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Rabies is a viral zoonosis caused by negative-stranded RNA viruses from the Lyssavirus genus. Genetic variants of the genotype 1 Lyssavirus (the cause of classical rabies) are maintained in different parts of the world by different reservoir hosts within ‘host-adaptive landscapes’. Although rabies can infect and be transmitted by a wide range of mammals, reservoirs comprise only mammalian species within the Orders Carnivora (e.g. dogs, raccoons, skunks, foxes, jackals) and Chiroptera (bats). From the perspective of human rabies, the vast majority of human cases (>90%) result from the bites of rabid domestic dogs and occur in regions where domestic dogs are the principal maintenance host.
Over the past three decades, there have been marked differences in efforts to control canine rabies. Recent successes have been demonstrated in many parts of central and South America, where canine rabies has been brought under control through large-scale, synchronized mass dog vaccination campaigns. As a result, not only has dog rabies declined, but human rabies deaths have also been eliminated, or cases remain highly localized. The contrast with the situation in Africa and Asia is striking; here, the incidence of dog rabies and human rabies deaths continue to escalate, and new outbreaks have been occurring in areas previously free of the disease (e.g. the islands of Flores and Bali in Indonesia –; http://wwwn.cdc.gov/travel/contentRabiesBaliIndonesia2008.aspx).
In this paper, we identify four major reasons commonly given for the lack of effective domestic dog rabies control including (1) low prioritisation, (2) epidemiological constraints, (3) operational constraints and (4) lack of resources (Table 1), focussing on the situation in Africa. We address each of these issues in turn, using outputs from modelling approaches and data from field studies to demonstrate that there are no insurmountable logistic, practical, epidemiological, ecological or economic obstacles. As a result, we conclude that the elimination of canine rabies is a feasible objective for much of Africa and there should be no reasons for further delay in preventing the unnecessary tragedy of human rabies deaths.
Bats are an important reservoirs of different pathogenic agents, and many of them have already caused disease outbreaks worldwide.More than 200 viruses have been associated with bats, and almost all are RNA viruses probably owing to their great ability to adapt to changing environmental conditions through a higher genetic variability.Bacteria in bats and their putative threat to humans remain poorly studied.
Rabies is caused by neurotropic viruses in the genus Lyssavirus, family Rhabdoviridae, and is transmissible to all mammals. Dogs are the main hosts responsible for human rabies in Africa, Latin Americas and Asia, especially in China, where rabies is re-emerging as a major public health threat, and its severity is only second to HIV and tuberculosis (TB) among all reportable infectious diseases. From the annual ~3000 human deaths, southeast China counts for most cases, with more than 90% attributed to rabid dog bites. Notably, both human population and dog density are high in the region with low rabies vaccination coverage in dogs. Given that the program of dog rabies elimination has not been listed in the priority of governmental agenda, it is possible that long term dog rabies enzootics will lead to spillover events of dog-associated rabies into wildlife species. In addition to rabies transmitted by rabid dogs, other sources of rabies exposure to humans, such as cats, ferret badgers (FB), and pigs, have been continuously reported in China. Interestingly, in provinces like Zhejiang, Jiangxi and Anhui, the percentage of dog-associated human rabies is relatively low. Meanwhile, up to 80% of the reported human rabies cases were inferred to be caused by FB bites in some districts in Zhejiang province from 1994 to 2004. Although rabies in badgers was previously recorded in other countries, FB-associated human rabies has never been reported except in China. The frequent occurrence of FB-associated human rabies cases in southeast China highlights the lack of laboratory-based surveillance and urges revisiting the potential importance of this animal in rabies transmission. Nevertheless, management of such animal bites in humans needs a clear guideline on post-exposure prophylaxis (PEP) for rabies. Currently, FB trading and its meat consumption are common in the related areas, resulting in a frequent source of FB bite to humans. Similar to severe acute respiratory syndrome (SARS) outbreaks through consumption of civet in south china, the close and frequent contact of FB by humans could be an important factor in human rabies cases in southeast China.
To determine if the FB actually contributes to human and dog rabies cases, and the possible origin of the FB-associated rabies in the region, we conducted an expanded retrospective/prospective epidemiological survey, which encompassed both descriptive and molecular epidemiological approaches.
Vesicular stomatitis is a viral disease which primarily affects cattle, horses, and swine. It occurs in enzootic and epizootic forms in the tropical and subtropical areas. The disease is rarely life-threatening but can have a significant financial impact on the horse industry. Vesicular stomatitis virus (VSV) is the prototype of the genus Vesiculovirus in family Rhabdoviridae. The virus has two serologically distinct serotypes, VSV-New Jersey (NJ) and VSV-Indiana (IND). The neutralizing antibodies generated by these two serotypes are not cross-reactive. The IND serogroup has three subtypes IND-1 (classical IND) IND-2 (cocal virus) and IND-3 (alagoas virus) The virus is endemic in South America, Central America, Southern Mexico, Venezuela, Colombia, Ecuador and Peru but the disease has been reported in South Africa in 1886 and 1897 and France in years 1915 and 1917.
The disease has been reported across continents in Belize, Bolivia, Brazil, Colombia, Costa Rica, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Pakistan, Panama, Peru, USA and Venezuela [91, 92]. Outbreaks historically occurred in all regions of the USA but have been limited to western states in 1995, 1997, 1998, 2004, 2005, 2006, 2009, 2010, and 2012 [93, 94]. While VS has been reported in horses at about 800 premises in eight states. VSV spread to Europe during the First World War and periodically appears in South Africa. The Chandipura virus, a Vesiculovirus caused encephalitis outbreaks in different states of India leading to mortalities in children. Isfahan another virus in this genus is endemic in Iran [89, 97]. The countries with incidence/serological evidence of vesicular stomatitis are presented in Fig. (2).
Clinical disease has been observed in cattle, horses, pigs and camels whereas sheep, goats and llamas tend to be resistant. White-tailed deer and numerous species of small mammals in the tropics are considered as wild hosts. Many species, including cervids, nonhuman primates, rodents, birds, dogs, antelope, and bats have shown serological evidence of infection. Experimentally different animals like mice, rats, guinea-pig, deer, raccoons, bobcats, and monkeys can be infected.
The virus is zoonotic and causes flu-like symptoms characterized by fever, chills, nausea, vomiting, headache, retrobulbar pain, myalgia, sub-sternal pain, malaise, pharyngitis, conjunctivitis, and lymphadenitis in humans. Vesicular lesions may be present in the pharynx, buccal mucosa, or tongue. Encephalitis is rare but may occur in children [107, 108].
The transmission is more likely by trans-cutaneous or transmucosal route. The virus can be transmitted through direct contact with infected animals having lesions of the disease or by blood-feeding insects. In endemic areas, Lutzomyia sp. (sand fly) is proven biologic vectors. Black flies (Simulidae) are the most likely biologic insect vector in USA. Other insects may also act as mechanical vectors. Saliva, exudates and epithelium from open vesicles are sources of virus. Plants and soil are also suspected as the source of virus.
Horses of all ages appear equally susceptible but lesions do not appear in all susceptible horses. The lesions of the disease resemble foot-and-mouth disease in cattle and the other viral vesicular diseases in pigs. The horses are resistant to foot and mouth disease and susceptible to VS. VSV is the only viral vesicular disease of livestock that infects horses. VSV is also the most important of these four viruses as a zoonotic agent for humans. When vesicular stomatitis occurs in horses, blanched raised or broken vesicles or blister-like lesions develop on the tongue, mouth lining, nose and lips. In some cases, lesions also develop on the udder or sheath or the coronary bands of horses. Animals may become anorectic, lethargic and have pyrexia. One of the most obvious clinical signs is drooling of saliva or frothing at the mouth. The rupture of the blisters creates painful ulcers in the mouth. The surface of the tongue may slough. Excessive salivation is often mistaken as a dental problem or colic. There may be weight loss due to mouth ulcers as animal finds it too painful to eat. The lesions around the coronary band may cause lameness and laminitis. In severe cases, the lesions on the coronary band may cause the hoof to slough. Animals usually recover completely within two weeks. Morbidity rates vary between 5 and 70% but mortality is rare. Vesicular stomatitis like disease disabled 4000 horses during the Civil War in 1862. Major epidemics in the US occurred in 1889, 1906, 1916, 1926, 1937, 1949, 1963, 1982, and 1995, with minor outbreaks during many other years. No specific treatment is available for the disease. Anti-inflammatory medications as supportive care help to minimize swelling and pain. Dressing the lesions with mild antiseptics may help avoid secondary bacterial infections. If fever, swelling, inflammation or pus develops around the sores, treatment with antibiotics may be required. The animals should be quarantined at least for 21 days after recovery of the last case before moving to other places. Vaccines for livestock are available in some Latin American countries.
The recognition that the AIDS pandemic originated as a simian retrovirus transmitted to humans has increased public health concerns about the risk that humans become infected by other pathogens prevalent in NHP. The human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2), etiological agents of AIDS that cause about 1 to 2 million annual deaths, have been linked to cross-species transmission of simian immunodeficiency virus (SIV) from chimpanzees (Pan troglodytes) and sooty mangabeys (Cercocebus atys) (1). Humans might have been infected with SIV either by NHP hunting and wild meat consumption or by keeping infected NHP as pets (2). In the past decades, viruses as deadly as rabies, Herpes B virus, Marburg and Ebola viruses were transferred from NHP to humans. It is likely that during centuries and until recently, the main route of simian pathogen transmission to human was NHP hunting and wild meat consumption (3).
Eastern equine encephalitis (EEE) commonly called triple E or, sleeping sickness is a rare but serious viral disease affecting horses and man. The disease is transmitted through mosquitoes and man and horses are dead-end hosts.
EEEV belongs to the genus Alphavirus of the family Togaviridae. It is closely related to Venezuelan equine encephalitis (VEE) virus and Western equine encephalitis (WEE) virus. This virus has North American and South American variants. The North American variant is more pathogenic. EEE is capable of infecting a wide range of animals including mammals, birds, reptiles and amphibians. The virus has been reported to cause disease in poultry, game birds and ratites. The disease has also been reported to occur in cattle, sheep, pigs, deer, and dogs though sporadically. The disease is present in North, Central and South America and the Caribbean. EEE was first recognized in the USA in 1831 from an outbreak where 75 horses died of encephalitic illness and EEE virus (EEEV) was first isolated from infection horse brain in 1933. The serological evidence and outbreaks of the disease have also been reported from horses in Canada and Brazil [119, 120]. Countries with incidence/serological evidence are presented in Fig. (3). EEEV infection in horses is often fatal. The human cases were identified first time in 1938 in the north-eastern United States. Thirty children died of encephalitis in this outbreak. The fatality rate in humans was 35%. The outbreaks of the disease also occurred in horses simultaneously in the same regions. A total of 19 human cases of the disease were reported in children between 1970-2010 in Massachusetts and New Hampshire. As per the CDC reports 220 confirmed human cases of the disease occurred in the U.S. from 1964 to 2004. In 2007, a citizen of Livingston, West Lothian, Scotland became the first European victim of this disease after infected with EEEV from New Hampshire. EEE has been diagnosed in Canada, the United States of America (USA), the Caribbean Islands and Mexico [122, 123]. Eighteen cases of Eastern equine encephalomyelitis occurred in six Brazilian states between 2005 and 2009.
Alternate infection of birds and mosquitoes maintains these viruses in nature. Culiseta melanura and Cs. morsitans species are primarily involved. Transmission of EEEV to mammals occurs via other mosquitoes which are primarily mammalian feeders and called as bridge vectors. Infected mammals do not circulate enough viruses in their blood to infect additional mosquitoes. The virus is introduced by mosquitoes, but feather picking and cannibalism also contribute towards the transmission of the disease within the flocks. Most people bitten by an infected mosquito do not develop any symptoms. The symptoms generally appear 3 to 10 days after the bite of an infected mosquito. The clinically affected patients may have pyrexia, muscle pains, headache, photophobia, and seizures. EEEV is one of the potential biological weapons. The disease in horses is characterized by fever, anorexia, and severe depression. Symptoms appear one to three weeks post-infection, and begin with a fever that may be as high as 106ºF. The fever usually lasts for 24–48 hours. In severe cases, the disease in horses progresses to hyper-excitability, blindness, ataxia, severe mental depression, recumbency, convulsions, and death. The nervous symptoms may appear due to brain lesions. This may be followed by paralysis, causing the horse to have difficulty raising its head. The horses usually suffer complete paralysis and die two to four days after symptoms appear. Mortality rates among horses range from 70 to 90%.
There is no cure for EEE. Severe illnesses are treated by supportive therapy consisting of corticosteroids, anticonvulsants, intravenous fluids, tracheal intubation, and antipyretics. Vaccines containing killed virus are used for prevention of the disease. These vaccinations are usually given as combination vaccines, most commonly with WEE, VEE, and tetanus. Elimination of mosquito breeding sites and use of insect repellents may help in control of the disease.
Rabies has been one of the most feared diseases throughout human history and has the highest human case-fatality proportion of any infectious disease. Every year over 7 million people receive post-exposure prophylaxis, and an estimated 55,000 people die from rabies (more than yellow fever, dengue fever, or Japanese encephalitis). Over 99% of these deaths occur in developing countries where rabies is endemic in domestic dog populations. However, the impacts of canine rabies are often overlooked, largely because human rabies deaths are now extremely rare in Western Europe and North America, where mass vaccination successfully eliminated the disease from domestic dog populations. Increasing incidence of canine rabies in Africa and Asia has prompted concerns that similar strategies may not be effective in these areas. The critical question now is whether global elimination of domestic dog rabies is achievable. Keys to answering this question include: a quantitative understanding of the transmission dynamics of rabies in domestic dog populations, particularly the basic reproductive number, R0; a quantitative understanding of domestic dog demography; and information about the practicality and effectiveness of various vaccination strategies. While recent data support the feasibility and practicality of domestic dog vaccination strategies [9–11], there are very little quantitative data on rabies transmission dynamics and the underlying demographic processes.
Transmission is the most important process underlying infectious disease dynamics, but it is also the least understood. Rates of transmission are usually inferred from population patterns of disease incidence, but population-level analyses do not capture between-individual variation in transmission resulting from differences in behaviour, genetics, immune status, and environmental and stochastic factors, which play an important role in determining disease dynamics. Contact tracing has been used to directly measure case-to-case transmission, and applications of the technique to emerging infections such as SARS have generated important insights into disease transmission and control in human populations, but transmission processes for diseases circulating in animal populations are much harder to study.
Rabies is an acute viral encephalitis that is spread through the saliva of infected hosts. Clinical manifestations vary, but the neurological phase often includes increased aggression and the tendency to bite and thereby transmit infection; rapid progression to death is inevitable. These distinctive signs make transmission of rabies easier to track than that of most other diseases and provide an unusual opportunity to explore epidemiological patterns at the scale of the individual.
Here, we present data on rabies transmission in two districts of rural Tanzania, Serengeti and Ngorongoro (Figure 1). We were able to monitor the spread of infection using contact-tracing methods, which were feasible due to the discrete and memorable nature of transmission events. We recorded >3,000 potential transmission events between 2002 and 2006 and reconstructed case histories of over 1,000 suspect rabid animals that illustrate heterogeneity in several aspects of transmission, including the latency, movement patterns, and biting propensity of infected individuals. Although these districts border the Serengeti ecosystem, we have argued that domestic dogs are the sole maintenance population of rabies in this community: they make up over 90% of our observations of rabid animals, and the >70 isolates that have been sequenced (from 13 host species) are all consistent with the Africa 1b canid strain. This is one of the most extensive datasets on individual transmission events assembled in an animal population; it has potential to shed light on critical, but often elusive, details of infectious disease transmission. We also analyze data from rabies outbreaks around the world, which provide a global and historical context for the Tanzania dataset.
Alkhurma hemorrhagic fever virus (AHFV) in humans was discovered in 1994. The first case reported in a butcher from the city of Alkhurma, a district south of Jeddah in Saudi Arabia, died of hemorrhagic fever after slaughtering a sheep. The viral infection has a reported fatality rate of up to 25%. Interestingly, one of the previous reports regarding this disease showed a misunderstanding of the real name of this infection, called Alkhurma, not Alkhumra. Because subsequent cases were diagnosed in patients from the small town known as Alkhurma in Jeddah from where the virus got its scientific name; the name was accepted by the International Committee on Taxonomy of Viruses. Thus, based on evidence, the first case was confirmed to be the butcher, following the slaughtered sheep. Therefore, a study was conducted among affected patients to address this disease as a public health issue. Blood samples were collected from household contacts of patients with laboratory-confirmed virus for follow-up testing by enzyme-linked immunosorbent serologic assay (ELISA) for AHFV-specific immunoglobulin (Ig) G. Samples from persons seeking medical care were tested by ELISA for AHFV-specific IgM and IgG using AHFV antigen. Viral-specific sequence was performed by reverse transcription PCR (TiBMolbiol, LightMix kit; Roche Applied Science, Basel, Switzerland). A total of 11 cases were identified through persons seeking medical care, whose illnesses met the case definition for AHFV, and another 17 cases were identified through follow-up testing of household contacts.
Subsequently, the virus was isolated from six other butchers of different ages (between 24 and 39 years) from the city of Jeddah, with two deaths. The diagnosis was established from their blood sample tests. The serological tests later confirmed four other patients with the disease. From 2001 to 2003, the study on the virus initial identification in the city of Alkhurma again identified 37 other suspected cases; with laboratory confirmation of the disease in 20 (~55%) of them. Among the 20, 11 (55%) had hemorrhagic manifestations and 5 (25%) died. The virus was later identified in three other locations: from the Western Province of Saudi Arabia (Ornithodoros savignyi and Hyalomma dromedarii were found by reverse transcription in ticks) and from samples collected from camels in Najran. AHFV virus was considered as one of the zoonotic diseases; however, the mode of transmission is not yet clear. Recently, it was suggested that the disease reservoir hosts may include both camels and sheep. The virus might also be transmitted as a result of skin wounds contaminated with the blood or body fluids of an infected sheep; through the bite of an infected tick, and through drinking of unpasteurized or contaminated milk from camels.
In humans, this zoonotic disease may present with clinical features ranging from subclinical or asymptomatic features to severe complications. It is related to Kyasanur Forest disease virus, which is localized in Karnataka, India. However, epidemiologic findings suggest another wider geographic location for the disease in western (including Jeddah and Makkah) and southern (Najran) parts of Saudi Arabia, and the virus infections mostly occur in humans. A study was conducted by Alzahrani et al. in the southern part of Saudi Arabia particularly in the city of Najran (with populations of ~250,000), an agricultural city in Saudi Arabia, where domestic animals are reared at the backyard of owners. After the initial virus identification, from January 2006 through April 2009, 28 persons with positive serologic test results were identified. Infections were suspected if a patient had an acute febrile illness for at least two days; when all other causes of fever have been ruled out. Additionally, data analysis indicated that patients infected with the virus were either in contact with their domestic animals, involved in slaughtering of the animals, handling of meat products, drinking of unpasteurized milk, and/or were bitten by ticks or mosquitoes. Symptoms consistent with AHFV infection—including fever, bleeding, rash, urine, color change of the feces, gum bleeding, or neurologic signs—then develop. Fortunately, infected patients responded to supportive care (including intravenous fluid administration and antimicrobial drugs when indicated), with no fatal cases.
In summary, AHFV is a zoonotic disease with clinical features ranging from subclinical or asymptomatic features to severe complications. Another study highlighted different characteristics of the exposure to the blood or tissue of infected animals in the transmission of AHFV to humans. Of the 233 patients confirmed with infections, 42% were butchers, shepherds, and abattoir workers, or were involved in the livestock industry. More recently, a study on infection using C57BL/6J mice cells showed that the clinical symptoms of the disease were similar to the presentations in humans. However, Alkhurma disease resulted in meningoencephalitis and death in Wistar rats, when high titers to the infection occurred. In addition, exposures to mosquito bites are regarded as potential sources of transmissions of the infection; however, very few available data support this. Although, available data shows that Alkhurma virus has been isolated following mosquito bites. However, another study suggested that mosquitoes may play a role only as a vector in the transmission of the disease.
Rabies is a viral disease that may affect the central nervous system of any species, but only circulates in mammals. Rabies virus is mainly passed from animal to animal or animal to human through bites or scratches. In addition the virus can also be transmitted by the contamination of wounds. Under very exceptional circumstances, the virus can cross mucous membranes when the patient inhales aerosol. Rabies epizootics may be divided into two interrelated cycles, urban and sylvatic. The red fox (Vupes vulpes) is one of major vectors of the disease and is it reservoir for sylvatic rabies in Eurasia and in parts of America, but it is not the most frequent risk for transmitting rabies virus directly to humans. The more serious rabies risk to human is imposed by urban rabies. The domestic dog plays a principal role as a reservoir and transmitter of urban rabies to humans in China. Humans are also at risk from affected domestic animals or pets such as cattle and cats at large, or wild animals such as the raccoon dog in Eurasia and different terrestrial or flying mammals in the New World. Moreover, direct human-to-human transmission has been observed. There is no effective treatment after the onset of the associated clinical symptoms. Therefore, the currently recommended intervention strategy is to remove and neutralize the infectious virus before it enters the nervous system.
According to the official World Health Organization (WHO) data, more than 2.5 billion people are at risk in over 100 countries reporting the disease. Rabies has the tenth highest mortality of all infectious diseases worldwide. There are still about 50000 to 60000 human deaths annually although effective vaccines for post-exposure treatment are available. Developing countries account for almost all of the reported human deaths, and most affected are the tropical countries or regions in Africa, Asia, South America and Oceania. During the period 1993–2002, the countries of the Americas reported a decrease of 82% in the number of human cases, with cases plummeting from 216 in 1993 (mortality rate of 0.03 per 100000 inhabitants) to 39 in 2002 (mortality rate of less than 0.01 per 100000 inhabitants). Rabies is considered as a source of economic loss and, above all, hampers the movement of animals between different countries or regions, which has serious implications for the 'open market' since some countries are currently rabies free and wish to maintain their disease-free status.
Rabies is a major public-health problem in most of the developing world. Prophylactic measures taken in the past, such as destroying foxes and reducing dog populations, did not prevent the spread of the rabies, although recently developed genetically modified rabies virus vaccines provide an effective method of prevention of rabies virus infection in dogs, foxes and raccoons. During recent years, most research into the control of rabies has concentrated on the development of post-exposure prophylaxis (PEP) of rabies. The use of human rabies immunoglobulin (HRIG) and of equine rabies immunoglobulin (ERIG) has saved the lives of countless patients who would have died if treated with vaccine alone. However, both products are often in short supply worldwide and virtually unaffordable in developing countries. Therefore, the high demand for PEP in Africa and Asia exerts a substantial economic burden, not only as a result of the high costs of human vaccine and rabies immunoglobulin (RIG) products, but also because of considerable indirect (patient) costs associated with travel and income loss for PEP. Additional economic losses relate to livestock deaths, which, although poorly quantified, may be significant, with an estimated annual incidence of 5 deaths per 100000 cattle, costing US$12.3 million annually in Africa and Asia. The total (direct and indirect) cost of PEP accounts for 5.8% of annual per capital gross national income in Africa (US$40 per treatment) and 3.9% (US$49 per treatment) in Asia.
In China, over a 55-year period between 1950 and 2004, 108412 human rabies cases were reported with three major epidemics occurring during this period. The first epidemic outbreak occurred in the mid-1950s when cases rose to a peak of about 2000 annually. After a decline in the 1960s, the number of cases again started to increase in the early 1970s reaching a peak in 1982, and then remained at the level of 5000–6000 cases per year until the end of the decade. Therefore, one of the purposes of this study was to conduct a comprehensive analysis of the rabies situation in the country using all of the official data to characterize the current epidemiological trends of rabies in China from 1990 to 2007. In order to define better recommendations for improving the PEP schedules delivered to patients, we also analysed the reasons for the post-exposure treatment failures (or the absence of PEP), based on the medical records of anti-rabies treatment of injuries or related incidents for 244 rabies patients, ascertained in Guangdong province of China in the years of 2003 and 2004.
The understanding of the mechanisms of viral persistence in bats remains unclear.Extensive studies are needed to improve our understanding of bat–human interactions in order to design new control measures in the future.Strategies on surveillance and monitoring of disease outbreaks in bat populations need to be further developed, in particular where bats and humans are in close contact.
Bats, mammals of the Chiroptera order, are present all over the world with the exception of the Arctic, the Antarctic and a few oceanic islands. Bats are the only mammals with the ability to fly and are present in >1100 different species.1 Bats are essential members of the global ecosystem and humans benefit from their presence in many ways. They are involved in seed dispersal and pollination activity: tropical bats are vital – as an example – in rebuilding cut down forests and in the pollination of wild plants as bananas, avocados and dates. Furthermore, the flying mammals are the major predators of night insects, including crop and human pests.1 Finally, their guano, which is rich in nitrogen, is used as biological fertilizer.
Despite the multiple benefits attributed to these animals, since the ancient times – through myths and misapprehensions – bats have gained a bad reputation in the general public. The classical literature is full of examples in which bats are associated with evil and darkness. The roman poet Ovid narrates in the Metamorphoses that the god Bacchus transforms the daughters of Mineus, king of Boeotia, into bats as a punishment for profanating his celebration (Figure 1 and Box A). In the Divine Comedy (Inferno – Canto XXXIV), Dante Alighieri, the father of the italian language, describes the devil Lucifer as bearing large bat wings (Figure 2 and Box B). In the eighteenth century, scientists called ‘vampire’ a bat that fed on blood, giving rise to the myth of human vampires that sucked blood from other men and could transform into bats. The Irish novelist Bram Stoker with his novel, Dracula (1897) did nothing but make this belief famous worldwide. More recently, Bob Kane, an American comic book artist, ideated a character called Batman a positive character that, however, disguises in a bat costume to scare his enemies: ‘Criminals are a superstitious cowardly lot. So my disguise must be able to strike terror into their hearts. I must be a creature of the night, black, terrible..... ‘Just then a huge bat flies in the open window’. A bat! That’s it! It’s an omen. I shall become a bat! In: Detective Comics no 33, 1939.
Bats, however, can be involuntarily dangerous to humans. Indeed, they are natural reservoir hosts and sources of infection for several microorganisms, including pathogens that can cause severe human diseases, and are more frequently implicated in zoonotic virus emergencies.1,2 Bats are widespread in urban areas and come in close contact with both domestic animals and humans, contaminating houses with guano and urine, additionally, humans occasionally encroach into bat habitats.3 Their characteristic ecology undoubtedly influences the maintenance and transmission of microorganisms within the colony and directly or indirectly to humans.1,3
Microbial transmission within bat colonies is promoted by the behavior of several species of these mammals aggregating in crowded roosts. Bats can transmit infectious agents to humans through intermediate hosts, which are in close contact with humans.4 These intermediate hosts can be infected in many ways, including ingestion of food partially digested by bats. Frugivorous bats, in fact, cannot ingest wide amounts of food because of the aerodynamics of flight,5 therefore, they extract nutrients by chewing fruits and spitting the residues. This partially digested food dropped on the ground can then be ingested by other animals and is a potential infectious source. A similar modality of viral transmission has also been described for insectivorous bats.5 Bats can also directly infect humans.4 This can occur through ingestion of infected bat meat, as in some areas bats are a food source, or through bat’s bite as in the case of rabies virus.
Other features of bat’s life make them a good host for infectious agents. The fact that several species of bats hibernate during the winter is one of these. Although the role of the hibernation in infection dynamics has not been widely studied, it is likely that this condition can contribute to the maintenance of pathogens in the cold weather (see below: white-nose syndrome (WNS)). Moreover, unlike many other small mammals, bats live >30 years. Their long life makes them a great reservoir for pathogens and gives them many occasions to transmit them to other species. In addition, some species of bats migrate – also for distances >1000 km – allowing them to spread diseases in big areas and acquire new microorganisms.6,7
Finally, most pathogens are not dangerous for bats and can therefore survive for long time in the host without killing it. Indeed, despite the fact that bats are infected with more different zoonotic viruses per host – with the exception of rabies virus and other Lyssaviruses – these are apparently not pathogenic for them, suggesting that they may control viral replication more efficiently than other mammals. It has been hypothesized that there may be a relationship between flight and low virulence.8 During flight, bats show an increase in the metabolic rate and in body temperature, comparable to the fever response rendering replication of infectious agents, which are temperature sensitive, less favorable.
In this review, we give a comprehensive overview of the microorganisms and viruses isolated from bats and their possible role in human disease.
Plant-made vaccines against influenza viruses are perhaps the poster children for molecular farming: many candidate vaccines made in plants have shown efficacy in animal models; candidate pandemic virus vaccines have been made to the scale of 10 million doses in less than a month, vaccines suitable for outbreak viruses similarly (see review9). Efficacy to homologous challenge has been shown in mice, ferrets and chickens; so too has efficacy to heterologous challenge with high pathogenicity avian influenza (HPAI) strain H5N1 in chickens.10 While most of this work is directed toward protecting humans against potentially pandemic influenza viruses, it is often overlooked that the same vaccine candidates could be equally useful in birds and in swine: indeed, breaking the chain of recycling of influenza viruses that seems to occur in intensively farmed pigs is a prime goal of One Health.11 Other targets for plant-made influenza vaccines include dogs12 and potentially horses.
Our group investigated the potential for making influenza pandemic rapid response vaccines in South Africa by making influenzavirus A/Vietnam/1204/04 (H5N1) haemagglutinin by transient expression in N. benthamiana:13 our success opened up the possibility of making H5 HA as a reagent and potentially as a vaccine, by means hitherto not available in Africa. We went on to use the HA2 portion of the protein as a virus-like particle (VLP)-based display vehicle in plant manufacture for the highly conserved M2e ectopic epitope as an elicitor of broadly neutralising antibodies to all influenzavirus A strains, as a candidate universal vaccine for humans and animals.14
Rudolf Virchow (1821–1902), one of the foremost 19th century German leaders in medicine and pathology, noted a relationship between human diseases and animals and then introduced the term “zoonosis” (plural: zoonoses) in 1880. Later, the World Health Organization (WHO) in 1959 specified that “zoonoses are those diseases and infections which are naturally transmitted between vertebrate animals and man”. Venkatesan and co-authors reported that the term zoonosis is derived from the Greek word “zoon” = animal and “noso” = disease. Zoonotic pathogens causing different kinds of diseases are of major public health issues worldwide. These zoonotic diseases include various infections such as viral, bacterial, fungal, protozoan and parasitic diseases shared in nature by man and animals (domestic and wildlife). Of these, an epidemiological study confirmed that about 61% of the total number of microbial diseases affecting man is zoonotic. Moreover, another study suggested that animals are the major sources of human zoonotic infections, globally and that among all the emerging infectious diseases, almost 75% are considered to be caused by animals. Thus, almost every year since the last two decades, a new virus has been emerging. During the last three decades, rats have been increasingly implicated in several emerging and reemerging human outbreaks of zoonotic diseases and have accounted for ~75% of the new zoonotic diseases in nature according to several studies. This constitutes about 61% of all communicable diseases causing illnesses in man. Furthermore, a study suggested that some zoonotic diseases could affect the socioeconomic output globally. A report on the impact of foodborne zoonotic diseases estimated its costs at about $1.3 billion every year worldwide.
Since zoonotic diseases can easily be transmitted to man in several ways, they target persons who work closely with animals; this plays a big role in zoonotic transmission. Such persons working with animals include veterinarians, slaughterers/butchers, farmers, researchers, pet owners (e.g., through bites and/or scratches of owners of indoor pet-animals), and animal feeders in animal companies using animal products, via animals used for food (e.g., meat, dairy, eggs, birds, infected domestic poultry, and other birds). Furthermore, transmission can also occur through animal vectors (e.g., tick bite, and insects like mosquitoes or flea). In addition, in the transmission of bacteria in comparison with viruses, the role of contaminated food and water, the importance of international travels as well as changes in land use and agriculture, are important. According to recent WHO data, more than 75% of the different zoonotic diseases that may cause illnesses in humans are transmitted through animals and/or animal products. Nevertheless, several zoonotic pathogens may be transmitted from various animals to man via several direct and/or indirect pathways such as close contact with the infected animals that might be shedding the infectious pathogen, when humans use contaminated sources of food or water, and/or by outdoor or indoor animal scratches or bites. The prevention and control strategies against zoonotic pathogens are considered important issues and a global challenge requiring efforts of all veterinarian and medical staff.
Animals have been domesticated for a long time in the Arabian Peninsula; and in Saudi Arabia, humans are living in close contact with animals. The spread of any zoonotic disease in Saudi Arabia is considered to be of a high public health importance because it might put the Saudi Arabia peoples, as well as millions of Muslim pilgrims from the about 184 Islamic countries worldwide, at great risk. Moreover, thousands of animals of unknown origin are sacrificed daily during the annual pilgrimage for all pilgrims in Makkah. Furthermore, pilgrims slaughter over one million sheep, cows, and camels in Mina to mark the successful completion of the Hajj, aside the 42,000 beasts that are slaughtered in Makkah abattoirs. While some people are at slaughterhouses to offer their sacrifices personally, others from nearby cities of Makkah, Jeddah, and Taif come to collect sacrificial meat.
Recently in Saudi Arabia, a huge number of new pet clinics and/or pet stores opened, selling all kinds of pets. They breed, shower, and clean pets, which bring major feeling of psychological well-being to the modern urbanized lifestyle of their Saudi Arabian owners. However, all these pet markets may need to be targeted by the Ministry of Health (MOH) and/or the Ministry of Agriculture because all kinds of pets—including cats, dogs, rodents, and monkeys—which are sold, may transmit several zoonotic diseases. In this review, we identified the most important and prevalent emerging and reemerging viral zoonotic pathogens in Saudi Arabia, taking into account the current incidence and prevalence of zoonotic diseases, the health situations, the zoonotic sources of human infection, and the current available control strategies that could prevent such infectious zoonotic diseases. In addition, we identified the primary sources of information on zoonotic pathogens in Saudi Arabia. Data sharing and dissemination of significant findings could make a remarkable difference in the global control; it could provide useful information, particularly to Muslims on pilgrimage, when they travel to Saudi Arabia during Umrah seasons and/or the annual Hajj pilgrimage.
In Central Africa, Asia and Latin America, wildlife is the primary source of meat for low-income people living in rural areas (4–6). The practice of NHP hunting is part of the culture; it has been happening for centuries and the sale of wild meat is considered legal in many countries despite being illegal in some. Even in France, in the French Guiana two species of NHP, the howler monkey (Alouatta maconnelli) and the squirrel monkey (Saimiri sciureus), are allowed on the hunt but prohibited for sale (7). This results in regular close contacts between animal carcasses and hunters as well as between raw meat and women who prepare food. The meat is usually cooked before being shared with children (8). Most recently, illegal hunting for wild meat consumption or traditional medicine, also known as the bushmeat trade, as well as extermination of wild animals by troops foraging for food during wars have accelerated the NHP populations decline. The impact on NHP populations varied from lightly to heavily hunted. Human predation went hand in hand with an increase in contacts between NHP carcasses and humans. Fa and collaborators (9) calculated that more 150,000 carcasses of NHP per year are traded in Nigeria and Cameroun. NHP meat in Congo basin's local market is a cheap source of food (10) (Figure 1). Although wild meat consumption is associated with an increased risk of acquiring zoonotic diseases, people eating NHP ignore or express indifference to the risk of contracting simian pathogens, mainly because their own experience suggests that they can do it without incident. Even when governments imposed a ban on the hunting and consumption of wild meat after the 2013 to 2016 outbreak of Ebola virus in West Africa, the trade and consumption of NHP meat were not deeply affected (14). Over the past decade, the washing-based Bush Meat Crisis Task Force has regularly reported alarming information about wild animals being harvested for food in the Congo basin every year (15). A study in Liberia reported that 9,500 NHP are trade annually on the Liberia-Ivory Coast wild meat markets. According to journalists from the Guardian, there has been a massive chimpanzee decline in DRC due to hunting, with more than 400 chimpanzees being slaughtered each year. The hunting of gorillas and chimpanzees by poachers in Cameroun was also reported by the Ape Action Africa in Mefou. However, in some tribes, women refuse to eat or cook ape as it goes against their beliefs. The consumption of NHP meat is not limited to people living in poverty in Central Africa, Asia, or Latin America; wealthier households consumed only slightly less wild meat than others. Spider monkey dishes are popular in Southern Mexico. Although currently banned from dishes, NHP brain has long been viewed as a prized delicacy in Asia. The CITES/GRASP (16), reported that in Indonesia orangutans could be purchased for $100 and that some restaurants prepare dishes containing orangutan meat if specifically requested by customers.
Rabies is an acute progressive encephalitis caused by viruses in the Genus Lyssavirus, Family Rhabdoviridae, with the highest fatality rate among conventional infectious diseases. Known in bats for well over a century, rabies is the best studied infection associated with the Chiroptera. Bats are the principal reservoirs for 10 of the 11 recognized lyssavirus species and are suspected as hosts of other putative species (5). Only one lyssavirus, Mokola virus (MOKV), has never been isolated from bats to date. However, the principal reservoir for MOKV is unknown (6). Another viral species, rabies virus (RABV), circulates in bats and other mammals (predominantly carnivores). Interestingly, RABV circulates in bats only in the Americas, whereas in carnivores, the disease circulates globally. In the Old World, bats maintain circulation of other lyssavirus species, such as Lagos bat virus (LBV), Duvenhage virus (DUVV), European bat lyssaviruses type 1 (EBLV-1) and 2 (EBLV-2), Australian bat lyssavirus (ABLV), Aravan virus (ARAV), Khujand virus (KHUV), Irkut virus (IRKV), West Caucasian bat virus (WCBV), and Shimoni bat virus (SHIBV). For these viruses, bats are the principal hosts, with only a few spillover infections documented in other mammals. Isolation of RABV from Eurasian bats has been suggested several times, but never confirmed (reviewed in Kuzmin and Rupprecht (7)). Indeed, the surveillance data from developing countries is very limited. We do not know which lyssaviruses circulate in bats of northern Africa and southern Asia, although historical reports (8, 9) along with more recent serological findings (10–12) indicate that bats do maintain lyssavirus circulation in these territories.
A paralytic disease in cattle and sporadically in humans bitten by a vampire bat has been reported from the time of the Spanish first colonized Latin America. However, the diagnosis of rabies was first confirmed by the identification of Negri bodies in the brain of cattle during an outbreak in Brazil in 1911 (13). Vampire bats probably maintained rabies virus circulation for a long time prior to the arrival of Europeans in the Americas. The association between vampire bites and the disease was understood by natives, who cauterized or washed the bites to prevent the disease (14). However, historical antecedents might be some other progenitor virus, quite different from those ones that circulate in bat populations presently.
Economic losses due to vampire bat rabies in livestock are tremendous. In the enzootic area there is an at-risk population of more than 70million head of cattle. Vampire bats usually bite many animals in a herd. The proportion of animals bitten may vary from 6 to 52% (15). Significant outbreaks of vampire bat rabies were documented in Amazon area (Brazil, Peru) during recent years. Up to 23–55% of respondents interviewed had vampire bat bites during the last year. During the outbreaks, up to 15% of such bites caused rabies in humans (reviewed in Kuzmin and Rupprecht (7)).
An idea that vampire bats may be asymptomatic rabies carriers, shedding the virus in their saliva for months, was popular during initial studies of vampire bat rabies (16). However, in a well-documented experimental study by Moreno and Baer (17), the disease in vampire bats was similar to rabies observed in other mammals. The bats that developed signs of disease and excreted the virus via saliva soon died, whereas those that survived the inoculation without clinical signs never excreted the virus or had it in the brain as demonstrated upon euthanasia. More recently, the asymptomatic excretion of RABV in the saliva of experimentally infected vampire bats, which survived the challenge during at least 2 years of observation, was documented again (18). Clearly, this phenomenon requires additional investigation.
Rabies of insectivorous bats was first documented in 1953 in Florida. Later it was documented across the United States, in Canada, and Latin America. Several RABV lineages were documented, and in general, they correspond to particular host species (reviewed in Kuzmin and Rupprecht (7)). Moreover, widely distributed bat species, such as Mexican free-tailed bat (Tadarida brasiliensis) and big brown bat (Eptesicus fuscus), maintain circulation of several RABV variants across their geographic range. Insectivorous bats are the major source of human rabies in the United States and Canada, which became especially prominent after elimination of RABV circulation among dogs. During 1958–2009, a total of 49 naturally acquired human rabies cases caused by bat RABV variants were reported in the United States and Canada (excluding four rabies cases caused by organ transplantation from a donor who died of unrecognized rabies) (19, 20). In 19 of these cases the exposure was ‘cryptic’, as the patients did not recall any contact with animals or a bat was seen flying in the residence but no direct physical contact was reported.Appears that some bat bites, especially if they were inflicted by small bat species, may be ignored or not recognized as dangerous by people (such as a previously unattended child, mentally disabled, or intoxicated person).
Two closely related RABV variants (previously considered as one), associated with the silver-haired bat (Lasionycteris noctivagans) and eastern tri-colored bat (Perimyotis subflavus) have caused about 60% of human rabies cases, where the virus variant could be identified. These bats are relatively small, do not form large colonies, and usually do not roost in close proximity to human dwellings. In contrast, the big brown bat RABV variant and the Myotis RABV variant caused one human case each, even if these bats frequently occupy house attics and crevices in men-made constructions. Furthermore, big brown bats constitute about 90% of all rabid bats, submitted to diagnostic laboratories in the United States and definitely have more contacts with humans (21, 22). The Mexican free-tailed bat RABV variant caused several human rabies cases as well, including four cases that occurred in 2004 after transplantation of organs and vessel from a donor who died of rabies (23). Several versions were suggested to explain the disproportional prevalence of the silver-haired bat and eastern tri-colored bat RABV variant among human rabies cases. Investigations suggested that these viruses have enhanced pathogenicity to humans, for example they may have a greater ability to replicate in fibroblasts and epithelial cells, being delivered into a superficial bat bite (24).
In the Old World, the significance of bat rabies for veterinary and public health is well addressed only in the countries with developed surveillance systems, such as Western Europe and Australia. The EBLV-1 and EBLV-2 circulate in Europe among insectivorous bats Eptesicus fuscus and Myotis spp, respectively. These viruses caused at least three cases of human rabies, where the virus was characterized, in Finland, Russia, and in the UK (reviewed in Kuzmin and Rupprecht (7)). The IRKV, first identified in insectivorous bat Murina leucogaster in eastern Siberia during 2002 (25), was known by this only one isolate until 2007, when it caused a human death after a bite of unidentified insectivorous bat in the Russian Far East (26). Moreover, at least three other cases, where the viruses were not identified but the disease was compatible with rabies and developed after bat exposure, were reported from the Ukraine and China (27–29). A few cases of spillover EBLV-1 infections were documented in terrestrial mammals, including domestic cats (30), and they represent a potential exposure risk for humans.
The EBLVs, as well as IRKV, are covered by the commercially available rabies biologics (31, 32), therefore the disease can be efficiently prevented by administration of standard rabies post-exposure prophylaxis (PEP). This is not the case for WCBV. This virus, isolated from insectivorous bat Miniopterus schreibersii in south-eastern Europe, is the most divergent member of the Lyssavirus genus, and rabies biologics are incapable of providing significant protection against it (32). Because of lacking surveillance, there is only one isolate of WCBV available to date. Ecology of this virus and its significance for public health are unknown. However, laboratory animals and bats, infected with WCBV, developed typical rabies and died (33).
A variety of bat lyssaviruses have been documented in Africa. The LBV, first documented in Nigeria in 1956 (34), was further isolated in many sub-Saharan countries (35). Moreover, in 1999 it was imported into France with fruit bats Rousettus aegyptiacus captured in Togo or Egypt (36). Fruit bats of several species serve as reservoir hosts for LBV, with infrequent spillover infections documented in dogs, cats, and a mongoose (37). The viruses, currently included into LBV, represent several divergent lineages and there is a possibility that further taxonomic efforts may facilitate separation of these viruses into two or three species (5, 38, 39). Another divergent lyssavirus, SHIBV, was isolated from insectivorous bat Hipposideros commersoni in Kenya in 2009. The SHIBV demonstrates similarity to MOKV and LBV, but cannot be included into any of these species (5). Significance of these viruses for public health is unknown however, as in the case of WCBV, they are pathogenic for laboratory animals, which develop rabies and die after intracranial or peripheral inoculation (5, 35, 40). Furthermore, due to their antigenic differences, they are not covered by current rabies biologics (32, 41).
Recently, serologic reactivity to WCBV was detected in Miniopterus bats of several species from Kenya (42). Given that WCBV does not cross-react serologically with other known lyssaviruses, this seroprevalence indicates that WCBV or some other antigenically similar virus circulates in Africa as well (and probably more broadly, corresponding to the distribution range of Miniopterus bats).
Another African bat lyssavirus, DUVV, is covered by rabies biologics, but still kills people because of insufficient knowledge, either in general public and health professionals. The DUVV is perhaps the most mysterious African lyssavirus. Of four isolates available, three came from humans who died of rabies after bat exposures and only one was isolated from an insectivorous bat, presumptive Miniopterus sp (43). The most recent human case occurred in 2007 in Kenya, where a Dutch tourist was attacked by a bat in a campsite of Tsavo West national park. The patient applied for medical help, but a local physician assured that bat rabies does not exist in Kenya and PEP was not administered. Several weeks later, back in the Netherlands, the patient developed rabies and died. The virus was identified as DUVV (44).
The discovery of ABLV in 1996 in the ‘rabies-free’ Australia was surprising. Following the discovery that flying foxes were a reservoir of Hendra virus, surveillance of these animals was increased. During this activity, ABLV was identified first in a sick black flying fox (Pteropus alecto). The second case was diagnosed retrospectively in another bat of the same species, sampled in 1995 with signs of unusual aggressiveness (45). Later ABLV was documented in each of the four flying fox species, present in continental Australia. Furthermore, a genetically divergent variant of ABLV was discovered in insectivorous bats Saccolaimus flaviventris(46).
Two human cases of ABLV infection have been documented to date. Both were fatal and clinical symptoms were compatible with rabies. The first one was reported very shortly after the virus discovery in 1996. The patient was a 39-year-old female presumably infected by a S.flaviventris bat in her care. The virus that was isolated was compatible with this bat species (46, 47). The second case occurred in a 37-year-old female who developed rabies in 1998, approximately 27 months after presumable exposure from a bite by an unspecified flying fox. This isolate belonged to the pteropid ABLV variant (48, 49).
Two features of human behavior throughout history are striking. The first has been the domestication of numerous animals for food production, as working animals for activities such as transport, and for hunting purposes. They are also, particularly in modern times, used as a source of companionship, and in the USA alone there are estimated to be over 77 million dogs.1 The second feature is our propensity to travel. This trait has accelerated in the modern age through technical innovations such as the motor car, air travel, and international shipping.2 Human travel through migration, leisure, or business continues to increase in parallel with a population increase and the spread of affluence. This provides opportunities for pathogens to move to new areas and cause outbreaks of disease. Commercial air travel has been particularly effective at transporting pathogens such as SARS coronavirus and influenza viruses.3 It is also contributing to the spread of disease vectors and the diseases they transmit.4 As we travel, we take animals with us either through trade in livestock or in the movement of companion animals.
In Europe, the free movement of people within the continent has been enabled by the formation of the European Union (EU) and liberalization of border controls. This was formalized by the Schengen Agreement signed by member states in 1985 and implemented in 1995. This created the Schengen Area that reduced border controls between member states and allowed free movement of people between countries. Some countries, including the UK and Ireland, have in the past, agreed opt-outs that retain limitations of movement into those countries.
When humans travel, they often take their companion animals, particularly dogs, and these in turn can relocate the pathogens and vectors they harbor. Canine parvovirus emerged in 1978 as a new disease in dogs causing hemorrhagic enteritis. Retrospective serology suggested that the disease appeared in Europe in 1976 and spread throughout the world by 1978.5 The mechanism that enabled global dissemination of the virus has been attributed to contaminated footwear. There are numerous canine-associated diseases but relatively few are significant zoonoses. However, of these, a number are fatal to humans and control is essential to protect public health. Globally, the most significant is the rabies virus. Infection leads to fatal encephalitis, for which there is no treatment.6,7 Pre-exposure vaccination protects against the disease in mammals, and due to the extended incubation period between contact with a rabid animal and development of disease, often measured in months, timely post-exposure vaccination is also effective in humans.8 The dog is the most important reservoir for the virus, and contact with dogs is responsible for virtually all human cases of the disease. Where efforts have been concentrated on controlling dog rabies, the reduction in human cases of disease has been dramatic.9 Dog rabies has been virtually eliminated from Europe, although there are examples of reintroduction10,11 and cross-border movement of rabid animals.12
Alveolar echinococcosis is caused by the tapeworm Echinococcus multilocularis. It is a fatal condition that is relatively rare in Europe although there are clear areas of endemicity, resulting in human infections in an area of Europe ranging from France in the west to Austria in the east.13 The disease manifests as a tumor-like growth of cysts containing the larval stage of the parasite in organs such as the liver. Detection of cysts often occurs many years after initial infection, and without intervention such as surgery to remove the cyst(s), the disease is fatal. Dogs act as the definitive host for the adult form of the parasite and movement of infected dogs can lead to the spread of tapeworm eggs and introduction of the disease into new areas. As the adult worm is very small (less than 5 mm) and does not cause clinical signs in the definitive host, spreading of eggs and human infection can remain undetected until clinical symptoms develop.
Leishmaniasis is caused by protozoa belonging to the genus Leishmania. Two forms are recognized, ie, cutaneous leishmaniasis causing skin lesions and the more serious visceral disease involving multiple organs. Natural transmission is through the bite of phlebotomine sandflies belonging to the genera Phlebotomus in the Old World.14 Distribution of leishmaniasis is limited by the presence of the vector. In Europe, the vector is indigenous to those countries around the Mediterranean Sea. The major mammalian reservoir is the domestic dog. Estimates of autochthonous human cases in Europe are approximately 700 a year.15 Numbers of cases in Turkey are higher, with over 3,000 annually. Non-endemic countries in Europe do encounter cases of canine leishmaniasis as a result of pet movements.16
In the absence of border restrictions, it is difficult to establish the true extent of regional movement of animals either for trade or through holiday travel. Monitoring of dogs and cats entering the UK through its pet travel scheme indicated that almost 100,000 animals entered the country annually (Table 1). A similar situation is likely to exist for most EU member states. In addition to this, there is the problem of illegal movement of animals either by organized groups for commercial purposes or inadvertent contraventions of legal requirements by holidaymakers through importation of their animals. Quantification of this is by its very nature difficult, but detection of noncompliance with legislation or deliberately smuggled animals is a regular occurrence,17 and the incidence of disease often highlights this activity.
The following sections review important zoonotic diseases of pet origin and the policies currently in place to control zoonotic diseases of companion animals and their limitations, concluding with recommendations on what more could be done.
Worldwide, rabies causes approximately 55,000 deaths per year. Rabies viruses are transmitted to humans via saliva from bites of carnivores and bats. Bats may be frugivorous, hematophagous or insectivorous. Vampire bats (3 main species Desmodus rotundus, Diphylla ecaudata and Diaemus youngi) feed on blood from warm-blooded animals, e.g. horses and cattle.
Rabies in 2005, transmitted to humans by vampire bats reached new heights in Latin America, where with several outbreaks reportedly concerned 55 human cases, 41 of them in the Amazon region of Brazil. Peru and Brazil had the highest numbers of reported cases from 1975 to 2006. Bats represent the main vector of human rabies in Brazil–. Near its border with French Guiana, other outbreaks were described in remote rural areas of Portel and Viseu Municipalities, Pará State, northern Brazil. Twenty-one human deaths were attributed to paralytic rabies in those 2 municipalities. Isolates were antigenically characterized as D. rotundus variant 3. During a recent outbreak, media reports noted that nocturnal biting coincided with the failure of a regional generator that left people without electricity for 6 weeks. Outbreaks of bat-transmitted rabies have been linked to the continued deforestation of the Amazon region, which has displaced vampire bats across northern Brazil and increased their contact with humans. The reasons for the outbreak in Brazil are not yet fully understood.
In French Guiana, a French Overseas Department located in South America, 10 cows, 2 dogs and 1 cat died of bat rabies-virus infection between 1984 and 2003,, but no human case had previously been reported there–. However, on 28 May 2008, the National Reference Center for Rabies (Institut Pasteur, Paris), confirmed the diagnosis of rabies for a 42-year-old French Guianan man, who had never left this Department and who died in Cayenne, after developing clinically typical meningoencephalitis. Since 14 May, he had complained of nonspecific symptoms, mainly fever, severe asthenia and pain, and had consulted at the Cayenne Hospital Emergency Unit 3 times before being admitted on 21 May in a state of mental confusion; his condition deteriorated rapidly thereafter. He became comatose on the same day and died on 27 May. On 28 May, rabies was diagnosed based on a new reverse-transcription hemi-nested polymerase chain reaction (RT-hnPCR) protocol applied to a skin biopsy and saliva specimens. This case illustrates the risk of under-reporting of human rabies based only on clinical criteria and highlights the need for laboratory confirmation to obtain accurate data on disease burden–. Phylogenetic analysis of the isolated virus identified a Lyssavirus (Rabies virus species), closely related to those circulating in hematophagous bats. This identification of the first human case of bat rabies in France resulted in the creation of a national multidisciplinary Crisis Unit under the authority of the French Ministry of Health in Paris. In French Guiana, it was coordinated by the local health authorities and the Center for Treatment Anti-Rabies (CTAR) of Institut Pasteur de la Guyane (IPG). Its objectives were to manage the crisis, implement an epidemiological investigation and a veterinary survey, provide control measures and establish a communications program. Herein, we review the methodology used by the Crisis Unit and the consequences of this case on the local perception of rabies.
Analyses of the contact-tracing data generated robust estimates of epidemiological parameters that have important implications for rabies control (Table 1, Figures 2 and 3, and Figure S1) and provide insight into how infectious disease transmission scales from individual behaviour to population-level dynamics. We estimated R0 for rabies in Serengeti and Ngorongoro districts directly from infectious histories, from reconstructed epidemic trees based on the spatiotemporal proximity of cases, and from the exponential rate of increase in cases at the beginning of an epidemic. Biting behaviour of rabid dogs during the course of infectious periods was highly variable (mean bites per rabid dog = 2.15, 95% confidence interval (CI) from fitting a negative binomial distribution: 1.95–2.37; variance = 5.61, CI: 4.63–6.92; shape parameter k = 1.33; CI: 1.23–1.42) (Figure 3A). The probability that an unvaccinated dog developed rabies after being bitten by an infectious animal was high (P
rabies|bite = 0.49, CI: 0.45–0.52) (Table 1) if the bitten dog was not vaccinated or killed immediately after exposure. Multiplying the average number of dogs bitten per rabid dog by the probability of developing rabies following exposure gave an R0 estimate of 1.05 (CI: 0.96–1.14) (Figure 3A and Table 1). These estimates should be regarded as lower bounds, because not all transmission events were observed (this calculation excludes rabid dogs that were killed before biting other animals or that disappeared and likely corresponded to unknown or unobserved rabid dogs in other areas; see Materials and Methods). Detailed data on the timing and location of transmission events and infections allowed us to estimate the spatial infection kernel and generation interval (distances and times between source cases and their resulting infections, respectively) (Figure 2) and probabilistically reconstruct transmission networks (Videos S1 and S2). Calculating the average number of secondary cases per rabid dog during the period of exponential epidemic growth (before vaccinations were implemented) from these reconstructions gave similar R0 estimates of 1.1 in Serengeti district and 1.3 in Ngorongoro (CIs: 1.04–1.10 and 1.26–1.42, respectively) (Table 1). The more traditional approach of estimating R0, by fitting a curve to incidence data over the same interval of exponential epidemic growth, also produced similar estimates of 1.2 in Serengeti and 1.1 in Ngorongoro (CIs: 1.12–1.41 and 0.94–1.32, respectively) (Table 1 and Figure 3B). This approach is robust to underreporting (Text S1 and Figure S2) but should likewise be considered a lower bound, because some local control measures were instituted (such as tying or killing). We also estimated R0 from the intrinsic growth rate of outbreaks of domestic dog rabies elsewhere in the world (Table 2) and obtained values between 1.05 and 1.85, which are consistent with our estimates from northwest Tanzania.
For many diseases, R0 is expected to increase with host density. Despite the domestic dog population density in Serengeti (9.38 dogs/km2) being considerably higher than the dog population density in Ngorongoro (1.36 dogs/ km2, see Table 3), we were unable to detect significant differences in our estimated values of R0 between the two districts. Nor did we find any conspicuous differences in R0 estimated from the outbreaks listed in Table 2, which represent a wide range of population densities. There may, in fact, be no relationship between R0 and population density for canine rabies. On the other hand, a subtle relationship between dog density and transmission rates might be difficult to detect for a number of reasons. To investigate whether it would be possible to decipher systematic differences in R0 across the range of values that we estimated, we simulated outbreaks using our epidemiological parameter estimates, but varied R0 (from R0 = 1 to R0 = 2), whilst maintaining individual variance in biting behaviour (same shape parameter k, see Text S2). Although the mean estimates of R0 from fitting to these simulated trajectories were accurate, they were surrounded by wide confidence intervals (Figures S2 and S5), suggesting that if only a small number of epidemics were sampled, any underlying relationship might not be apparent.
Human rabies has been a notifiable disease in Taiwan since 1952. Rabies surveillance mandates physicians to notify clinically suspected cases to the health authority within 24 hours of diagnosis and submit clinical specimens including saliva, serum and cerebrospinal fluid (CSF) to TCDC laboratories. Rabies is confirmed if any of the specimens tested positive for rabies virus by diagnostic RT-PCR targeting both L and N genes of Rabies virus. PCR products were sequenced in both directions to characterize the rabies amplicon. In addition, specific anti-rabies antibody testing by enzyme-linked immunosorbent assay was performed in unvaccinated individuals. In addition, TCDC has conducted sentinel surveillance of human encephalitis of undetermined etiology since 2010. Physicians from 46 sentinel hospitals were requested to submit serum, throat swabs and CSF from patients with either encephalopathy or ataxia of unknown etiologies, plus any one of the following: fever, seizure, focal neurological signs, abnormal CSF profile, abnormal electroencephalography (EEG) and brain images. Submitted specimens were tested for viruses using a multiplex PCR panel containing probes targeting viruses causing encephalitis. Retrospective testing to detect rabies virus was conducted on stored CSF taken during January 1, 2010 to July 15, 2013, by rabies RT-PCR. The multiplex real-time PCR detected the following pathogens using primers designed based on previously published sequences: Herpes simplex virus 1 and 2, VZV, CMV, Human Herpesvirus 6 and 7, Hendra virus, Nipah virus, Dengue virus, chikungunya virus, Japanese encephalitis virus, West Nile virus, adenovirus, bocavirus, coronavirus (229E, HKU1, OC43 and NL63), enterovirus, human metapneumovirus, human parechovirus, influenza virus (types A and B), parainfluenza virus (types 1–3, 4A and 4B), parvovirus B19, polyomavirus (JC and BK), respiratory syncytial virus (RSV) and rhinovirus.
Rabies is not a simple long-ago vestige, nightmarish myth, or literary allegory but rather a significant viral encephalitis with the highest case fatality of any conventional infectious disease. Who else, besides those afflicted and affected, should care about rabies today? Legions—including the true animal lover, anthropologist, administrator, caver, educator, environmentalist, farmer, medical professional, traveler, health economist, hiker, historian, humanist, industrialist, legislator, modeler, philanthropist, sociologist, student, conservation biologist, and life scientist, to name a few by vocation or avocation—curious for elevated self and situational awareness, caring for the common good, intrigued by this view of life from an applied microbiological and ecological perspective or challenged by the allure for professional intervention in nature, represented by the less-than-apparent “
To simplify the infectious cycle of rabies, exposure is direct, not by environmental deposition, but rather individual-to-individual intra- and inter-specific transmission, usually occurring via bite. Millions of highly neurotropic virions are excreted intermittently in the saliva of a rabid host, days to weeks before overt morbidity and eventual demise, entering the peripheral nervous system of a bite recipient.
In vivo, from local depots and centripetal transit in the axoplasm, primary replication occurs within neurons of the central nervous system (CNS). Thereafter, centrifugal passage occurs from the CNS to a number of highly innervated sites, including the salivary glands. Oral, mucosal, or transdermal delivery of virions occurs by normal daily mammalian interactions. Failing these routine modus operandi pathways, altered unusual behaviors offer a variety of options for secondary contacts. These may range from mania to paresis and paralysis, with deliberate transmission options of agonistic encounters and biting, increased movement outside of normal home range/territories, or acute death, with predation by others upon virion-laden tissues and organs of the affected host. If a productive infection ensues, the entry-reproduction-exit cycle is poised to begin anew after initiation, taking days, weeks, months, or (rarely) years of incubation before excretion or obvious clinical manifestation. Such obligate, parasitic virions ensure elegant self-transfer by exploitation of the normal through to the bizarre. Relatively distant viral familial relatives hail among invertebrates and plants, but warm-blooded vertebrates are the rabies-prone hosts. Although these agents predated
Homo sapiens, their current distribution, abundance, and diversity likely exceed pre-historic comparisons, especially mediated during the Anthropocene period.
Among warm-blooded vertebrates, birds are susceptible to infection, but rabies predominates naturally among various mammalian populations. Within the Mammalia, a virtual alphabet soup of cases has been recorded, from the armadillo to the zebra. Rabies is a significant disease of domestic and wild mammals alike, yet its zoonotic aspect is the cause of major historical infamy. Few and privileged were the civilizations that did not describe the ravages of an entity akin to rabies, such that this infection has impacted art, literature, and cultural practices for millennia. By one small measure, during the time taken by a typical reader to peruse this article, more than 1,300 people will have been exposed to rabies virus (RABV). Annually, tens of thousands of persons will succumb, the majority children. Most are poor, have no access to modern medical care, and will die unreported, frequently at home in a rural village. If among other scales—on the basis of disability-adjusted life-year scores or health economic measures—rabies ranks within the top-ten list of neglected viral zoonoses, one would anticipate that the degree of philanthropic input would be roughly equivalent among such pathogens. Unfortunately, such is not the case. For example, several other neglected viral diseases may have a somewhat smaller presumed impact yet receive far greater attention for international support (
Table 1). Not rooted entirely in science, a more holistic transdisciplinary philosophy assists in a better partial understanding of why such biomedical disparities persist between need and assistance, provoking a bootstraps approach in the field out of frustrated necessity in the face of apparent contradictions.
In light of meaningful global action for the public good, at what level should one come to terms with rabies in the 21st century? Management, control, prevention, elimination, eradication, and so on are often freely bandied about together in today’s lexicon of disease deliberations but are not synonymous terms. Unlike smallpox or rinderpest, rabies is not a candidate for actual eradication today, given the extent of host breadth and diversity. However, rabies has at least three major attributes in common with those other two extinct viral pathogens: validated diagnostic protocols, safe and effective vaccines, and the epidemiological insight to apply those laboratory tools and licensed biologics for sound prevention and control practices. Somewhat paradoxically, based upon a century of experience, modern rabies management accomplishes, in a truly One Health capacity, what no other comparable zoonosis program can achieve in tandem: human cases prevented by avoiding defined exposure and seeking prophylaxis after exposure; primary canine and secondary species infections eliminated, by mass immunization; and significantly, wild carnivore viral perpetuation interrupted via oral vaccination efforts on a landscape scale. Building upon such apparent progress, this review aims to provoke renewed discussions on several of the current issues and challenges related to modern lyssavirus taxonomy, phylogeny, surveillance, prevention, treatment, control, and elimination, based in part upon the opinions of the authors, representing more than a century of collective person-years of introspective knowledge, skills, and abilities in the field—not as an historical aside alone, but rather within the context of evidence from the peer-reviewed literature, focusing upon relevant publications primarily within the past few years
115. Our hope is, in some small manner, to educate, enlighten, engage, and enable others to participate meaningfully in these remaining endeavors, within the realm of a ‘science of conviction’.
In an applied One Health context, rabies diagnosis is the only routine procedure applied to a suspect animal that will directly determine the need for specific, life-saving medical intervention in a human at risk (
http://www.cdc.gov/rabies/pdf/rabiesdfaspv2.pdf). Laboratory diagnosis is critical to confirm the status of a suspect case, in part, to justify prophylaxis in exposed persons or animals, to measure objectively the impact of disease prevention programs, and to support certification of a country as free of disease.
Sensitive, specific, economical, and timely diagnostic tests have been available for more than 50 years, and there has been increasing augmentation by molecular methods for routine rabies diagnosis
37. Yet despite the innumerable rabies cases that occur in wildlife, domestic animals, and humans on a daily basis, only a very small fraction are diagnosed. Few resources are provided, because no cases are diagnosed, owing to a lack of support, producing a cycle of neglect that minimizes the true understanding of disease burden. Those at highest risk are often of lowest priority, such as the poor, the disenfranchised, and the non-agricultural commodities represented by free-ranging wildlife or community dogs.
Misdiagnosis may result with the presentation of fever and coma in children because of confusion with other diseases, such as cerebral malaria
38. Conversely, in some situations, a history of animal bite may be missing because the patient does not realize that exposure has occurred, such that rabies does not enter the original differential diagnosis of encephalitis
39. The relationship between exposure and illness may be forgotten, and patient recall may be disconnected because of the lag from the incubation period, which can extend beyond weeks to months or even years
40. Moreover, the national laboratory may be located centrally in an urban capital, far from case occurrence in rural areas.
The consequences of neglect are obvious. For example, when juveniles contact rabid puppies, the diagnostic event is missed, the prophylaxis opportunity is gone, and the child dies
41. If rabies is not suspected in an infected donor, organs may be transplanted from a patient that dies acutely, producing additional fatal cases in the recipients
42. Beyond the individual, at a global level, the frequent lack of inclusion of wildlife in surveillance efforts may mean the difference between a misjudged, rabies-free locality and a newly appreciated enzootic area
43. Similarly, translocation of a rabid dog from a canine-enzootic area can threaten the status of another area that has eliminated canine RABV circulation, after great cost and years of effort
44. Such reports of importation are not uncommon in the literature, online sources such as ProMED, or communication in the daily news (
Although it is highly desirable to document the presence of new lyssaviruses during pathogen discovery, the basic surveillance information needed to prevent and control what is already known about RABV and its impact upon public health, agriculture, and conservation biology, using available, practical diagnostic tools, is more important (
mAbs can be isolated from immunized or infected humans or animals using a library of displayed antibodies (Fig. 1). Genes encoding the antibody heavy and light chains from B cells of immunized or infected humans or animals are cloned as Fab or scFv fragments and displayed, for instance on filamentous phage. Virus-specific antibodies are isolated by panning the libraries against antigens. This approach has been used to isolate potent neutralizing antibodies from the B cells of rhesus macaques immunized with recombinant adenoviruses carrying a synthetic gene encoding hemagglutinin (HA) of the influenza virus6 and from human IgM+ memory B cells of recent seasonal influenza vaccines.5 In addition to panning libraries constructed from antibody repertoires following infection, panning of native antibody libraries has yielded potent neutralizing antibodies against viral infections. For example, a broadly neutralizing HIV antibody (D5) was isolated from panning a native antibody library.21 It might be difficult to identify highly neutralizing antibodies when panning against native phage libraries, because of the lack of antibody somatic hypermutation process. This disadvantage may be overcome by an in vitro affinity maturation step or by panning of libraries constructed from immunized or infected human or animal donors in which antibody somatic hypermutations took place against a given virus. While phage display is an efficient way to generate viral neutralizing antibodies from immunized, or infected, or non-immune humans or animals, the resulting antibodies do not necessarily represent the natural antibody repertoire, since the antibody fragments are generated from the random paring of IgG heavy and light variable regions.22 Further, since a predefined and well-characterized antigen is required to pan the library, the approach is not suitable to identify new neutralizing epitopes of viral pathogens.22
Vaccination programs are one of the most effective means of controlling infectious diseases and with the development of oral vaccines and bait delivery systems, the elimination of diseases circulating in wildlife populations has become a realistic possibility. The large-scale oral rabies vaccination (ORV) campaigns that have eliminated fox-mediated rabies from Western Europe and North America and substantially reduced disease incidence in central Europe are pre-eminent examples for the success of such control programs.
ORV programs in foxes are aimed at increasing herd immunity in the target population using oral rabies vaccines distributed into the environment. Over the past four decades several oral rabies vaccines, mainly live replication-competent attenuated rabies virus vaccines, have been successfully used in ORV campaigns. In Canada for example, the ERA-BHK21vaccine virus strain, a derivative of the cell culture adapted vaccine virus strain Street Alabama Dufferin (SAD), was the only live attenuated vaccine deployed in fox ORV campaigns. In Europe, with the exception of a recombinant vaccinia virus expressing the rabies virus glycoprotein, all constructs have been based on live attenuated rabies virus strains, derived from the SAD Bern original (SAD Bernorig) vaccine virus strain, a successor of the ERA strain. While all these vaccines have been highly efficient in fox rabies control, the first generation of SAD-derived vaccines demonstrated residual pathogenicity in non-target species particularly in rodents. Although several cases of vaccine virus-induced rabies were observed even in species other than rodents over the course of vaccination campaigns in a number of countries, including Germany, Austria, Slovenia, Romania, Poland, and Canada, such cases were without epidemiological relevance.
While previous analyses using high-throughput sequencing approaches revealed substantial genetic heterogeneity within commercial SAD-derived oral rabies virus vaccines, the sub-consensus genetic heterogeneity of viruses isolated from these vaccine virus-induced rabies cases on the contrary revealed nearly clonal genotypes, indicating the presence of a strong bottleneck during infection.
In this study, we attempted to further analyze and elucidate the mechanisms of genetic selection using a combined deep sequencing, variant, and haplotype analysis of a large set of vaccine-induced rabies cases that included additional SAD- and ERA-induced rabies cases from Poland and Canada alongside vaccine virus batches. With this comprehensive approach, we could demonstrate the utility of this approach for identity and genetic stability (revision to virulence) testing of vaccines with a heterogeneous genetic background. Additionally, we were interested to know whether viruses from vaccine-induced rabies cases differ from virulent field rabies viruses (RABV) at a population level.
The global loss of biological diversity affects the well being of both animals and people. Human impact on ecosystems and ecological processes is well documented. Habitat destruction and species loss have led to ecosystem disruptions that include, among other impacts, the alteration of disease transmission patterns (i.e., emerging diseases), the accumulation of toxic pollutants and the invasion of alien species and pathogens. Ecological perturbations are creating a medium for new disease patterns and health manifestations. For example, in the marine environment, new variants of Vibrio cholerae have been identified within red tide algal blooms. These toxic blooms are occurring in greater frequency and size throughout the temperate coastal zones of the world. In arid zones of the southwestern United States, Brazil and Argentina, hantavirus epidemics have emerged in ecosystems that exhibit habitat degradation and climatic disturbances. These brief examples illustrate our growing awareness of the interrelationship between health and the environment. When the natural resilience of ecosystems is stressed and barriers to disease transmission are reduced the emergence, resurgence and redistribution of infectious diseases are obvious symptoms of a deteriorating planet. According to the World Health Organization, 30 new diseases have been described in people including AIDS, Legionnaire's disease, and toxic E. coli infections since the mid 1970s. Diseases like tuberculosis, temperate-zone malaria, hemorrhagic dengue fever and diphtheria are also re-emerging as threats.
Anthropogenic change can be considered the primary factor causing the emergence of infectious diseases including vector-borne diseases. Global warming, human population growth, deforestation, globalisation, wildlife trade and pollution of oceans and freshwater bodies may have an impact on the prevalence and distribution of infectious pathogens. The dynamics of disease emergence from wildlife are complex and bring human and domestic animal populations into increasing contact with wild animals potentially infecting wildlife with new pathogens causing high mortality, decline and even local extinctions. In some cases, wildlife will survive infection and will become reservoirs. As human populations continue to augment exponentially and globalisation is imminent with increased travel and trade, these anthropogenic pressures on wildlife habitat and populations also will increase. The result can be predicted as a continuing spillover of new pathogens shared among wildlife, domestic animals and humans.
Infectious diseases have been emerging and reemerging over millennia. Human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus (SARS-CoV), and the most recent 2009 pandemic H1N1 influenza virus are only a few of many examples of emerging infectious pathogens in the modern world. Each of these diseases has global societal and economic impact related to unexpected illnesses and deaths, as well as interference with travel, business, and daily activities. To overcome emerging, reemerging, as well as stable infectious diseases, the demand for development of efficient vaccines has greatly increased. Historically, live attenuated vaccines have provided the most effective protection against viral infection and disease. However, there have been safety concerns with the risk of reversion to the wild-type pathogen phenotype as shown with some traditional live attenuated vaccines such as the polio vaccine. Furthermore, development of live attenuated vaccines has not been successful for many important pathogens. On the other hand, inactivated vaccines are generally not very effective and require a high containment laboratory for cultivation of highly virulent pathogens. Also, there is a risk of incomplete inactivation for inactivated vaccines. Therefore, there is a need for an alternative approach for development of vaccines.
Replicating viral vector vaccines offer a live vaccine approach without requiring involvement of the complete pathogen or cultivation of the pathogen. Replicating viral vectors have the ability to synthesize the foreign antigen intracellularly and induce humoral, cellular, and mucosal immune responses. Specifically, vectored vaccines can have advantages for (i) viruses for which a live attenuated vaccine might not be feasible (i.e., HIV); (ii) viruses that do not grow well in vitro (i.e., human papillomavirus, hepatitis C virus, and norovirus); (iii) highly pathogenic viruses that present safety challenges during vaccine development (i.e., SARS-CoV and Ebola virus); (iv) viruses that lose infectivity due to physical instability (i.e., respiratory syncytial virus (RSV)); and (v) viruses that can exchange genes with circulating viruses (i.e., coronaviruses, influenza viruses, and enteroviruses). A vectored vaccine can be rapidly engineered against a newly emerging pathogenic virus by inserting the gene of the protective antigen of the virus into the genome of the viral vector. In general, the magnitude of the immune response to live viral vector vaccines is substantially greater and broader than that induced by vaccines based on subunit proteins or inactivated viruses. Furthermore, manufacturing of vectored vaccines against highly pathogenic viruses do not require a high level of biosafety containment laboratories.
Newcastle disease virus (NDV) is a fast-replicating avian virus that is prevalent in all species of birds. In most avian species, NDV infections do not result in disease. In chickens, NDV causes a highly contagious respiratory and neurologic disease, leading to severe economic losses in the poultry industry worldwide. NDV strains vary widely in virulence. Based on the severity of the disease in chickens, NDV strains are classified into three pathotypes: lentogenic strains which cause mild or asymptomatic infections that are restricted to the respiratory tract; mesogenic strains which are of intermediate virulence; and velogenic strains which cause systemic infections with high mortality. Naturally occurring low-virulent NDV strains, such as LaSota and B1, are widely used as live attenuated vaccines to control Newcastle disease in poultry. Although NDV primarily infects avian species, many non-avian species have also been shown to be naturally or experimentally susceptible to infection. The advent of a reverse genetics system to manipulate the genome of NDV not only allowed us to study the molecular biology and pathogenesis of NDV but also to develop NDV as a vaccine vector against diseases of humans and animals. NDV vector has several advantages over other replicating viral vectors.
Avirulent NDV strains are highly safe in avian and non-avian species. NDV replicates well in vivo and induces a robust immune response. In contrast to adeno, herpes, and pox virus vectors whose genome encodes a large number of proteins, NDV encodes only seven proteins and is thus less competition for immune responses between vector proteins and the expressed foreign antigen. NDV replicates in the cytoplasm, does not integrate into the host cell DNA, and does not establish persistent infection. Recombination involving NDV is extremely rare. NDV has a modular genome that facilitates genetic manipulation. NDV infects via the intranasal route and therefore induces both mucosal and systemic immune responses. A wide range of NDV strains exists that can be used as vaccine vectors. NDV-vectored vaccine can also be used as a “differentiating infected from vaccinated animals” (DIVA) vaccine. In this review article, we have reviewed the biology of NDV, development of reverse genetic systems for generation of NDV-vectored vaccines, and use of NDV vector for development of human and veterinary vaccines.