titres after intramuscular or intravenous inoculation with live DBV or DUV-1 virus; these dogs were protected against an intramuscular canine street rabies virus challenge. We conclude that the rabies vaccines tested protect against DBV/DUV-1 and classic street rabies strains, but not Mokola.
In an attempt to compare intrinsic and extrinsic genetic diversity of the lyssavirus genotypes, 69 rabies virus isolates from various part of the world were partially sequenced and compared to 13 representative isolates of the 6 lyssavirus genotypes. The analysis of their phylogenetic relationships, performed on the complete nucleoprotein (N) coding gene (1350 bases), established that the rabies virus isolates all belonged to genotype 1 and that at least 11 phylogenetic lineages could be identified in accordance with their geographical localization and species of origin. These lineages diverged mostly by the accumulation of synonymous mutations. Stabilizing selection, possibly related to host specificity, limits amino acid sequence and antigenic drift. Analyses were also performed either on the highly variable 400-base region coding for the amino terminus of the N protein or on the 93-base noncoding region corresponding to the 3' end of the N mRNA, the intergenic N-phosphoprotein (M1) region, and the 5' end of the M1 mRNA. These shorter nucleotide sequences were shown to provide phylogenetic data suitable for the completion of large epidemiological studies, but with less robustness. This latter noncoding sequence, despite a 3.1 times higher mutation rate than its adjacent coding N gene, followed a parallel evolutionary pattern.
The sequence of 5568 nucleotides of the 3' moiety of the Mokola virus genome (serotype 3 of lyssaviruses) encompassing the nucleoprotein (N), phosphoprotein, matrix protein, and glycoprotein genes is presented and compared to that of the vaccinal strains of serotype 1. It allowed us to determine consensus sequences derived from the transcriptional start/stop signals and the order of protein conservation (nucleoprotein > matrix protein > phosphoprotein) in lyssaviruses. The sequences of the N gene of a fox rabies virus isolate from France (serotype 1), Lagos bat virus (serotype 2), Duvenhage virus (serotype 4), two European bat lyssaviruses (EBL) subtype 1, and two EBL subtype 2 were also determined to study the genetic diversity throughout the whole Lyssavirus genus and reinvestigate the classification of this genus. Six clearly distinct genotypes can be distinguished according to their percentage of amino acid similarity. Genotypes 2 (Lagos bat virus) and 3 (Mokola virus) are the most phylogenetically distant from the vaccinal and classical rabies viruses of genotype 1. Genotypes 4 (Duvenhage virus) and 5 (EBL1) are closely related to each other. Genotype 6 is represented by EBL2. Compared to the N proteins of the four principal serotypes of the Vesiculovirus genus (vesicular stomatitis virus serotype New Jersey and serotype Indiana, Chandipura virus, and Piry virus), the N gene of lyssaviruses exhibits a lower genetic variability.
Rabies continues to be an important public health problem in India and many other developing countries. In India, annually some 700,000 persons are given post-exposure vaccine prophylaxis using Semple (sheep brain) vaccine. It is manufactured by government institutions and given free to the public. It is presumed to be cheap, although the actual cost of production may not be low. However, it is not a safe vaccine as it causes demyelinating central or peripheral nervous system side-effects in 1/3000-7000 persons vaccinated; this adverse reaction is occasionally fatal. Cell culture rabies vaccines are also available in India; unlike the Semple vaccine they are safe and can be used for pre-exposure vaccination, but they are more expensive. The dilemma is whether it is ethically acceptable to continue to use the Semple vaccine in humans while safer products are available. What is urgently needed is a decision tree which would enable economical use of cell culture vaccines together with the backing of professional bodies in medical practice, who will declare that cost is not the only factor in choosing a rabies vaccine-safety is also of paramount importance. We must also strive to reduce the cost of cell culture vaccines.
During recent years, most of the research on the control of sylvatic rabies has concentrated on developing methods of oral vaccination of wild rabies vectors. In order to improve both the safety and the stability of the vaccine used, a recombinant vaccinia virus which expresses the immunizing glycoprotein of rabies virus (VRG) has been developed and extensively tested in the laboratory as well as in the field. From 1989 until 1995, several million VRG vaccine doses have been dispersed in western Europe for vaccination of red foxes. In Europe, the use of VRG has lead to the elimination of sylvatic rabies from large areas, which have consequently been freed from vaccination. This may have consequences on the regulation of pets movements within the whole European Union.
According to official WHO data more than 2.5 billion people are at risk in over 100 countries reporting the disease. Rabies mortality ranks ten in all infectious diseases worldwide. There are still about 50,000 to 60,000 human deaths annually although effective vaccines for post-exposure treatment are available. Most affected are the tropical countries in Africa, Asia, South America, and Oceania. The mortality figures range from about 0.001 per 100,000 for the US to 18 per 100,000 in Ethiopia. The vast majority (95-98%) of the 60,000 annual human death cases worldwide occur in canine (dog rabies) endemic regions with large stray dog population. Control of the disease is hampered by cultural, social and economic realities. In the rabies infested developing countries modern cell culture vaccines are hardly affordable. Dangerous neural tissue derived vaccines are still used. Three dose-saving treatment schedules have been developed: The reduced dose intramuscular 2-1-1 regimen, the two-site intradermal and the 8-site intradermal regimen. There is a critical shortage of human and purified equine rabies immunoglobulins, which are essential biologicals in the treatment of severe exposures.
A rapid and sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) assay for the detection of classical rabies virus (genotype 1) and the rabies related European bat lyssaviruses (EBLs) (genotypes 5 and 6) was developed. When combined with specific oligonucleotide probes and a PCR-enzyme linked immunosorbent assay (PCR-ELISA), genotype 5 and 6 viruses can be distinguished from each other and from genotype 1 viruses. Ninety-two isolates from the six established genotypes of rabies and rabies-related viruses were screened by RT-PCR and PCR-ELISA to determine the specificity of the assays. All genotype 1, 5 and 6 viruses were detected by RT-PCR while none of the genotype 2, 3 and 4 viruses were detected. All the genotype 5 and 6 viruses were detected by the two PCR-ELISA probes when used in combination while none of the genotype 1-4 viruses were detected. When used individually, the PCR-ELISA probes also distinguished between the genotype 5 and 6 viruses. This new discriminatory test should allow the rapid genotyping of all lyssaviruses likely to be encountered in Europe and as such could provide useful epidemiological information in the event of an outbreak.
Rabies encephalitis is a feared, virtually uniformly fatal form of central nervous system infection. The incidence of rabies encephalitis in the United States is almost certainly underestimated because of the predominance of bat-borne rabies, which can be spread without traumatic exposure. Because of its rarity in developed countries, rabies encephalitis has been seldom studied with modern imaging techniques.
University-based teaching hospital.
A case of pathologically confirmed rabies encephalitis is presented. Diagnosis of rabies was made by seroconversion testing while the patient was alive and was confirmed postmortem by the presence of rabies antigens and Negri bodies in the brain. The patient had 2 magnetic resonance studies done that showed dramatic abnormalities in the medulla and pons that correlated with features of the neurologic examination and hypothalamic-pituitary abnormalities.
The patient had a fulminant encephalitic course that ended in death.
Rabies is an uncommon cause of fatal encephalitis. Anatomic imaging studies such as computed tomographic and magnetic resonance scans have generally been negative in confirmed cases of rabies. We report a case of confirmed rabies with extensive brainstem and hypothalamic-pituitary abnormalities on magnetic resonance imaging. Although these findings are nonspecific, they should raise the clinical suspicion of rabies in the setting of aggressive encephalitis of unclear cause, and appropriate diagnostic tests should be performed.
Antigenic characterisation of over 350 chiropteran rabies viruses of the Americas, especially from species reported rabid in Canada, distinguished 13 viral types. In close accord with this classification, nucleotide sequencing of representative isolates, at both the N and G loci, identified four principal phylogenetic groups (I-IV), sub-groups of which circulated in particular bat species. Amongst the North American bat viruses, there was a notable division between group I specimens associated with colonial, non-migratory bats (Myotis sp. and Eptesicus fuscus) and those of group II harbored by solitary, migratory species (Lasiurus sp. and Lasionycteris noctivagans). Certain species of Myotis were clearly identified as rabies reservoirs, an observation often obscured previously by their frequent infection by viral variants of other chiroptera. An additional group (III) apparently circulates in E. fuscus, whilst viruses harbored by both insectivorous and haematophagus bats of Latin America clustered to a separate clade (group IV). Comparison of the predicted N and G proteins of these viruses with those of strains of terrestrial mammals indicated a similarity in structural organisation regardless of host species lifestyle. Finally, these sequences permitted examination of the evolutionary relationship of American bat rabies viruses within the Lyssavirus genus.
Free-roaming dogs or cats are domestic dogs and cats that are not confined to a yard or house. Free-roaming dogs and cats have long caused major public-health problems and animal-welfare concerns in many countries. Free-roaming dogs have been considered to be more of a problem than cats for several reasons, but the literature addressing dogs focuses primarily on their role in rabies spread and control. Free-roaming cats are becoming more of an issue in countries where free-roaming dog problems are coming under control. The change in perception of pets, beyond their value as a commodity, has also contributed to the increase in concern and attention focused on free-roaming dogs and cats. Epidemiologists have contributed much to these studies of these populations and have potential to contribute even more. The epidemiologic methods and approaches, the experience of epidemiologists in interdisciplinary teams and the importance of considering the separate sub-populations in study design and analysis all are critical in designing and evaluating interventions for free-roaming dogs and cats. In this paper, I will (1) describe a set of useful definitions regarding free-roaming dogs and cats, (2) summarize past and present topics of study in free-roaming dogs and cats, using selected examples, (3) describe the limitations of existing work and how epidemiologists might strengthen and improve this work, and (4) outline areas needing more attention by epidemiologists and why these are important.
The genetic diversity of Australian bat lyssavirus (ABL) was investigated by comparing 24 ABL isolate glycoprotein (G) gene nucleotide sequences with those of 37 lyssaviruses representing Lyssavirus genotypes 1-6. Phylogenetic analyses indicated that ABL forms a monophyletic group separate from other lyssaviruses. This group differentiates into two clades: one associated with Pteropus (flying fox) species, the other with the insectivorous bat Saccolaimus flaviventris. Calculation of percentage nucleotide identities between isolates of the two clades revealed up to 18.7 % nucleotide sequence divergence between the two ABL variants. These observations suggest that ABL is a separate lyssavirus species with a similar epidemiology to chiropteran rabies virus (RV), where two distinct ABL variants co-exist in Australia in bat species with dissimilar ecology. Analyses of selection pressures in ABL G gene sequences provided some evidence of weak positive selection within the endodomain at amino acids 499 and 501, although in general the dominant evolutionary process observed was purifying selection. This intimates that, in nature, isolates of ABL, like those of RV, are subject to relatively strong selective constraints, suggesting a stability of host species, cell tropisms and ecological conditions.
Rabies is a worldwide zoonosis caused by a lyssavirus, with many host species acting as reservoirs for infection. The epidemiology of rabies has changed over recent years, as this disease has been brought under control or eliminated in many terrestrial animal species in Europe and North America. A large number of Lyssavirus variants have now been characterised, and their distribution and animal hosts have become known. However, new lyssaviruses have been isolated from bats, prompting scientists to question the efficacy of the existing human and veterinary vaccines against these new strains. The epidemiology of bat rabies should be fully explored, so that the precise risks to the health of humans and domestic and wild carnivores may be determined and methods of preventing the disease among people who handle bats can be discovered. Rabies is still a significant public health problem, particularly in areas where canine rabies is still endemic, such as countries in Africa and Asia.
New causative agents of rabies continue to emerge as shown by the recent description of four novel lyssaviruses from bats in Eurasia, Aravan (ARAV), Khujand (KHUV), Irkut (IRKV), and West Caucasian bat virus (WCBV). The effect of rabies vaccination prior to exposure to these new lyssaviruses was investigated in two animal models (i.e., Syrian hamsters and ferrets). The hamsters were vaccinated intramuscularly with a commercial human or veterinary vaccine or with an experimental vaccinia-rabies glycoprotein recombinant vaccine. At 5 weeks after vaccination, animals were challenged with ARAV, KHUV, IRKV, or WCBV, or with a traditional rabies virus of dog/coyote origin. Previously vaccinated and rabies-naive ferrets were also challenged with the four new isolates. In addition, the combined effect of rabies immunoglobulin and vaccine after exposure to the four isolates was investigated in hamsters using commercially available human products or an experimental monoclonal antibody. Results showed reduced protection with pre-exposure vaccination and with conventional rabies post-exposure prophylaxis against all four new bat viruses. In general, protection was inversely related to the genetic distance between the new isolates and traditional rabies viruses. For example, the WCBV is the most divergent of these lyssaviruses, and neither pre-exposure vaccination nor conventional post-exposure prophylaxis provided significant protection. The potential impact of these new lyssaviruses on human and domestic animal health and the impact on the putative bat reservoir populations will require further field and laboratory investigation.
Three patients received solid organ transplants from a common donor and were subsequently discharged from the hospital following an uneventful hospital course. Within 30 days, all 3 organ recipients returned to the hospital with varying symptoms that progressed to rapid neurological deterioration, coma, and death.
To describe the clinical, neuroradiological, and pathological findings of rabies virus infection in organ transplant recipients infected from a common donor.
Case series involving a common donor and 3 organ recipients ascertained through review of clinical course and autopsy findings. A fourth case was determined by review of pending autopsy cases in which death occurred within the same time interval. Portions of postmortem central nervous system and organ tissues were frozen and formalin-fixed. Fluids and tissues were also collected for cultures, serology, and molecular studies. Postmortem fluids and tissues and antemortem fluids and tissues from all 4 transplant recipients and serum and banked lymphocyte or spleen cells from the donors were sent to the Centers for Disease Control and Prevention for further evaluation.
Transplant unit of an urban teaching hospital.
Antemortem cerebrospinal fluid analysis for 3 of the 4 recipients was consistent with a viral etiology. Neuroimaging and electroencephalogram studies were suggestive of an infectious encephalitis or a toxic encephalopathy. Initial laboratory testing did not demonstrate an infectious etiology. Postmortem histologic analysis, immunohistochemistry, electron microscopy, and direct fluorescence antibody testing revealed rabies virus infection. Serological testing done postmortem confirmed rabies virus infection in the common donor.
These cases demonstrate a risk for transmitting rabies virus infection through solid organ and tissue transplantation, and this diagnosis should be considered in any rapidly progressing neurological disease.
The effect that the relatedness of the viral seed strain used to produce rabies vaccines has to the strain of challenge virus used to measure rabies virus neutralizing antibodies after vaccination was evaluated. Serum samples from 173 subjects vaccinated with either purified Vero cell rabies vaccine (PVRV), produced from the Pittman Moore (PM) seed strain of rabies virus, or purified chick embryo cell rabies vaccine (PCECV), produced from the Flury low egg passage (Flury-LEP) seed strain of rabies virus, were tested in parallel assays by RFFIT using a homologous and a heterologous testing system. In the homologous system, CVS-11 was used as the challenge virus in the assay to evaluate the humoral immune response in subjects vaccinated with PVRV and Flury-LEP was used for subjects vaccinated with PCECV. In the heterologous system, CVS-11 was used as the challenge virus in the assay to evaluate subjects vaccinated with PCECV and Flury-LEP was used for subjects vaccinated with PVRV. Although the difference in G protein homology between the CVS-11 and Flury-LEP rabies virus strains has been reported to be only 5.8%, the use of a homologous testing system resulted in approximately 30% higher titers for nearly two-thirds of the samples from both vaccine groups compared to a heterologous testing system. The evaluation of equivalence of the immune response after vaccination with the two different vaccines was dependent upon the type of testing system, homologous or heterologous, used to evaluate the level of rabies virus neutralizing antibodies. Equivalence between the vaccines was achieved when a homologous testing system was used but not when a heterologous testing system was used. The results of this study indicate that the strain of virus used in the biological assays to measure the level of rabies virus neutralizing antibodies after vaccination could profoundly influence the evaluation of rabies vaccines.
Thailand is a canine rabies endemic country with an annual prevalence above 1,000 reported animals diagnosed rabid . Over 345,000 humans are treated for possible rabies exposures annually . Lack of perception of the disease burden, social, cultural and traditional beliefs play an important role in the failure of canine rabies control. It is unfortunate that health care budgets are increasingly allocated to human post-exposure treatment rather than to the eradication of rabies in the canine animal vector. Children under the age of 15 years represent up to one-half of dog bite victims and of human rabies deaths, but accurate data of dog bite prevalence are not available . Large scale pre-exposure immunization of children has been advocated but financial and logistic barriers have hindered implementation. This study analyzes direct medical costs of pre-exposure vaccination (PREP) as a human rabies preventive strategy, against the cost of post-exposure prophylaxis (PEP) in Thai children. Three pre- and post-exposure vaccine regimens are in use and this impacts on cost calculations. It was found that costs of both strategies, PREP of children or PEP of exposed, become equal when the dog bite incidence is 2-30%; depending on which post-exposure treatment regimens (PEP) are used.
Safe and effective vaccination is important for rabies prevention in animals. Although several genetically engineered rabies vaccines have been developed, few have been licensed for use, principally due to biosafety concerns or due to poor efficacy in animal models. In this paper, we describe the construction and characterization of a replication-competent recombinant canine adenovirus type-2 expressing the rabies virus glycoprotein (SRV9 strain) by a different strategy from that reported previously, i.e., the recombinant genome carrying the glycoprotein cDNA was generated by a series of strictly gene cloning steps, infectious recombinant virus was obtained by transfecting the recombinant genome into a canine kidney cell line, MDCK. This recombinant virus, CAV-E3delta-CGS, was subcutaneously injected into dogs. All vaccinated dogs produced effective neutralizing antibodies after one inoculation and a stronger anamnestic immune response was produced after booster injection. The immunized dogs could survive the challenge of 60,000 mouse LD50 CVS-24, which is lethal to all unimmunized dogs and is comparable to the conventional vaccines. The immunity lasts for months with a protective level of neutralizing antibody. This recombinant virus would be an alternative to the attenuated and the inactivated rabies vaccines and be prospective in immunizing dogs against rabies.
This paper reviews the broader benefits of canine vaccination to human and animal health and welfare with an emphasis on the impacts of mass dog vaccination against rabies in countries of the less-developed world. Domestic dogs are the source of infection for the vast majority (>95%) of cases of human rabies worldwide, and dogs remain the principal reservoir throughout Africa and Asia. Canine vaccination against rabies has been shown to dramatically reduce the number of cases in dogs, the incidence of human animal-bite injuries (and hence the demand for costly post-exposure prophylaxis) and the likely number of human cases, primarily in children. Further benefits include the mitigation of the psychological consequences of rabies in a community, improved attitudes towards animals and animal welfare and reduced livestock losses from canine rabies. Mass vaccination has recently been used in the conservation management of wild carnivore populations threatened by transmission of rabies and canine distemper virus from domestic dog populations. Vaccination of wildlife hosts directly may also provide an option for mitigating infectious disease threats. The development of integrated control measures involving public health, veterinary, wildlife conservation and animal welfare agencies is needed to ensure that control of canine diseases becomes a reality in Africa and Asia. The tools and delivery systems are all available--all that is needed is the political will to free the world from the ongoing tragedy of these diseases.
Rhabdovirus is a negative strand RNA virus that packages a ribonucleoprotein (RNP) complex. The RNP is composed of a genome that is encapsidated completely by the nucleoprotein (N). Structural comparisons of the RNA-nucleoprotein complexes from two members, vesicular stomatitis virus (VSV) and rabies virus (RABV), revealed highly conserved characteristics of folding, RNA binding, and assembly despite their lack of significant homology in amino acid sequence. The RNA binding cavity is located between two conserved domains formed by alpha-helices, but the positively charged residues that coordinate with the phosphate groups are at different sites. The intermolecular interactions among N molecules have a conserved pattern that is rendered, however, by different residues. The curvature of the RABV N-RNA complex in the crystal structure is larger than that of the VSV N-RNA complex. The more relaxed curvature allows the bases in the RNA to stack more tightly, and at the same time, the helices near the C-terminus move into the created space in order to cover the bound RNA. This may explain how the RNP can adopt different conformations from being packed as a superhelix in the virion to a relaxed linear structure once being delivered into the cytoplasm.