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Summary: Objective: Human rabies has been endemic in India since time immemorial, and the true incidence of the disease and nationwide epidemiological factors have never been studied. The main objectives of the present study were to estimate the annual incidence of human rabies in India based on a community survey and to describe its salient epidemiological features. Methods: The Association for Prevention and Control of Rabies in India (APCRI) conducted a national multi-center survey with the help of 21 medical schools during the period February–August 2003. This community-based survey covered a representative population of 10.8 million in mainland India. Hospital-based data were also obtained from the 22 infectious diseases hospitals. A separate survey of the islands of Andaman, Nicobar, and Lakshadweep, reported to be free from rabies, was also undertaken. Results: The annual incidence of human rabies was estimated to be 17137 (95% CI 14109–20165). Based on expert group advice, an additional 20% was added to this to include paralytic/atypical forms of rabies, providing an estimate of 20565 or about 2 per 100000 population. The majority of the victims were male, adult, from rural areas, and unvaccinated. The main animals responsible for bites were dogs (96.2%), most of which were stray. The most common bite sites were the extremities. The disease incubation period ranged from two weeks to six months. Hydrophobia was the predominant clinical feature. Many of the victims had resorted to indigenous forms of treatment following animal bite, and only about half of them had sought hospital attention. Approximately 10% of these patients had taken a partial course of either Semple or a cell culture vaccine. The islands of Andaman, Nicobar, and Lakshadweep were found to be free of rabies. Conclusion: Human rabies continues to be endemic in India except for the islands of Andaman, Nicobar, and Lakshadweep. Dogs continue to be the principal reservoir. The disease is taking its toll on adult men and children, the majority from rural areas, due to lack of awareness about proper post-exposure immunization. The keys to success in the further reduction of rabies in India lies in improved coverage with modern rabies vaccines, canine rabies control, and intensifying public education about the disease. [Copyright &y& Elsevier]

Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

We determined the prevalence of diseases and pathogens associated with mortality in beef cattle in the State of Rio Grande do Sul, Brazil, based on pathology laboratory submissions. Postmortem examinations were conducted on 1,277 beef cattle that died between 2008 and 2018. Information regarding age, time of the year, breed, and regional location were analyzed statistically. Most cattle were from the surrounding region of Porto Alegre, and 78.7% of the analyzed cases had diagnostic value. The diagnostic category with most cases was infectious and/or parasitic diseases (60%), followed by toxic and toxicoinfectious (25%). Most cases occurred in the fall. Major disease conditions identified included hemoprotozoal infection (18.2%), rabies (8.2%), and plant intoxications by Senecio spp. (8.5%) and Pteridium arachnoideum (4.6%). Hemoprotozoal infection occurred at a higher frequency in young cattle, mainly in animals up to 1 y old. Intoxication by Senecio spp. was more frequent in cattle 2-3 y old.

Dog vaccination is a cost-effective approach to preventing human rabies deaths. In Haiti, the last nation-wide dog vaccination campaign occurred in 2018. We estimated the number of human lives that could be saved by resuming dog vaccination in 2021 compared to 2022 and compared the cost-effectiveness of these two scenarios. We modified a previously published rabies transmission and economic model to estimate trends in dog and human rabies cases in Haiti from 2005 to 2025, with varying assumptions about when dog vaccinations resume. We compared model outputs to surveillance data on human rabies deaths from 2005 to 2020 and animal rabies cases from 2018 to 2020. Model predictions and surveillance data both suggest a 5- to 8-fold increase in animal rabies cases occurred in Haiti's capital city between Fall 2019 and Fall 2020. Restarting dog vaccination in Haiti in 2021 compared to 2022 could save 285 human lives and prevent 6541 human rabies exposures over a five-year period. It may also decrease program costs due to reduced need for human post-exposure prophylaxis. These results show that interruptions in dog vaccination campaigns before elimination is achieved can lead to significant human rabies epidemics if not promptly resumed.

Background: Post-exposure prophylaxis (PEP) is highly effective at preventing human rabies deaths, however access to PEP is limited in many rabies endemic countries. The 2018 decision by Gavi to add human rabies vaccine to its investment portfolio should expand PEP availability and reduce rabies deaths. We explore how geographic access to PEP impacts the rabies burden in Madagascar and the potential benefits of improved provisioning., Methodology & Principal Findings: We use spatially resolved data on numbers of bite patients seeking PEP across Madagascar and estimates of travel times to the closest clinic providing PEP (N = 31) in a Bayesian regression framework to estimate how geographic access predicts reported bite incidence. We find that travel times strongly predict reported bite incidence across the country. Using resulting estimates in an adapted decision tree, we extrapolate rabies deaths and reporting and find that geographic access to PEP shapes burden sub-nationally. We estimate 960 human rabies deaths annually (95% Prediction Intervals (PI): 790-1120), with PEP averting an additional 800 deaths (95% PI: 640-970) each year. Under these assumptions, we find that expanding PEP to one clinic per district (83 additional clinics) could reduce deaths by 19%, but even with all major primary clinics provisioning PEP (1733 additional clinics), we still expect substantial rabies mortality. Our quantitative estimates are most sensitive to assumptions of underlying rabies exposure incidence, but qualitative patterns of the impacts of travel times and expanded PEP access are robust., Conclusions & Significance: PEP is effective at preventing rabies deaths, and in the absence of strong surveillance, targeting underserved populations may be the most equitable way to provision PEP. Given the potential for countries to use Gavi funding to expand access to PEP in the coming years, this framework could be used as a first step to guide expansion and improve targeting of interventions in similar endemic settings where PEP access is geographically restricted and baseline data on rabies risk is lacking. While better PEP access should save many lives, improved outreach, surveillance, and dog vaccination will be necessary, and if rolled out with Gavi investment, could catalyze progress towards achieving zero rabies deaths., Competing Interests: The authors have declared that no competing interests exist.

Rabies is a vaccine-preventable fatal zoonotic disease. Uganda, through the veterinary surveillance system at National Animal Disease Diagnostics and Epidemiology Centre (NADDEC), captures animal bites (a proxy for rabies) on a monthly basis from districts. We established trends of incidence of animal bites and corresponding post-exposure prophylactic anti-rabies vaccination in humans (PEP), associated mortality rates in humans, spatial distribution of animal bites, and pets vaccinated during 2013-2017. We reviewed rabies surveillance data at NADDEC from 2013-2017. The surveillance system captures persons reporting bites by a suspected rabid dog/cat/wild animal, human deaths due to suspected rabies, humans vaccinated against rabies, and pets vaccinated. Number of total pets was obtained from the Uganda Bureau of Statistics. We computed incidence of animal bites and corresponding PEP in humans, and analyzed overall trends, 2013-2017. We also examined human mortality rates and spatial distribution of animal bites/rabies and pets vaccinated against rabies. We identified 8,240 persons reporting animal bites in Uganda during 2013-2017; overall incidence of 25 bites/ 100,000population. The incidence significantly decreased from 9.2/100,000 in 2013 to 1.3/100,000 in 2017 (OR = 0.62, p = 0.0046). Of the 8,240 persons with animal bites, 6,799 (82.5%) received PEP, decreasing from 94% in 2013 to 71% in 2017 (OR = 0.65, p<0.001). Among 1441 victims, who reportedly never received PEP, 156 (11%) died. Western region had a higher incidence of animal bites (37/100,000) compared to other regions. Only 5.6% (124,555/2,240,000) of all pets in Uganda were vaccinated. There was a decline in the reporting rate (percentage of annual district veterinary surveillance reports submitted monthly to Commissioner Animal Health by districts) of animal bites. While reported animal bites by districts decreased in Uganda, so did PEP among humans. Very few pets received anti-rabies vaccine. Evaluation of barriers to complete reporting may facilitate interventions to enhance surveillance quality. We recommended improved vaccination of pets against rabies, and immediate administration of exposed humans with PEP., Competing Interests: The authors have declared that no competing interests exist.

Background: Zoonoses are a major threat to human health. Worldwide, rabies is responsible for approximately 59 000 deaths annually. In Zimbabwe, rabies is one of the top 5 priority diseases and it is notifiable. It is estimated that rabies causes 410 human deaths per year in the country. Murewa district recorded 938 dog bite cases and 4suspected rabies deaths between January 2017 and July 2018, overshooting the threshold of zero rabies cases. Of the 938dog bite cases reported in the district, 263 were reported in Ward 30 and these included all the 4suspected rabies deaths reported in the district. This necessitated a study to assess risk factors for contracting rabies in Ward 30, Murewa., Methodology/ Principal Findings: A descriptive cross sectional survey was used for a retrospective analysis of a group of dog bite cases reported at Murewa Hospital, in Ward 30. Purposive sampling was used to select dog bite cases and snowball sampling was used to locate unvaccinated dogs and areas with jackal presence. The dog bite cases and relatives of rabies cases were interviewed using a piloted interviewer-administered questionnaire. Geographical Positioning System (GPS) coordinates of dog bite cases, vaccinated and unvaccinated dogs and jackal presence were collected using handheld GPS device. QGIS software was used to spatially analyse and map them. Dog owners were 10 times more likely to contract rabies compared to non-dog owners (RR = 10, 95% CI 1.06-93.7). Owners of unvaccinated dogs were 5 times more likely to contract rabies compared to owners of vaccinated dogs (RR = 5.01, 95% CI 0.53-47.31). Residents of the high density cluster (area with low cost houses and stand size of 300 square meters and below) were 64 times more likely to contract rabies compared to non-high density cluster residents (RR = 64.87, 95% CI 3.6039-1167.82). Participants who were not knowledgeable were 0.07 times more likely to contract rabies, compared to those who had knowledge about rabies. (RR = 0.07, 95% CI 0.004-1.25). Our study shows that the risk factors for contacting rabies included; low knowledge levels regarding rabies, dog ownership residing in the high density cluster, owning unvaccinated dogs and spatial overlap of jackal presence with unvaccinated dogs., Competing Interests: The authors have declared that no competing interests exist.

Rabies is a highly fatal disease that is endemic in Nigeria. The poor community awareness and knowledge of canine rabies have thwarted the realization of zero deaths from dog mediated human rabies. This study aimed to assess the awareness and knowledge of canine rabies in Kwara state. A total of 1,460 questionnaires were administered to respondents in the three senatorial zones of the state using open data kit (ODK) on mobile phones between September 2019 to January 2020. The rabies awareness rate was 38.1%. The mean knowledge score was 3.78 ± 2.15. Only 10.6% (n = 59/557) of the respondents had satisfactory knowledge of canine rabies. Respondents had poor knowledge of the mode of transmission, symptoms, prevention, and the control measures needed to eliminate canine rabies. Only 20.1% of respondents owned at least a dog. Dog owners were 3.85× (95% CI: 2.89, 5.13; p < 0.01) more likely to be aware of canine rabies and were 1.78× (95% CI: 1.22-2.60; p = 0.003) more likely to have satisfactory knowledge about canine rabies than non-dog owners. Respondents with tertiary education were at least 6.81× (95% CI: 4.24, 10.92; p < 0.01) more likely to be aware of rabies than respondents with no formal education. The findings of this study showed very low awareness and knowledge of canine rabies among residents of Kwara state. Mass sensitization of the populace on the dangers of rabies should be intensified. Such interventions should be targeted at the general public and dog owners., Competing Interests: The authors have declared that no competing interests exist.

Objective: The aim of this study is to describe the epidemiological characteristics about regional and age difference of human rabies in the past fourteen years in China, and provide a reliable epidemiology basis for further control and prevention of human rabies., Methods: The database of "China Public Health Science Data Center" affiliated Chinese CDC was searched with the key words of "rabies" or "epidemiology" or "morbidity" or "mortality" from 2004 to 2018 and the corresponding data about human rabies cases was collected referred to regional and age difference for describing the epidemiological characteristics of human rabies., Results: In this study, a total of nearly 26,315 rabies cases (1754 ± 253) and 25,691 rabies-related deaths (1712 ± 255) (Mean ± SE) were reported, and a decreasing trend about the morbidity and mortality of human rabies existed from 0.2039 and 0.2039 (1/100,000) in 2004 to 0.0304 and 0.0295 in 2018. Otherwise, regional difference of human rabies prevalence significantly existed, and juvenile and middle-aged population especially in 50-60 years old were more easily attacked and infected with rabies (all p < 0.05)., Conclusion: This study proved that human rabies still is a major public health problem in China though a decreasing trend about the morbidity and mortality of human rabies existed in the past fourteen years., (Copyright © 2020. Published by Elsevier B.V.)

Rabies remains a public health challenge of unknown magnitude in Liberia in spite of the goal of ensuring that no human in the country dies of rabies by 2030. The annual prevalence of Dog Bite Victims (DBVs) and true load of Annual Human Deaths (AHDs) due to rabies were not known. We investigated three selected cities of Liberia for annual prevalence of DBVs and true load of AHD due to suspected rabies, using 10-year retrospective record, 2008-2017 obtained from Buchanan, Gbarnga, and Voinjama, three socio-economically important cities in post-conflict Liberia. Data were sourced at County Reference Hospitals and at the Liberia National Institute of Health for these cities and their local environs. In addition, household questionnaire survey was used to identify and audit data quality for unreported DBVs, and treatment received from traditional caregivers. The proportion was used to audit the 10-year data on unreported DBVs in the cities. Descriptive statistics was used to summarize annual DBVs over the 10-year period in the three cities, respectively. A standardized clinical decision tree model was used to estimate AHDs due to suspected rabies. Based on questionnaire survey, 140/365, 148/375 and 146/350 DBVs did not visit any orthodox health facility in Buchanan, Gbarnga and Voinjama cities, respectively in 2014. An estimated total of 559 DBVs died of suspected rabies in the three cities and their environs during the 10-year period. Mean yearly prevalence of DBVs was 179±106.82, 393±257.85 and 76.9±38.11 per 100,000 population, while mean AHDs due to suspected rabies was 14.3±8.47, 35.5±23.25, and 6.1±3.21 per 100,000 population in Buchanan, Gbarnga, and Voinjama cities, respectively. The present findings provide annual prevalence of suspected rabies cases, corrected for under-reporting in three selected cities of Liberia. The findings would be useful in planning for stepwise actions towards rabies elimination, ensuring that no human dies of rabies in Liberia by 2030., Competing Interests: The authors have declared that no competing interests exist.

Background: Rabies is a fatal viral zoonosis mainly transmitted via dog bites. The estimated 59'000 annual deaths caused by the disease are preventable through correct and timely administration of post-exposure prophylaxis (PEP). PEP should be initiated as soon as possible after an exposure to a rabies suspected animal and consists of a course of active vaccinations and administration of rabies immunoglobulin (RIG) in case of severe exposure. However, RIG is not accessible in most rabies endemic countries and its impact on survival in combination with modern vaccines and its cost-effectiveness is unclear. We examined the effect of equine RIG (eRIG) in a field-trial in Côte d'Ivoire, a developing country with low but chronic rabies burden and persistent lack of RIG, similar to a majority of rabies endemic countries attempting elimination of the disease., Methods: Data from 3367 patients attending anti-rabies centers (Centres Anti-Rabiques, CARs) of the National Institute for Public Hygiene (Institut National d'Hygiène Publique, INHP) in the departments of Bouaké and San Pédro in Côte d'Ivoire was prospectively collected between April 2016 and March 2018. We identified 1594 patients at risk of rabies infection as eligible for RIG administration. Depending on local availability of eRIG and vaccination protocol applied, PEP consisted of active immunization only (non-eRIG group, n = 1145) or active and passive immunization (eRIG group, n = 449). Patients were followed-up by phone interviews at least 15 months after their exposure to assess for rabies suspected deaths., Results: Follow-up data was available for 641 patients in the non-eRIG group (56%) and 242 in the eRIG group (54%). Three suspected or possible rabies deaths occurred in each of the two groups, corresponding to a possible rabies mortality of 1.2% (95% CI 0.3-3.6%) in the eRIG group and 0.5% (95% CI 0.1-1.4%) in the non-eRIG group. The difference in proportions was small and not statistically significant (0.7%, p = 0.21). Deaths in both groups were associated with treatment delay after exposure and non-compliance to PEP protocol. No death occurred after correct and timely active immunization independent of eRIG administration., Conclusion: The provision of eRIG did not lead to a measurable reduction of rabies burden in our study population. This underlines that improved access to active vaccines will be effective in reducing rabies deaths even if access to eRIG remains difficult in developing countries. A possible benefit of eRIG administration for severely exposed patients cannot be excluded based on these results., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Street rabies virus (RABV) usually infects hosts at peripheral sites and migrates from motor or sensory nerves to the central nervous system. Several studies have found that inflammation is mild in a mouse model of street RABV infection. However, the pathogenetic mechanisms of street RABV in naturally infected dogs or humans are not well understood., Methods: Brain tissues collected from 3 dogs and 3 humans were used; these tissue samples were collected under the natural condition of rabies-induced death. The inflammatory response and pathway activation in the brain tissue samples of dogs and humans were evaluated by HE, IHC, ARY006, WB and ELISA. The clinical isolate street RABV strains CGS-17 and CXZ-15 from 30 six-week-old ICR mice were used to construct the mouse infection model presented here., Results: Neuronal degeneration and increased lymphocyte infiltration in the cerebral cortex, especially marked activation of microglia, formation of glial nodules, and neuronophagy, were observed in the dogs and humans infected with the street RABV strains. The various levels of proinflammatory chemokines, particularly CXCL1, CXCL12, CCL2, and CCL5, were increased significantly in the context of infection with street RABV strains in dogs and humans in relation to healthy controls, and the levels of MAPK and NF-κB phosphorylation were also increased in dogs and humans with natural infection. We also found that the degrees of pathological change, inflammatory response, MAPK and NF-κB signaling pathway activation were obviously increased during natural infection in dogs and humans compared with artificial model infection in mice., Conclusion: The data obtained here provide direct evidence for the RABV-induced activation of the inflammatory response in a dog infection model, which is a relatively accurate reflection of the pathogenic mechanism of human street RABV infection. These observations provide insight into the precise roles of underlying mechanisms in fatal natural RABV infection.

Rabies, caused by rabies virus (RABV), is an ancient zoonosis and still a major public health problem for humans, especially in developing countries. RABV can be recognized by specific innate recognition receptors, resulting in the production of hundreds of interferon-stimulated genes (ISGs), which can inhibit viral replication at different stages. Interferon-inducible GTPase 1 (IIGP1) is a mouse-specific ISG and belongs to the immunity-related GTPases (IRGs) family. IIGP is reported to constrain intracellular parasite infection by disrupting the parasitophorous vacuole membrane. However, the role of IIGP1 in restricting viral replication has not been reported. In this present study, we found that IIGP1 was upregulated in cells and mouse brains upon RABV infection. Overexpression of IIGP1 limited RABV replication in cell lines and reduced viral pathogenicity in a mouse model. Consistently, deficiency of IIGP1 enhanced RABV replication in different parts of mouse brains. Furthermore, we found that IIGP1 could interact with RABV phosphoprotein (P protein). Mutation and immunoprecipitation analyses revealed that the Y128 site of P protein is critical for its interaction with IIGP1. Further study demonstrated that this interaction impeded the dimerization of P protein and thus suppressed RABV replication. Collectively, our findings for the first reveal a novel role of IIGP1 in restricting a typical neurotropic virus, RABV, which will provide fresh insight into the function of this mouse-specific ISG. IMPORTANCE Interferon and its downstream products, ISGs, are essential in defending against pathogen invasion. One of the ISGs, IIGP1, has been found to constrain intracellular parasite infection by disrupting their vacuole membranes. However, the role of IIGP1 in limiting viral infection is unclear. In this study, we show that infection with a typical neurotropic virus, RABV, can induce upregulation of IIGP1, which, in turn, suppresses RABV by interacting with its phosphoprotein (P protein) and thus blocking the dimerization of P protein. Our study provides the first evidence that IIGP1 functions in limiting viral infection and provides a basis for comprehensive understanding of this important ISG., (Copyright © 2020 American Society for Microbiology.)

Rabies is a neurological disease with 100% lethality. Some of the rare human patients who survived after multiple drug treatment had severe sequelae. The present study showed that after 48 h of RABV inoculation, mice injected intracerebrally with anti-RABV F (ab') 2 plus Bioporter® showed 70% survival compared to the control group, suggesting that transfection of anti-RABV antibodies to the brain may prevent or delay the spread of RABV at an early stage of infection. This result may provide important protocol results in intracellular antibody delivery to prevent the fatal outcome of the disease.

Background: This study aimed to assess the extent of knowledge and understanding of rabies disease in rural and urban communities of Pakistan. It also identified malpractices after suspected dog bite that might pose a risk for humans contracting rabies., Methods: A cross-sectional study was conducted (n = 1466) on people having different age groups and educational levels in four different geographic regions of Punjab and Khyber Pakhtunkhwa provinces in Pakistan. Knowledge, attitude, and practices of people were assessed using a structured questionnaire. We used a bivariate and multivariate analysis to study the association between rabies related mortalities in near or extended family members and different risk behaviors., Results: Our results demonstrate that the majority of the juvenile population (less than 18 years of age) were not aware of the clinical signs of rabies in animals. 75% of the total respondents were not vaccinated against rabies, 60% did not seek a doctor's advice after a suspected animal bite, and 55% had inadequate health care facilities for rabies patients in local hospitals. Respondents that had pets at home had not vaccinated (38%; p < 0.05; odds ratio 1.58) themselves against rabies due to lack of knowledge and awareness of pre-exposure prophylaxis for rabies (51%; p < 0.05; odds ratio 1.25). They also tend to not visit doctor after suspected bite (52%; p < 0.05; odds ratio 1.97), which may had resulted in more deaths (65%; p < 0.05; odds ratio 1.73) of someone in their near or extended family due to rabies., Conclusions: Lack of knowledge about the nature of rabies disease and prophylaxis has contributed to increase of rabies related deaths. Inadequate health care facilities and poor attitude of not seeking medical attention after suspected dog bite are the major reasons of rabies related deaths. These findings could help in devising a targeted management strategy and awareness program to control and reduce the incidence of human rabies related deaths in Pakistan.

Objectives: Once symptoms appear, rabies is almost always fatal and accounts for 200-300 deaths annually in the Philippines. Available rabies vaccines can be administered either in pre- exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). After exposure, PrEP-immunized individuals require fewer doses of PEP and no rabies immunoglobulin., Methods: A static decision-tree model was developed to assess cost-effectiveness of a PrEP+PEP program vs PEP alone. Philippines-specific data for people seeking medical advice at the Research Institute for Tropical Medicine between July 2015 and June 2016 were used in the model, together with data from published literature., Results: Over a 20-year period, in a cohort of 1 million 5-year-old children in the Philippines, PrEP+PEP was expected to prevent 297 deaths compared with PEP alone. From both payer and societal perspectives, the resulting incremental cost-effectiveness ratios were 36 035 (US$759; 2016 US$ conversion) and 18 663 (US$393) Philippine Pesos (PHP) - quality-adjusted life-years gained - respectively, which are both below the willingness-to-pay threshold of PHP140 255 (US$2 953)., Conclusion: These data suggest that a universal PrEP program targeting 5-year-olds would be cost-effective in the Philippines., (Copyright © 2020 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Rabies is an ancient zoonosis that continues to be an important health problem worldwide. Vaccination with rabies vaccine is the most important strategy to prevent rabies. Adjuvants contribute to the immune response of viral vaccine. The aim of this study was to investigate whether artemisinin derivatives artesunate and dihydroartemisinin could enhance the immunogenicity of inactivated rabies virus in mice. Administration of artesunate or dihydroartemisinin by intramuscular injection at a dose of 5 mg/kg did not cause body weight loss and unusual symptoms in mice. Mice were immunized with inactivated CVS-11 or inactivated rHEP-dG together with either artesunate or dihydroartemisinin through intramuscular injection. Blood samples were collected to investigate the virus-neutralizing antibody (VNA) titers, and challenge assays were then conducted. The results showed that the rabies VNA titers in mice co-treated with artesunate rather than dihydroartemisinin were significantly higher than in the control animals treated with the phosphate buffered saline (PBS). In addition, mice co-treated with artesunate survived from lethal rabies virus challenge compared with those treated with PBS. In contrast, co-treatment with dihydroartemisinin did not improve the survival rate of the challenged mice. The findings indicate that artesunate could be used as a new candidate adjuvant for rabies vaccination., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Since 2008, we in Himachal Pradesh have used a "pooling strategy" to help patients save money by pooling vials of antirabies vaccine at a centralized hospital and sharing them using the intradermal technique. In 2014, there was an acute shortage of rabies immunoglobulins (RIG) and two patients died after four injections of rabies vaccine were administered without RIG, which was not commercially available. After an extensive literature review and technical and ethical committee clearances, in June 2014 we started to infiltrate equine RIG (eRIG) into wound/s only without the recommended systemic intramuscular (IM) injection. WHO recommended this technique in 2018. During the four-year period June 2014 to June 2018, 7506 of 10,830 patients exposed to suspected rabid animals were injected with eRIG in and around the wounds in a single clinic at DDU Hospital Shimla without any adverse outcomes. The average volume of eRIG used per patient was 0.75 mL and cost US$ 0.75. Of the 80% of patients who were followed up, all were healthy at the end of a year, including 26 patients bitten by laboratory-confirmed rabid dogs. The reaction rate after PEP administration also declined significantly. Since February 2018, Himachal has started following the new WHO recommendations on PEP regimens of three intradermal antirabies vaccines instead of four, thereby saving hundreds of vaccine vials that became useful during shortages of rabies vaccine in India. To date, more than 700 vaccine vials have been saved in a single clinic at DDU hospital during the past 6 months alone. Not giving PEP to patients who have consumed raw milk from a suspected rabid cow has also saved 62 vials. Currently, 90 "pooling centers" have been established for sharing of vaccine and eRIG vials in Himachal State, generating huge savings that have enabled the government to provide PEP free of charge to all. The new WHO guidelines are a positive step towards a rabies-free world by 2030., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Adhering to post-exposure prophylaxis (PEP): wound treatment, vaccine, and rabies immunoglobulin (RIG) is a crucial step in preventing rabies mortality. When PEP is widely available, a lack of adherence to the recommended treatment guidelines can also lead to death. Our objective was to understand characteristics associated with adherence to the vaccine regimen and RIG in Vietnam., Methods: We obtained individual-level data on PEP adherence from registries at 10 sites located in five provinces. From these registries, we extracted epidemiologic characteristics of patients including the timing of PEP initiation and completion. We used descriptive analyses and logistic regression to examine patient characteristics associated with initiation and completion of RIG and vaccine. Based on reported rabies mortality, the government defined provincial rabies burden as medium-burden (<5 and >2 deaths) and high-burden (≥5 deaths)., Results: During 2014-2016, 15,646 patients received PEP in our study. Among 14,296 vaccinated patients, only 41.4% (5847) completed their five-dose intramuscular (IM) injections and 81.6% (133) of patients completed their eight-dose intradermal (ID) injections. Approximately 26% of patients received RIG. Patient characteristics associated with vaccine completion were females (44%), <15 years of age (44%), category 1 exposure (68%, bite location on leg (46%), bite from bat (56%), bite from a healthy animal (45%), high-burden province (86%), and district preventive center (49%). Disparities were revealed among provinces, with high-burden provinces having highest (86%) and lowest (7%) vaccine completion rates., Conclusions and Relevance: Vietnam has made tremendous progress towards reducing the burden of rabies. However, despite the wide availability of PEP, we found relatively low rates of vaccine completion. Our findings suggest provider training and patient education is needed to ensure appropriate treatment is completed. Moreover, our data suggest changes to information reported through the national surveillance system for monitoring good clinical practice for rabies prevention and control., (Published by Elsevier Ltd.)

In Madagascar, dog-mediated rabies has been endemic for over a century, however there is little data on its incidence or impact. We collected data over a 16-month period on provisioning of post-exposure prophylaxis (PEP) at a focal clinic in the Moramanga District and determined the rabies status of biting animals using clinical and laboratory diagnosis. We find that animal rabies cases are widespread, and clinic-based triage and investigation are effective ways to increase detection of rabies exposures and to rule out non-cases. A high proportion of rabies-exposed persons from Moramanga sought (84%) and completed PEP (90% of those that initiated PEP), likely reflecting the access and free provisioning of PEP in the district. Current clinic vial sharing practices demonstrate the potential for intradermal administration of PEP in endemic African settings, reducing vaccine use by 50% in comparison to intramuscular administration. A high proportion of PEP demand was attributed to rabies cases, with approximately 20% of PEP administered to probable rabies exposures and an additional 20% to low-to-no risk contacts with confirmed/probable animal or human cases. Using a simplified decision tree and our data on rabies exposure status and health-seeking behavior, we estimated an annual incidence of 42-110 rabies exposures and 1-3 deaths per 100,000 persons annually. Extrapolating to Madagascar, we estimate an annual burden of 282-745 human rabies deaths with current PEP provisioning averting 1499-3958 deaths each year. Data from other clinics and districts are needed to improve these estimates, particularly given that PEP availability is currently limited to only 31 clinics in the country. A combined strategy of mass dog vaccination, enhanced surveillance, and expanded access to PEP along with more judicious guidelines for administration could effectively reduce and eventually eliminate the burden of rabies in Madagascar., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rabies continues to poses serious threats to the public health in many countries. The development of novel inexpensive, safe and effective vaccines has become a high priority for rabies control worldwide. We previously generated a novel recombinant rabies vaccine by cloning rabies virus glycoprotein into a chimpanzee adenoviral vector, termed ChAd68-Gp. The present study evaluated the immune responses and protection afforded by this vaccine in beagle dogs. The results demonstrated that intramuscular immunization with both low-dose and high-dose of ChAd68-Gp induced strong immune responses and provided complete protection in beagles even at low-dose. However, when administered orally, high-dose vaccination was protective while low-dose vaccination was ineffective. Further investigation indicated that the low-pH value of gastric juice in the stomach of beagles might decompose the adenovirus. Therefore, suitable formulation for adenovirus-based oral vaccine should be considered and developed. The chimpanzee adenovirus-vectored rabies vaccine ChAd68-Gp warrants extensive test for clinical application., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Rabies virus infects almost all mammals resulting in lethal disease. To date there is no treatment available for symptomatic rabies and there is an urgent need to develop treatment strategies that would prolong survival, thereby providing a window of opportunity for the host to mount a protective immune response. We hypothesized that both virus and excessive immune response contribute to disease and that interfering with both is necessary to prevent lethal disease. Here, we have inhibited the pro-inflammatory response associated with pyroptosis and showed that inhibition of CASP-1 had a beneficial effect on survival time. Our results confirm that some inflammatory responses may be involved in the pathogenesis of severe disease and the results suggest that effective intervention includes inhibition of virus and host response., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Objective: To understand epidemiological characteristics of human rabies in China in 2017 and provide evidence for the development of strategy of human rabies control and prevention. Methods: The descriptive epidemiological analysis was conducted based on the epidemic data from Chinese Infectious Disease Surveillance Reporting System, sentinel surveillance system in 6 provinces (Hunan, Guangxi, Anhui, Guizhou, Jiangsu and Shandong) and National Bureau of Statistics in 2017. Results: A total of 516 human rabies cases, including 502 deaths, were reported by 27 provinces in 2017 with the morbidity rate and mortality rate of 0.037/100 000 and 0.036/100 000, respectively. The case number and death number decreased by 19.88% (128/644) and 15.20% (90/592) respectively compared with 2016. Rabies epidemics were mainly found in southern and central areas. The first 5 provinces reporting high case numbers were Hunan (71 cases), Henan (52 cases), Guangxi (41 cases), Anhui (39 cases) and Hubei (39 cases), their cases accounted for 46.90% (242/516) of the total reported cases in China. Rabies mainly occurred in summer and autumn, and the majority of patients were farmers, students and children outside child care settings. The male to female ratio of the cases was 2.46 ∶ 1 (367 ∶ 149). Cases was reported in all age groups, and more cases occurred in middle aged and old adults than in adolescents. Questionnaires survey was conducted for 186 cases, the results indicated that 94.89% (167/176) of exposures were caused by dog bites. The exposure degree was mainly category Ⅲ, accounting for 68.86% (115/167), and only 6.02% (10/166) of cases were immunized after exposure. The median of latent period of these cases was 72 days. Conclusions: By 2017, the human rabies incidence in China had declined consecutively for ten years, more cases were reported in southern area than in northern area. The case number showed downward trends in provinces with high incidences and fluctuant increase in provinces with low incidence. Rabies cases mainly occurred in rural areas, and most cases were men and farmers. Low rate of post exposure prophylaxis, low rates of vaccination and passive immunization product injection were main causes for the onset of human rabies. It is necessary to strengthen the surveillance for human rabies, especially in rural areas, health education about treatment after rabies exposure and expend the coverage of canine immunization.

Nucleoprotein (N) is a key element in rabies virus (RABV) replication. To further investigate the effect of N on RABV, we manipulated an infectious cDNA clone of the RABV HEP-Flury to rearrange the N gene from its wild-type position of 1 (N-P-M-G-L) to 2 (P-N-M-G-L), 3 (P-M-N-G-L), or 4 (P-M-G-N-L), using an approach that left the viral nucleotide sequence unaltered. Subsequently, viable viruses were recovered from each of the rearranged cDNA and examined for their gene expression levels, growth kinetics in cell culture, pathogenicity in suckling mice and protection in mice. The results showed that gene rearrangement decreased N mRNA transcription and vRNA replication. As a result, all viruses with rearranged genomes showed worse replication than that of rHEP-Flury in NA cells at a MOI of 0.01, but equivalent or slightly better replication levels at a MOI of 3. Consequently, the lethality in suckling mice infected with N4 was clearly attenuated compared with rHEP-Flury. However, the protection to mice was not enhanced. This study not only gives us insight into the understanding of the phenotype of RABV N gene rearrangement, but also helps with rabies vaccine candidate construction.

Background: Tens of thousands of people die from dog-mediated rabies annually. Deaths can be prevented through post-exposure prophylaxis for people who have been bitten, and the disease eliminated through dog vaccination. Current post-exposure prophylaxis use saves many lives, but availability remains poor in many rabies-endemic countries due to high costs, poor access, and supply., Methods: We developed epidemiological and economic models to investigate the effect of an investment in post-exposure prophylaxis by Gavi, the Vaccine Alliance. We modelled post-exposure prophylaxis use according to the status quo, with improved access using WHO-recommended intradermal vaccination, with and without rabies immunoglobulin, and with and without dog vaccination. We took the health provider perspective, including only direct costs., Findings: We predict more than 1 million deaths will occur in the 67 rabies-endemic countries considered from 2020 to 2035, under the status quo. Current post-exposure prophylaxis use prevents approximately 56 000 deaths annually. Expanded access to, and free provision of, post-exposure prophylaxis would prevent an additional 489 000 deaths between 2020 and 2035. Under this switch to efficient intradermal post-exposure prophylaxis regimens, total projected vaccine needs remain similar (about 73 million vials) yet 17·4 million more people are vaccinated, making this an extremely cost-effective method, with costs of US$635 per death averted and $33 per disability-adjusted life-years averted. Scaling up dog vaccination programmes could eliminate dog-mediated rabies over this time period; improved post-exposure prophylaxis access remains cost-effective under this scenario, especially in combination with patient risk assessments to reduce unnecessary post-exposure prophylaxis use., Interpretation: Investing in post-exposure vaccines would be an extremely cost-effective intervention that could substantially reduce disease burden and catalyse dog vaccination efforts to eliminate dog-mediated rabies., Funding: World Health Organization., (© This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Rabies, a zoonotic viral encephalitis, continues to be a serious public health problem in India and several other countries in Asia and Africa. Survival is rarely reported in rabies, which is considered to be almost universally fatal. We report the clinical and radiological findings of eight patients with laboratory-confirmed rabies who survived the illness. With the exception of one patient who recovered with mild sequelae, all survivors had poor functional outcomes. The reported survival from rabies in recent years may reflect an increased awareness of the disease and greater access to better critical care facilities in rabies-endemic countries. Nonetheless, there is an urgent need to focus on preventive strategies to reduce the burden of this dreadful disease in rabies-endemic countries.

A severe, often fatal encephalitis needs to be extensively and carefully clarified, especially when it occurs in a patient weeks or months after an organ transplantation. If the donor was viremic at the time of the organ removal or living viruses were present in the organ tissue, many viruses can be transferred to the organ recipient. This has been repeatedly reported in recent years and decades. In this overview rabies is discussed as a particularly important form of viral encephalitis, which is transferred via organs and always has a fatal outcome, because patients carry a high risk of infection for all caregivers. Bornavirus has been known in veterinary medicine for many decades and in human medicine has been discussed as possibly being associated with psychiatric diseases. Very recently Bornavirus has been identified as the causative pathogen of fatal encephalitis in organ recipients. The aim of this article is to raise awareness for rabies and Bornavirus disease in intensive care medicine and neurology for organ donors and those taking care of organ recipients. Prevention by knowledge can be lifesaving.

Background: Rabies, as the most important zoonotic disease, is transmitted through a bite or scratch by an infected domestic or wild carnivores and bats or contact of open wound with infected saliva. The fluorescent antibody test (FAT) is the "gold standard" diagnostic method for suspected brain samples. For close monitoring of unknown encephalitis, rabies surveillance, and also the limitations for post-mortem diagnosis of rabies in human and performing fast prophylactic measures for other individuals in contact with rabid patients, ante-mortem diagnosis based on molecular methods such as real-time polymerase chain reaction (PCR) seems to be more reliable. In this study, we detected 2 positive rabid cases using SYBR Green real-time PCR for the first time in Iran., Methods: In this study, 3 saliva samples at intervals up to 6 hours were collected from any of the nine suspected patients with nonspecific symptoms between March 2016 and March 2017. Total RNA extraction, cDNA synthesis and real-time PCR were performed along with confirmed negative and positive controls. Then, we tracked the patients for follow-up and understanding of their status. On brain samples of patients who died, FAT and MIT (mouse inoculation test) were performed to obtain definitive results., Results: In this study, the patients were 4 females and 5 males, between 8 and 80 years old from different geographical areas of Iran. The ante-mortem saliva samples of 2 out of nine patients who died were positive by SYBR Green real-time PCR. Positive results of FAT test on these samples confirmed the presence of rabies virus infection in their brains and also the ante-mortem diagnosis results., Conclusion: The results of this study suggest that SYBR Green real-time PCR technique on saliva sample can be used as an applicable method for ante-mortem diagnosis of rabies to avoid infection of other people such as the treating medical staff or family members of the patient., (© 2018 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

The highest rate of human rabies deaths reported in the Americas is in Haiti, and most of these deaths result from rabies virus infections that occur after individuals are bitten by infected dogs and do not receive rabies post-exposure prophylaxis. One barrier to rabies prevention in Haiti is a lack of knowledge about this disease among healthcare professionals and community members. During the past 4 years, The US Centers for Disease Control and Prevention has collaborated with public health officials and partners to develop, test and refine educational materials aimed at filling this need for rabies education. This report summarizes the use of feedback from knowledge, attitudes and practises surveys; key informant interviews; and focus groups to develop culturally appropriate rabies prevention materials for community members, health officials, clinicians, laboratory professionals, veterinary professionals, government officials and national and local district leaders about ways to prevent rabies. These formative research methods were critically important in ensuring that the materials would be culturally appropriate and would stand the greatest likelihood of motivating Haitians to protect themselves from rabies. Centers for Disease Control and Prevention is using lessons learned in Haiti to develop and test materials in other countries with high rates of canine rabies., (© 2018 Blackwell Verlag GmbH.)

Background: In the absence of accurate data on trends and the burden of human rabies infection in developing countries, animal bite injuries provide useful information to bridge that gap. Rabies is one of the most deadly infectious diseases, with a case fatality rate approaching 100%. Despite availability of effective prevention and control strategies, rabies still kills 50,000 to 60,000 people worldwide annually, the majority of whom are in the developing world. We describe trends and geographical distribution of animal bite injuries (a proxy of potential exposure to rabies) and deaths due to suspected human rabies in Uganda from 2001 to 2015., Methods: We used 2001-2015 surveillance data on suspected animal bite injuries, collected from health facilities in Uganda. To describe annual trends, line graphs were used and linear regression tested significance of observed trends at P<0.05. We used maps to describe geographical distribution of animal bites by district., Results: A total of 208,720 cases of animal bite injuries were reported. Of these, 27% were in Central, 22% in Eastern, 27% in Northern and 23% in Western regions. Out of 48,720 animal bites between 2013 and 2015, 59% were suffered by males and 81% were persons aged above 5 years. Between 2001 and 2015, the overall incidence (per 100,000 population) of animal bites was 58 in Uganda, 76 in Northern, 58 in Central, 53 in Western and 50 in Eastern region. From 2001 to 2015, the annual incidence (per 100,000 population) increased from 21 to 47 (P = 0.02) in Central, 27 to 34 (P = 0.04) in Eastern, 23 to 70 (P = 0.01) in Northern and 16 to 46 (P = 0.001) in Western region. A total of 486 suspected human rabies deaths were reported, of which 29% were reported from Eastern, 28% from Central, 27% from Northern and 17% from Western region., Conclusion: Animal bite injuries, a potential exposure to rabies infection, and mortality attributed to rabies infection are public health challenges affecting all regions of Uganda. Eliminating rabies requires strengthening of rabies prevention and control strategies at all levels of the health sector. These strategies should utilize the "One Health" approach with strategic focus on strengthening rabies surveillance, controlling rabies in dogs and ensuring availability of post exposure prophylaxis at lower health facilities., Competing Interests: The authors have declared that no competing interests exist.

Background: Rabies, for which the mortality rate is almost 100%, is a zoonotic viral disease that can be transmitted via solid organs or tissue allotransplantation. Dozens of deaths from rabies via solid organs or tissues allotransplantation (ROTA) have been documented during the last decades. In 2015 and 2016, two cases of rabies virus transmission via solid organs or tissue allotransplantation were reported in China, which further underscore the risk and importance of this special type of rabies for organ transplant recipients., Main Text: From 1978 to 2017, at least 13 cases of ROTA, causing dozens of deaths, have been reported worldwide, whether in the high-risk or low-risk countries of rabies. The reported incubation period of ROTA ranges from 11 days to more than 17 months, while the historical incubation period of rabies is generally considered to range from ~ 1 week to several years. The pathogenesis of ROTA is not clear, but the use of post-exposure prophylaxis (PEP) can play a protective role in the transplant recipients. We also summarize reports about ROTA in China, combined with the actual situation regarding work on rabies surveillance and elimination, and suggest countermeasures for the prevention and control of ROTA in the future., Conclusions: Understanding the significance of ROTA, screening the suspected organs, assessing the risk and protecting the related population will be effective way to prevent and control further occurrence of ROTA.

Since antiquity, rabies has remained one of the deadliest infectious diseases known to humankind, with a case fatality rate approaching 100% following the onset of clinical disease. It is present on all continents where terrestrial mammals exist, with the majority of animal and human cases being reported in the resourcelimited countries of Africa and Asia, with thousands of human rabies deaths being recorded annually. It is likely, however, that the global figure of approximately 59,000 annual human rabies fatalities is an underestimate. The impact of the disease has been reduced substantially across vast regions of the globe since the development of effective rabies vaccines. The success of different vaccines and vaccination policies in the defined 'at risk' populations has been born out of scientific innovation. Mass vaccination campaigns of animals, using parenteral vaccines to immunise companion animals, and advances in oral vaccines for wildlife, have allowed the elimination of rabies in terrestrial carnivores in several regions worldwide, including Western Europe and much of North America. In addition, human vaccines, largely used for post-exposure treatments, have reduced the burden of rabies in endemic areas.

The impact of infectious disease may become progressively more harmful to a species' survival as a wild population approaches an 'extinction vortex'. This risk is especially relevant for pathogens that spread rapidly and result in high mortality rates. Rabies, a virus that infects many mammalian species, can be efficiently transmitted through infected saliva, and is fatal without prior vaccination or rapid post-exposure prophylaxis (in humans). The authors conducted an extensive literature review to identify all wild mammal species reported to have been infected with rabies virus. They found reports of infection in 190 mammalian species, including 16 with elevated risk of extinction and two for which rabies is a direct conservation threat: the Ethiopian wolf (Canis simensis) and the African wild dog (Lycaon pictus). This paper discusses selected examples in which rabies has contributed to the population decline of a species of conservation concern. In addition, the authors note the importance of the transmission of rabies virus (RABV) from domestic dogs to wildlife, and the many challenges associated with the vaccination of wild animals. With this in mind, they present potential solutions to reduce the burden of rabies on wildlife. Once stable control of RABV is achieved in domestic dogs, remaining rabies threats to wildlife conservation can be addressed more effectively.

Rabies is an acute neurological infection of humans and animals, caused by rabies virus and usually transmitted by animal bites. After an incubation period usually lasting weeks or longer, a variety of prodromal symptoms may occur. Encephalitic rabies (80% of cases) is associated with episodes of generalised arousal or hyperexcitability and hydrophobia, in which spasms involve the contraction of inspiratory muscles with swallowing. Paralytic rabies (in 20% of cases) is characterised by progressive lower motor neuron weakness. Laboratory investigations are important for confirming an ante mortem diagnosis of rabies. Cardiopulmonary and many other complications, including multiple organ failure, are common in aggressively managed rabies patients in critical care units. No effective therapy is available for rabies and survivors are uncommon. In contrast, preventative measures for rabies are highly effective after recognised exposures.

The Indian subcontinent comprises Afghanistan, Bangladesh, Bhutan, India, Nepal, the Maldives, Myanmar, Pakistan and Sri Lanka. In all of these countries, except the Maldives, rabies is endemic. An estimated 59,000 people die from rabies each year; 45% of these deaths occur on the Indian subcontinent and approximately 33% take place in India. The majority of these deaths are attributable to dog bites, and those most affected are children and the poor. Access to post-exposure prophylaxis is limited and costly, the supply of immunoglobulins and vaccines can be irregular and public awareness of rabies is low. Moreover, the vaccination of domestic dogs is not widely implemented. There is a need for increased laboratory capacity and expertise across the continent, as well as better data, improved surveillance and more user-friendly and economical diagnostic tests. An animal birth control programme has met with mixed success in India. However, a greater focus on mass dog vaccination could eliminate the disease at its source, reducing the large burden of mortality for at-risk communities. In this paper, the authors examine the situation in each of the countries on the Indian subcontinent, discuss current needs, obstacles and progress, and examine future strategies, with the objective of eliminating dog-mediated rabies from the subcontinent by 2030.

Background: The Philippine government has an extensive network of 513 Animal Bite Treatment Centers (ABTCs) to supply rabies post exposure prophylaxis (PEP), reaching over 1 million bite victims in 2016. The network was evaluated using a review of existing national and provincial data, key informant interviews and surveys in sample ABTCs to determine the cost-effectiveness of this network in preventing human rabies deaths., Methodology and Principal Findings: One urban and one rural ABTC in each of three selected provinces were studied in more detail. PEP delivery generally followed national guidance based on best practices, but there was evidence of operational challenges in supplying all ABTCs with adequate biologics and recently trained staff. Funding was contributed by different levels of government and in some clinics, patients paid for a significant fraction of the total cost. From a health provider perspective including both fixed and variable costs, the average PEP course delivered cost USD 32.91 /patient across urban ABTCs (with higher patient throughput) and USD 57.21 /patient across rural ABTCs. These costs suggests that PEP provision in the Philippines cost USD 37.6 million in 2016, with a cost per life saved of USD 8,290. An analysis of the 2,239 suspected rabies deaths from 2008 to 2016 showed no significant decline, and from 2014-16 an average of 8,534 years of life were lost annually. The incidence of rabies deaths from 2014-16 was not clearly related to the provision of ABTCs (per 100,000 population) or human population density, but deaths were more common in higher income provinces., Conclusions/significance: In the context of comprehensive rabies control (including dog vaccination and public awareness) ways to reduce this high expenditure on PEP should be explored, to most cost-effectively reach the elimination of human rabies deaths. This paper is accompanied by another containing data on the operation of ABTCs network from a patient perspective., Competing Interests: Funding for this investigator-sponsored study was provided by GlaxoSmithKline Biologicals SA. ACBA, SIJ, LHT, MCR, and MCLQ were funded proportionate to their time spent on the study. GlaxoSmithKline Biologicals SA reviewed and approved the protocol, but did not influence the project implementation, data collection, analysis or interpretation. They were also provided with an opportunity to review a preliminary version of this report for factual accuracy but the authors are solely responsible for final content and interpretation. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Due to the increasing number of DCD transplantations since 2015, the transmission of rabies through solid organ transplantation has become a notable problem in China and has attracted the attention of the public., Case Presentation: From 2015 to 2017, four solid organ recipients in our centre were successively diagnosed with rabies that was considered to have been transmitted from two donors who died due to viral encephalitis of unknown cause and acute disseminated encephalomyelitis. The incubation periods were 44, 48, 158 and 303 days. The four patients had neurological symptoms associated with rabies and died. The survival times were 44, 34, 8 and 6 days. Another kidney transplant recipient received timely post-exposure prophylaxis and has remained asymptomatic., Conclusions: Organs should be discarded whenever rabies is confirmed or suspected, especially in cases diagnosed as encephalitis of unknown cause. It is important to establish a supervisory system to manage donor-derived infectious diseases. When rabies-infected donor organs are inadvertently transplanted, the recipients must receive post-exposure prophylaxis in a timely manner, which may be the only possible effective method to prevent the transmission of rabies.

Background: Dog rabies annually causes 24,000-70,000 deaths globally. We built a spreadsheet tool, RabiesEcon, to aid public health officials to estimate the cost-effectiveness of dog rabies vaccination programs in East Africa., Methods: RabiesEcon uses a mathematical model of dog-dog and dog-human rabies transmission to estimate dog rabies cases averted, the cost per human rabies death averted and cost per year of life gained (YLG) due to dog vaccination programs (US 2015 dollars). We used an East African human population of 1 million (approximately 2/3 living in urban setting, 1/3 rural). We considered, using data from the literature, three vaccination options; no vaccination, annual vaccination of 50% of dogs and 20% of dogs vaccinated semi-annually. We assessed 2 transmission scenarios: low (1.2 dogs infected per infectious dog) and high (1.7 dogs infected). We also examined the impact of annually vaccinating 70% of all dogs (World Health Organization recommendation for dog rabies elimination)., Results: Without dog vaccination, over 10 years there would a total of be approximately 44,000-65,000 rabid dogs and 2,100-2,900 human deaths. Annually vaccinating 50% of dogs results in 10-year reductions of 97% and 75% in rabid dogs (low and high transmissions scenarios, respectively), approximately 2,000-1,600 human deaths averted, and an undiscounted cost-effectiveness of $451-$385 per life saved. Semi-annual vaccination of 20% of dogs results in in 10-year reductions of 94% and 78% in rabid dogs, and approximately 2,000-1,900 human deaths averted, and cost $404-$305 per life saved. In the low transmission scenario, vaccinating either 50% or 70% of dogs eliminated dog rabies. Results were most sensitive to dog birth rate and the initial rate of dog-to-dog transmission (Ro)., Conclusions: Dog rabies vaccination programs can control, and potentially eliminate, dog rabies. The frequency and coverage of vaccination programs, along with the level of dog rabies transmission, can affect the cost-effectiveness of such programs. RabiesEcon can aid both the planning and assessment of dog rabies vaccination programs., Competing Interests: The authors have declared that no competing interests exist. All authors contributed to this work whilst employees of the U.S. Centers of Disease Control and Prevention (CDC). One author (RHB) now works at Merck, Inc. Another author (CER) is affiliated with the Wistar Institute. Both of these authors completed their contributions to this paper, except for reading of the final draft, before they left the U.S. CDC.

Human rabies deaths are preventable through prompt administration of postexposure prophylaxis (PEP) with rabies immune globulin and rabies vaccine after exposure to a rabid animal (1); there are no known contraindications to receiving PEP (1,2). Despite widespread availability of PEP in Vietnam, in 2015 the Ministry of Health (MoH) received reports of pregnant and breastfeeding women with clinically diagnosed rabies. MoH investigated factors associated with these rabies cases. MoH found that, during 2015-2016, among 169 cases reported in Vietnam, two probable cases of rabies were reported in breastfeeding mothers and four in pregnant women, all of whom had been bitten by dogs. All six patients died. Three of the four pregnant women had cesarean deliveries. One of the three newborns died from complications believed to be unrelated to rabies; the fourth pregnant woman contracted rabies too early in pregnancy for the fetus to be viable. Two of the patients sought care from a medical provider or traditional healer; however, none sought PEP after being bitten. In each case, families reported the patient's fear of risk to the fetus or breastfed child as the primary barrier to receiving PEP. These findings highlight the need for public health messaging about the safety and effectiveness of PEP in preventing rabies among all persons with exposures, including pregnant and breastfeeding women., Competing Interests: No conflicts of interest were reported.

Rabies is one of the oldest known infectious diseases and certainly one of the most feared because of its impressive course. Despite continuous improvement in medical treatment, the disease continues to be almost always fatal after onset of symptoms. Due to urbanization, rabies has lately somewhat disappeared from the public focus in Central Europe. Because of the remaining high number of fatal cases due to rabies infection worldwide and the persistent risk of contagion on holiday or within Switzerland, e.g. due to illegal import of infected animals, the disease is becoming a frequent topic in the media again.

More than 100 years of research has now been conducted into the prevention, control and elimination of rabies with safe and highly efficacious vaccines developed for use in human and animal populations. Domestic dogs are a major reservoir for rabies, and although considerable advances have been made towards the elimination and control of canine rabies in many parts of the world, the disease continues to kill tens of thousands of people every year in Africa and Asia. Policy efforts are now being directed towards a global target of zero human deaths from dog-mediated rabies by 2030 and the global elimination of canine rabies. Here we demonstrate how research provides a cause for optimism as to the feasibility of these goals through strategies based around mass dog vaccination. We summarize some of the pragmatic insights generated from rabies epidemiology and dog ecology research that can improve the design of dog vaccination strategies in low- and middle-income countries and which should encourage implementation without further delay. We also highlight the need for realism in reaching the feasible, although technically more difficult and longer-term goal of global elimination of canine rabies. Finally, we discuss how research on rabies has broader relevance to the control and elimination of a suite of diseases of current concern to human and animal health, providing an exemplar of the value of a 'One Health' approach., (© 2017 The Authors.)

Background: Rabies is a fatal viral encephalitic disease that is caused by lyssaviruses which can affect all mammals, including human and bats. In Europe, bat rabies cases are attributed to five different lyssavirus species, the majority of rabid bats being attributed to European bat 1 lyssavirus (EBLV-1), circulating mainly in serotine bats (Eptesicus serotinus). In France, rabies in bats is under surveillance since 1989, with 77 positive cases reported between 1989 and 2016., Case Presentation: In the frame of the bat rabies surveillance, an unusual mortality of serotine bats was reported in 2009 in a village in North-East France. Six juvenile bats from an E. serotinus maternity colony counting ~200 individuals were found to be infected with EBLV-1. The active surveillance of the colony by capture sessions of bats from July to September 2009 showed a high detection rate of neutralising EBLV-1 antibodies (≈ 50%) in the colony. Moreover, one out of 111 animals tested was found to shed viable virus in saliva, while lyssavirus RNA was detected by RT-PCR for five individuals., Conclusion: This study demonstrated that the lyssavirus infection in the serotine maternity colony was followed by a high rate of bat rabies immunity after circulation of the virus in the colony. The ratio of seropositive bats is probably indicative of an efficient virus transmission coupled to a rapid circulation of EBLV-1 in the colony.

Essen regimen, the Thai Red Cross two-site ID regimen, Zagreb schedule, and the eight-site ID regimen are the standard rabies vaccines recommended by the World Health Organization (WHO). In this study, a liposomal rabies vaccine (LipoRV) was developed, which was found to facilitate the production of rabies virus neutralizing antibody (RVNA) in BALB/c mice. Liposome solution was prepared with hydrogenated soya phosphatide and cholesterol. LipoRV composed of liposome solution and inactivated rabies vaccine (IRV). The immune responses were compared between the mice treated with either LipoRV or IRV. Higher levels of interleukin-2 (p < 0.05), interferon-γ (p < 0.01), and natural killer cell activity (p < 0.05) were observed in the mice immunized with LipoRV than those with IRV. The potency of LipoRV was significantly higher than that IRV (p < 0.05). In addition, three injections of LipoRV on days 0, 3, and 14 could elicit similar RVNA levels as the five shots of IRV. Our data also showed a higher survival rate in mice treated with three shots of LipoRV (56.2%) than five shots of IRV (40.6%). In conclusion, liposome enhances the immune response of mice to rabies vaccine and could be applied as a potential immunopotentiator.

Rabies is an essentially 100% fatal, zoonotic disease, caused by Lyssaviruses. Currently, the disease is vaccine-preventable with pre- and post-exposure prophylaxis (PrEP and PEP). Still, rabies virus is estimated to cause up to 60,000 human deaths annually, of which the vast majority occurs in rural Asia and Africa, due to the inaccessibility of prophylaxis and non-existence of treatment. Despite these unmet clinical needs, rabies control mainly focuses on the sylvatic reservoir and drug innovation receives relatively little attention compared to other neglected tropical diseases (NTDs). As such, the lag of innovation in human rabies prophylaxis and treatment cannot be explained by limited return on investment alone. Strategies countering rabies-specific innovation barriers are important for the acceleration of innovation in human rabies prophylaxis and treatment. Barriers throughout society, science, business development and market domains were identified through literature review and 23 semi-structured interviews with key opinion leaders worldwide. A subsequent root cause analysis revealed causal relations between innovation barriers and a limited set of root causes. Finally, prioritization by experts indicated their relative importance. Root causes, which are fundamental to barriers, were aggregated into four types: market and commercial, stakeholder collaboration, public health and awareness, and disease trajectory. These were found in all domains of the innovation process and thus are relevant for all stakeholders. This study identifies barriers that were not previously described in this specific context, for example the competition for funding between medical and veterinary approaches. The results stress the existence of barriers beyond the limited return on investment and thereby explain why innovation in human rabies medication is lagging behind NTDs with a lower burden of disease. A re-orientation on the full spectrum of barriers that hinder innovation in rabies prophylaxis and treatment is necessary to meet unmet societal and medical needs., (© 2017 The Authors. Zoonoses and Public Health Published by Blackwell Verlag GmbH.)