One step closer to a transmissible vaccine for rabies virus.

A recent study in PLOS Biology shows that a betaherpesvirus circulating with the vampire bat, Desmodus rotundus, could serve as an effective vector for a transmissible vaccine capable of reducing the risk of rabies virus spillover in Peru.

The first confirmed human case of rabies, Timor-Leste, 2024.

In March 2024, the first ever human case of rabies, following a dog bite, was detected in Timor-Leste. This paper briefly discusses the circumstances of transmission, clinical presentation, palliative care of the case and public health measures taken. Timor-Leste was previously considered rabies-free. Any person who is bitten or scratched by an animal that could potentially transmit rabies virus (especially dogs, bats, monkeys or cats) in Timor-Leste should be assessed for consideration of provision of rabies post-exposure prophylaxis.

Virulence mismatches in index hosts shape the outcomes of cross-species transmission.

Whether a pathogen entering a new host species results in a single infection or in onward transmission, and potentially an outbreak, depends upon the progression of infection in the index case. Although index infections are rarely observable in nature, experimental inoculations of pathogens into novel host species provide a rich and largely unexploited data source for meta-analyses to identify the host and pathogen determinants of variability in infection outcomes. We analyzed the progressions of 514 experimental cross-species inoculations of rabies virus, a widespread zoonosis which in nature exhibits both dead-end infections and varying levels of sustained transmission in novel hosts. Inoculations originating from bats rather than carnivores, and from warmer- to cooler-bodied species caused infections with shorter incubation periods that were associated with diminished virus excretion. Inoculations between distantly related hosts tended to result in shorter clinical disease periods, which are also expected to impede onward transmission. All effects were modulated by infection dose. Taken together, these results suggest that as host species become more dissimilar, increased virulence might act as a limiting factor preventing onward transmission. These results can explain observed constraints on rabies virus host shifts, describe a previously unrecognized role of host body temperature, and provide a potential explanation for host shifts being less likely between genetically distant species. More generally, our study highlights meta-analyses of experimental infections as a tractable approach to quantify the complex interactions between virus, reservoir, and novel host that shape the outcome of cross-species transmission.

Risk factors for rabid animal bites: a study in domestic ruminants in Mymensingh district, Bangladesh.

Rabies is endemic in Bangladesh. To identify risk factors, a case-control study was conducted based on hospital-reported rabid animal bite (RAB) cases in domestic ruminants, 2009 - 2018. RAB cases (n = 449) and three controls per case were selected. Dogs (87.8%) and jackals (12.2%) were most often identified as biting animals. In the final multivariable model, the risk of being a RAB case was significantly higher in cattle aged >0.5-2 years (odds ratio (OR) 2.89; 95% confidence interval (CI): 1.56-5.37), >2-5 years (OR 3.63; 95% CI: 1.97-6.67) and >5 years (OR 6.42; 95% CI: 3.39-12.17) compared to those aged <0.5 years. Crossbred cattle were at higher risk of being a RAB case (OR 5.48; 95% CI: 3.56-8.42) than indigenous. Similarly, female cattle were more likely to be a RAB case (OR 1.26; 95% CI: 1.15-2.29) than males. Cattle in rural areas (OR 39.48; 95% CI: 6.14-254.00) were at a much higher risk of being RAB cases than those in urban areas. Female, crossbred and older cattle, especially in rural areas should either be managed indoors during the dog breeding season (September and October) or vaccinated. A national rabies elimination program should prioritise rural dogs for mass vaccination. Jackals should also be immunised using oral bait vaccines. Prevention of rabies in rural dogs and jackals would also reduce rabies incidence in humans.

Modeling Rabies Transmission in Spatially Heterogeneous Environments via [Formula: see text]-diffusion.

Rabies among dogs remains a considerable risk to humans and constitutes a serious public health concern in many parts of the world. Conventional mathematical models for rabies typically assume homogeneous environments, with a standard diffusion term for the population of rabid animals. It has recently been recognized, however, that spatial heterogeneity plays an important role in determining spatial patterns of rabies and the cost-effectiveness of vaccinations. In this paper, we develop a spatially heterogeneous dog rabies model by using the [Formula: see text]-diffusion equation, where [Formula: see text] reflects the way individual dogs make movement decisions in the underlying random walk. We numerically investigate the dynamics of the model in three diffusion cases: homogeneous, city-wild, and Gaussian-type. We find that the initial conditions affect whether traveling waves or epizootic waves can be observed. However, different initial conditions have little impact on steady-state solutions. An "active" interface is observed between city and wild regions, with a "ridge" on the city side and a "valley" on the wild side for the infectious dog population. In addition, the progressing speed of epizootic waves changes in heterogeneous environments. It is impossible to eliminate rabies in the entire spatial domain if vaccination is focused only in the city region or only in the wild region. When a seasonal transmission is incorporated, the dog population size approaches a positive time-periodic spatially heterogeneous state eventually.

Transmission dynamics of re-emerging rabies in domestic dogs of rural China.

Despite ongoing efforts to control transmission, rabies prevention remains a challenge in many developing countries, especially in rural areas of China where re-emerging rabies is under-reported due to a lack of sustained animal surveillance. By taking advantage of detailed genomic and epidemiological data for the re-emerging rabies outbreak in Yunnan Province, China, collected between 1999 and 2015, we reconstruct the demographic and dispersal history of domestic dog rabies virus (RABV) as well as the dynamics of dog-to-dog and dog-to-human transmission. Phylogeographic analyses reveal a lower diffusion coefficient than previously estimated for dog RABV dissemination in northern Africa. Furthermore, epidemiological analyses reveal transmission rates between dogs, as well as between dogs and humans, lower than estimates for Africa. Finally, we show that reconstructed epidemic history of RABV among dogs and the dynamics of rabid dogs are consistent with the recorded human rabies cases. This work illustrates the benefits of combining phylogeographic and epidemic modelling approaches for uncovering the spatiotemporal dynamics of zoonotic diseases, with both approaches providing estimates of key epidemiological parameters.

Evaluation of Online Risk Assessment To Identify Rabies Exposures Among Health Care Workers - Utah, 2019.

On November 7, 2018, the Utah Department of Health (UDOH) reported the first confirmed human rabies death in the state since 1944 (1). The case occurred in a person who had been treated over a period of 19 days at four health care facilities and an emergency medical transport service across three counties and two states. Human rabies is preventable through preexposure or postexposure vaccination but is invariably fatal upon symptom onset. Timely identification of persons who might have been exposed to rabies virus is therefore crucial to administer postexposure prophylaxis (PEP). Because of the large number of health care workers who had been involved in the patient's care, a standardized online risk assessment survey was developed by UDOH based on Advisory Committee on Immunization Practices recommendations (2). This online tool was evaluated for accuracy, acceptability, and administrative obligation by reviewing the results from the tool and conducting focus group discussions and a follow-up survey. Among 90 health care workers initially identified by the online risk assessment as being potentially exposed to infectious material, 74 were classified as exposed. All 74 health care workers received PEP following consultation with occupational health staff members, indicating a positive predictive value of the assessment tool of 82%. In a follow-up survey, 42 (76%) of the 55 respondents reported that they were satisfied with the assessment process. In focus group discussions, participants suggested that the survey could be improved by providing additional information about rabies exposures because many of them were unfamiliar with human-to-human rabies transmission. This evaluation highlighted the importance of adopting clear communication strategies, demonstrated the benefits of using an online risk assessment during a mass rabies exposure, and provided specific feedback for CDC to improve resources available for states and health care facilities after mass rabies exposures.

Towards the elimination of dog-mediated rabies: development and application of an evidence-based management tool.

BACKGROUND: International organizations advocate for the elimination of dog-mediated rabies, but there is only limited guidance on interpreting surveillance data for managing elimination programmes. With the regional programme in Latin America approaching elimination of dog-mediated rabies, we aimed to develop a tool to evaluate the programme's performance and generate locally-tailored rabies control programme management guidance to overcome remaining obstacles. METHODS: We developed and validated a robust algorithm to classify progress towards rabies elimination within sub-national administrative units, which we applied to surveillance data from Brazil and Mexico. The method combines criteria that are easy to understand, including logistic regression analysis of case detection time series, assessment of rabies virus variants, and of incursion risk. Subjecting the algorithm to robustness testing, we further employed simulated data sub-sampled at differing levels of case detection to assess the algorithm's performance and sensitivity to surveillance quality. RESULTS: Our tool demonstrated clear epidemiological transitions in Mexico and Brazil: most states progressed rapidly towards elimination, but a few regressed due to incursions and control lapses. In 2015, dog-mediated rabies continued to circulate in the poorest states, with foci remaining in only 1 of 32 states in Mexico, and 2 of 27 in Brazil, posing incursion risks to the wider region. The classification tool was robust in determining epidemiological status irrespective of most levels of surveillance quality. In endemic settings, surveillance would need to detect less than 2.5% of all circulating cases to result in misclassification, whereas in settings where incursions become the main source of cases the threshold detection level for correct classification should not be less than 5%. CONCLUSION: Our tool provides guidance on how to progress effectively towards elimination targets and tailor strategies to local epidemiological situations, while revealing insights into rabies dynamics. Post-campaign assessments of dog vaccination coverage in endemic states, and enhanced surveillance to verify and maintain freedom in states threatened by incursions were identified as priorities to catalyze progress towards elimination. Our finding suggests genomic surveillance should become increasingly valuable during the endgame for discriminating circulating variants and pinpointing sources of incursions.

Ocular and Lacrimal Gland Lesions in Naturally Occurring Rabies of Domestic and Wild Mammals.

Investigations describing the ocular and lacrimal gland lesions associated with rabies are sparse. Here we characterize the pathological changes and distribution of rabies viral antigen in the eye, optic nerve, and lacrimal gland of 18 rabies cases from different mammalian species. Histology and immunohistochemistry for rabies virus, CD3, CD20, and Iba1 were performed on tissue sections of eye, optic nerve, and lacrimal gland. Polymerase chain reaction (PCR) for rabies was performed on all cases, including 7 formalin-fixed, paraffin-embedded (FFPE) and 11 frozen tissue samples of eye and lacrimal gland. Pathological changes in the eye consisted of retinal necrosis (12/18 cases) with occasional viral inclusions within ganglion cells (8/12 cases). Immunohistochemically, viral antigen was detected within the nerve fiber layer, ganglion cells, and inner plexiform layer in all 12 cases with retinal lesions and in 2 cases with no retinal lesions, as well as optic nerve (6/18 cases) and lacrimal gland epithelium (3/18 cases). CD3+ T lymphocytes were present in the retina (11/18 cases), optic nerve (2/18 cases), and lacrimal gland (11/18 cases). No CD20+ B lymphocytes or Iba1+ macrophages were detected. PCR for rabies virus was positive in 9 of 11 frozen samples but in only 2 of 7 FFPE samples. Five samples that were negative for rabies by PCR were positive by immunohistochemistry, and 2 samples were negative by both tests. These results provide evidence that rabies virus infection extends to the eye, likely via the ocular nerve, and that the lacrimal gland might be a source of viral infection.

Prevention of human rabies: a challenge for the European Union and the European Economic Area.

Rabies is enzootic in over one hundred countries worldwide. In the European Union/European Economic Area (EU/EEA), the vast majority of human rabies cases are travellers bitten by dogs in rabies-enzootic countries, mostly in Asia and Africa. Thus, EU/EEA travellers visiting rabies enzootic countries should be aware of the risk of being infected with the rabies virus when having physical contact with mammals. They should consider pre-exposure vaccination following criteria recommended by the World Health Organization and if unvaccinated, immediately seek medical attention in case of bites or scratches from mammals. As the majority of the EU/EEA countries are free from rabies in mammals, elimination of the disease (no enzootic circulation of the virus and low number of imported cases) has been achieved by 2020. However, illegal import of potentially infected animals, mainly dogs, poses a risk to public health and might threaten the elimination goal. Additionally, newly recognised bat lyssaviruses represent a potential emerging threat as the rabies vaccine may not confer protective immunity. To support preparedness activities in EU/EEA countries, guidance for the assessment and the management of the public health risk related to rabies but also other lyssaviruses, should be developed.

Rabies Acquired through Mucosal Exposure, China, 2013.

In China in 2013, a man acquired rabies after sucking wounds of his son, who had been bitten by a stray dog. The man declined postexposure prophylaxis (hyperimmunoglobulin and vaccine) and died; the son accepted prophylaxis and survived. Physicians should be aware of rabies transmission through mucosal exposure and encourage postexposure prophylaxis.

Using phylogeographic approaches to analyse the dispersal history, velocity and direction of viral lineages - Application to rabies virus spread in Iran.

Recent years have seen the extensive use of phylogeographic approaches to unveil the dispersal history of virus epidemics. Spatially explicit reconstructions of viral spread represent valuable sources of lineage movement data that can be exploited to investigate the impact of underlying environmental layers on the dispersal of pathogens. Here, we performed phylogeographic inference and applied different post hoc approaches to analyse a new and comprehensive data set of viral genomes to elucidate the dispersal history and dynamics of rabies virus (RABV) in Iran, which have remained largely unknown. We first analysed the association between environmental factors and variations in dispersal velocity among lineages. Second, we present, test and apply a new approach to study the link between environmental conditions and the dispersal direction of lineages. The statistical performance (power of detection, false-positive rate) of this new method was assessed using simulations. We performed phylogeographic analyses of RABV genomes, allowing us to describe the large diversity of RABV in Iran and to confirm the cocirculation of several clades in the country. Overall, we estimate a relatively high lineage dispersal velocity, similar to previous estimates for dog rabies virus spread in northern Africa. Finally, we highlight a tendency for RABV lineages to spread in accessible areas associated with high human population density. Our analytical workflow illustrates how phylogeographic approaches can be used to investigate the impact of environmental factors on several aspects of viral dispersal dynamics.

A metapopulation model of dog rabies transmission in N'Djamena, Chad.

Rabies transmission was interrupted for several months in N'Djamena, the capital city of Chad, after two mass vaccination campaigns of dogs. However, there was a resurgence in cases, which was not predicted by previous models of rabies transmission. We developed a deterministic metapopulation model with importation of latent dogs, calibrated to four years of weekly incidence data from passive surveillance, to investigate possible causes for the early resurgence. Our results indicate that importation of latently infective dogs better explains the data than heterogeneity or underreporting. Stochastic implementations of the model suggest that the two vaccination campaigns averted approximately 67 cases of dog rabies (out of an estimated 74 cases without vaccination) and 124 human exposures (out of an estimated 148 human exposures without vaccination) over two years. Dog rabies vaccination is therefore an effective way of preventing rabies in the dog population and to subsequently reduce human exposure. However, vaccination campaigns have to be repeated to maintain the effect or reintroduction through importation has to be prevented.

Vital Signs: Trends in Human Rabies Deaths and Exposures - United States, 1938-2018.

INTRODUCTION: Each year, rabies causes approximately 59,000 deaths worldwide, including approximately two deaths in the United States. Before 1960, dogs were a common reservoir of rabies in the United States; however, increasingly, species of wildlife (e.g., bats, raccoons) are the main reservoirs. This report characterizes human rabies deaths, summarizes trends in rabies mortality, and highlights current rabies risks in the United States. METHODS: Rabies trends in the United States during 1938-2018 were analyzed using national rabies surveillance data. Data from the Healthcare Cost and Utilization Project for 2006-2014 were used to estimate the number of postexposure prophylaxis (PEP) visits per 100,000 persons during 2017-2018. The Centers for Medicare & Medicaid Services' average sales price data were used to estimate PEP costs. RESULTS: From 1960 to 2018, a total of 125 human rabies cases were reported in the United States; 36 (28%) were attributed to dog bites during international travel. Among the 89 infections acquired in the United States, 62 (70%) were attributed to bats. In 2018, approximately 55,000 persons sought PEP after contact with a potentially rabid animal. CONCLUSIONS AND COMMENTS: In the United States, wildlife rabies, especially in bats, continues to pose a risk to humans. Travelers also might be exposed to canine rabies in countries where the disease is still present; increased awareness of rabies while traveling abroad is needed. Vaccinating pets, avoiding contact with wildlife, and seeking medical care if one is bitten or scratched by an animal are the most effective ways to prevent rabies. Understanding the need for timely administration of PEP to prevent death is critical.

Phylodynamic and transmission pattern of rabies virus in China and its neighboring countries.

Rabies is a fatal disease caused by infection with rabies virus (RABV), and human rabies is still a critical public-health concern in China. Although there have been some phylogenetic studies about RABV transmission patterns, with the accumulation of more rabies sequences in recent years, there is an urgent need to update and clarify the spatial and temporal patterns of RABV circulating in China on a national scale. In this study, we collected all available RABV nucleoprotein gene sequences from China and its neighboring countries and performed comparative analysis. We identified six significant subclades of RABV circulating in China and found that each of them has a specific geographical distribution, reflecting possible physical barriers to gene flow. The phylogeographic analysis revealed minimal viral movement among different geographical locations. An analysis using Bayesian coalescent methods indicated that the current RABV strains in China may come from a common ancestor about 400 years ago, and currently, China is amid the second event of increasing RABV population since the 1950s, but the population has decreased gradually. We did not detect any evidence of recombination in the sequence dataset, nor did we find any evidence for positive selection during the expansion of RABV. Overall, geographic location and neutral genetic drift may be the main factors in shaping the phylogeography of RABV transmission in China.

Using roaming behaviours of dogs to estimate contact rates: the predicted effect on rabies spread.

Domestic dogs display complex roaming behaviours, which need to be captured to more realistically model the spread of rabies. We have previously shown that roaming behaviours of domestic dogs can be categorised as stay-at-home, roamer and explorer in the Northern Peninsular Area (NPA), Queensland, Australia. These roaming behaviours are likely to cause heterogeneous contact rates that influence the speed or pattern of rabies spread in a dog population. The aim of this study was to define contact spatial kernels using the overlap of individual dog utilisation distributions to describe the daily probability of contact between pairs of dogs exhibiting these three a priori roaming behaviours. We further aimed to determine if the kernels lead to different predicted rabies outbreaks (outbreak duration and number of rabid dogs) by incorporating the spatial kernels into a previously developed rabies spread model for the NPA. Spatial kernels created with both dogs in a pair being explorers or one dog explorer and one dog roamer (who roamed away from their residence) produced short but large outbreaks compared with spatial kernels with at least one stay-at-home dog. Outputs from this model incorporating heterogeneous contacts demonstrate how roaming behaviours influence disease spread in domestic dog populations.

Frugivorous bats in the Colombian Caribbean region are reservoirs of the rabies virus.

BACKGROUND: Bats are an important ecological group within ecosystems. The rabies virus is a Lyssavirus, and haematophagous bats are the principal reservoir; however, the virus has also been detected in non-haematophagous bats. The objective was to determine the rabies virus in non-haematophagous bats in the Colombian Caribbean region. METHODS: In 2017, a cross-sectional study was carried out with a base-risk sampling in twelve geographic zones of the Colombian Caribbean area that included the main ecosystems of two departments. 286 bats were captured, which were euthanized with a pharmacological treatment following the ethical protocols of animal experimentation. The taxonomic identification was done with dichotomous keys. The necropsy was carried out at the capture site, and brain samples were kept in liquid nitrogen. The extraction of the RNA was carried out from the frozen brains with Trizol™; a fragment of 914 bp of the glycoprotein G of the rabies virus was amplified with RT-PCR. The amplicons were sequenced with the Sanger method. RESULTS: Twenty-three genera of bats were identified, and, in two frugivorous, Artibeus lituratus and Artibeus planirostris, amplicons were obtained and sequenced as the rabies virus. CONCLUSIONS: This is the first evidence of natural infection of the rabies virus in frugivorous bats in the Colombian Caribbean area; this result is important for the surveillance and control of rabies.

Modeling the Transmission Dynamics of Rabies for Dog, Chinese Ferret Badger and Human Interactions in Zhejiang Province, China.

Human rabies is one of the major public health problems in China with an average of 1977 cases per year. It is estimated that 95% of these human rabies cases are due to dog bites. In recent years, the number of wildlife-associated human rabies cases has increased, particularly in the southeast and northeast regions of mainland China. Chinese ferret badgers (CFBs) are one of the most popular wildlife animals which are distributed mostly in the southeast region of China. Human cases caused by rabid CFB were first recorded in Huzhou, Zhejiang Province, in 1994. From 1996 to 2004, more than 30 human cases were caused by CFB bites in Zhejiang Province. In this paper, based on the reported data of the human rabies caused by both dogs and CFB in Zhejiang Province, we propose a multi-host zoonotic model for the dog-CFB-human transmission of rabies. We first evaluate the basic reproduction number [Formula: see text] discuss the stability of the disease-free equilibrium, and study persistence of the disease. Then we use our model to fit the reported data in Zhejiang Province from 2004 to 2017 and forecast the trend of human or livestock rabies. Finally by carrying out sensitivity analysis of the basic reproduction number in terms of parameters, we find that the transmission between dogs and CFB, the quantity of dogs, and the vaccination rate of dogs play important roles in the transmission of rabies. Our study suggests that rabies control and prevention strategies should include enhancing public education and awareness about rabies, increasing dog vaccination rate, reducing the dog and CFB interactions, and avoiding CFB bites or contact.

Rabies post-exposure prophylactic vaccination for returning travelers to Japan.

BACKGROUND: Rabies post-exposure prophylaxis (PEP) in Japan is administered using 6 subcutaneous doses (on days 0, 3, 7, 14, 30, and 90), which is not in line with international recommendations of 4 or 5 intramuscular doses. For reducing dose frequency, we evaluate the immunogenicity of PEP with a regimen of 6 subcutaneous doses. METHOD: This prospective single-center cross-sectional study was performed between September 2013 and December 2014. We included patients underwent rabies PEP by purified chick embryo-cultured rabies vaccine Kaketsuken (PCEC-K) at our clinic, and excluded patients with a history of pre-exposure prophylaxis or PEP using rabies immunoglobulin. The rabies virus-neutralizing antibody tests were performed at the first visit to our office (doses 1-4) and at the fifth and sixth doses. RESULTS: Data were available for 43 of 59 enrolled patients. Thirty-two patients did not start PEP within 48 h after exposure to animals. The seroprotection rates (≥0.5 IU/mL) were 90.7% and 75.7%, at days 30 and 90, respectively. Despite receiving a fifth dose, 85.3% of the patients exhibited decreasing antibody titers during days 30-90 (p < 0.001). CONCLUSIONS: The seroprotection rates of PCEC-K induced subcutaneously were insufficient to prevent rabies at day 30 and 90.

An integrated health delivery platform, targeting soil-transmitted helminths (STH) and canine mediated human rabies, results in cost savings and increased breadth of treatment for STH in remote communities in Tanzania.

BACKGROUND: Achieving the Sustainable Development Goal of a 90% reduction in neglected tropical diseases (NTDs) by 2030 requires innovative control strategies. This proof-of-concept study examined the effectiveness of integrating control programs for two NTDs: mass drug administration (MDA) for soil-transmitted helminths in humans and mass dog rabies vaccination (MDRV). METHODS: The study was carried out in 24 Tanzanian villages. The primary goal was to demonstrate the feasibility of integrating community-wide MDA for STH and MDRV for rabies. The objectives were to investigate the popularity, participation and cost and time savings of integrated delivery, and to investigate the reach of the MDA with respect to primary school-aged children and other community members. To implement, we randomly allocated villages for delivery of MDA and MDRV (Arm A), MDA only (Arm B) or MDRV only (Arm C). RESULTS: Community support for the integrated delivery was strong (e.g. 85% of focus group discussions concluded that it would result in people getting "two for one" health treatments). A high proportion of households participated in the integrated Arm A events (81.7% MDA, 80.4% MDRV), and these proportions were similar to those in Arms B and C. These findings suggest that coverage might not be reduced when interventions are integrated. Moreover, in addition to time savings, integrated delivery resulted in a 33% lower cost per deworming dose and a 16% lower cost per rabies vaccination. The median percentage of enrolled primary school children treated by this study was 76%. However, because 37% of the primary school aged children that received deworming treatment were not enrolled in school, we hypothesize that the employed strategy could reach more school-aged children than would be reached through a solely school-based delivery strategy. CONCLUSIONS: Integrated delivery platforms for health interventions can be feasible, popular, cost and time saving. The insights gained could be applicable in areas of sub-Saharan Africa that are remote or underserved by health services. These results indicate the utility of integrated One Health delivery platforms and suggest an important role in the global campaign to reduce the burden of NTDs, especially in hard-to-reach communities. TRIAL REGISTRATION: clinicaltrials.gov NCT03667079 , retrospectively registered 11th September 2018.