GENERAL INTRODUCTION: RHABDOVIRIDAE

Introduction

Rabies (rabidus, L. = mad) is a highly fatal disease of humans and all other warm-blooded vertebrates, caused by a lyssavirus which is present in the saliva during the late stage of the disease and which is generally transmitted by the bite of diseased animals, most commonly dogs. From the bite wound the virus enters peripheral nerves and, during an incubation period of weeks to months, it spreads to the spinal cord and brain to produce a range of severe neurological clinical signs.

Rabies occurred widely in Europe, Asia and Africa throughout recorded history, but did not had a significant impact on human and livestock populations similar to diseases such as bubonic plague, smallpox, contagious bovine pleuropneumonia or rinderpest. Descriptions of the disease can be traced back further in early Chinese, Egyptian, Greek and Roman records than descriptions of any other infectious disease.^{252, 301} Controversy raged for centuries as to whether the disease arose spontaneously, or was caused by an agent transmitted by a bite, and it was not until 1804 that Zinke³⁰⁹  published a description of the experimental transmission of the disease to dogs and cats by brushing saliva from a rabid dog into wounds. Galtier¹⁰² described the transmission of the disease to a laboratory rabbit, and Pasteur soon thereafter established the  association of the causative agent of rabies with nerve tissue. He demonstrated by serial intracerebral passage of infected nerve tissue in laboratory animals that wild or ‘street virus’ could be transformed into ‘fixed virus’ with a shortened and reproducible incubation period.²⁰⁵ In a logical extension of their work, Pasteur and his associates reasoned that vaccine could be administered to humans after exposure to rabies virus to induce immunity before the infection became established in the victim. They 'attenuated’ the virus by desiccating strips of infected rabbit spinal cord over potassium hydroxide and administered suspensions of increasing ‘virulence’ to patients, starting with material dried for 14 days and ending with material dried for two days. The technique was first applied in 1885 on a nine-year-old boy, who survived, and within a short period the technique found widespread application and had a lasting impact on rabies immunization practices.²⁰³ Despite the development of a vaccine, the true nature of the infectious agent remained obscure and it was not until 1903 that Remlinger²¹³ demonstrated that it passed through filters that retained bacteria, and thus conformed to the newly defined group of agents known as viruses. In the same year, Negri¹⁹⁵ described the occurrence of cytoplasmic inclusions in infected nerve cells.

Aetiology

Viruses in the order Mononegavirales, family Rhabdoviridae (rhabdos, Gr. = rod), genus Lyssavirus cause rabies. The genus was initially divided into serotypes according to antigenic cross-reactivity and later genotypes based on genetic characterization. It is now delineated according to viral species based on several criteria including genetic distance, antigenic patterns in reaction with anti-nucleocapsid monoclonal antibodies and, where available, information on ecological properties such as host and geographic range.  Currently, 16 lyssavirus species are recognized by the International Committee on Taxonomy of Viruses (ICTV); comprising rabies lyssavirus, the type species and the other 15 species are referred to as rabies- related lyssaviruses^{3, 261} (Table 1). Two additional bat- associated viruses, Taiwan bat lyssavirus from Taiwan¹¹⁸ and Kotalahti bat lyssavirus from Finland²⁰¹ are not yet officially classified. Lyssavirus species are also divided into phylogroups I, II and III (Table 1) based on immunological and pathological characteristics.

Table 1 Lyssavirus species occurring worldwide

Lyssavirus virions are bullet-shaped, rounded at one end and plano-concave at the other with a diameter of 60-110 nm and a length that varies from 130 to 250 nm.^{6, 79, 188} The genome consists of a segment of single-stranded, negative-sense RNA (complementary to mRNA), and there are five structural proteins.^{168, 246} The virions consist of a nucleocapsid, 160 × 50 nm, which is surrounded by a bilayer lipid envelope, derived from host cell membranes during budding, and through which flattened spikes (10 nm in length) or peplomers, each composed of three molecules of glycoprotein (G protein), project over the entire surface, except at the blunt end.^{87, 188} Underlying the lipid membrane is a layer of membrane or matrix protein (M protein), which binds to the nucleocapsid (N) protein of the viral core and holds the envelope in place. The ribonucleoprotein core of the nucleocapsid consists of the RNA genome, MW 4,5 × 10⁶ and about 12 kb in length^{247, 267} intimately bound to the phosphorylated N protein and this complex forms a tightly wound helix of 30 to 35 coils. The genome consists of a leader sequence followed by structural proteins 3’-N-P-M-G-L-5’ separated by intergenic regions and a 70 nt trailer sequence. Minor quantities of two more proteins are associated with the ribonucleoprotein complex: a phosphorylated protein, plus a large (L) protein which constitutes the viral transcriptase, an RNA-dependent RNA polymerase. The G protein consists of three domains; signal peptide ectodomain, transmembrane peptide and a cytoplasmic domain. It is responsible for the recognition of receptor sites for the attachment of virus on the surfaces of susceptible cells and for inducing production of and binding with protective, virus-neutralizing antibodies. Antigens associated with the N protein and possibly with the other proteins of the ribonucleoprotein complex can also induce a degree of protective immunity.^{86, 88, 101} There is high homology in the deduced amino acid sequences of the N proteins of different strains of rabies virus (RABV) and this is reflected in the highly conserved antigenic structure of the N protein generally observed in tests with polyclonal antisera, although differences are readily discernible with monoclonal antibodies.^{62, 158, 227, 229, 256}

Lyssaviruses are sensitive to sunlight and ultraviolet irradiation, heat, detergents, halogens and lipid solvents. Infectivity is destroyed within minutes by 0,2 per cent quaternary ammonium compounds, 1 per cent soap solution, 5 to 7 per cent iodine solution or 45 to 70 per cent alcohol.¹³⁷ Heating up to 56°C for 30 minutes also inactivates the virus, or exposure to 50 per cent ether or low concentrations of sodium desoxycholate, formalin or beta-propriolactone for a few hours. Infectivity is labile in suspensions of less than 0,1 per cent tissue extract without the addition of protective protein but is stable for weeks in nerve tissue held in glycerol saline at room temperature (22°C) or for months at 4°C. The virus can be preserved for years at temperatures below -60°C, or by freeze drying and storing at 40°C.¹⁴²

Epidemiology

The prototype species of the lyssavirus genus, RABV, is distributed worldwide among several mammalian species and responsible for most animal and human deaths with the domestic dog constituting the major vector (Table 1). Only a few countries or territories, mostly islands, are considered terrestrial rabies free.²⁹⁶ Rabies virus occurs worldwide in terrestrial carnivores, but occurs in bats only in the Americas. Although RABV is not present in bats in the rest of the world, it was hypothesized that bat ancestry is common to all classical RABV variants affecting terrestrial carnivores, with multiple introductions at different time points.^{15, 122, 165} These variants can be distinguished based on antigenic characteristics using monoclonal antibodies^{220, 242} or by nucleotide changes in the genome (molecular epidemiology).^{193, 225} A specific variant usually circulates in a specific reservoir host with transmission to other species (spillover) dependent on the opportunities for interaction and the characteristics of the virus and host.⁴⁵

Molecular epidemiology has enabled division of RABV into two distinct phylogenetic groupings, dog-related RABV and bat-related RABV both which are further divided into several distinct lineages with the cosmopolitan dog related lineage the most widely distributed.^{47, 269} The similarity of canine variants from different continents suggests a common source with historical origins in the Palearctic region including Europe, Middle East and Northern Africa, with dissemination due to translocation of dogs by early European colonialists to the rest of the world. Within this lineage several unique clades can be identified.^{46, 141, 182, 241} Spillover infections are also observed in other species that may or may not lead to sustained transmission by the second species. In addition to the cosmopolitan lineage other unique lineages also exist; Africa 2 is widely distributed in sub-Saharan western and central Africa in dogs,²⁵⁸ Africa 3 circulates in carnivores of the Herpestidae family in southern Africa.¹⁴¹ The Arctic lineage was originally reported to be associated only with the red and artic fox populations in the Arctic regions of North America but recent studies indicate that it emerged from Asia and spread rapidly and within several species.¹⁵⁴ The Indian sub-lineage is unique to dogs in Sri-lanka and southern India, with frequent spillover to other domestic animals.^{9, 128} The Asian lineage is widespread throughout Asia with dogs as the most important vector.⁴⁷ A lineage present in several bat species in the Americas, with spillover and sustained transmission in terrestrial carnivores, is evolutionarily distinct from all other RABV lineages.

Successful dog vaccination campaigns in Europe and North America markedly reduced the occurrence of dog-associated rabies, and recent improvements in dog vaccination coverage in Latin America has similarly reduced the disease burden in humans significantly.^{32, 230} However, an alarming number of animal and human cases are still reported from the developing continents of Asia and Africa. Accurate estimates of human rabies are impossible to establish due to lack of surveillance and laboratory confirmation. There is however always a close relationship between rabies in domestic dogs and human deaths. Globally dog-mediated rabies is estimated to cause about 59 000 human deaths, 3.7 million disability-adjusted life years (DALYs) and 8.6 billion USD worth of economic losses annually.^{107, 143} Significant losses also occur in livestock, a particular example being the heavy losses of cattle associated with rabies transmitted by vampire bats in Central and South America.¹³⁰ Although the disease is completely preventable, control of rabies in developing nations is hampered by poverty, the inexorable trend toward uncontrolled urbanization, sociopolitical turmoil and wars, as well as the lack of political will, national infrastructure and financial resources required for dealing with the disease.¹⁶³ Dog-mediated rabies occurs particularly where there are large populations of unrestricted dogs and in much of the world. The concept of dog ownership varies with socioeconomic class and ethnicity of people. Not all dogs which are left unrestricted to fend for themselves are genuine strays, and there may be repercussions when, for instance, decisions are made to eliminate dogs which are found to be inaccessible for rabies vaccination.¹⁸⁶  

Africa

An estimated 36 per cent of global human rabies deaths occur on the African continent, with the domestic dog as the major vector.^{90, 107} Even though surveillance is inadequate, it can be accepted that RABV is endemic in all countries in Africa, with the history of the disease before the 20th century poorly recorded.²⁵⁷ The cosmopolitan lineage, Africa 1, is the most widespread with Africa 2 and 3 having more restricted geographical distributions.

Rabies was diagnosed for the first time on the African continent during an outbreak in dogs in the Eastern Cape Province of South Africa in 1893, although historic writings suggest that suspected rabies cases had previously occurred in that country some time prior to this, in dogs and in humans. Since then Africa 1 has become well adapted to domestic dogs, with infection assuming epidemic proportions in some geographic areas. Surveillance is deficient in wildlife, but animals affected include the side-striped jackal (Canis adustus) and black-backed jackals (Canis mesomelas) (Figure 1),^{34-37, 40} bat-eared foxes (Otocyon megalotis) (Figure 2),^{81, 263} the kudu antelope (Tragelaphus strepsiceros),^{26, 27, 119, 172} civets (Civettictis civetta), honey badgers (Mellivora capensis),several antelopes, genets, hyraxes (Procavia capensis), the brown hyena (Hyaena brunnea) and Selous’, banded and dwarf mongooses (Paracynictis selousi, Mungos mungo and Helogale parvula). The virus has also emerged in wildlife vectors with serious conservation implications, for example, in the Ethiopian wolf (Canis simensis) in Ethiopia²³⁵ and African wild dogs (Lycaon pictus) in Tanzania and South Africa.^{110, 116, 117} The distribution in wildlife vectors overlaps the geographic distribution of the specific host.²²³ For example the black-backed jackal has a wide distribution from South Africa to Sudan and has been identified in several studies as an important maintenance host with spillover to other species like the bat-eared fox that can also act as a maintenance host in certain regions.^{35-37, 40, 224, 310}

Figure 1 Black-backed jackal (Canis mesomelas)

Figure 2 Bat-eared foxes (Otocyon megalotis)

Figure 3 Yellow mongoose (Cynictis penicillata)

The only herbivorous species that has maintained transmission in Africa is the kudu antelope (Tragelaphus strepsiceros) in Namibia where the Africa 1 lineage is endemic.²³² The first outbreak occurred in 1977-1985 during which an estimate of 30 000 to 50 000 kudus died.^{119, 257} With several peaks and troughs in the numbers of observed cases through the decades, this is still ongoing.^{172, 232} An increase in jackal rabies was noted prior to the epidemic and it was surmised that rabid jackals initiated the infection in the kudus but the number of cases recorded in the antelope was disproportionately high in comparison to that in jackals, suggesting that the disease was also transmitted directly between kudus. In recent years, phylogenetic and full genome sequence analyses showed several correlations between RABV strains from Namibia and attenuated strains. Since these vaccine strains originated from Europe, the relatedness with viruses circulating in Namibia can be expected given that dog rabies was introduced into southern Africa during the mid-20th century via Europe. However, it is significant that several unique mutations were found in RABV strains from kudu, suggesting that these occurred due to the adaptation of the virus to the host. Such evidence strongly supports the argument that an independent RABV cycle is maintained in kudu and that this cycle can be distinguished from jackal rabies cycles in Namibia.²³² Rabies virus is not ordinarily resistant enough for indirect transmission to occur through contamination of the environment with infected saliva, and it is believed that transmission between kudus was favoured by their propensity to indulge in self and mutual grooming, and by the fact that oral transmission would have been facilitated by the mouth injuries which kudus sustain when browsing on the Acacia thorn trees which predominate in the affected area. The infection was apparently communicated to other herbivores, since the epidemic in kudus was followed by a surge of rabies in cattle and to a lesser extent in eland antelope (Taurotragus oryx), which are grazers by preference.

A different RABV virus lineage, Africa 2, circulates in West Africa (Mauritania, Guinea, Ivory Coast, Burkina Faso, Cameroon, Benin, Nigeria and Chad) together with Africa lineage 1.^{111, 112, 141} A unique RABV variant, Africa 3, that is distinct from the cosmopolitan canine virus in Africa, is well adapted to various herpestid or mongoose species in southern Africa,¹⁹⁷ also referred to as the mongoose biotype (Figure 3). This mongoose RABV is present in several different and geographically defined lineages,^{198, 278} lending strong support to the historical view that mongoose RABV, unlike the cosmopolitan canine variant (canid biotype), is indigenous to southern Africa and has been present in the region for an unknown number of centuries.^{81, 244} Hosts associated with a specific biotype/lineage tend to excrete the virus more readily than other biotypes, leading to more efficient maintenance although spillover to other species is also possible.

Asia

Rapid population growth and urbanization in much of Asia have created conditions which are highly conducive to the occurrence of rabies and the cosmopolitan lineage is wide spread throughout the Asian continent.^{153, 180} Several thousand cases of rabies in dogs are recorded each year in China, India, Pakistan, Indonesia, Thailand and Vietnam. Countries such as Bangladesh, Burma, Iran, Iraq and the Philippines report thousands of human cases or post-exposure prophylaxis of humans compared to very few cases of animal rabies reported.^{106, 307} India has the highest number of human rabies deaths in the world, with estimates ranging from 15 000 to 25 000 cases per annum, but it has been argued that the true figure may be as low as 4 000 cases per annum.⁵ Monitoring of rabies in livestock and wild vertebrates is even more deficient than in dogs and humans, but mongoose, jackal, foxes and wolves have been incriminated as wildlife hosts.^{106, 153}  

Europe

In Western Europe, outbreaks of rabies involving dogs, foxes and wolves were described in the eleventh and thirteenth centuries, but rabies only became widespread after the industrialization of the eighteenth century.^{52, 251} From the time of the Second World War, rabies in the red fox (Vulpes vulpes) spread steadily westwards from an original focus in eastern Poland in 1935, to reach France by 1968, with simultaneous eastward extension of the epidemic into the former USSR, and many countries in Europe each reported one to several thousand cases of the disease in foxes per annum in the 1970s and 1980s.⁴¹

Field trials on oral vaccination of foxes were conducted in Switzerland in 1978 and a sustained oral vaccination campaign was started in Switzerland in 1985, in France in 1986, and in 13 other European countries shortly after that.^{12, 13} After minor setbacks, fox rabies was virtually eliminated from Western Europe by the end of the century, and it became necessary to extend the campaign into Eastern Europe to prevent re-introduction of the virus to the west.

Dog rabies was still highly prevalent in western Europe in the 1940s and 1950s, but the use of increasingly effective vaccines and the rigorous application of control methods over four decades reduced the annual incidence of the disease from thousands of cases to the point where the few cases in dogs, cats, domestic ruminants and occasional deer, badgers and martens represented spill-over of infection from foxes.⁴¹ Fortunately, cats and dogs are partially resistant to the fox virus strain of RABV.⁴² To date, several European countries have become terrestrial rabies-free. Human rabies virtually disappeared from Western Europe with the decline in dog rabies; people seldom acquire infection from foxes and most of the occasional cases of the disease seen recently have occurred in persons exposed to infection elsewhere.

Dog rabies remains a problem in parts of Eastern and Southern Europe, especially in the Balkans and in enclaves in the southernmost areas of the former USSR. Elsewhere in the western and southern portions of the former USSR, the red fox is the major host of rabies, but the raccoon dog (Nyctereutes procyonoides), a fur-bearing animal translocated from eastern to western USSR in the 1930s and 1940s, is an increasingly important vector that has migrated westwards through the Baltic republics to become established in Poland and Finland.⁶³ Arctic rabies, regarded as an ancient and epidemiologically distinct lineage, extends across the northern part of the former USSR, Finland, the Svalbard Islands of Norway, Greenland, the Northwest Territories of Canada, and Alaska. The Arctic fox (Alopex lagopus) is the principal vector throughout but there is spill-over of infection to wolves, bears, seals, sled dogs and reindeer. Wolves (Lupus lupus) are extinct in much of Europe but are still important vectors in parts of Iran, Afghanistan, Iraq and the former USSR.

North America

In North America, rabies was first described in dogs and foxes in New England in the mid-eighteenth century and it has been suggested that the disease was introduced via dogs by European colonists.^{303, 304} In contrast, there is a long history of the disease in Inuit folklore, and Arctic rabies may have been introduced into North America from northern Asia during the migration of humans and other animals across the Bering land bridge 30 000 to 75 000 years ago.^{303, 304} Dog rabies became widely distributed in the United States of America (USA) in the second half of the nineteenth century following the civil war but following the institution of increasingly effective control measures in the 1940s and 1950s, the incidence of dog rabies declined steadily with no cases being recorded in humans 1988. At the same time, however, there was a steady increase in sylvatic (wildlife) rabies and by 1988 wild vertebrates (mainly skunks, raccoons, bats and foxes) accounted for 88 per cent of cases of rabies in the USA, with the remaining cases occurring in domestic cats and herbivores, and in dogs particularly in the Texas–Mexico border area. Dog rabies extended across the USA border into central and eastern Canada early in the twentieth century and, as in the USA and western Europe, was brought under control following the introduction of effective vaccines in the 1940s and 1950s. Again, there was an increase in sylvatic rabies as the disease in dogs declined, and by 1988 wild vertebrates accounted for 80 per cent of confirmed cases of the disease in Canada. 

The escalation of sylvatic rabies in Europe and North America after the 1940s arose as a series of outbreaks that involved the spread of infection in specific hosts within separate geographic regions.²³⁸ In a given area, the disease is manifested predominantly by a single host species, or rarely by more than one, and this same host appears to be responsible for the maintenance and spread of the virus. Disease in other animals represents spill-over of infection resulting from sporadic contact with the major host species.^148-150 Proof that the circulation of RABV strains is compartmentalized in vertebrate species came from monoclonal antibody and phylogenetic studies, which in effect resulted in the recognition of virus biotypes/strain/lineages. It was found that RABV which affects the North American red fox (Vulpes fulva) in south-eastern Canada and northern New York State, USA, corresponds to the Arctic fox virus lineage that emerged from Asia;^{153, 193} that virus in the striped skunk (Mephitis mephitis), which engulfed the north-central states of the USA and south-central Canada, is of a different lineage from that which occurs in skunks in the south-central states and another occurring in northern California;^{192, 194, 276}  virus associated with rabies in the raccoon (Procyon lotor) in the Atlantic states corresponds to the endemic raccoon lineage of south-eastern USA, from which it was apparently derived through translocation of raccoons by hunters in 1977¹²⁹ and that separate lineages occur in grey foxes (Urocyon cinereoargenteus) in Arizona and Texas.²¹⁴ Rabies virus which affects dogs all over the world, appears to have transferred between canine species, an example being the spread of dog virus in coyotes (Canis latrans) in southern Texas.²⁷⁵

Despite early reports to the contrary^{202, 243} infection of bats with RABV has been confirmed as occurring only in the Americas.²³⁸ The first isolations of RABV from non-haematophagous bats were made in the course of investigations into vampire bat-associated rabies in Trinidad in the 1930s, but these aroused little interest until 1953, when recovery of the virus from an insectivorous bat which attacked a child in Florida, USA, prompted an investigation. This culminated in isolations being made from most indigenous species of insectivorous bats of the USA and temperate Canada, and from virtually all of the countries of Central and South America. The occurrence of rabies in bats does not exhibit the same marked geographic bias as that which occurs in terrestrial vertebrates in North America, but there does appear to be analogous compartmentalization of circulation of the virus in some species with spill-over of infection to others. Transmission seems to be limited to closely related bat species and monoclonal antibody and phylogenetic studies revealed that more than 30 distinct lineages of virus circulate in insectivorous and vampire bats in the Americas. There is a tendency for migratory species of bats, either colonial or solitary, to yield the same lineage in different locations while sedentary species may yield a variety of lineages.^{80, 241, 254} Interestingly, the sporadic cases of rabies in humans and livestock which occur in parts of North America, where the disease is not known to be present in terrestrial vertebrates, are most frequently found to be associated with bat lineages of RABV and the isolated cases of rabies which occur in humans in the USA each year are almost all caused by RABV associated either with the silver-haired bat (Lasionycteris noctivagans) or the eastern pipistrelle bat (Pipistrellus subfavus).^{181, 185} A limited number of cases of rabies occur in immigrants exposed to infection with dog RABV abroad. A bat variant of RABV had become established in skunks in northern Arizona in 2001. A control programme of trapping, vaccinating and releasing skunks was instituted, and it remains to be seen whether the transmission has been successfully interrupted.¹⁵⁵

At the end of the twentieth century, the USA was still experiencing thousands of cases of animal rabies per annum, with over 80 per cent occurring in wildlife. Raccoon rabies extended from Florida to Maine, and had spread northwards into Ontario, Canada, and westwards to Ohio, overlapping fox rabies in the north, and skunk rabies in the west.²⁸¹ Control of wildlife rabies has proved to be more difficult in North America than in Europe, largely because the problem is more complex, with vast areas and multiple vector species being involved.²³⁶

Central and South America

At the USA-Mexico border there is an abrupt transition from the predominantly wildlife rabies of North America to the dual problem of dog mediated rabies (cosmopolitan lineage) and sylvatic rabies in vampire and other bat species. Vampire bat-associated rabies was apparently first encountered by Spanish colonists early in the sixteenth century. The problem was exacerbated by the growth of the ranching industry in the late nineteenth and early twentieth centuries, which provided highly suitable hosts for vampire bats, and roosting sites in otherwise inhospitable grasslands through the digging of wells.¹³⁰ There are three species of the vampire bat, each belonging to a separate genus, but Desmodus rotundus is the most common and the most important transmitter of rabies.^{144, 145} Vampire bats occur only in Central and South America and Trinidad, from 28°N in Mexico to 33°S in Argentina, and throughout this region they are associated with a paralytic form of rabies which affects mainly cattle, but also to a lesser extent humans and other animals.^{76, 287} The disease of cattle, known colloquially as derriengue (limping illness) or mal de caderas (hip illness), is most prevalent in Brazil, Mexico, Venezuela and Argentina, and total losses have been estimated at 100 000 to more than 500 000 cattle per annum. The true figure may be much greater since more than 260 000 cattle are believed to have succumbed in part of Bolivia alone in one year. Although there are no records of humans acquiring infection from butchering the carcasses of rabid cattle in South America, it is known that virus occurs in saliva and salivary glands of a low proportion of such cattle.⁸⁴  

Dog mediated rabies constituted a serious problem in Latin American cities such as Mexico City, Lima, Bogota, Sao Paulo and Buenos Aires, which are among the most populous cities in the world. Concerted urban vaccination campaigns have improved the situation markedly since 1980.² The concomitant reduction in human rabies cases has been a notable success.^{83, 277}

Caribbean countries

During the 1860s and 1870s, the small Indian mongooses (Herpestes auropunctatus) of India was deliberately introduced into certain Pacific and Caribbean islands and a few mainland countries in South America with the intention that it would control rats and snakes in sugar cane plantations. However, it filled a vacant carnivore niche and in less than two decades had multiplied to the extent that it had itself become a pest.⁹⁴ Rabies was first recognized in the mongoose in Puerto Rico in 1950, and since then the disease has been diagnosed in Cuba, Dominica, Haiti, Grenada and the Virgin Islands. The mongoose is the dominant host of the virus (cosmopolitan lineage) in most instances, although dogs are also important hosts on some of the islands as well as the vampire bat where present.²⁶⁶ Many Caribbean countries which are currently free of rabies have large mongoose populations, and thus have the potential for the spread of the disease. The incidence of rabies in dogs in the Caribbean has decreased dramatically due to successful vaccination campaigns.²⁷⁷

Pathogenesis

There are many variations to the pattern of rabies pathogenesis and this can be ascribed to differences in virus strain and dose, route of infection and host factors, including inherent susceptibility of the species and immune status.¹²⁶ Johnson and Murphy have drawn attention to the fact that the sequence of events in the pathogenesis of rabies is diabolically well suited to the perpetuation and spread of the disease: virus is hidden from immune surveillance until it is too late to matter; early selectivity for the limbic system and relative sparing of the neocortex result in behavioral changes which promote confrontation between rabid and susceptible animals; the occurrence of the brain infection and onset of altered behaviour coincide with virus being available for transmission in saliva; the high mortality serves to ensure that there is minimal accumulation of immune animals in the population; and the occasional occurrence of long incubation periods ensures that the virus survives until susceptible individuals are recruited to the population.^{132, 189}  

Rabies is ordinarily transmitted by the bite of an infected animal accompanied by the presence of the virus in saliva that varies with virus type and species of infected animal.⁵⁷ Following a deep introduction by bite, the virus enters the peripheral nervous system either through neuromuscular spindles (stretch proprioceptors consisting of modified muscle cells wrapped in unmyelinated nerve endings) or through motor end plates (motor nerve endings in muscle cells).²⁸⁹ There is evidence that infection of the nervous system can occur through the attachment of the virus to the nicotinic acetylcholine receptors at neuromuscular junctions,⁵⁵ the neuronal cell adhesion molecule²⁶⁴ and the p75 neurotrophin receptor. Other components of the cell membrane such as carbohydrate moieties of the phospholipids and glycolipids may also participate in cell entry¹²⁶ and it can be concluded that the virus probably uses different receptors for different cells.¹⁵⁷ Following their attachment to the cell surface, virus particles are internalized by endocytosis and the virus in cytoplasmic vesicles is uncoated by fusion with lysosomes.¹⁸³ The ribonucleoprotein complexes are released into the cytoplasm and constitute active templates for transcription of the genome. Transcription and replication occur in the cytoplasm of the infected cell, and virus matures and is released by budding through the cell surface membrane.^{71, 207, 268}

After a variable period of hours following inoculation, RABV enters a so-called eclipse, during which infectivity can no longer be demonstrated at the site of inoculation or elsewhere, but during which the virus may nevertheless have initiated infection of cells at the site of inoculation, or have been transported in non-demonstrable low concentration in nerves towards the central nervous system (CNS).¹⁶ The virus is capable of entering nerve endings immediately and leaving the site of inoculation rapidly: virus particles may accumulate at motor nerve endings within one hour of inoculation, nerve resection or amputation of limbs within four hours may fail to save the lives of a proportion of mice inoculated with a fixed (laboratory passaged) strain of virus in the foot-pad, and virus inoculated into a front paw in mice can initiate replication in neurons of the dorsal root ganglia and spinal cord within 18 hours.²⁸⁹ In contrast, mice inoculated with a strain of virus producing incubation periods of one to three months, similar in duration to those occurring commonly in humans, can be saved by limb amputation up to 18 days after inoculation, i.e. the virus can remain at the site of inoculation for a prolonged period, implying that there is replication of virus in non-neural tissue at the site of inoculation.²⁰ Such replication has been demonstrated in myocytes within 36 hours of inoculation of the virus, and it appears that the virus can remain in muscle at the site of inoculation for up to 28 and possibly 35 days, but ultimately the muscle infection is abortive.⁶¹ Theoretically, infection of muscle can proceed in parallel with the infection of nerves, but there is the clear implication that in some instances replication of the virus in muscle occurs as a preliminary to the infection of nerves, and this may account for the delay in disease development which occurs in incubation periods of intermediate duration. However, it is not universally accepted that infection of myocytes is a link in the pathogenesis of the disease and the site of sequestration of the virus during long to extreme incubation periods remains undetermined.⁵⁸  

Once the virus has entered nerves, there is passive centripetal transport of subviral genome-containing particles, presumably ribonucleocapsids, by retrograde axoplasmic flow to the CNS.¹⁸⁹ Spread of virus in the spinal cord proceeds via axons and dendrites, and the process is thought to involve either prior maturation of virions by budding on intracytoplasmic membranes or direct transfer of genome-containing moiety through membrane fusion at synaptic junctions.¹⁸⁹ Hence, the spread of infection occurs between neurons that have nerve connections and it is notable that there does not appear to be direct spread of infection from cell body to cell body between contiguous neurons in the spinal cord.⁷² The initial cycle of virus replication in the spinal cord is followed by further cycles at intervals of several hours with an exponential increase in the number of infected neurons. Spread does not proceed in a strictly progressive fashion: the virus can leap-frog via nerve connections from an infected neuron to another in a distant segment of the spinal cord, and infection can reach the brain stem in a matter of days. Spread of infection is rapid within the brain, with some tendency to occur in a spatially integrated manner whereby adjacent structures are involved in turn,²²⁶ i.e. infection tends to spread from the medulla and pons to the cerebellum, thalamus and hypothalamus, the limbic system (palaeocortex) and ultimately to the neocortex.  In nerve cells, the virus matures predominantly on internal membranes.¹⁷⁹ Accumulations of viral proteins in the cytoplasm constitutes the inclusions seen histologically in infected cells, and accretions of virus particles account for the 'inner structure' described for Negri bodies.^{166, 177, 178} The replication of RABV is slower, less abundant and less inhibitory of host cell macromolecular synthesis than that of vesiculoviruses, and the virus is less inclined to produce readily discernible cytopathic effects.⁷⁵

Although infection is usually widespread in the brain in the agonal stages of the disease, there is a tendency for lesions to be most advanced and for highest concentrations of virus antigen to occur in particular locations, and these localizations may account for characteristic signs of the disease.⁵⁷ Thus, early selectivity for the limbic system which controls the emotions, with relative sparing of the neocortex, could explain the initial retention of alertness with the manifestation of aggressiveness, sexual arousement and loss of fear which often characterizes the disease. Indeed, most of the signs of the disease can be ascribed to neural dysfunction, but there is some uncertainty as to the extent to which this represents dysfunction of neurons, or interference with neurotransmission, possibly resulting from blockage of post-synaptic receptors by virus particles. From the time that the infection reaches the CNS, passive centrifugal spread of the virus by anterograde axoplasmal flow proceeds simultaneously with centripetal spread. Within hours of virus reaching a point in the spinal cord ipsilateral to the inoculation site, for instance, the infection may become demonstrable in contralateral dorsal root ganglia and nerves.⁷² Centrifugal spread proceeds throughout the body, resulting in a variable degree of infection of non-neural cells, and virus or antigen has been demonstrated in terminal illness in a range of tissues and organs, including the cornea, nerve fibres surrounding hair follicles, the interscapular brown fat in bats, myocardium, lungs, pancreas, adrenal medulla, kidneys and bladder, as well as in milk, tears and urine.⁵⁷

Spread to the salivary glands coincides with widespread dissemination of infection in the brain, and the virus, which matures predominantly on internal membranes of neurons up to this stage, exhibits a remarkable adaptation during replication in the acinar epithelial cells of the salivary glands by budding from the apical surfaces of the cell plasma membranes directly into intercellular caniculi and acinar lumens, apparently in a highly infective form, i.e. uniform virions free of debris and DI particles.⁸⁵ However salivary gland infection is not always present and shedding of the virus in the saliva is intermittent. For example, salivary gland infection rates of more than 80 per cent have been recorded in naturally infected cattle, kudus and black-backed jackals; infection rates of 20 to 74 per cent have similarly been recorded in the salivary glands of naturally and experimentally infected dogs, and 70 to 80 per cent in cats.⁵⁷ The infection has been demonstrated in salivary glands or saliva up to 13 days before the onset of illness in dogs and three days in cats.^{96, 274} Titres of virus detected in the salivary glands of experimentally infected dogs ranged from 10¹ to 10^7,3 mouse intracerebral 50 per cent lethal doses (MICLD₅₀) per gram of tissue and were slightly higher in cats than in dogs.^{96, 273}

The actual amount of virus transferred by bite presumably varies markedly and would be difficult to determine. For comparative purposes, the susceptibility of vertebrate species to rabies has been determined by a standard method that involves the inoculation of salivary gland virus from a naturally infected host into the masseter muscle and where experimental data are lacking, estimates have been based on cumulative epidemiological information. Foxes, coyotes and jackals have been rated as extremely susceptible; skunks, raccoons, cats, cattle, mongooses and most rodents as highly susceptible; dogs, sheep, goats, horses and primates including humans as moderately susceptible, while opossums are considered to have a low susceptibility to infection with RABV.⁹⁸ Generalizations are misleading, however, and susceptibility to a particular virus is not invariably predictable by either the size of an animal or its phylogenetic relationships.

The severity, location and multiplicity of bites inflicted on the victim also influence the outcome of exposure to infection, and bites on the head and neck are generally associated with the shortest incubation periods and the highest mortality rates. Most reports of non-bite transmission of rabies have dealt with sporadic incidents, but the phenomenon may assume greater significance in particular circumstances. Oral infection through the ingestion of infected milk from the mother has been recorded in a lamb and a human baby.⁴ The occurrence of infection through scavenging, cannibalism or predation is potentially of epidemiological importance.⁵⁷ Oral transmission of RABV between herbivores is believed to have been an important factor in the epidemic which occurred in kudus in Namibia and was earlier suspected to have occurred in an outbreak of rabies in deer in Britain during the nineteenth century.^{26, 27, 124} Aerosol transmission may have occurred in two humans who were exposed to the breath of a rabid wolf without being bitten or scratched, according to an early report from Europe,¹⁴ but no similar events have subsequently been recorded. In 1957 and 1960, rabies was diagnosed in two humans who had separately visited a bat cave in Texas, USA, and it was shown that animals placed in insect-proof cages in the cave acquired the aerosol infection, and subsequently, virus was isolated from the atmosphere of the cave.^{69, 70} It was stressed that conditions were unique in the cave, with rabies being highly endemic in the more than 20 million bats which roosted there.^{303, 304} Non-contact transmission was subsequently observed in a poorly ventilated laboratory animal colony where experiments were being conducted with bat isolates.³⁰⁵ In 1972 and 1977, infection occurred in two persons who worked with a high titre of RABV in laboratory equipment which generated aerosols.⁷  Nerve tissue is particularly exposed in the nasal cavity and experimental infection with RABV by the intranasal route has been demonstrated in laboratory rodents, rabbits, bats and skunks.^{18, 60, 190} Transplacental transmission of infection has been demonstrated in the foetus of a pregnant cow which had died of the disease,¹⁷⁵ and it has been recorded in dogs, and once in a human patient.²⁸⁸ There have also been cases in which infection was transmitted by the transplantation of corneas from cadavers in the USA, France, Thailand, and Iran, while a further potential case in France is believed to have been averted by intensive post-exposure prophylaxis and treatment with interferon. Cases after  organ transplants (kidney, lung, pancreas and liver) have been reported from the USA, Germany and China.^{131, 169, 249, 279, 308}

Immunity

The role of the immune response is complex in rabies. There is no doubt that pre-exposure vaccination is protective in humans and animals and that post-exposure immunization is effective in humans.^{22, 221} The response to the administration of inactivated virus or attenuated live virus is three-fold: there is the production of interferon, circulating antibody and induction of cell-mediated immunity, with antibody becoming demonstrable and interferon and cell mediated responses being maximal six to ten days after inoculation of virus.²⁹⁷ Attenuated strains of virus used as veterinary vaccines produce abortive infection of the CNS, and all three components of the response to infection contribute to the clearance of virus; immunosuppression renders infection of adult mice with the attenuated virus fatal.²⁴⁰

Peripheral immunization does not necessarily protect against intracerebral challenge since antibody does not penetrate the blood–brain barrier, and the demonstration of antibody in cerebrospinal fluid implies that virus has reached immunocompetent cells within the CNS.³¹ The blood–brain barrier is only breached late in symptomatic or fatal infection.¹⁶⁷ The intracellular location of RABV in nerve tissue and its direct manner of spread from cell to cell renders it inaccessible to an antibody, as evidenced by the inability of an antibody overlay to prevent the spread of infection in in vitro cell cultures.⁸⁹ Apart from the possible direct action of antibody on extracellular virus in the infective inoculum, it is postulated that humoral immunity protects through antibody- and complement-mediated lysis of infected cells, such as myocytes, which express viral antigen on their surfaces, neutralization of released virus and sequestration of the immune complexes formed by virus and antibody in phagocytic cells.¹⁶⁷

Mice that have been rendered T-cell deficient are more susceptible to infection with attenuated or virulent virus than B-cell deficient mice, confirming that both humoral and cell-mediated immunity are required for optimum clearance of infection. Survival correlates better with cytotoxic T-cell response than with interferon or antibody responses.^{138, 139, 184, 298, 299} Cell-mediated immunity acts through cytotoxic lysis of infected cells, but it appears that the induction of antibody responses is also dependent on T-helper (T_h – also known as CD4) cells since athymic nude mice succumb to infection without producing antibody.^{298, 299} Furthermore, T-cells, including helper-suppressor and cytotoxic cells, are responsible for the release of interferon.¹⁶⁷ It has been shown that timely administration of exogenous interferon or interferon inducers is beneficial in overcoming rabies infection.²⁹⁷

In contrast to killed or attenuated virus, infection with the street virus does not induce a cell-mediated immune response, although antibody responses become demonstrable in seven to ten days if a high dose of virus is inoculated.^{298, 299} Following inoculation of low doses of street virus or occurrence of natural infection, antibody response only becomes demonstrable after the onset of illness, irrespective of the duration of the incubation period. In humans, antibody is detectable five to ten days or more after the onset of signs of the disease.¹²⁶ It appears that little or inadequate antigen is presented to immuno-competent cells in the inoculum in natural transmission and once nervous infection occurs, virus is protected in its intra-cellular environment and is further protected from host immune surveillance by myelin sheaths and the blood–brain barrier, as well as by the paucity of lymphatic drainage and lymphocyte trafficking in nerve tissue.¹⁸⁹ Moreover, virus replication produces little cytopathology which would facilitate the presentation of antigen to immune surveillance. Following its long trajectory in the nervous system, virus antigen ‘surfaces’ from its immunologically privileged position when the blood-brain barrier is breached during the spread of infection in the brain, and when non-neural tissues, such as salivary glands, become infected as a result of centrifugal spread of the virus.

The relative lack of inflammatory response in the CNS of non-immunized animals which develop rabies^{189, 208} as opposed to other viral infections of the nervous system, has been attributed in the past partly to the relative lack of antigenic stimulus early in the infection and partly to the suppression of cell-mediated immunity which occurs in rabies, as discussed above. It was shown in monoclonal antibody studies in lethally infected mice that there is virtual disappearance of the T-lymphocyte subpopulation responsible for cytotoxic response.³⁰⁰ However, it is now known that the nervous system, including eyes, brain and nerves, is an immunoprivileged site for a number of reasons: tight endothelial cell junctions and lack of lymph ducts constituting the so called blood–brain barrier not only restrict lymphocyte migration, but also passage of antibodies and complement.¹⁵⁶ Moreover, there is a lack of antigen presenting cells in the nervous system; the MHC I and II molecules are down-regulated in healthy neurons, which are consequently unable to present antigen to activate T cells. Following injury, infection or stress that occurs late in rabies infection, glial cells can act as antigen presenting cells but they cannot migrate from the CNS to secondary lymphoid organs to trigger a primary immune response. Dendrocytes in meninges, the choroid plexus and cerebrospinal fluid can migrate to regional lymph nodes to initiate a response, but when activated lymphocytes bearing Fas molecules on their surface subsequently enter the nervous system, they die on encountering resident cells bearing Fas ligand molecules. Furthermore, glial cells secrete a range of immunosuppressive factors including tumour growth factor-beta and alpha-melanocyte stimulating hormone.¹⁵⁶

It is clear that the immune response can either prevent infection from taking place or act to clear virus in non-lethal infections, such as those associated with attenuated viruses. As in many other infectious diseases, however, the immune response is double-edged in rabies. It was observed that peripherally inoculated virus reaches the brain in mice a week or more before illness is discernible, suggesting that the presence of virus alone is not the crucial factor which precipitates signs and symptoms of rabies and that there is an immunopathological basis to the disease.^{21, 57} Immunosuppression of mice increases the mortality produced by attenuated and street viruses to 100 per cent but profoundly lengthens the incubation period by one or two weeks, despite the fact that virus is present in the brain during this time.²⁴⁰ Administration of antibody to the immunocompromised mice with brain infection results in death some 48 hours later, the so-called early death phenomenon, while administration of immune spleen cells results in death about six days later, indicating that there can be both humoral and cell-mediated immunopathological effects.²¹¹ In infected mice in which immunosuppression is discontinued, deaths tend to coincide with the return to immune responsiveness as marked by the appearance of antibody in serum.²⁴⁰ The early death phenomenon is observed when infection occurs in partially immune or inadequately immunized animals. In such instances, the immune response is capable of not only accelerating the course of the disease but also limiting centrifugal spread of infection to non-neural tissues, such as salivary glands, and the same effect is seen when the inoculation of large doses of street virus in susceptible animals stimulates the occurrence of an early antibody response.⁵⁷

Clinical signs

Humans

The incubation period in humans may be as short as nine days after infection has occurred through the infliction of severe bites on the head but, at the other extreme, an incubation period of 19 years was suspected to have occurred in one patient.¹⁰⁹ It was demonstrated by means of molecular studies that three immigrants who developed rabies in the USA had been infected with virus associated with their native lands up to seven years prior to developing the disease.²³⁹ However, only about 14 per cent of incubation periods in humans are longer than 90 days, and for example in South Africa most fall between 20 and 60 days, with a mean of 54 days and most victims are under the age of 10.²⁹³

At the end of the incubation period there may be a prodromal phase of one to four days during which patients develop non-specific symptoms of illness including fever, headache, malaise, sore throat, nausea, anorexia, diarrhoea and fatigue. One- to two-thirds of patients experience paraesthesia or pain at the site of the infecting bite or in the affected extremity, and in some there is intense itching leading to frenzied scratching of the wound site.^{108, 288} Some display characteristic anxiety, irritability, depression and insomnia at this stage. Patients next enter an acute neurologic or agitated phase corresponding to the furious form of rabies seen in dogs. They display hyperactive episodes of running or thrashing about, or undergo convulsive seizures, which may arise spontaneously or be precipitated by tactile, auditory, visual or olfactory stimuli. In between such episodes they may be anxious, but lucid and co-operative. They lose the ability to swallow, hypersalivate and manifest hydrophobia, which is variously ascribed to painful spasms of the pharynx and larynx or clonic reflex contractions of the diaphragm and accessory inspiratory muscles, triggered by being offered water to drink. Aerophobia is an analagous reaction which occurs when patients are exposed to a draught of air.¹³⁶ Rabid humans hyperventilate and develop muscular fasciculations, and occasionally priapism. Their mental state passes through stages of disorientation, hallucinations, confusion, stupor and coma. Death may supervene abruptly after one to ten days or paralysis may set in gradually as patients enter the final comatose phase of the illness and develop cluster breathing marked by apnoeic periods. The patients may be kept alive for weeks on life support systems, but most succumb within hours to two days of admission to hospital. Five to 20 per cent of human patients do not manifest agitated behaviour, and paralytic signs predominate throughout the course of an illness which corresponds to the so-called dumb form of rabies in dogs. Onset of paralysis may be diffuse and symmetrical, or more severe in the extremity where the infection occurred, or be of the ascending Landry type, but progresses and spreads until ultimately there is respiratory paralysis.¹⁰⁸

There have been reports of human survival of rabies although this is very rare. Intensive supportive hospital care appears to have been an essential element in each of these cases.^{292, 302, 306} The first case involved a boy bitten by a bat in the USA in 1970 and another a woman bitten by a dog in Argentina in 1972, both of whom received post-exposure vaccination and recovered without sequelae, and the third involved a pre-immunized laboratory worker who gained aerosol infection with an ostensibly attenuated strain of virus in the USA in 1977 and recovered with severe neurological sequelae. The fourth survivor was a Mexican boy who received vaccine after being bitten by a dog in 1992 and developed neurologic disease and coma, from which he recovered with severe sequelae, including quadriparesis and visual impairment, only to die four years later. Since then nine more cases have been reported²⁹² with a USA teenage girl becoming the first survivor in 2004 without receiving any form of immunization. Her treatment resulted in the development of the Milwaukee protocol,³⁰² using an induced coma and antiviral cocktail therapy, which has been used with limited success in subsequent cases. These reported recoveries have inspired intense efforts to treat patients, but at most prolongation of the morbid period has been achieved.

Domestic animals

Because rabies affects the CNS, it is usually associated with behavioral changes. However, these changes are not necessarily species specific and can manifest in different ways.

 Incubation periods in dogs commonly range from two to eight weeks, and, although an incubation period of three years was recorded,¹¹⁴ the longest incubation period observed in a dog imported into Britain was just under eight months^{33, 199} with most incubation periods recorded in dogs fall between two and four weeks.²⁵ A prodromal phase of illness analogous to that which occurs in humans is likely to be noticed only in closely observed pet animals, but it is notable that non-specific febrile illness of four to five days’ duration was commonly encountered as a prelude to paralytic illness in dogs when rabies first entered the KwaZulu-Natal Province in South Africa in 1961.²⁶⁰ There may be a subtle change in temperament at this stage, with, for instance, highly strung dogs becoming affectionate or devoted pets becoming shy and irritable. Pupils may become dilated and pupillary reflexes slowed. Dogs may manifest photophobia, preferring to shun people and hide in dark places.²⁶⁵ Within two to three days after the onset of illness, dogs pass into the acute neurologic or furious phase of the disease, showing restlessness, nervousness and exaggerated responses to visual or auditory stimulation. They may snap at imaginary flies and inflict self-injury at the site of the infecting wound, sometimes tearing away flesh down to the bone. As they become increasingly irritable and aggressive they may attack and bite anything they encounter, including restraining chains or cages, and damage their teeth and injure their mouths in the process. Rabid dogs may develop a depraved appetite, swallowing a variety of objects, including wood, stones and soil. At this stage they may become disoriented and wander aimlessly, attacking people and other animals, and sometimes return home in an advanced stage of illness. They develop a fixed stare, described as a far-away look, lose the ability to swallow, drool saliva and develop a hoarse howl as spasm and paralysis of the laryngeal muscles set in. Dogs may develop bouts of convulsive seizures which leave them exhausted or die suddenly during a seizure. After one to seven days they become uncoordinated, develop progressive paralysis, become comatose and die.²⁶⁵ Dogs that develop so-called dumb (paralytic) rabies may show transient signs of furious rabies or progress directly to the paralytic disease and may be difficult to recognize as being rabid. The most characteristic sign is drooping of the jaw. The muscles of mastication and deglutition are paralyzed and owners are often convinced that the dog has a bone stuck in its throat. The dogs drool saliva and may emit a choking sound or hoarse cough. After two to four days the paralysis spreads to the rest of the body and they die.²⁶⁵  

Classification of a case of rabies as either dumb or furious may also vary with the stage of illness at which the animal is examined. Foggin noted that 11,7 per cent of rabid dogs in Zimbabwe conformed to neither the furious nor the dumb rabies categories, and that many of these exhibited signs suggestive of cerebellar ataxia: aimless wandering and circling with the head held at a tilt, and emesis.⁹⁸ He also noted that a significantly greater proportion of dogs that developed non-furious forms of rabies had been vaccinated than of those which developed furious disease. Rabies does not appear to have a carrier phase in which the animal sheds virus but does not succumb to the disease. Animals infected almost invariable succumb to the disease. A few reports of dogs surviving rabies or developing chronic infection are available for West Africa, Ethiopia, India and China⁹⁵ but these are isolated reports and unconfirmed.

Less is known of incubation periods following natural infection in cats than in dogs, presumably because they are often exposed to infection during their nocturnal wanderings, but it is generally agreed that they have somewhat shorter incubation periods than dogs.³³ Cats are also considered more likely to acquire infection from wild vertebrates than dogs because of their propensity to prowl and hunt at night, and it is notable that the disease may be more common in cats than in dogs in parts of North America and Europe where dog rabies has been controlled and sylvatic rabies is present.²⁷² Cats are also more likely than dogs to develop the furious form of the disease and are generally more aggressive than rabid dogs. Foggin noted that 89 per cent of unvaccinated cats that developed rabies in Zimbabwe manifested the furious form of the disease.⁹⁸ There may be a brief prodromal phase of less than a day during which there is a change in temperament, followed by the furious or excitatory phase that commonly lasts one to five days. Cats may froth at the mouth, show muscular tremors, dilated pupils and cast flashing stares at animate beings in their presence. They may assume a threatening posture, with back arched and claws extended. They are less likely than rabid dogs to recognize or to respond to familiar persons and make unprovoked attacks, sometimes from behind, and often seek out the face of their victim. They may bite without releasing their grip and have to be prised off the victim. As the disease progresses, they may develop convulsions, an uncoordinated gait with ascending paralysis, become comatose and die. In the paralytic form of the disease cats may become affectionate and purr, or hide as paralysis sets in, and death usually supervenes in one to two days.²⁷²  

Incubation periods of two to 12 weeks have been recorded in cattle in southern Africa, but longer periods have been recorded elsewhere, including 87 weeks in experimental infections.^{26, 27, 33, 98} About half of the rabid cattle for which information is available in South Africa, and a higher proportion in Zimbabwe, manifested aggressive behavior.⁹⁸ Often several animals in a herd develop the disease within a short space of time in areas where sylvatic or dog rabies is prevalent. Early signs of illness observed include separation from the rest of the herd, anorexia and docility or irritability. Milk production drops and there may be increased sexual excitability, particularly in bulls. Pupils become dilated and cattle assume a fixed stare, grind their teeth, and sometimes develop pica. There is frequently paralysis of the tongue and jaw with copious salivation (Figure 4), and cattle often develop a characteristic hoarse bellow (Figures 5 and 6) which is recognized by stockmen.

Figure 4 Note profuse salivation in a rabid bovine (By courtesy of Dr H. van de Pypekamp, Department of Animal Health, Private Bag X138, Pretoria 0001, South Africa)

Figure 5 Rabid Afrikander ox showing salivation, bellowing and loss of condition (By courtesy of Dr H. van de Pypekamp, Department of Animal Health, Private Bag X138, Pretoria 0001, South Africa)

Figure 6 Rabbit cross-bred cow: note bellowing (By courtesy of Dr H. van de Pypekamp, Department of Animal Health, Private Bag X138, Pretoria 0001, South Africa)

Aggression varies from a tendency to butt other cattle to mania with vicious attacks being made on humans, other animals or even inanimate objects such as fence posts. As the disease progresses there is locomotory disturbance, sometimes with posterior paresis, a swaying gait, tail paralysis, dragging of the hooves and tenesmus with diarrhoea and frequent urination. There is usually a rapid loss of condition. After a morbid period of one to five days animals may assume ventral or lateral recumbency and die in convulsion, or become progressively paralyzed, comatose and die. Sometimes there is subcutaneous emphysema originating from pulmonary emphysema as a result of bellowing. In the paralytic form of the disease the excitatory phase is short or absent.^{120, 121}

Incubation periods of two to four weeks have been recorded in sheep and goats in South Africa, but periods of up to 17 weeks have been recorded elsewhere.^{25, 33} The disease in these animals generally resembles that in cattle, but sexual excitability is more common in sheep, while goats tend to bleat incessantly and are more frequently aggressive than cattle.^{120, 121, 248}

Incubation periods of up to six weeks have been recorded in horses, and prodromal signs may include low grade fever, altered behaviour and rubbing or biting the site of the infecting wound.³³ Rabid horses frequently develop the furious form of the disease and may be extremely dangerous, and the same is true of the few donkeys in which the disease has been observed in southern Africa.³³ Horses become restless, excitable and show signs of colic such as abdominal straining, and whinny as if in great pain. They may display marked sexual excitability, and attack furiously by biting and kicking at humans and any inanimate objects which they perceive as a threat or a restraint. The disease runs a course of five to eight days and as paralysis sets in the animals may fall repeatedly and finally remain down and thrash their legs about until they become comatose and die. Some horses develop the paralytic form of the disease and wander or stagger about aimlessly, pressing their heads against solid objects and ultimately enter a rapidly progressive terminal paralysis.^{120, 121}

Rabies is seldom diagnosed in pigs, but rabid pigs may attempt to hide in corners of their pen, displaying aggressive behaviour and attempt to bite humans if approached, and sows may kill their offspring.³³

Wild animals

Wild animals will typically lose their fear of humans and other animals. For example, rabid yellow mongooses in South Africa are often found in or close to farm homesteads, outbuildings or stables. Only about 38 per cent of rabid mongooses are overly aggressive and humans are usually bitten when they attempt to handle what are perceived to be tame animals.²⁵ Dogs frequently attack and kill rabid mongooses, while cattle and sheep are bitten when they display curiosity towards the mongooses. The other species of mongoose which develop rabies in southern Africa behave similarly to yellow mongooses, except that nocturnal species may become active in daylight.^{26, 27, 98} Aggressive and non-aggressive patterns of behaviour appear to have been observed with almost equal frequency in rabid jackals.^{26, 27, 98} Aggressive rabid jackals have been reported to attack the wheels of moving vehicles, enter human dwellings and attack sleeping residents, or to attack cattle gathered at watering points. Non-aggressive rabid jackals lose their fear of humans and dogs and approach farm buildings in daylight but do not initiate attacks.

Rabid wild cats and genets behave similarly to rabid domestic cats in that they make unprovoked and vicious attacks on humans and other animals, including humans who are asleep at night indoors or outdoors, and they may also bite without releasing their hold on the victim. Like mongooses, they frequently approach farm buildings when rabid and can be particularly vicious if cornered.^{26, 27} Honey badgers (Mellivora capensis) are ordinarily vicious and fierce fighters, and although they seldom approach human dwellings, they can be formidable opponents for humans or dogs when rabid. In one instance a rabid badger was responsible for the deaths of 47 sheep in a flock in Zimbabwe.⁷⁸  

The most frequently observed signs of disease in rabid kudus were salivation, docility and paresis or paralysis.^{26, 27, 119} The antelope approached and even attempted to enter farm buildings (Figure 7) and could not be scared away easily. They sometimes displayed a playful attitude towards humans and farm animals and readily entered pens with cattle. In contrast, rabid small antelope such as duikers, were sometimes found to be very aggressive towards humans and livestock and capable of inflicting severe wounds with their sharp horns.⁸

As in all wild animals, the features of rabies in major reservoir hosts, such as foxes, raccoons, skunks, coyotes and bats, have been described as difficult to discern.^{64, 199} All are said to have very short morbid periods, less than a week. It is more important to be aware of abnormal behaviour than to look for classical signs of aggressive rabies: nocturnal animals become active in daylight, animals lose their fear of humans and may enter buildings and public spaces, either ignoring or attacking road traffic. Those that appear abnormally tame and approachable constitute a particular threat.

Figure 7 Rabid kudu that entered a farm building. (By courtesy of Dr. B.J.H. Barnard, Section of Virology, OVI, Onderstepoort 0110, South Africa)

Figure 8 Negri bodies in a neuron. Acid fuchsin-methylene blue staining method

Pathology

There are no consistent macroscopic lesions in animals that die of rabies; often the only visible abnormality is congestion of the blood vessels of the leptomeninges. Animals may be emaciated and there may be self-inflicted injury, particularly at the site of infection in carnivores, or injuries sustained in fights. Foreign bodies may be found in the stomach, particularly in monogastric animals, and dogs that have strayed may harbour numerous ectoparasites, such as ticks. The most significant microscopic lesions occur in the CNS, and cranial and spinal ganglia, and were first described in the 1870s.²⁰⁹ They consist of perivascular cuffing, focal and diffuse gliosis, neuronal degeneration, and intracytoplasmic inclusions, or Negri bodies (Figure 8), in neurons.^{123, 159, 209} Negri bodies are sharply defined, rounded, acidophilic inclusions, which measure 2 to 8 nm in diameter, but they assume an elongated shape in axons and dendrites. They may contain a basophilic internal structure, or one or more vacuoles, and are sometimes surrounded by a clear halo.

Negri bodies tend to vary in size depending on the host, being large in dogs and cattle, and are found most commonly in neurons of the hippocampus, or in Purkinje cells of the cerebellum in cattle. They are found less frequently in glial cells, in ganglion cells of the salivary glands and adrenal medulla, and in the retina.^{255, 270} The degree and distribution of neuronal degeneration, satellitosis, neuronophagia and inflammatory infiltration are extremely variable in rabies, and are generally most pronounced in dogs, and may be slight in ruminants.²⁵⁵ The perivascular infiltrate consists primarily of lymphocytes, with fewer macrophages and plasma cells, and with the number of plasma cells generally increasing with the duration of the illness. Neuronophagic nodules, also termed Babes’ nodes, consist mainly of activated microglial cells. The nodules are not invariably associated with degenerative neurons and occur in both white and grey matter, as does diffuse gliosis, and there is a variable degree of meningitis.²⁰⁹

Vacuolar lesions similar to those of the subacute spongiform encephalopathies of humans and lower animals have been described in naturally or experimentally infected cats, dogs, cattle, sheep, horses, foxes and skunks.⁵⁷ Electron microscopic examination reveals that viral infection is usually widespread in the brain at the time that death, despite the fact that demonstrable viral antigen and the lesions seen by light microscopy, may have limited distribution.¹⁹⁰ However, the use of immunofluorescence or immunohistochemistry reveals that virus antigen is far more widely distributed in nerve tissue than are the Negri bodies visible by light microscopy.¹⁹⁰ Ganglioneuritis occurs particularly in the Gasserian ganglion, and it has been recommended that this site should be examined when traumatic destruction or putrefaction renders it impossible to examine brain tissue for Negri bodies. In the absence of Negri bodies, however, lesions in ganglia are not specific for rabies, but lack of lesions in the Gasserian ganglion is considered to be an indication that a diagnosis of rabies is unlikely.^{159, 209} Lesions in salivary glands consist of degeneration and necrosis of acinar epithelial cells, with infiltration of lymphocytes, neutrophils and plasma cells.^{98, 255}

Diagnosis

It is important to be aware, as discussed above, that rabies induces abnormal behavior. Suspicion of rabies is heightened when the affected animal comes from an area where the disease is known to be active, or when there is a history that suggests possible exposure to infection (http://www.who.int/rabies/human/generalconsid/en/). A history of immunization renders a diagnosis of rabies less likely, but there are numerous instances on record of the disease occurring even in animals which have received multiple vaccinations. In instances where a domestic animal has been provoked to furious behaviour or to attack humans or other animals, yet appears to exhibit its normal pattern of behaviour on examination, authorized persons (in most countries these are state veterinary officials) may make the decision to confine the animal and keep it under observation for a period of ten days, and to kill it for laboratory examination if it develops overt signs of the disease. This applies particularly to vaccinated animals in situations where exposure of the animal to infection appears to have been unlikely. Feral animals, animals showing signs of illness considered to be suggestive of rabies, or animals whose owner and history cannot be traced should be killed for examination at the time that the suspicion of rabies arises. 

In the 19^th century, clinical diagnosis was the only way to confirm rabies until the Seller’s stain, was developed in 1903 as a histopathological test for Negri bodies.¹⁹⁵ This test was widely used until 1958 when it was replaced with the direct fluorescent antibody test (DFA). Subsequent studies indicated that the Seller’s stain produced a significant amount of false negative results and was therefore discontinued as a recommended test for rabies.²⁹⁵ Unfortunately, due to lack of infrastructure, it is still used in developing countries.²⁶² Rabies diagnosis based on gross pathology or histopathology is not reliable and specific laboratory tests are needed to demonstrate rabies infection.

A number of laboratory techniques can be applied for the diagnosis of rabies and, to achieve standardization, the details have been published²⁹⁶ (OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animals 2017, http://www.oie.int/standard-setting/terrestrial-manual/access-online/). Diagnostic tests should preferably be performed on CNS tissue and therefore animals should be killed in such a manner as to avoid damaging the cranium. Protective clothing (Figure 9) should be worn while collecting specimens and should include gloves, an impermeable apron, face mask or visor, and personnel involved should be immunized. The hippocampus is commonly used for the diagnosis of rabies, but the distribution of lesions or virus antigen and infectivity varies, and it should be routine to take tissue samples from a variety of sites in the brain, with the brain stem the most important component.²⁹⁰ Brain specimens to be submitted for laboratory examination include Ammon’s horn, thalamus, cerebral cortex and medulla ablongata preserved in 50 per cent glycerol-saline solution for virological examination and where possible kept refrigerated to avoid virus degradation. An alternative transport method is the use of the FTA Gene Guard system^{103, 210} that preserves viral RNA and can be used in molecular testing. In the past samples were also submitted in 10 per cent buffered formalin for histopathological examination; however, these techniques are less sensitive and no longer recommended for primary diagnosis. Formalin also inactivates the virus and therefore excludes tests involving virus isolation. Where small animals are involved, the whole brain may simply be placed in the glycerol-saline preservative.

Figure 9 Veterinarian in full protective clothing removing the head of an ox that died of rabies

Adequate samples for making an accurate diagnosis may also be collected in 5 mm wide-bore, plastic drinking straws or a 2 ml disposable pipette by a method which obviates the need to skin the head and saw the cranium to expose the brain. In this method, the occipital foramen is exposed using a knife and the sample collected by inserting the straw/pipette through the foramen and pushing it with a slight twisting motion towards one of the eyes.^{28, 29, 115} The end of the straw containing the plug of brain tissue is cut off into the container with preservative. In large animals, straw samples may be taken through a hole made by driving a metal punch or large nail through an orbit or the forehead into the cranium. Virus antigen or infectivity may be demonstrated in other tissues for example salivary glands or nuchal skin biopsies when brain material is not available. Examination of salivary glands also provides valuable epidemiological information on the excretion of the virus by different vertebrates.

Specimen containers needed to be sealed tightly and packed in sufficient absorbent material to soak up the entire liquid contents of the containers should they leak or break during transmission to the laboratory. Sample packaging and transport must comply with national and international specimen transport packaging regulations and laboratories must adhere to national bio-containment and biosafety regulations and comply with the guidelines for Risk Group 3 (OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animals 2017, http://www.oie.int/standard-setting/terrestrial-manual/access-online/).

The most widely used test and gold standard for rabies diagnosis is the direct fluorescent antibody tests (DFA) as recommended by the World Health Organization (WHO) and World Organization for Animal Health (OIE). This gold standard method demonstrates lyssavirus antigen in impression smears of fresh brain by immunofluorescence.^{82, 105} An anti-rabies immunoglobulin (monoclonal or polyclonal), conjugated with fluorescein isothiocynate (FITC) is reacted with acetone fixed brain smears preferable made from several parts of the CNS. The conjugates are either available commercially or manufactured locally and should be validated for sensitivity and specificity against the diversity of virus lineages and variants in the region before use. The test requires only one to three hours to perform, and provides reliable results on fresh specimens in 98-100 per cent of cases.^{48, 290} Immunofluorescence may demonstrate antigen in a small proportion of instances in which specimens are too decomposed to yield virus isolates and, conversely, virus which is present in low concentration can occasionally be isolated in mice or cell culture in instances where immunofluorescence is negative. Inclusion bodies frequently lose their intracellular position in impression smears, and the structures demonstrated by immunofluorescence range from characteristic Negri bodies with inner structure, to fine particles, sometimes termed rabies dust. Most laboratories use immunofluorescence as the sole diagnostic test and resort to confirmatory testing (RT-PCR, cell culture or mouse inoculation test) in instances where a negative result is recorded in an animal which has potentially been involved in the exposure of a human to infection or cases of an inconclusive DFA result. Routine DFA testing uses an immunoglobulin that will detect all lyssavirus species, and characterization of the lyssavirus species or strains can be performed by using monoclonal antibodies in the DFA or the reverse transcription polymerase chain reaction (RT-PCR) followed by DNA sequencing. These tests are usually only performed in specialized laboratories.²⁴ Formalin-fixed brain tissue has been used successfully in immunofluorescence tests.²⁹⁴ However formalin fixation may mask virus antigen. When only fixed tissue is available for examination, the tissue can be treated with trypsin to unmask antigen prior to performing the immunofluorescence test.²⁷

Immunoperoxidase methods can be used as an alternative to the DFA test with the same sensitivity,^{68, 164} for example, the rapid immunohistochemical test (DRIT).^{68, 200} The test relies on an anti-lyssavirus antibody conjugated to biotin. This test has now been evaluated in several countries and can be used as a diagnostic assay for rabies, with a performance equal to that of the DFA.^{68, 91} The test requires an additional incubation step but have the advantage that only a light microscope is needed.

Rapid immunochromatographic diagnostic tests (RIDT) or lateral-flow devices (LFD) are available^{93, 135, 174} for use in low resource settings. However, specificity and sensitivity are lower in comparison to the DFA, and batch-to-batch variation has been observed, implying that these devices do not produce consistent results.⁹² Some studies found a diagnostic sensitivity of 0 per cent when testing field samples,⁹² and therefore the tests are not currently recommended for routine diagnosis of rabies by the OIE or WHO.

The isolation of virus by intracerebral inoculation of brain suspension into weaned mice was the standard diagnostic method before the widespread adoption of the immunofluorescence test. The method is sensitive, yielding isolates from virtually all infected specimens received at the laboratory in a well preserved state, but it may take up to four weeks or longer to obtain a final result. Quicker results may be obtained by using suckling mice and sacrificing individuals for examination by immunofluorescence from the third or fourth day after inoculation onwards.¹⁰⁴ Wherever possible virus isolation in cell culture should be considered instead of mouse inoculation because expense is spared, results are quicker and it avoids the use of animals. The virus may be isolated in a variety of cell line cultures and greatest sensitivity is claimed for neuroblastoma cells of murine and human origin.^{125, 216-218, 237} Brain or other tissue suspensions may be toxic to cells, and it is usually necessary to subculture cells to isolate virus. Since lyssaviruses are poorly cytopathic, isolation needs to be demonstrated by immunofluorescence (DFA) of test cultures. Under optimum conditions, isolation of virus can be achieved in two to four days.⁴⁸

Various molecular diagnostic tests for detecting viral RNA have been described including  RT-PCR and real-time PCR. These tests are  rapid and sensitive methods for rabies diagnosis.^{66, 100, 111-113, 191, 280} The use of real-time RT-PCR assays have largely superseded the use of conventional RT-PCR methods, where such diagnostic capacity exists, and several assays have been developed targeting specific lyssavirus species. Real-time RT-PCR assays are significantly more sensitive (up to 200-fold)^{111, 112} than conventional RT-PCR assays, and are also more successful in the detection of viral nucleic acid in formalin-fixed tissues⁶⁶ and severely decomposed material.¹⁷³ Polymerase chain reaction assays can be combined with nucleotide sequencing to identify the lyssavirus species or to obtain information about the specific lyssavirus strain.¹⁰⁰ Although molecular tests are sensitive, they are not recommended for routine diagnosis of rabies due to high levels of false positives or negatives if stringent quality control protocols are not followed. Therefore, these tests should only be performed in suitably equipped and staffed laboratories.

Ante- mortem rabies diagnosis is not routinely performed on animals but can be used to diagnose rabies in humans to determine patient care and to exclude other infectious diseases.²⁵⁹ This is however not often performed²⁹¹ due to limited resources and lack of diagnostic capabilities in the developing world. Clinical diagnosis is unreliable, as demonstrated in a retrospective study in Malawi where 11.5 per cent of cases diagnosed as malaria proved to be rabies.¹⁷¹ The demonstration of virus antigen by DFA can be performed ante-mortem in nuchal skin biopsies (taken from the nape of the neck),^{77, 82} or corneal impressions.¹⁷⁶ Reverse transcription polymerase chain reaction can be performed on saliva, cerebrospinal fluid or nuchal biopsy sections,²⁸⁰ however, serial testing of saliva is recommended due to intermittent virus shedding.⁷⁴

Antibodies to lyssaviruses may be demonstrated by a variety of methods including indirect immunofluorescence, complement fixation, haemagglutination-inhibition, radioimmunoassay, enzyme-linked immunoassay and neutralization tests^{56, 65} with the rapid fluorescent focus inhibition (RFFIT) and the fluorescent antibody virus neutralization assay (FAVN) most often used. These tests can be used to establish a diagnosis of rabies ante- mortem in human patients who developed an antibody response but are rarely useful because antibody production tends to occur late in the course of the disease. This approach is even less practical in animals because antibody production is inconsistent.⁵⁶ The main application of serological assays is not to diagnose infection but to monitor response to vaccination before international animal movement; to evaluate the efficacy of vaccination campaigns or new vaccines and to determine the efficiency of pre-exposure prophylaxis in humans.

Differential diagnosis

Rabies can be confused clinically with other encephalitic animal diseases²⁹⁶ including distemper, ehrlichiosis, cerebral babesiosis in dogs, toxoplasmosis, cerebral cysticercosis, tetanus, cerebral theileriosis and babesiosis in  cattle, thrombotic meningoencephalitis due to Histophilus somni infection, sporadic bovine encephalomyelitis caused by Chlamydia spp. infection, botulism, coenurus cerebralis, heartwater, encephalomyelitis caused by equid herpesvirus 1, alphavirus, flavivirus or orthobunyavirus infections, leukoencephalomalacia (caused by fumonisin B1 produced by the fungus Fusarium moniliforme) and poisoning by Senecio spp. in horses.¹⁹⁹ Lead and pesticide poisonings should also be considered.¹⁴⁰ Some of these conditions can be diagnosed on histological examination of sections of the brain, but most have to be diagnosed by undertaking appropriate epidemiological, microbiological or toxicological investigations. In humans rabies can be confused with tetanus, bacterial and viral meningitis, cerebritis and acute flaccid paralysis poliomyelitis as well as non-infectious conditions caused by drug abuse and mental disorders.²⁹⁶

Control

Control of dog- mediated rabies

The mainstay of successful rabies control programmes is the immunization of a sufficient proportion of the main reservoir host population to achieve herd immunity and thus to prevent outbreaks of the disease. Even though rabies has been preventable by vaccination since the 19th century, it still causes more human deaths than any other zoonotic disease^{99, 204} and dog mediated rabies is still the principal source of human infections with most cases reported from Africa, Asia, and Latin America. Elimination of dog rabies has been shown to be a feasible strategy in several parts of the world including the United Kingdom, Western Europe and North America.²⁸⁴ Although rabies can be prevented in humans by effective pre- and post-exposure prophylaxis, the disease has to be controlled at the animal source and the most cost-effective control measure to eliminate dog-mediated human rabies is the routine vaccination of dogs.^{32, 196, 231}

The immunogenicity of the inactivated nerve tissue vaccines originally used in humans and lower animals was generally poor but improved after potency assays were introduced in 1940. However, the vaccines caused paralytic neuritis and encephalomyelitis in a proportion of recipients due to an auto-allergic demyelinating reaction induced by the lipoprotein myelin, present in the nerve tissue from which the vaccines were prepared (the myelins of different species share antigens). From the 1950s onwards, there was a trend in developed nations towards replacing nerve tissue vaccines with attenuated or so-called modified live virus vaccines for veterinary use. These included the LEP derivative¹⁴⁷ of the Flury strain of virus¹⁶¹ for use in dogs, the HEP derivative of the Flury strain for use in cats and cattle,²²⁸ the ERA vaccine strain¹ derived from the Street Alabama Dufferin (SAD) strain of virus⁹⁷ for use in dogs and other animals, the Vnukovo-32 vaccine strain derived from the SAD strain in the former USSR,²³³ the SAD-B19 clone of virus used for oral immunization of foxes in Europe²²⁸ and the Kelev vaccine strain developed from RABV isolated from a dog in Israel.¹⁴⁶ The modified live vaccines were used successfully to control dog rabies in many western nations, but carried the potential danger of reversion to virulence and were associated with a small proportion of vaccination failures.^{53, 54}

A range of highly effective, safe and thermostable, inactivated veterinary vaccines, prepared from virus grown in a variety of primary and cell line cultures, is now available.^{30, 212, 234} The duration of the protective immunity to challenge with RABV induced in the target species varies from one to three years with the antigen content of the vaccines. The more potent vaccines may be used in pups and the progeny of other carnivores as young as four to six weeks of age, or 11 weeks if the dam has been immunized, and booster doses need to be administered at three yearly intervals. Young herbivores may be vaccinated initially at the age of four months, or nine months if the dam has been immunized, with boosters being administered every one, two or three years depending on the antigen content of the vaccine and the prevailing challenge rate. For mass canine vaccination campaigns, the use of inactivated rabies vaccine is recommended by the WHO and OIE since it is less sensitive to changes in temperature.²⁹⁶

The components of a rabies control programme is multifaceted and typically include among others aspects of vaccinology, epidemiology, diagnostics, animal primary health, human health, dog ecology, dog population management, and knowledge, attitudes, and practices of the affected communities.^{99, 162} The global community, led by the WHO, OIE, and the Food and Agricultural Organization (FAO) in collaboration with the Global Alliance for Rabies Control (GARC), has set a globally agreed upon goal to eliminate dog-mediated human rabies deaths by 2030¹²⁷ in line with the Sustainable Development Goals (SDGs).²⁷¹ It should be possible for national governments to replicate successful control programs that have reduced or eliminated human rabies deaths in Europe and the Americas by controlling or eliminating the disease from dogs.^{32, 296} To address the neglect of rabies control the Stepwise Approach towards Rabies Elimination (SARE) tool embedded in a Rabies Blueprint Platform (BP/SARE) (www. rabiesblueprint.org)⁶⁷ was developed. In summary, the BP/SARE tool provides countries with measurable steps to progress from Stage 0 to Stage 5 in their efforts towards becoming canine-rabies free as follows:

Stage 0: No data, but rabies is suspected to be present

Stage 1: Assessment of rabies epidemiology, development of a short- term rabies action plan

Stage 2: Development of a detailed national rabies prevention and control strategy

Stage 3: Full-scale implementation of the national rabies control strategy

Stage 4: Maintenance of human rabies freedom and elimination of dog rabies

Stage 5: Freedom from human and dog-transmitted rabies being monitored

The BP/SARE tool delineates seven main categories of control activities with each category having detailed stage-specific activities that need to be addressed. Specific critical activities determine whether a country progresses to the next stage. Not all of the activities are mandatory for advancement, but they nevertheless provide guidelines towards control and elimination of rabies. The categories are:

1. Legislation pertaining to rabies control and elimination.
2. Data collection and analysis for an effective surveillance network.
3. Laboratory diagnostic capacity at national and regional levels.²⁴
4. Information, education and communication pertaining to advocacy initiatives.
5. Disease prevention and control strategies.^{107, 282}
6. Dog population related matters (population size/turnover).^{10, 51}
7. Cross cutting issues relating to collaboration between various stakeholders in the development and implementation of control strategies.

The frequency with which campaigns need to be conducted depends on the prevalence of the disease, the age structure of the dog population, and the rate of recruitment of susceptible individuals to the population. For practical purposes, vaccination campaigns are generally conducted at yearly intervals and all dogs over the minimum age are vaccinated or re-vaccinated on these occasions unless the owner can produce proof of immunization status.  Once control of dog rabies has been achieved, it may be necessary to maintain a cordon sanitaire by continuing to conduct vaccination campaigns along borders where the disease could be reintroduced. Other animals including cats generally play a lesser role in the propagation of rabies and should be included in vaccination campaigns where they are a problem in rabies transmission.

The success of campaigns is judged by continuing to monitor for the occurrence of the disease, and it cannot be assumed that complete control has been achieved until the affected area has remained free of rabies for at least two years. It is generally claimed that 70 to 80 per cent vaccination coverage is required in order to achieve control of the disease in dogs, but this depends on the transmission rate in the area concerned.⁹⁸ Excellent control of urban rabies has been attained recently in certain South American cities with 64,8 to 99,6 per cent vaccination coverage of dogs.¹⁶⁰

Fully susceptible domestic pets which are exposed to infection by a proven rabid animal should be destroyed, but dogs which are immunized in conformity with legal requirements should be given a booster and kept under observation for three months. Immunization of wild animals in captivity are generally discouraged and in many countries may be performed only with the express approval of the state veterinary service when, for instance, valuable breeding animals of endangered species are involved. Uncertainty or a false sense of security may arise when wild animals that are kept as pets are immunized since the efficacy of the vaccine in the species concerned may be unknown, as may be the history of possible exposure of the animal to infection. Vaccination of farm herbivores is generally made optional, to be performed at the discretion and expense of the owner when problems with rabies are encountered.

The removal or destruction of unvaccinated dogs has been found to be counter-productive as a means of controlling rabies where dogs are unrestricted. Owing to the recuperative reproductive capacity of populations of unrestricted dogs, it is estimated that 50 to 80 pet cent of individuals must be removed each year if the campaign is to have a sustained effect on the population, and it is much more effective to reduce the carrying capacity of the neighbourhood through proper refuse disposal.²⁸³ Alternatives include offering and promoting a service to sterilize dogs. Import and quarantine regulations constitute another important facet of rabies control. Some countries which are free of rabies in terrestrial species, require imported dogs to have proof of vaccination status.

Oral vaccination

In regions where dog rabies was eliminated, the incidence of rabies in wildlife increased dramatically. In Europe, it was the red fox that became the principal rabies vector and reservoir, while species such as raccoons, skunks, various fox species and coyotes became important reservoirs in North America.^{219, 276, 284} Extensive vaccination and breakthroughs in oral vaccination allowed for the eradication of fox rabies in Western Europe, but wildlife rabies persists in North America, where its control through oral vaccination campaigns remains exceedingly costly.^{44, 45} Importantly, rabies in wildlife poses a much lesser threat to human health, as opposed to rabies in dogs, and regions where dog rabies has been eliminated report almost no human rabies deaths, even in those countries where wildlife rabies is abundant.

The basic requirements for oral immunization of animals are that the viruses or recombinants used in oral vaccines should be easy to produce in high concentration, stable at high ambient temperatures, and immunogenic for the target species without being pathogenic for non-target species. Baits should be capable of mass production, attractive to the target species and readily chewed so that the immunizing agent is liberated when the bait is taken.¹⁷⁰ The concept of oral vaccination arose from the demonstration of susceptibility to oral infection in laboratory animals²⁴⁵ and the feasibility of immunizing foxes by this route was demonstrated in the USA using the ERA derivative of SAD virus since the other available attenuated strains of RABV were known to be pathogenic for foxes.¹⁷ Following successful field trials in Switzerland in 1978, in which foxes were immunized with SAD-Berne virus in capsules inserted into chicken head baits²⁵⁰ immunization of foxes was extended with good effect to Germany, Italy, Austria, Luxembourg, Belgium and France, using the SAD-B19 clone of virus enclosed in artificial baits produced industrially from fat and fishmeal.¹⁷⁰

The possibility was raised that SAD virus derivatives could produce disease and become established in non-target species which took baits, particularly rodents and mustelids, but the problem did not materialize in the field.¹⁷⁰ Nevertheless, the SAG-1 (SAD-Avirulent- Gif) and SAG-2 strains were developed as further derivatives of the SAD strain in order to improve safety.⁴³ A vaccinia RABV glycoprotein recombinant (VRG) vaccine was also produced to overcome concerns about safety in non-target species and was found safe and effective for use in raccoons in the USA and foxes in Europe.^{49, 50, 222} Other poxviruses used successfully to produce recombinants expressing RABV antigens included racoonpox, fowlpox and canarypox viruses.⁹³ Adenovirus-vectored recombinants expressing RABV glycoprotein were also developed successfully, eg. ONRAB.⁵⁹  

Baits can be distributed economically by helicopter or fixed-wing aircraft but are generally attractive to a wide range of vertebrates, and greater selectivity for the intended target species can be attained by placing baits by hand in appropriate niches.^{134, 284, 286} The taking of baits by target and non-target species is assessed by the incorporation of biological markers, such as tetracycline which is deposited in bone and can be demonstrated in cross-sections of teeth.^{285, 286} or by the use of automatic cameras. Other markers include Du Pont Oil Blue A, Rhodamine B, and sulphadimethoxine which is a serum marker.

During the 1990s, the vaccination of foxes in Europe was extended to 15 countries and proved to be extremely successful, with minor setbacks where vaccination was discontinued too soon, allowing infection to be reintroduced from areas where the disease was still present to areas where eradication had already been achieved. Nevertheless, before the turn of the century control had been achieved in western Europe, and it became necessary to extend the campaign to eastern Europe.^{11, 206, 253} It was suggested that to ensure eradication of fox rabies in Europe, 70 per cent vaccination coverage should be maintained for at least six years and that the immunization campaigns should be combined with strategic reduction of populations in certain locations.

Control of rabies in wildlife is considerably more complex in North America than it is in Europe, with more vector species, sometimes overlapping in distribution, and much vaster areas being involved. Immunizing agents tested in target and non-target species include SAG-1 and -2 attenuated RABV, vaccinia-RABV glycoprotein recombinant, racoon pox-RABV glycoprotein recombinant, baculovirus-expressed RABV glycoprotein, and canine adenovirus 2-RABV glycoprotein recombinant, in racoons, skunks, arctic foxes, red foxes, grey foxes, and coyotes.¹⁷⁰ A variety of specific baits were developed and tested for coyotes, grey foxes, and raccoons and in general, the immunizing agents all performed well, but canine adenovirus 2 recombinant proved to be potentially pathogenic for racoons. Only VRG and ONRAB have been registered for use in rabies control programmes in wildlife in the USA, and their use is restricted to state authorities.

Although no universal approach to the control of rabies in wildlife in North America is possible, a number of programmes have been instituted to address specific problems. In Ontario, Canada, where there is a complicated situation, with rabies in raccoons, skunks and foxes all being involved as vectors, a programme of capture, vaccination and release of animals and oral immunization of raccoons with the ERA derivative of SAD virus has proved to be effective in controlling the threat of infection to humans.²¹⁵ Oral vaccination of raccoons with VRG has met with initial successes in a number of locations from Florida to Massachusetts, chosen as strategic sites to limit further spread of infection.¹³³

The efficacy of oral vaccination, and/or the suitability of baits, has also been explored for use in foxes in Israel, jackals in Zimbabwe, African wild dogs in South Africa, and mongooses in Antigua.^{35-40, 73} It has been mooted that oral immunization could be extended to populations of unrestricted dogs which are inaccessible to vaccination by ordinary means.^{17, 19}

Human immunization and post-exposure prophylaxis

Rabies is a notifiable disease and it is the duty of state veterinary officials, including veterinarians and animal health inspectors, to investigate incidents of potential exposure of humans to infection and to report diagnostic findings on the animal concerned to the medical personnel responsible for treating the exposed humans. Human exposures must be assessed for potential risk and whether post-exposure prophylaxis is required (http://www.who.int/rabies/human/generalconsid/en/). This assessment should include the behaviour and health status of the animal concerned, rabies vaccination history, animal species and geographical location. If possible, the suspect animal should be identified and euthanized, if rabies are suspected, for laboratory examination. If a reliable negative laboratory result is obtained, prophylactic treatment may be discontinued but should not be delayed awaiting laboratory confirmation. When the history is unclear or uncertain prophylaxis should be initiated according to the guidelines. The guidelines produced by WHO are only recommendations, and the decision to implement such schedules resides with the government agencies which select policies for their own countries. All clinicians, health professionals and veterinarians should be familiar with current recommendations on pre- and post-exposure prophylaxis as published periodically in Reports of the World Health Organization Expert Consultation of Rabies (WHO, 2013; http://www.who.int/rabies/human/postexp/en/).  Rabies is fatal and it is important to prevent it by immunization immediately (within 48 hours) after a suspect or proven exposure to the virus in addition to wound management.

Rabies post-exposure prophylaxis consists of administration of the vaccine and anti-rabies immunoglobulin. Immunoglobulin is used to provide immediate protection until vaccine-induced immunity becomes effective, but the timing and dosage of passively administered antibody must be controlled or else there is interference with the response to the vaccine. An inactivated and purified vaccine prepared from virus grown in human diploid cell cultures was developed during the 1960s and became increasingly available for use in humans during the 1970s and 1980s.¹⁵¹ Only two disputed instances of transient peripheral neuritis resembling the Guillain- Barré syndrome were recorded among the first 533 000 patients to be treated, although minor local and systemic reactions such as itchiness, urticaria, arthralgia and fever were observed in a small proportion of patients.¹⁵² Poor virus yields are obtained from diploid cells so that the human vaccine is expensive to produce and this has limited its use in many countries. Consequently, cheaper inactivated vaccines for use in humans have been developed from virus grown on primary chick embryo cells or Vero line cells or from virus grown in duck embryos and subjected to a high degree of purification and concentration. Several other vaccines of a similar nature have been developed, but have not found wide usage, or are used mainly in eastern Europe, the former USSR and China. Nerve tissue vaccines induce more severe adverse reactions and are less immunogenic and since 1984, the WHO has recommended discontinuation of production and use of these vaccines. WHO prequalifies vaccines to ensure the quality, safety and efficacy and this involves a review of the production process and quality control procedures, testing the consistency of lots and an audit of the manufacturing facilities.  The list of rabies vaccines pre-qualified for intramuscular use is regularly updated and use of these vaccines is encouraged (http://www.who.int/rabies/vaccines/human_vaccines/en/)

Three classes of biological products are available for passive immunization; human rabies immunoglobulin, equine rabies immunoglobulin and highly purified Fab immunoglobulin. Equine rabies immunoglobulin is considerably less expensive than the human product and has very few adverse effects although anaphylactic reaction has been reported (1/150 000). The dosage is 20 IU/kg body weight for human anti-rabies immunoglobulin, or 40 IU/kg for immunoglobulin prepared in horses. Rabies immunoglobulins are in short supply throughout the world and new technologies are being explored including the use of monoclonal antibodies.^{23, 187}   

High risk occupational groups can also receive pre-exposure prophylaxis. The inactivated vaccines are all effective and there is generally no need to monitor antibody responses; however, it is advised that people at constant risk of rabies should have their neutralizing antibody titres checked regularly and booster doses administered when titres fall below 0,5 IU/ml. Booster doses are usually administered every two to three years depending on the level of risk, i.e. the frequency with which rabid animals or infected materials are handled. All vaccinated individuals subsequently exposed to rabies, according to the WHO definition of exposure (http://www.who.int/rabies/human/postexp/en/), should receive an abbreviated course of post- exposure prophylaxis.

There are no contraindications for post-exposure prophylaxis in infants, pregnant women or immunocompromised individuals. However, rabies immunoglobulin should be administered in category II and III exposures if the patients are immunocompromised. People taking chloroquine for malaria treatment or prophylaxis may have a reduced response to intradermal rabies vaccination and should receive the vaccine intramuscularly.  There have been a few instances of vaccine failure, but most cases involved patients in whom treatment was delayed, or who failed to receive immunoglobulin or the full course of treatment, or who had underlying disease.¹⁵²

References

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