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Objective: To quantify the public health and economic burden of endemic canine rabies in Africa and Asia., Methods: Data from these regions were applied to a set of linked epidemiological and economic models. The human population at risk from endemic canine rabies was predicted using data on dog density, and human rabies deaths were estimated using a series of probability steps to determine the likelihood of clinical rabies developing in a person after being bitten by a dog suspected of having rabies. Model outputs on mortality and morbidity associated with rabies were used to calculate an improved disability-adjusted life year (DALY) score for the disease. The total societal cost incurred by the disease is presented., Findings: Human mortality from endemic canine rabies was estimated to be 55 000 deaths per year (90% confidence interval (CI) = 24 000-93 000). Deaths due to rabies are responsible for 1.74 million DALYs lost each year (90% CI = 0.75-2.93). An additional 0.04 million DALYs are lost through morbidity and mortality following side-effects of nerve-tissue vaccines. The estimated annual cost of rabies is USD 583.5 million (90% CI = USD 540.1-626.3 million). Patient-borne costs for post-exposure treatment form the bulk of expenditure, accounting for nearly half the total costs of rabies., Conclusion: Rabies remains an important yet neglected disease in Africa and Asia. Disparities in the affordability and accessibility of post-exposure treatment and risks of exposure to rabid dogs result in a skewed distribution of the disease burden across society, with the major impact falling on those living in poor rural communities, in particular children.

Purified Vero cell rabies vaccine was used to treat 19 patients who experienced fox bite. Seventeen patients survived, and 2 patients died of rabies. Maximum antibody titers determined using a rapid fluorescent focus inhibition test were 25 IU, < or =90 days after the first vaccination and were 30 IU on day 1050 after booster vaccination.

More than 99% of all human rabies deaths occur in the developing world, and although effective and economical control measures are available, the disease has not been brought under control throughout most of the affected countries. Given that a major factor in the low level of commitment to rabies control is a lack of accurate data on the true public health impact of the disease, this report of a WHO Expert Consultation begins by providing new data on the estimated burden of the disease and its distribution in the world. It also reviews recent progress in the classification of rabies viruses, rabies pathogenesis and diagnosis, rabies pre- and post-exposure prophylaxis, the management of rabies patients, and canine as well as wildlife rabies prevention and control. Considering the emergence of new lyssaviruses and changes in animal and human rabies epidemiology observed on different continents, the definition of a rabies-free country or area has been revised to assist public health authorities in better assessing the risk of human rabies resulting from contact with animals. Measures aiming at preventing the spread of rabies through the international transfer of animals, mainly with regard to pets, are discussed as well as the new systems in place within and outside WHO to share rabies data and information. As certain tools currently used in rabies prevention and control, such as biologicals, tests for intra vitam and postmortem diagnosis, vaccines and immunoglobulin quality control, need improvement, the report ends by outlining the priorities for basic research, as well as those for operational research for sustainable canine rabies control, including dog population management schemes complying with animal welfare principles. Such operational research is necessary for removing or alleviating the main constraints to rabies control in dogs, as these are the source of most human rabies cases worldwide.

Objectives: To estimate the incidence of rabies and the effectiveness of post-exposure treatment (PET) in Pakistan., Methods: Rabies cases admitted from July 1993 to December 1994 to a public rabies isolation hospital were analyzed. Two samples (one sample each from a separate peripheral site) of a single batch of sheep brain vaccine (SBV) were also tested for potency by the National Institute of Health (NIH) test in May 1997., Results: Forty patients were admitted with a history of clinical rabies. The median age was 22 years and 55% were under 15. Thirteen (23%) victims did not receive any vaccine; the remaining 27 (67%) received SBV only, and of these, 16 (40%) received a full course of SBV. No rabies immunoglobulins (RIG) or cell culture vaccines were administered. There were frequent power blackouts and no back-up supply at the public hospital. In-house potency testing of the vaccine batch by the manufacturer was adequate, although it was not tested by the World Health Organization (WHO) recommended NIH test. Samples of SBV of the same batch collected at the peripheral sites showed no potency. Rabies incidence was estimated to range between 7.0 to 9.8 cases per million annually., Conclusion: A multi-sectorial approach is needed to decrease rabies incidence in Pakistan. Public and healthcare practitioner education on prompt and appropriate PET, especially the use of cost-effective cell culture intradermal regimens, is needed urgently. The NIH test should be employed for vaccine potency testing. An independent agency is needed for monitoring vaccine quality and strategies are needed for maintaining cold chain. SBV should be replaced by locally manufactured second-generation cell culture rabies vaccine. Purified equine rabies immunoglobulin (ERIG) should be manufactured locally to meet national needs. Furthermore, effective dog control strategies should be implemented to decrease the rabies reservoir.

A total of 1820 dogs and 332 cats that appeared ill or had bitten humans or animals were observed for >or=10 days. Of these, 957 dogs and 94 cats that were confirmed to be rabid survived <10 days after admission to our institution. This study supports current recommendations that dogs and cats that are suspected of being rabid should be euthanized and examined or, if this is inappropriate, confined and observed for 10 days.

The authors have previously reported that the glycoprotein of the pathogenic Nishigahara strain of rabies virus is required to lethality for adult mice. A cluster region of amino acid substitutions exists at the positions 164 to 303 on the glycoprotein between avirulent and virulent strains. In this study, the authors generated a chimeric strain having the region at the positions 164 to 303 of the glycoprotein derived from the pathogenic Nishigahara strain in the genetic background of the avirulent RC-HL strain. The chimeric R(G 164-303) strain restores the lethality for adult mice. This result clearly shows that the region at the position 164 to 303 of glycoprotein plays an important role in the lethality for adult mice. Moreover, the authors observed that the lethality for adult mice correlated well with the viral growth in a brain but not with the pH-dependent fusion activity in vitro.

From 1991 to 2002 10 patients with rabies were treated, all the patients died. Epidemiology, clinical picture, specific symptoms are described, rarity of this severe disease is noted. The necessity of urgent preventive vaccination immediately after bites is emphasized.

We wish to report the first recorded case of indigenous human rabies caused by a bat bite in the United Kingdom in 100 years. This instructive case report highlights a number of key lessons: first, bites from insectivorous bats indiginous to the United Kingdom can cause rabies in humans; second, rabies immunization is essential for bat-handlers, and postexposure treatment for rabies is essential for patients bitten by bats; third, patients able to give a history who present with acute flaccid paralysis and/or presumptive viral encephalitis should be asked if they have been bitten by bats, irrespective of travel history, or this history should be obtained from family or friends; fourth, antemortem diagnosis of bat rabies (EBLV type 2a infection) in humans is possible using RT-PCR.

Objective: To determine effect of route of challenge and strain of rabies virus on efficacy of inactivated rabies vaccines in mice., Animals: 3,056 mice., Procedure: Challenge was performed with fixed and street rabies virus strains by use of footpad and intracerebral routes as well as IM injection into the hip, shoulder, neck, and masseter muscles. Intraperitoneal and IM vaccination was performed with 1 or 2 doses of 1 of 3 vaccine-strain inactivated rabies vaccines. For 2 of the vaccine strains, the vaccines were adjuvanted and nonadjuvanted., Results: Incubation periods were dependent on route, dose, and virus strain used for challenge. Use of an intramasseter challenge route with challenge virus-strain rabies virus, which more accurately models natural exposure to rabies virus, resulted in reproducible mortality rates in mice. Use of this route revealed that differences among vaccines and challenge virus strains affected mortality rate less than that observed in the National Institutes of Health potency test, even when street isolates of widely variant origin were used for challenge., Conclusions and Clinical Relevance: These results, combined with earlier data, support a proposal for a new rabies potency test that more closely models current vaccine administration practices and natural infection routes.

The medical records of 48 red foxes (Vulpes vulpes) and 35 gray foxes (Urocyon cinereoargenteus) examined at the Wildlife Center of Virginia (Waynesboro, Virginia, USA) from 1993 to 2001 were reviewed. The most common diagnosis in red foxes was orphaned (33%), followed by trauma (27%), undetermined diagnosis (23%), and sarcoptic mange (17%). Trauma (46%) was the most frequent cause of morbidity and mortality in gray foxes followed by orphaned (23%), undetermined (20%), toxoplasmosis (6%), presumptive canine distemper (3%), and rabies (3%). One gray fox had concurrent toxoplasmosis and presumptive canine distemper (3%). Similar diseases were detected in previous studies at a diagnostic laboratory; however in this study, trauma and orphaned animals were more common than infectious diseases. The lack of diagnostic information on some cases limited the usefulness of this study, and more emphasis should be placed on performing postmortem examinations of wildlife presented to wildlife rehabilitation centers.

Most human rabies deaths in the United States can be attributed to unrecognized exposures to rabies viruses associated with bats, particularly those associated with two infrequently encountered bat species (Lasionycteris noctivagans and Pipistrellus subflavus). These human rabies cases tend to cluster in the southeastern and northwestern United States. In these regions, most rabies deaths associated with bats in nonhuman terrestrial mammals are also associated with virus variants specific to these two bat species rather than more common bat species; outside of these regions, more common bat rabies viruses contribute to most transmissions. The preponderance of rabies deaths connected with the two uncommon L. noctivagans and P. subflavus bat rabies viruses is best explained by their evolution of increased viral infectivity.

Treatment with Semple or suckling mouse brain rabies vaccines persists in many countries of Asia, Africa and South America. Its replacement depends on the immediate accessibility of effective affordable alternative treatment with tissue culture vaccines (TCVs). The use of the expensive European TCVs has been possible in Asia by means of economical intradermal (ID) post-exposure vaccine regimens. Implementation of this effective economical treatment has been delayed by the complexity and inconvenience of the regimens, and the reluctance to change prophylaxis against a fatal disease. Up to now, the ID regimens have been used only where passive immunisation with rabies immune globulin (RIG) is usually available. Rabies deaths despite optimal vaccine treatment have been attributed to lack of RIG. The ID regimens might soon be promoted in areas where RIG is not even available for severe exposure. It is therefore vital that economical vaccine regimens should be used which induce protective immunity rapidly. Improvements in rabies pet in developing countries could be made by: (i). publicising the urgency and efficacy of wound cleaning; (ii). facilitating the replacement of nervous tissue vaccines by economical ID treatment with TCVs; (iii). using an ID regimen with a large dose of vaccine on the first day of treatment especially when no RIG is available; and (iv). promoting pre-exposure prophylaxis to eliminate the need for RIG and provide better rabies prophylaxis.

Rabies is a fatal disease in humans, and, to date, the only survivors of the disease have received rabies vaccine before the onset of illness. The approach to management of the rabies normally should be palliative. In unusual circumstances, a decision may be made to use an aggressive approach to therapy for patients who present at an early stage of clinical disease. No single therapeutic agent is likely to be effective, but a combination of specific therapies could be considered, including rabies vaccine, rabies immunoglobulin, monoclonal antibodies, ribavirin, interferon-alpha, and ketamine. Corticosteroids should not be used. As research advances, new agents may become available in the future for the treatment of human rabies.

The lethality and distribution of rabies virus were evaluated in swiss mice experimentally infected with street rabies virus, vaccinated and submitted to immunomodulation by P .acnes (formerly Corynebacterium parvum). The animals were sacrificed at different times,when the different tissues were collected and submitted to fluorescent antibody test (FAT) and mouse inoculation test (MIT). The group submitted to vaccination and P. acnes treatment presented a percentage of survival superior to that observed in infected mice only treated with P. acnes. Control infected animals had the lowest survival rates. The distribution of rabies virus in spleen of infected mice, vaccinated and submitted to P. acnes was superior to that verified in infected mice not treated with P.acnes. The increased survival correlated with the distribution of rabies virus in lymphoid tissues, could be interpreted as the consequence of P. acnes activity on macrophages. The results suggest the role of macrophages against rabies virus infection in mice and the importance of vaccination in the post expositive treatment of rabies.

Human rabies is rare in the United States; however, an estimated 40,000 patients receive rabies postexposure prophylaxis each year. Misconceptions about the transmission of rabies are plentiful, particularly regarding bats. Most cases of human rabies caused by bat variants have no definitive history of animal bite. Three hypotheses are proposed and reviewed for the transmission of rabies from bats to human beings. They include nonbite transmission (including aerosol transmission), the alternate host hypothesis (an intermediate animal host that acquires rabies from a bat and then transmits rabies to human beings), and minimized or unrecognized bat bites. Nonbite transmission of rabies is very rare, and aerosol transmission has never been well documented in the natural environment. The known pathogenesis of rabies and available data suggest that all or nearly all cases of human rabies attributable to bats were transmitted by bat bites that were minimized or unrecognized by the patients.

Recombinant tumor necrosis factor-alpha (TNF-alpha) improved the survival of random-bred albino mice vaccinated with antirabies vaccine after infection with rabies CVS strain. The agent dose of 0.1 microgram/animal, injected 1 day postvaccination, was the most effective. Improvement of antiviral resistance of non-vaccinated mice under the effect of TNF-alpha suggests that the effect of this factor on nonspecific resistance factors is one of the probable mechanisms of its modulating effect.

The study on the prevalence of rabies was conducted on a retrospective data gathered from EHNRI rabies diagnostic laboratory Addis Ababa, in the years 1979-1987. During this period a total of 8036 animals were brought to the rabies diagnostic laboratory. Ninety one percent (7329) of these animals were dogs. The remaining 8.8% (707) comprised of cats, domestic animals (donkeys, cows, sheep) and wild animals (monkeys, jackals and hyenas). Out of 7329 dogs examined 832 were positive for rabies. Dogs accounted for the majority of animal rabies (94.01% of the total positive animals). The remaining 5.99% (53) of the animals diagnosed with rabies-comprised of cats, domestic animals and some wild animals. A total of 15,940 people were given post exposure anti-rabies prophylaxis treatment that came from different parts of the country in the years 1979-1987. The prevalence rates of rabies were found to be higher soon after dogs' breeding seasons. Such an observation indicates that among dogs infection, transmission through biting is significant during the breeding season. However, despite the high incidence of rabies in Ethiopia, only 320 people were reported to have died of rabies in the years 1979-1984. This supports, the hypothesis that there is a lack of appropriate reporting system on prevalence of rabies and its impact on humans in Ethiopia.

Objective: To make quantitative predictions about the magnitude of underreporting of human rabies deaths in the United Republic of Tanzania., Methods: Human rabies deaths were estimated by using a series of probability steps to calculate the likelihood of rabies developing after the bite of a suspected rabid dog, incorporating field data on the incidence of animal bite injuries, the accuracy of rabies recognition, the distribution of bite wounds, and post-exposure treatment., Findings: Predicted human rabies mortality was estimated to be (a) 1499 deaths per year (95% confidence interval 891-2238), equivalent to an annual incidence of 4.9 (2.9-7.2) deaths/100,000, when active surveillance data on bite incidence were used, and (b) 193 deaths per year (32-409), corresponding to an annual incidence of 0.62 (0.1-1.32) deaths/100,000, when national bite statistics were used. The annual mean number of rabies deaths officially recorded for the same period was 10.8 (7.7-14.0)., Conclusion: In the United Republic of Tanzania, cases of rabies in humans have been greatly underreported. Dog bite injuries are an accessible source of epidemiological data that may be used to estimate the public health burden of rabies and to monitor epidemiological trends in developing countries.

Narrow-skulled voles (Microtus gregalis) were inoculated with tick-borne encephalitis (TBE) and rabies (RV) viruses isolated in the steppe zone of West Siberia. TBE infection was asymptomatic and nonlethal in all voles. The virus was eliminated from the voles between days 14 and 60 postinoculation. Only 1 of 26 tested animals produced anti-TBE antibodies in titer 1:20. RV infection was acute and lethal. All sick animals contained RV in the brain, 42.1% in salivary glands, 5.3% in the lungs and kidneys. The voles which survived RV inoculation had no RV. The voles inoculated with RV after TBE were less sensitive and had a longer incubation period in comparison with the animals challenged with RV alone. The differences augmented from day 0 to day 14 after TBE inoculation and became statistically significant on day 14. Later, 21 day after challenge with TBE virus, the differences almost disappeared. The role of possible interference in the evolution of virus-host interaction of Lyssaviruses is discussed.

Three Israelis died of rabies in a single year following a hiatus of almost 40 years since the last case of human rabies in Israel. These tragic deaths from a uniformly lethal disease, preventable by correct post-exposure treatment, were highly publicized in the mass media and led to substantial public anxiety and professional concern. In this investigation we examine public response, as well as changes in the behavior of public health physicians responsible for human rabies control, in the face of the reappearance of human rabies in Israel. In the weeks following each new case of human rabies, animal-contact visits to public health offices increased five-fold, and public health physicians initiated post-exposure prophylaxis in 25% of all applicants, compared to 10% in the no-rabies era. Together, these changes in public and professional behavior led to marked increases in rabies vaccine and rabies immune globulin consumption, and resulted in severe shortages necessitating strict rationing. Within four months of the last case, population and physician behavior had returned to baseline levels. Rabies prevention is a multi-level activity involving eliminating stray animals, immunization of pets, oral immunization of selected wild animal populations, pre-exposure immunization of persons at very high exposure risk and rapid evaluation and appropriate treatment of humans following exposure. Moreover, the public must be educated to avoid potentially dangerous animal contacts and to seek immediate professional guidance after an accidental exposure has occurred.

Over a million Americans are bitten by animals every year. Since the rabies vaccine is uniformly effective and the disease is uniformly fatal when the vaccine is not given, management decisions must be made promptly.

A pathophysiological mechanism of cerebral damage and impairment of neuronal function during rabies virus infection was examined. Synthesis of nitric oxide (NO) and expression of the inducible nitric oxide synthase (iNOS) gene are strongly upregulated during rabies virus infection. Treatment of rabies virus-infected mice with a selective inhibitor of iNOS, aminoguanidine (AG), significantly delayed their death. Prolonged survival was not due to suppression of an inflammatory response in the central nervous system. One effect of iNOS inhibition was at the level of viral replication. Treatment with AG delayed rabies virus replication by 2 days. Moreover, iNOS inhibition also suppressed an early phase of expression of an apoptotic gene, Caspase-1, which resulted in slow progression of infected cells into apoptotic death. iNOS inhibition had no effect on expression of the anti-apoptotic gene, bcl-2. In conclusion, iNOS inhibition delayed the death of rabies virus-infected mice by affecting viral replication and apoptotic death of infected cells.

Introduction: In 1996, rabies was responsible for more than 35,000 deaths worldwide. Three cases of human rabies that had been contracted abroad were diagnosed in France during the same year. Cases notified in 1997 followed exposure outside the country. Fox, bat, and dog rabies are reviewed on the basis of the latest epidemiological data obtained in France., Current Knowledge and Key Points: Two cases of fox rabies diagnosed in 1998 occurred at the border between France and Germany, thus preventing five French departments bordering Germany from being officially declared rabies-free in 1999. The campaigns for oral immunization of foxes that are led since 1986 are responsible for the decrease in rabies incidence. Though not well known, bat rabies is a reality in France, involving either European virus strains (five cases all over the country) or African virus strains that are carried along by imported tropical bats. Dogs rabies is also today an imported disease., Future Prospects and Projects: The decrease in risk for rabies has resulted from the conjunction of multiple efforts: extensive programs aimed at oral vaccination of foxes in France and its neighboring countries, efficient epidemiological survey, sanitary controls at borders, ban on importing tropical bats. Furthermore, recommendations for preventive pre-exposure immunization have recently been changed, leading to modifications of the French licensing form.

Transference and interference of maternal immunity to offspring after rabies vaccination were studied in hamsters. Females were vaccinated or not before mating and offspring were vaccinated at the age of 7, 14, 21 and 30 days. Other pups were maintained as controls. Thirty days after vaccination pups were challenged intracerebrally with CVS virus. Mouse neutralization tests were used to verify antibody titers. Mortality of 97.0, 76.9, 60.9 and 24.0% was observed in pups vaccinated at 7, 14, 21 and 30 days respectively, born from vaccinated dams, while in pups from non-vaccinated dams, mortality was 51.4, 28.6, 8.7 and 0.0%. Statistically significant associations were found between mortality and age at vaccination, by simple linear regression with y=-3.1169x + 120.8 (p = 0.008; r2=0.98) for litters vaccinated and born from vaccinated dams and y=-2.2541x + 62.7495 (p = 0.03; r2=0.93) for pups vaccinated and born from non-vaccinated dams. Immunological response to vaccination in pups born from vaccinated mothers was delayed 11 days, when compared to that observed in pups of non-vaccinated mothers.

In the spring of 1996, multiple cases of an acute febrile illness resulting in several deaths in remote locations in Peru were reported to the Centers for Disease Control and Prevention (CDC). The clinical syndromes for these cases included dysphagia and encephalitis. Because bat bites were a common occurrence in the affected areas, the initial clinical diagnosis was rabies. However, rabies was discounted primarily because of reported patient recovery. Samples of brain tissue from two of the fatal cases were received at CDC for laboratory confirmation of the rabies diagnosis. An extensive array of tests on the formalin-fixed tissues confirmed the presence of both rabies viral antigen and nucleic acid. The virus was shown to be most closely related to a vampire bat rabies isolate. These results indicate the importance of maintaining rabies in the differential diagnosis of acute febrile encephalitis, particularly in areas where exposure to vampire bats may occur.

This paper is concerned with Bartoszyński's process for rabies viruses introduced by Bartoszyński [R. Bartoszyński, A model for risk rabies, ISI invited paper No. 9, ISI 1-9, IX Warsaw, 1975, pp. 545-552; Math. Biosci. 24 (1975) 355; W. Klonecki (Ed.) Proceedings of the IASPS Symposium to honour Jerzy Neyman, Warsaw, 1976, pp. 19-28]. Our main interests are in developing mechanisms of a symptom--how the probability of the occurrence of the symptom is related to the process. Four mechanisms are suggested based on various biological backgrounds. The main variable of interests is the survival time--the time elapsing between initial infection and the occurrence of the symptom. Analytical results about the survival functions induced from the four suggested mechanisms are studied.

Previous reports strongly suggest that, in addition to the nicotinic acetylcholine receptor, rabies virus can use other, as-yet-unidentified receptors. We found that laboratory cell lines susceptible to rabies virus infection express the neural cell adhesion molecule (NCAM) (CD56) on their surface, whereas resistant cells do not, supporting the idea that NCAM could be a rabies virus receptor. We observed that (i) incubation with rabies virus decreases the surface expression of NCAM; (ii) treatment of susceptible cells with heparan sulfate, a ligand for NCAM, or with NCAM antibodies significantly reduces the rabies virus infection; and (iii) preincubation of rabies virus inoculum with soluble NCAM protein as a receptor decoy drastically neutralizes the capacity of rabies virus to infect susceptible cells. Moreover, we demonstrated that transfection of resistant L fibroblasts with the NCAM-encoding gene induces rabies virus susceptibility whereas absence of NCAM in the primary cortical cell cultures prepared from NCAM-deficient mice reduces the rabies virus infection and virus production. This provides evidence that NCAM is an in vitro receptor for the rabies virus. Moreover, the in vivo relevance for the use of NCAM as a receptor was demonstrated by the infection of NCAM-deficient mice, in which rabies mortality was delayed and brain invasion by rabies virus was drastically restricted. Our results showed that NCAM, which is expressed mainly in the adult nervous system, plays an important role in rabies infection. However, it cannot be excluded that receptors other than NCAM are utilized. Thus, the description of NCAM as a new rabies virus receptor would be another example of the use by viruses of more than one receptor to gain entry into the host.

Following nearly 10 yr of extensive laboratory evaluation, a vaccinia-rabies glycoprotein (V-RG) vaccine was the first recombinant virus to undergo limited North American field release on 20 August 1990. The free-ranging raccoon population on Parramore Island (Virginia, USA) was exposed to a high density (10 baits/ha) of vaccine-laden baits distributed on a 300 ha vaccination area. An annual total of 887 raccoons were live-trapped for sedation, physical examination and blood collection for rabies antibody determination; there was no evidence of adverse effects or lesions due to the vaccine. Age and sex distributions, mean body weights, and live-capture histories of raccoons from the vaccination and non-baited control areas were compared. There were no statistically significant differences in survivorship between the baited and non-baited areas, nor between rabies antibody-positive and antibody-negative raccoons from the vaccination area. There was no trend in field mortality that suggested an association with either tetracycline or sulfadimethoxine, used as biomakers, or with vaccine contact determined by antibody status. No gross or histopathologic lesions due to the vaccine were demonstrated among a subsample of live-trapped raccoons collected for gross necropsy, biomarker analysis, histopathologic examination, and V-RG virus isolation attempts. Recovery of V-RG virus was limited to the tonsils of two biomarker-positive, clinically healthy raccoons collected from the vaccination area for postmortem examination on days 2 and 4 following bait distribution. These data reinforce the extensive body of safety data on the V-RG virus and extend it to include field evaluation where vaccine is offered free-choice in abundance, in baits designed to attract free-ranging raccoons, in a relatively simple ecosystem.

Passage of the mouse-adapted rabies virus strain CVS-24 (where CVS is challenge virus standard) in BHK cells results in the rapid selection of a dominant variant designated CVS-B2c that differs genotypically and phenotypically from the dominant variant CVS-N2c present in mouse-brain- or neuroblastoma-cell-passaged CVS-24. The glycoprotein of CVS-B2c has 10 amino acid substitutions compared with that of CVS-N2c. Because CVS-B2c can be reproducibly selected in BHK cells, it is likely to be a conserved minor subpopulation of CVS-24. CVS-N2c is more neurotropic in vitro and in vivo than CVS-B2c, which replicates more readily in nonneuronal cells in vitro and in vivo. These characteristics appear to be relevant to the pathogenicity of the two variants. CVS-N2c is more pathogenic for adult mice than CVS-B2c. In contrast, CVS-B2c is more pathogenic for neonatal mice. These differences in pathogenicity are reflected in the selection pattern when mixtures of CVS-N2c and CVS-B2c were used to infect neonatal and adult mice. Although CVS-N2c was highly selected in adult mice, no selection for either variant was seen in neonates, suggesting that certain aspects of development, such as maturation of the nervous and immune systems, may contribute to the selection process. We speculate that the existence of different variants within a rabies virus strain may facilitate the virus in overcoming barriers to its spread, both within the host and between species.

We previously demonstrated that recombinant plant virus particles containing a chimeric peptide representing two rabies virus epitopes stimulate virus neutralizing antibody synthesis in immunized mice. We show here that mice immunized intraperitoneally or orally (by gastric intubation or by feeding on virus-infected spinach leaves) with engineered plant virus particles containing rabies antigen mount a local and systemic immune response. After the third dose of antigen, given intraperitoneally, 40% of the mice were protected against challenge infection with a lethal dose of rabies virus. Oral administration of the antigen stimulated serum IgG and IgA synthesis and ameliorated the clinical signs caused by intranasal infection with an attenuated rabies virus strain.

We describe a rabies epizootic in northwest Alaska (USA) during 1989 and 1990 which resulted in mortality to several different wolf (Canis lupus) packs. Four radio-collared wolves were confirmed to have rabies while evidence for seven others was strongly suggestive but not confirmed. The wolf population declined during the rabies epizootic; thus rabies may have been a significant limiting factor.

Rabies is one of the oldest known diseases of mankind, yet it has been only slightly more than 100 years since Pasteur developed the first vaccine for post-exposure treatment. Since this first crude nerve tissue vaccine, numerous other rabies vaccines for human use have been developed and used with varying degrees of effectiveness and safety. When used appropriately, new cell culture vaccines provide nearly 100% protection with a high degree of safety: yet over 40,000 people world-wide die from rabies each year. Several pre- and post-exposure controlled vaccine trials and clinical studies have shown that the purified chick embryo cell (PCEC) vaccine, Rabipur, is as safe and effective as the rabies human diploid cell vaccine (HDCV), which is currently considered the gold standard. Additionally, PCEC vaccine does not result in immune-mediated hypersensitivity reactions following booster doses seen in about 6% of those receiving HDCV boosters following an initial series of HDCV.

Viruses such as human immunodeficiency virus, herpes simplex virus, cytomegalovirus, hepatitis B, hepatitis C, and rabies can be transmitted to the recipient by corneal transplantation. Very few cases of rabies have been reported. Here we report two cases of rabies transmitted by the same donor. Both of the recipients died of rabies.

Between October 1991 and February 1992, 41 of 53 known adult and subadult Ethiopian wolves (Canis simensis) in five adjacent packs in the Bale Mountains National Park, Ethiopia, died or disappeared. Brain smears from two carcasses were positive for rabies by the immunofluorescence test, and rabies virus was isolated from the brains by mouse inoculation. Based on monoclonal antibody tests on the mouse brains, we identified the virus as a minor variant of the serotype 1 rabies viruses found in domestic dogs and wild canids of Africa. Sera from two of 15 Ethiopian wolves had rabies virus neutralizing antibody.

Ten raccoons were divided into two random groups (groups 1 and 2) of five animals each. Group 1 raccoons were inoculated intramuscularly in the masseter muscle with a raccoon rabies virus isolate obtained from a natural case of raccoon rabies from the northeastern USA. Group 2 raccoons were infected by a similar route with a Latin American canine isolate of rabies virus. Raccoons either died suddenly or developed neurologic signs compatible with rabies. Clinical signs of rabies in group 1 raccoons were more severe than in group 2. Raccoons in group 1 either died acutely or were euthanized within 25 days (mean +/- SD = 20.6 +/- 2.7 days) postinfection, whereas all group 2 raccoons showed neurologic signs and were euthanized within 17 days (14.2 +/- 2.2 days) postinfection. Light microscopic findings revealed extensive nonsuppurative encephalitis predominantly located in the cerebrum and brain stem of raccoons in group 1, whereas in group 2 raccoons the lesions were confined to the brain stem regions. In group 1 raccoons, Negri bodies were commonly seen on hematoxylin and eosin (HE)-stained sections of brain and in ganglion cells of 5 other tissues (trigeminal nerve, salivary glands, duodenum, pancreas, adrenal gland). Negri bodies, however, were either absent or were only occasionally observed in corresponding tissues of raccoons infected with the canine strain (group 2). Paraffin-embedded tissue sections were also examined for Negri bodies by an immunoperoxidase test, which revealed results similar to the HE findings. Results of this study are compared with histopathologic and immunohistochemical findings in raccoons naturally infected with rabies.