On the Use of Phylogeographic Inference to Infer the Dispersal History of Rabies Virus: A Review Study.

Rabies is a neglected zoonotic disease which is caused by negative strand RNA-viruses belonging to the genus Lyssavirus. Within this genus, rabies viruses circulate in a diverse set of mammalian reservoir hosts, is present worldwide, and is almost always fatal in non-vaccinated humans. Approximately 59,000 people are still estimated to die from rabies each year, leading to a global initiative to work towards the goal of zero human deaths from dog-mediated rabies by 2030, requiring scientific efforts from different research fields. The past decade has seen a much increased use of phylogeographic and phylodynamic analyses to study the evolution and spread of rabies virus. We here review published studies in these research areas, making a distinction between the geographic resolution associated with the available sequence data. We pay special attention to environmental factors that these studies found to be relevant to the spread of rabies virus. Importantly, we highlight a knowledge gap in terms of applying these methods when all required data were available but not fully exploited. We conclude with an overview of recent methodological developments that have yet to be applied in phylogeographic and phylodynamic analyses of rabies virus.

History of Rabies Incidence and Rabies Control in Serbia in Support of the Zero by 2030 Campaign to Eliminate Dog-Mediated Human Rabies.

Urban (principally canine-mediated) rabies has been a public health risk for people living in Serbia for centuries. The first legal act in urban rabies prevention in Serbia was established in 1834 by introducing high taxes for pet dog owners. Five years later in 1839, the first set of literature describing rabies prevention was issued by the health department from The Serbian Ministry of Interior. An overview of cauterization of rabies wounds was presented as the principal method of rabies post exposure prophylaxis. In 1890, a human rabies vaccination was introduced in Serbia with the royal government directive which ordered patients to be treated at the Pasteur Institute in Budapest in receipt of rabies vaccination. Urban (canine) rabies was eliminated during the 1980s, but sylvatic (principally fox-mediated) rabies still prevailed. The last human rabies case was recorded in the Province of Kosovo and Metohija in 1980. Sylvatic rabies in Serbia is in the final stages of elimination by orally vaccinating foxes (Vulpes vulpes). The only published finding of a lyssavirus among Serbian bats was made in 1954 by Dr Milan Nikolic in the vicinity of Novi Sad. In 2006, a comprehensive two-year active surveillance program of lyssaviruses in bats in Serbia was undertaken. In this single study, all of the bats from Serbia tested negative for a lyssavirus.

Sir Marc Armand Ruffer, MD: The early years, 1878-1896.

A founder of paleopathology, the study of disease in ancient human remains, Sir Marc Armand Ruffer, MD (1859-1917) served in Egypt, from 1896 to 1917, as a public-health administrator, epidemiologist, and pathologist. He was professor of Bacteriology at the Cairo Medical School, President of the Sanitary, Maritime, and Quarantine Council, member of the Indian Plague Commission, and author or co-author of 40 papers in palaeopathology. However, little is known of his early professional life, which encompassed his education, medical training, and research in England and France. The pre-Egyptian period, 1878 to 1896, was a time of extraordinary activity. Acquiring four academic Degrees at Oxford University and clinical experience at the University College Hospital, London (1878-1889), he was the clinical assistant of Louis Pasteur during the anti-rabies campaign (autumn 1889), interim President of the British Institute of Preventive Medicine (1893-1896), and immunology researcher (1890-1895), in London and Paris, under the guidance of Élie Metchnikoff (1845-1916). Ruffer developed the diphtheria antitoxin in Britain. In addition to a dissertation on hydrocephalus, he composed or co-authored 34 papers. A prolific writer, linguist, clinician, and administrator, he explored several medical sub-disciplines before concentrating on palaeopathology.

La rabia en la Historia. Prevención y tratamiento / No disponible

La rabia es una zoonosis conocida desde la más remota antigüedad, siendo ya citada en el Código de Eshunna, en el siglo XX antes de Cristo. Durante siglos, la mortalidad, una vez iniciados los síntomas, fue del 100%, lo que la convirtió en una enfermedad muy temida en la población, puesto que no se disponía de ningún tratamiento eficaz, salvo la cura de la herida y su posterior cauterización. Las terribles características de la enfermedad han fomentado un miedo atávico en la población, que ha desarrollado múltiples leyendas y mitos inspirados en gran medida en esta enfermedad. Actualmente, todavía fallecen alrededor de 60.000 personas cada año de la enfermedad, la mayor parte de las cuales pertenecen a países en vías de desarrollo, en los que no se han establecido programas eficaces que hayan logrado erradicar la rabia canina. Hasta finales del siglo XIX no se pudo disponer de una profilaxis eficaz como consecuencia del descubrimiento realizado por Louis Pasteur de la vacuna, que modificó radicalmente el pronóstico de la enfermedad. En 1885, se administró con éxito, la primera vacuna a un niño que había sido mordido por un perro rabioso. Desde entonces, las distintas modificaciones realizadas en la vacuna junto con el uso generalizado de la inmunoglobulina específica, desde mediados del siglo pasado, han permitido mejorar los resultados en la profilaxis de la enfermedad en humanos. El éxito definitivo ha llegado con la implementación por la OMS y la FAO de efectivos programas de vacunación canina en los países desarrollados y, en menor medida, en los países en desarrollo, donde todavía representa un importante problema de salud. Algunos recientes tratamientos (Protocolo de Milwaukee) parecen aportar un poco de esperanza a la curación de los enfermos ya sintomáticos, pero su efectividad sigue siendo todavía muy baja

Rabies is a zoonotic disease known since ancient times, already cited in the Code of Eshunna in the XX century BC. For centuries, mortality, after symptom onset, was 100%, which made her a much-feared disease in the population, since no effective treatment was available, except wound healing and subsequent cauterization The terrible disease characteristics have fostered an atavistic fear in the population, hich has developed many legends and myths inspired largely in this disease. Currently, about 60,000 people still die each year from the disease, most of which belong to developing countries, which have not established effective programs that have achieved eradication of canine rabies. Until the end of the nineteenth century it could not have an effective prophylaxis, as a result of the discovery by Louis Pasteur vaccine, which radically changed the prognosis of the disease. In 1885, he successfully managed the first vaccine to a child who had been bitten by a rabid dog. Since then, various modifications to the vaccine along with the widespread use of specific immunoglobulin, since mid-last century, have improved the results in the prevention of disease in humans. The ultimate success has come with the implementation by WHO and FAO effective dog vaccination programs in developed countries and, to a lesser extent in developing countries, where it still represents a major health problem. Some recent treatments (the Milwaukee Protocol) seem to bring some hope to cure the already symptomatic patients, but their effectiveness is still very low

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.

In Memory of Dr. Mahmoud Bahmanyar, an International Researcher of the Pasteur Institute of Iran.

In Iran and also throughout the world, Dr. Mahmoud Bahmanyar (1919-2007) is acknowledged as a well-known researcher mainly in the field of rabies and plague. As an expert of plague for the World Health Organization (WHO), he accomplished many missions in several countries such as India, Cambodia, Myanmar, Indonesia, Vietnam, Yemen, and Brazil. His research on rabies has played an important role leading to the successful combined use of immune-serum and anti-rabies vaccine for prevention of human rabies worldwide. He also conducted many studies in the field of typhus, relapsing fever, and polio. The present article aimed to review his activities.

Rabies in Alaska, from the past to an uncertain future.

Rabies is a serious zoonotic disease with significant public health consequences in the circumpolar North. Recent studies have advanced our understanding of the disease ecology in Alaska. In this paper, we review historical records of rabies in Alaska ranging from the late nineteenth century to the present, analyse the public health impact in the state and review studies on disease ecology before assessing challenges and anticipated altered disease dynamics in the face of a rapidly changing North. Rabies is a disease that has been present in Alaska continuously for over 100 years. It is maintained in bats and foxes with the arctic fox likely playing a bigger role in maintaining the virus, although a multi-host system with both red and arctic foxes cannot be excluded. Some modelling evidence suggest a possible decrease in rabies due to a changing climate, although uncertainty is high around these predictions for rabies distribution in Alaska into the future.

Rabies control in Europe: an overview of past, current and future strategies.

Europe's step-by-step approach to tackling canine and wildlife-mediated rabies has proven that the disease can be controlled and eliminated at the animal source. A decade of development work and support by the European Union has resulted in a successful oral rabies vaccination campaign for foxes and raccoon dogs, and provided the blueprint for eliminating wildlife-mediated rabies. In this paper, the authors examine the historical stages of animal rabies control and its eventual elimination in parts of Europe, particularly Western Europe. In addition, they consider current control measures and predict future challenges, many of which are faced by the vast and sparsely populated, rabies-endemic areas of Eastern Europe.

L'approche par étapes appliquée en Europe pour combattre la rage canine ainsi que celle transmise par la faune sauvage a démontré que cette maladie peut être contrôlée et éliminée à sa source animale. La stratégie conçue et soutenue par l'Union européenne pendant une décennie s'est concrétisée par une campagne de vaccination antirabique orale des renards et des chiens viverrins qui a été couronnée de succès et constitue un modèle pour l'élimination de la rage transmise par les animaux sauvages. Les auteurs examinent le déroulement des étapes successives de la lutte contre la rage animale et de son élimination dans certaines régions européennes, en particulier en Europe occidentale. Ils examinent également les mesures actuelles de lutte et annoncent les difficultés auxquelles il faudra faire face à l'avenir, en particulier dans les vastes régions d'Europe orientale où la population est clairsemée et la rage endémique.

El método gradual (por etapas) aplicado en Europa para combatir la rabia canina y la transmitida por animales silvestres ha demostrado que es posible controlar y eliminar la enfermedad en su foco animal de origen. Diez años de trabajo de desarrollo y de apoyo de la Unión Europea desembocaron en una fructífera campaña de vacunación antirrábica oral de zorros y mapaches, convertida ahora en un modelo para eliminar la rabia transmitida por animales silvestres. Los autores repasan las etapas históricas de la lucha contra la rabia animal hasta su eliminación final en ciertas partes de Europa, en particular en Europa Occidental. Además, examinan las medidas de control vigentes y auguran futuras dificultades, muchas de ellas en las vastas zonas de Europa Oriental donde la población es escasa y dispersa y la rabia es endémica.

Rabies control in North America - past, present and future.

In the first half of the 20th century, rabies in dogs affected Canada, Mexico and the United States of America (USA). However, the role of wildlife in the transmission of the rabies virus was also recognised and outbreaks affecting both wildlife and domestic animals were documented. Canine rabies has since been eliminated from Canada and the USA, and is now only found sporadically in a few southern states of Mexico. Wildlife variant rabies viruses, found throughout the continent and geographically associated with specific reservoir species, have notable public and animal health, as well as economic, impacts. Early rabies control efforts included legislated dog management strategies and wildlife population reduction, which met with varying success. In the last 30 years, programmes for the control of rabies in dogs and wildlife have benefited from an 'Integrated Management Approach', combining education, vaccination (parenteral and oral), strategic population control, responsible pet ownership and effective stewardship of natural resources, in addition to cooperation and collaboration among local, national and international stakeholders. Looking ahead, the goal of eliminating specific wildlife virus variants will be challenged by the potential range expansion of reservoir species, due to climate change and other factors, and the risk of re-introducing eliminated virus variants. To be successful, programmes must be sustained and accompanied by advances in vaccines, enhanced distribution strategies, monitoring in the field and effective modelling of disease spread. They should also be informed by robust case surveillance, phylogenetics and an increased knowledge of vector ecology.

Au Canada, au Mexique et aux États-Unis d'Amérique, la rage canine a sévi jusqu'au milieu du xxe siècle. Le rôle de la faune sauvage dans la transmission du virus de la rage y était également connu et des foyers affectant aussi bien des espèces sauvages que domestiques étaient observés et étudiés. Depuis, le Canada et les États-Unis ont réussi à éliminer la rage canine de leur territoire, de sorte que cette maladie ne se déclare plus que sous forme sporadique dans certains états du Sud du Mexique. En revanche, les variants des virus de la rage qui affectent la faune sauvage circulent sur tout le territoire continental, leur présence étant géographiquement associée à celle de certaines espèces déterminées qui font office de réservoirs, avec des conséquences importantes pour la santé tant publique qu'animale et pour l'économie. Les premières mesures de lutte appliquées contre la rage, essentiellement des stratégies de contrôle des populations de chiens à travers une législation appropriée et une réduction de certaines populations d'animaux sauvages, ont rencontré un succès variable. Depuis une trentaine d'années, les programmes de lutte contre la rage chez les chiens et les animaux sauvages font l'objet d'une « démarche de gestion intégrée ¼ associant des campagnes de sensibilisation, l'application de la vaccination (par voies parentérale et orale), la maîtrise stratégique des populations, la responsabilisation des propriétaires de chiens et la gestion efficace des ressources naturelles, en plus de la coopération et de la collaboration entre les parties prenantes à l'échelle locale, nationale et internationale. En ce qui concerne l'avenir, l'objectif d'éliminer les variants du virus affectant spécifiquement la faune sauvage se heurte à l'expansion potentielle du spectre d'espèces réservoirs à la faveur du changement climatique et d'autres facteurs, ainsi qu'au risque de réintroduction de variants du virus précédemment éliminés. Pour réussir, les programmes doivent être soutenus dans le temps et s'accompagner d'avancées en matière de vaccins, de stratégies de distribution renforcées, d'un meilleur suivi sur le terrain et d'une modélisation efficace de la propagation de la maladie. Ils doivent également reposer sur une surveillance robuste des cas, sur des données phylogénétiques et sur une connaissance accrue de l'écologie des vecteurs.

En la primera mitad del siglo XX, la rabia estaba presente en la población canina del Canadá, México y los Estados Unidos de América, aunque también se conocía la función de los animales silvestres en la transmisión del virus y se habían descrito brotes que afectaron a la vez a animales domésticos y silvestres. Posteriormente la rabia canina fue eliminada del Canadá y los EE.UU. mientras que en México, a día de hoy, solo hace apariciones esporádicas en unos pocos estados meridionales. Las variantes del virus rábico que afectan a la fauna silvestre, presentes en todo el continente y geográficamente ligadas a determinadas especies que actúan de reservorio, tienen notables repercusiones en la salud pública, la sanidad animal y la economía. Entre las primeras iniciativas de lucha contra la rabia había medidas de reducción de las poblaciones de animales silvestres y estrategias de gestión de la población canina impuestas por vía legislativa que se aplicaron con éxito variable. En los últimos 30 años, los programas de lucha antirrábica en perros y animales silvestres han incorporado métodos de «gestión integrada¼ que aúnan labores de pedagogía, vacunación (parenteral y oral), control estratégico de poblaciones, propiedad responsable de los animales de compañía y eficaz administración de los recursos naturales, además de la cooperación y colaboración entre los interlocutores locales, nacionales e internacionales. De cara al futuro, el objetivo de eliminar variantes víricas específicas de la fauna silvestre se verá comprometido por el posible crecimiento del área de distribución de las especies reservorio (debido al cambio climático y otros factores) y por el riesgo de reintroducción de variantes víricas eliminadas. Para que los programas tengan éxito deben ser duraderos y acompañarse de avances en las vacunas, mejores estrategias de distribución, tareas de seguimiento sobre el terreno y elaboración de modelos eficaces de diseminación de la enfermedad. También deben alimentarse de una sólida vigilancia de casos, estudios filogenéticos y un mejor conocimiento de la ecología de los vectores.

Rabies Outbreaks and Control during the Japanese Colonial Period in Korea.

Rabies became one of the critical zoonoses in the modern urban environment since pet keeping culture became widespread in the Western countries in the 18th century. The sanitary policy against rabies was a forceful tool for the colonial rulers in the 19th century. This study describes the rabies outbreaks in the context of prevention methods, experts' engagement and the public response to the policies based on the statistics, regulations and newspaper articles on rabies in Korea during the Japanese colonial period. Based on the changes in the rabies policies, this study divides the time period into three phases. First phase (1905- 1914) was characterized with the first epizootics investigation in Korea in 1905 and the "Domestic dog control regulation" in 1909, which legitimated elimination of dogs without owners' name tags. In the second phase (1915-1926), rabies was designated as a reportable disease by the "Act on Prevention of Domestic Animal Infectious Diseases (1915)" and thousands of dogs were slaughtered every year for rabies prevention. In the third phase (1927-1945), vaccination for dogs became a main intervention. From 1927 to 1942, 760,515 dogs were vaccinated. However, the broad scale rabies control projects over these decades did not seem to decrease the outbreaks of rabies because they did not reflect the rabies situation in Korea. Furthermore, the rabies control policy of the Japanese colonial government was criticized by the public for its violence against dogs and humans, for causing conflicts between social classes, and for lack of understanding of traditional human-dog relationship.

The history of rabies in the Western Hemisphere.

Before the introduction of control programs in the 20th century, rabies in domestic dogs occurred throughout the Western Hemisphere. However, historical records and phylogenetic analysis of multiple virus isolates indicate that, before the arrival of the first European colonizers, rabies virus was likely present only in bats and skunks. Canine rabies was either rare or absent among domestic dogs of Native Americans, and first arrived when many new dog breeds were imported during the period of European colonization. The introduction of the cosmopolitan dog rabies lyssavirus variant and the marked expansion of the dog population provided ideal conditions for the flourishing of enzootic canine rabies. The shift of dog-maintained viruses into gray foxes, coyotes, skunks and other wild mesocarnivores throughout the Americas and to mongooses in the Caribbean has augmented the risk of human rabies exposures and has complicated control efforts. At the same time, the continued presence of bat rabies poses novel challenges in the absolute elimination of canine and human rabies. This article compiles existing historical and phylogenetic evidence of the origins and subsequent dynamics of rabies in the Western Hemisphere, from the era preceding the arrival of the first European colonizers through the present day. A companion article reviews the current status of canine rabies control throughout the Western Hemisphere and steps that will be required to achieve and maintain its complete elimination (Velasco-Villa et al., 2017).

The rise and fall of rabies in Japan: A quantitative history of rabies epidemics in Osaka Prefecture, 1914-1933.

Japan has been free from rabies since the 1950s. However, during the early 1900s several large-scale epidemics spread throughout the country. Here we investigate the dynamics of these epidemics between 1914 and 1933 in Osaka Prefecture, using archival data including newspapers. The association between dog rabies cases and human population density was investigated using Mixed-effects models and epidemiological parameters such as the basic reproduction number (R0), the incubation and infectious period and the serial interval were estimated. A total of 4,632 animal rabies cases were reported, mainly in dogs (99.0%, 4,584 cases) during two epidemics from 1914 to 1921, and 1922 to 1933 respectively. The second epidemic was larger (3,705 cases) than the first (879 cases), but had a lower R0 (1.50 versus 2.42). The first epidemic was controlled through capture of stray dogs and tethering of pet dogs. Dog mass vaccination began in 1923, with campaigns to capture stray dogs. Rabies in Osaka Prefecture was finally eliminated in 1933. A total of 3,805 rabid dog-bite injuries, and 75 human deaths were reported. The relatively low incidence of human rabies, high ratio of post-exposure vaccines (PEP) and bite injuries by rabid dogs (minimum 6.2 to maximum 73.6, between 1924 and 1928), and a decline in the proportion of bite victims that developed hydrophobia over time (slope = -0.29, se = 3, p < 0.001), indicated that increased awareness and use of PEP might have prevented disease. Although significantly more dog rabies cases were detected at higher human population densities (slope = 0.66, se = 0.03, p < 0.01), there were fewer dog rabies cases detected per capita (slope = -0.34, se = 0.03, p < 0.01). We suggest that the combination of mass vaccination and restriction of dog movement enabled by strong legislation was key to eliminate rabies. Moreover, the prominent role of the media in both reporting rabies cases and efforts to control the disease likely contributed to promoting the successful participation required to achieve rabies elimination.

Dog-Mediated Human Rabies Death, Haiti, 2016.

Haiti has experienced numerous barriers to rabies control over the past decades and is one of the remaining Western Hemisphere countries to report dog-mediated human rabies deaths. We describe the circumstances surrounding a reported human rabies death in 2016 as well as barriers to treatment and surveillance reporting.

A Systematic Review of Human Bat Rabies Virus Variant Cases: Evaluating Unprotected Physical Contact with Claws and Teeth in Support of Accurate Risk Assessments.

In the United States and Canada, the most recent documented cases of rabies have been attributed to bat rabies viruses (RABV). We undertook this systematic review in an effort to summarize and enhance understanding of the risk of infection for individuals who have been potentially exposed to a suspect or confirmed rabid bat. United States rabies surveillance summaries documented a total of 41 human bat-rabies virus variant verified non-transplant cases between 1990 and 2015. All cases were fatal. Seven (17.1%) of 41 cases reported a bite from a bat. Ten (24.3%) cases had unprotected physical contact (UPC); these included seven cases that had a bat land or crawl on them (contact with claws) and one case that touched a bat's teeth. Seven (17.1%) cases had probable UPC. Insectivorous bat teeth are extremely sharp and highly efficient for predation upon arthropod prey. Bats also have sharp claws on the end of their thumbs and feet. One of the most common bat RABV variants has an ability to replicate in non-neural cells. Questioning individuals about unprotected contact with bat teeth and claws (including a bat landing or crawling on a person) may help identify additional exposures.

Electrotherapy in the treatment of patients affected by rabies: experiments conducted at the "Maggiore" hospital of Milan in 1865.

During the nineteenth century, the scientific context of rabies treatment was weak due to the lack of the literature on specific nosology of the rabies disease, and unspecific and ineffective therapy approaches. Electrotherapy already represented an important therapeutic approach for nervous system diseases, although not specifically for rabies. In the present paper, the authors discuss the use of electrotherapy in the treatment of humans affected by rabies in an experimental study conducted at the Maggiore Hospital of Milan, with the aim of establishing the discovery of a possible specific therapy. By analyzing the printed scientific sources available in the Braidense Library of Milan, the authors describe four experiments conducted on patients of different ages. Symptoms and effects both during and after the electrotherapy are also highlighted. The experiments demonstrated that electricity is not an effective therapy in the treatment of rabies, being rather able to cause serious functional and organic alterations in all the patients. Analyzing the Milanese experiments, the authors reported specific Italian history of a scientific and medical approach to rabies at the end of the 18th century, which led to the promotion of health education, reinforced prevention strategies and opened the way to the vaccination era.

Estimating the probability distribution of the incubation period for rabies using data from the 1948-1954 rabies epidemic in Tokyo.

Data of 98 rabies cases in dogs and cats from the 1948-1954 rabies epidemic in Tokyo were used to estimate the probability distribution of the incubation period. Lognormal, gamma and Weibull distributions were used to model the incubation period. The maximum likelihood estimates of the mean incubation period ranged from 27.30 to 28.56 days according to different distributions. The mean incubation period was shortest with the lognormal distribution (27.30 days), and longest with the Weibull distribution (28.56 days). The best distribution in terms of AIC value was the lognormal distribution with mean value of 27.30 (95% CI: 23.46-31.55) days and standard deviation of 20.20 (15.27-26.31) days. There were no significant differences between the incubation periods for dogs and cats, or between those for male and female dogs.