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RHABDOVIRIDAE There are currently more than 100 viruses that are classiﬁed as being members of this family, which has a remarkable host-range encompassing vertebrates (including reptiles and ﬁsh), invertebrates and plants. They all have a bulletshaped (sometimes conical) or, in the case of plant viruses, bacilliform morphology as well as other biophysical and biochemical features in common.1 Subdivision of the family into genera and serogroups has so far been based entirely on serological cross-reactivities which are extensive but often asymmetric.2 An abridged classiﬁcation for the viruses associated with vertebrates and haematophagous arthropods is shown in Table 1. Table 1 An abridged classification of rhabdoviruses of vertebrates and haematophagous arthropods. (Adapted from Calisher et al.2) Most members of the family Rhabdoviridae have no known association with disease, but among them are the causative agents of three very different and important diseases — rabies, bovine ephemeral fever, and vesicular stomatitis. Rabies in particular is an increasingly troublesome health problem in humans and animals. This and its complex epidemiology portends the necessity for increasingly complex control strategies, despite the availability of excellent vaccines. Rabies control, therefore, will be more and more dependent upon the existence of efﬁcient veterinary infrastructures. Rabies-related viruses, although so far unimportant as causes of either human or animal disease, add RHABDOVIRIDAE ORIGINALLY COUNTRY YEAR France 1882 ISOLATED FROM Lyssavirus Rabies Cow Lagos bat Bat Nigeria 1956 Mokola Shrew Nigeria 1968 Duvenhage Human South Africa 1970 Kolongo Bird Central African Republic 1970 Sandjimba Bird Central African Republic 1970 Nasoule Bird Central African Republic 1970 Kotonkan Ceratopogonid midges Nigeria 1967 Obodhiang Mosquitoes Sudan 1963 Rochambeau Mosquitoes French Guiana 1973 Charleville Phlebotomine flies Australia 1969 Cow South Africa 1967 Ephemerovirus Bovine ephemeral fever Adelaide River Cow Australia 1981 Kimberley Cow Australia 1980 Berrimah Cow Australia 1981 Coastal Plains Cow Australia 1981 Humpty Doo Phlebotomine flies Australia 1975 Tibrogargan Ceratopogonid midges Australia 1976 Ngaingan Ceratopogonid midges Australia 1970 Bivens Arm Ceratopogonid midges USA 1982 Sweetwater Branch Ceratopogonid midges USA 1982 Oak-Vale Mosquitoes USA 1981 Malakal Mosquitoes Sudan 1963 Muchong Mosquitoes Malaysia 1965 Parry Creek Mosquitoes Australia 1977 Vesiculovirus (26 viruses) 1121 1122 SECTION FOUR: Viral diseases: Rhabdoviridae to the complexity of the problem. The antigenic relationship between the rabies and bovine ephemeral fever serogroups is interesting and has been used as a basis for speculation on the phylogeny and intercontinental spread of lyssaviruses.2 Vesicular stomatitis, important in its own right but also because it is difﬁcult to distinguish clinically from footand-mouth disease, is fortunately conﬁned to the western hemisphere, although other vesiculoviruses which could potentially cause animal disease are not.2 It is thought that ‘an enormous number of rhabdoviruses are yet to be discovered’.2 This, and the fact that there is serological evidence of infection of mammals with some members of the family Rhabdoviridae which have so far only been isolated from haematophagous arthropods, indicate that not all the diseases caused by viruses within this family are recognized at present. References 1 brown, f., bishop, d.h.l., crick, j., francki, r.i.b., holland, j.j., hull, r., johnson, k., martelli, g., murphy, f.a., obijeski, j.f., peters, d., pringle, c.r., reichmann, m.e., schneider, l.g., shope, r.e., simpson, d.i.h., summers, d.f. & wagner, r.r., 1979. Rhabdoviridae. Intervirology, 12, 1–7. 2 calisher, c.h., karabatsos, n., zeller, h., digoutte, j-p., tesh, r.b., shope, r.e., travassos da rosa, a.p.a. & st. george, t.d., 1989. Antigenic relationships among rhabdoviruses from vertebrates and hematophagous arthropods. Intervirology, 30, 241–257. 99 Rabies Synonyms: Hondsdolheid (Afrik.) r swanepoel Introduction Rabies (rabidus, L. = mad) is a highly fatal disease of humans and all other warm-blooded vertebrates, caused by a virus which is present in saliva late in infection and which is generally transmitted by the bite of diseased animals, most commonly dogs and other carnivores. Virus introduced into the bite wound enters peripheral nerves and, during an incubation period of weeks to months, spreads to the spinal cord and brain to produce severe nervous disease that lasts from a few days to weeks. The disease is usually marked by excitability, furious behaviour, inability to swallow, salivation, convulsions, paralysis, coma and death. Human patients often exhibit fear of water and this has given rise to the alternative name of hydrophobia for the disease in humans. The disease appears to have occurred widely in Europe, Asia and Africa throughout recorded history, but it never had the signiﬁcant impact on human and livestock populations classically associated with diseases such as bubonic plague, smallpox, bovine pleuropneumonia or rinderpest. Nevertheless, the dramatic nature of the signs and symptoms and the invariably fatal outcome of infection has long caught the imagination, and recognizable descriptions of the disease can be traced back further in early Chinese, Egyptian, Greek and Roman records than descriptions of any other infectious disease.765 Controversy raged for centuries as to whether the disease arose spontaneously, or was caused by an agent transmitted by bite, and it was not until 1804 that Zinke784 published a description of the experimental transmission of the disease to dogs and cats by brushing saliva from a rabid dog into wounds. In 1879, Galtier276 described the transmission of the disease to a laboratory host, the rabbit, and thereby paved the way for the historic work of Pasteur and his associates. Pasteur soon established the essential association of the causative agent of rabies with nerve tissue, and 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 repro- ducible incubation period.520 The concept of speciﬁc immunization against infectious diseases had recently been developed by Pasteur and his associates for fowl cholera and anthrax, and in logical extension of their work they reasoned that vaccine could be administered to humans after exposure to rabies virus in order to induce immunity before the infection became established in the victim. They ‘attenuated’ rabies 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.519 It can be deduced that Pasteur’s method of preparing vaccine did not constitute attenuation of virus in the modern sense of the term, but resulted in the initial administration of inactivated virus followed by increasing doses of live virus. Despite the development of a vaccine, the true nature of the infectious agent remained obscure and it was not until 1903 that Remlinger554 demonstrated that it passed through ﬁlters which retained bacteria, and thus conformed to the newly deﬁned group of agents known as viruses. In the same year, Negri492 described the occurrence of cytoplasmic inclusions in infected nerve cells, and while the discovery of these ‘Negri bodies’ facilitated the speciﬁc diagnosis of rabies, the author himself considered the inclusions to be protozoan parasites, thereby fuelling controversy about the aetiology of the disease which was to continue for many years. Pasteur’s vaccine had the disadvantage that fresh batches had to be prepared constantly, and hence Fermi introduced a method in 1907 of preserving vaccine, while at the same time achieving partial inactivation of virus, through treating infected nerve tissue with phenol.251 The method was modiﬁed by Semple in 1911 to achieve more complete inactivation of virus.601 Semple-type vaccines prepared from infected nerve tissue from a variety of animals (particularly mouse brain) and inactivated with a variety of 1123 1124 SECTION FOUR: Viral diseases: Rhabdoviridae chemicals, especially formalin, remained in general use for humans and domestic animals for many decades, in some countries up to the present day, until superseded by inactivated or attenuated vaccines prepared from virus grown in chick embryos, duck embryos and cell cultures. In parallel with the development of an understanding of the mode of transmission of rabies infection, the early literature reﬂects growing opinion that the disease could be controlled by restriction and muzzling, or quarantine, of dogs, plus the destruction of strays.765 Elimination of rabies through the application of such measures was achieved in very few instances only, when the control of the disease was uniquely favoured by the insularity of the country concerned and by the lack of wild reservoirs of infection. Control was ﬁrst achieved in the Scandinavian countries of Norway, Denmark and Sweden in 1826345 and in Britain in 1902 after the promulgation of Anti-rabies Regulations in 1897, and again in 1922 following re-introduction of the disease in 1918.648 Japan was the ﬁrst country to attempt mass vaccination of dogs, in 1920,611, 648 and it ﬁnally achieved eradication of the disease in 1956.649 Taiwan and Portugal are among the few other countries to have eradicated rabies.649, 681 Several other countries were historically free of rabies, and apart from rare instances of importation of human cases, or animals in quarantine, have remained free of the disease. In many parts of the world, however, rabies is rampant to this day. Since many epidemics have been observed to develop and spread in recent times, such as those involving wild vertebrates (sylvatic rabies) in Europe and North America, the current high prevalence of rabies in the world cannot simply be ascribed to increased recognition of the disease through the application of improved surveillance and diagnostic procedures. Ironically, the highly developed nations of western Europe and North America, which had virtually eliminated dog and human rabies, recorded the highest annual numbers of cases of the disease in wild vertebrates during the second half of the twentieth century, although the position in Europe has been reversed dramatically since the introduction of oral vaccination of foxes (see below). In the developing nations of Central and South America, Africa and Asia, dog rabies (urban rabies) is predominant and there may be as many as 50 000 human cases each year, over 90 per cent of which result from transmission by dogs and many of which involve young children.125, 126, 252, 338, 606 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.252 Control of rabies in the developing nations is hampered by poverty, the inexorable trend toward uncontrolled urbanization, sociopolitical turmoil and wars, and the lack of the national infrastructure and ﬁnancial resources required for dealing with the problem.125, 252, 408, 606 Southern Africa, and South Africa in particular, has a high prevalence of the disease with a unique blend of urban and sylvatic rabies.376, 634, 667 Aetiology The family Rhabdoviridae (rhabdos, Gr. = rod) includes the genus Lyssavirus (lyssa, Gr. = rage or fury; also the ﬁbrous structure in the tip of a dog’s tongue, the removal of which prevented the development of madness according to superstitious belief as related by Pliny the Elder), the genus Ephemerovirus (named for bovine ephemeral fever virus), and the genus Vesiculovirus (named for vesicular stomatitis virus), plus a genus of ﬁsh viruses, two genera of plant viruses and a number of unassigned viruses. The genus Lyssavirus in turn includes rabies virus (designated lyssavirus genotype 1) and the so-called rabies-related viruses, Lagos bat, Mokola and Duvenhage (lyssavirus genotypes 2, 3 and 4), which are associated with bats, shrews and rodents in Africa, plus European bat lyssaviruses 1 and 2 (lyssavirus genotypes 5 and 6), which are associated with serotine and myotine bats respectively in Europe, and the Australian bat lyssavirus (lyssavirus genotype 7).123, 146, 284, 375, 376, 411, 488, 624, 694, 732 Within the lyssaviruses, the genetic relatedness is closest between488 (genotype 1) and Duvenhage, European bat lyssaviruses 1 and 2, plus the Australian bat lyssavirus (genotypes 4, 5, 6 and 7), which are consequently placed together in a phylogroup I, and between Lagos bat and Mokola viruses (genotypes 2 and 3), which constitute phylogroup II lyssaviruses.58, 624 The genetic relationships are reﬂected in antigenic relationships, and have implications for immunization: rabies vaccines can be used to immunize against Duvenhage, the Euopean bat and the Australian bat lyssaviruses, but are less effective against Lagos bat and Mokola viruses.58, 59 Mokola virus, which is capable of sustained subculture in mosquito cells and live mosquitoes,9, 136 provides a biological and antigenic link between the lyssaviruses and the ephemeroviruses.146 A Nigerian equine encephalitis virus, described in the literature as an unclassiﬁed virus,353, 544 has been identiﬁed as rabies virus, lyssavirus 1.373 From phylogenetic analysis of 36 carnivoran and 17 bat lyssavirus isolates, representing all major genotypes and variants, it was concluded that lyssaviruses probably developed in bats, and that host switching to carnivores occurred approximately 1 000 years ago.59 The results of monoclonal antibody and phylogenetic studies led to the recognition that strains of rabies virus proper, lyssavirus 1, which circulate in particular host species within given geographic regions tend to undergo genetic adaptation, resulting in the development of so-called biotypes, with subtle changes in antigenicity and pathogenicity which are of great epidemiological signiﬁcance.163, 215, 375, 569, 577, 589, 591, 623, 624, 625, 626–631, 662, 663, 694, 744, 758, 760, 761 Despite the relative ease with which mutations can be induced experimentally, the antigenic structure of rabies virus biotypes appears to have remained remarkably stable over many years in nature and is not ordinarily affected by passage in laboratory hosts or cell cultures.215 Nevertheless, the results of Rabies phylogenetic analysis of 87 canine lyssavirus 1 isolates from Asia, Africa, Europe and the Americas indicates that there has been nucleotide sequence divergence which can be estimated to date back to the times of European colonization of each region, so that the introduction of dog rabies may have been a legacy of colonization.215, 628 Rhabdoviruses are rod- or bullet-shaped, rounded at one end and plano-concave at the other, and tend to have a constant diameter of 75 nm with a length that varies from 130 to 300 nm, but some are conical, with the sides tapering to a point.14, 168, 200, 250, 456, 465, 485 The genome consists of a single segment of single-stranded, negative-sense RNA (complementary to mRNA), and there are ﬁve structural proteins.230, 283, 445, 642 Rabies virus particles are bullet-shaped, measure 180 × 75 nm and consist of a nucleocapsid, 160 × 50 nm, which is surrounded by a bilayer lipid envelope, derived from host cell membranes, and through which ﬂattened spikes or peplomers, each composed of three molecules of glycoprotein (G protein), project over the entire surface of the virion, except at the blunt end.214, 485 Underlying the lipid membrane is a layer of membrane or matrix protein (M protein, also designated M2 protein), which binds to the nucleocapsid (N) protein of the viral core, and holds the envelope in place.229 The ribonucleoprotein core of the nucleocapsid consists of the RNA genome, MW 4,5 × 106 with 11 932 nucleotides643, 695, 696 intimately bound to the phosphorylated N protein, which covers the RNA molecule along its entire length, and this complex forms a tightly wound helix of 30 to 35 coils. Minor quantities of two more proteins are associated with the ribonucleoprotein complex: a phosphorylated protein, misleadingly named non-structural (NS) protein (earlier termed M1 protein since at one time it was believed to be associated with the membrane), plus a large (L) protein which constitutes the viral transcriptase, an RNA-dependent RNA polymerase. The G protein 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. It also stimulates and is a target for T cell-mediated immune response.151, 152, 187, 191, 192, 440, 709, 759, 763, 775 Although there is greater than 94 per cent sequence homology between the amino acids of the G proteins of strains of rabies virus that have been studied, the substitution of even a single amino acid at a critical site may result in marked changes in pathogenicity, glycosylation or antigenicity.183, 184, 185, 215, 220, 547, 597, 772, 773, 776, 777, 779 Antigens associated with the N protein and possibly with the other proteins of the ribonucleoprotein complex can also induce a degree of protective immunity.216, 217, 273, 427, 657 Consequently, the efﬁcacy of a vaccine against a particular street virus cannot be predicted solely on the basis of the compatibility of their G protein antigens, but should be based on potency tests in animals, preferably involving the 1125 intended target species.215 The protective mechanism is believed to involve stimulation of T cell-mediated immunity.150, 216, 230 There is 98 to 99 per cent homology in the deduced amino acid sequences of the N proteins of strains of rabies virus that have been studied,697, 698, 777 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.163, 216, 402, 569, 589, 594, 629, 631, 663, 744, 761 Attachment of rabies virus to susceptible cells is as yet imperfectly understood. Infection can occur in the absence of the virus envelope, but with greatly reduced efﬁciency.229 There is evidence that infection of the nervous system can occur through the attachment of virus to the acetylcholine receptors at neuromuscular junctions,140, 413, 740 but cultured cells which lack or have few acetylcholine receptors, nevertheless have receptors which are broadly speciﬁc for rhabdoviruses, and which appear to be associated with particular carbohydrate moieties of the phospholipids and glycolipids of cell membranes.339, 551, 552, 703, 705, 778 Recently, a neural cell adhesion factor has been identiﬁed as a rabies virus receptor.684 It can be concluded that the virus probably uses different receptors on different cells.195, 339, 704 Following their attachment to the cell surface, virus particles are internalized by endocytosis (viropexis) and the virus in cytoplasmic vesicles is uncoated by fusion with lysosomes.474, 534 The ribonucleoprotein complexes which are released, constitute active templates for transcription of the genome. As with all negative-strand RNA viruses, the nucleic acid is non-infectious in the absence of viral transcriptase. Replication occurs in the cytoplasm of the infected cell, and virus matures and is released by budding through the cell surface membrane,180, 229, 314, 396, 526, 697, 698, 774, 777 but in nerve cells the virus matures predominantly on internal membranes.458 Accumulations of viral proteins in the cytoplasm constitute the inclusions seen histologically in infected cells, and accretions of virus particles apparently account for the ‘inner structure’ described for Negri bodies.282, 324, 430, 456, 457, 492 The replication of rabies virus is slower, less abundant and less inhibitory of host cell macromolecular synthesis than that of vesiculoviruses, and the virus is therefore less inclined to produce readily discernible cytopathic effects.195, 696 During replication, rabies virus readily gives rise to mutants with part of the genome deleted, resulting in shorter nucleocapsids and hence truncated mature virions. These so-called defective interfering (DI) particles are able to replicate only in the presence of standard virus, but at the same time they interfere with replication of the standard virus. Production of DI particles is enhanced by subculture of undiluted virus, and the presence of the particles can lead to loss of infectivity or help to induce and maintain a state of persistent viral infection with low output of virus and minimal deleterious effect on the cells.193, 195, 229, 362, 753, 754 Induction of interferon production also plays a role in the 1126 SECTION FOUR: Viral diseases: Rhabdoviridae generation of persistent infection.315 It is not known whether DI particles inﬂuence the course of infection in intact animals, but interferon induced within the central nervous system during infection appears to be inconsequential to the outcome of infection.428 Rabies virus is sensitive to sunlight and ultraviolet irradiation, heat, detergents, halogens and lipid solvents. Infectivity is destroyed in 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. The virus is also inactivated by heating to 56 °C for 30 minutes, or by 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 glycerolsaline at room temperature (22 °C) or for months at 4 °C. Virus can be preserved for years at temperatures below −60 °C, or by freeze drying and storing at 4 °C.345, 356, 379 Rabies virus has been cultured in a variety of laboratory hosts for diagnostic and research purposes, and for production of vaccine, from the time of Pasteur onwards, but mice have been the most commonly used animals since 1935.742 Culture of the virus in embryonated eggs was introduced in 1938.380 Various tissue suspension, explant and cell cultures were used from 1913 onwards,195, 415, 509, 753 but successful serial subculture of rabies virus in cell cultures was ﬁrst reported in 1958,378 and shortly after that it was shown that cell cultures could be used for the production of vaccine.379 Currently, a wide range of primary cell cultures as well as diploid and transformed cell lines are used for different purposes. Rabies virus generally has to be adapted to cell cultures by passage to obtain efﬁcient replication, and uptake of virus can be enhanced by treating cells with the polycation DEAE-dextran prior to initial infection.195, 358, 751 Cell lines commonly used in research and the diagnosis of rabies include BHK21, CER and Nil2, all of hamster origin, Vero cells derived from vervet monkey kidney, and neuroblastoma cell lines of murine and human origin.124, 147, 171, 195, 336, 566, 567, 585, 620, 621, 632, 633, 761 Cells used for the largescale production of virus for vaccines include a variety of primary cultures, such as chick embryo ﬁbroblasts, foetal bovine kidney and dog kidney cells, as well as line cells such as Vero, Nil2 and NL-ST-1 (swine testicle cells), and the human diploid cell lines WI38 and MRC5.89, 90, 431, 479, 548, 565, 602, 716, 757 The rabies-related viruses can also be cul196, 687 tured in cells, including Mokola virus in invertebrate cells.136 Epidemiology Rabies-free countries Countries reported to be free of rabies in recent years are mainly islands and peninsulas. They include Great Britain, Ireland, Iceland, Sweden, Norway (apart from the Svalbard Islands to the north of the mainland), Denmark, Portugal, Spain, Gibraltar, Malta, Albania, Cyprus, Bahrain, Oman, Qatar, United Arab Emirates, Hong Kong, the Malaysian peninsula, Singapore, certain Indonesian and Philippine islands, Republic of Korea, Japan, New Zealand, Fiji, Hawaii and certain other western Paciﬁc and Caribbean islands, Libya, Cape Verde, Sao Tome, Comores, Mauritius and Antarctica, but several of the countries mentioned in the Persian Gulf and South East Asia occasionally experience reintroductions of the disease.34, 37, 111 Several countries in western Europe are on the point of eradicating rabies of terrestrial vertebrates (lyssavirus 1) as a result of conducting successful oral vaccination campaigns on fox populations,52, 53, 782 but have nevertheless reported the presence of bat-associated lyssaviruses (see below). In 1996, European bat lyssavirus 2 was also found in a bat in Britain, hitherto considered to be free of lyssaviruses.747 Apart from rare imported cases of the disease,286 Australia has always been free of rabies proper, lyssavirus 1, but recently the presence of a lyssavirus genotype 7 has been recognized in fruit bats (ﬂying foxes) as well as in insectivorous bats, and there have been two human infections with fatal disease resembling rabies.253, 270, 301, 317, 579, 617, 645 The degree of genetic divergence between fruit and insectivorous bat isolates in Australia suggests that bat lyssavirus was probably present before European colonization.739 The remaining countries of the world have endemic rabies with marked variations in prevalence and species affected, but the disease is poorly monitored and under-reported in many instances.111 Europe In western Europe, outbreaks of rabies involving dogs, foxes and wolves were described in the eleventh and thirteenth centuries, but urban rabies only became widespread after the industrialization of the eighteenth century.133, 345, 648 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.34, 37, 63, 111, 692 Field trials on oral vaccination of foxes were conducted in Switzerland in 1978.647 A sustained oral vaccination campaign was started in Switzerland in 1985, in France in 1986, and in 13 other European countries shortly thereafter.52, 53 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.51, 52, 53, 652, 782 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 Rabies disease from thousands of cases to the point where the few residual cases in dogs, cats, domestic ruminants and occasional deer, badgers and martens represented spill-over of infection from foxes.34, 37, 111, 353 Fortunately cats and dogs are partially resistant to fox virus.114 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 Yugoslavia and in enclaves in the southernmost areas of the former USSR.111 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.111, 166 Arctic rabies, regarded as an ancient and epidemiologically distinct entity, extends across the northern part of the former USSR, Finland, the Svalbard Islands of Norway, Greenland, the Northwest Territories of Canada, and Alaska.111, 188, 353 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.111 Asia Rapid population growth and urbanization in much of Asia have created conditions which are highly conducive to the occurrence of urban rabies. Several thousand cases of rabies in dogs are recorded each year in India, Pakistan, Indonesia, Thailand and Vietnam, while countries such as Bangladesh, Burma, Iran, Iraq and the Philippines, which report comparatively few cases of animal rabies, nevertheless report thousands of human cases or post-exposure treatments of humans.111, 733 India has the highest number of human deaths from rabies 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.8, 111 Monitoring of rabies in livestock and wild vertebrates is even more deﬁcient than in dogs and humans, but mongoose and jackal rabies occur in India and possibly elsewhere in Asia.8 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 brought in with dogs by European colonists.133, 612, 768 On the other hand, 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 1127 other animals across the Bering land bridge 30 000 to 75 000 years ago.188, 768 Dog rabies became widely distributed in the USA in the second half of the nineteenth century following the civil war, and by 1944 dogs accounted for 86 per cent (9 067/10 540) of cases of rabies recorded in that year, with only 3 per cent of cases being recorded in wild vertebrates.133, 646 Following the institution of increasingly effective control measures in the 1940s and 1950s, the incidence of dog rabies declined steadily to 128 cases in 1988, with no cases being recorded in humans in that year.37, 646 At the same time, however, there was a steady increase in sylvatic rabies and by 1988 wild vertebrates (mainly skunks, raccoons, bats and foxes) accounted for 88 per cent (4 173/ 4 723) of cases of rabies in the USA, with the remaining 422 (9 per cent) cases occurring in domestic cats and herbivores, and in dogs particularly in the Texas–Mexico border area37 Moreover, it was found that ordinary passive surveillance detects only 1 to 10 per cent of the number of cases of rabies which are diagnosed when wild animals are deliberately trapped for examination.95, 516, 724 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, but here too 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.37, 95 Despite early reports to the contrary,451, 507, 513, 635 infection of bats with rabies virus proper, lyssavirus 1, has been conﬁrmed as occurring only in the Americas.95, 623, 625 The ﬁrst isolations of rabies virus 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 investigations which culminated in isolations being made from 30/39 indigenous species of insectivorous bats of the USA and temperate Canada, and from virtually all of the countries of Central and South America.60, 62, 177, 524, 581, 623, 723 In the late 1950s, when sylvatic rabies was only beginning to assume its subsequent proportions in Europe and North America, the hypothesis was developed that rabies virus is maintained in vertebrates which only sporadically manifest disease and that epidemics occur when infection spreads to aberrant hosts such as wild or domestic canids which regularly develop encephalitis.344, 345 Mustelids, vivverids and bats were implicated as the cryptic maintenance hosts in various parts of the world and it was postulated that a climax state of host–parasite relationship had evolved through long association between the virus and these vertebrates.154, 333, 344, 345 A corollary to the theory was that effective control or eradication of the disease could only be achieved by identifying such cryptic maintenance hosts and directing 1128 SECTION FOUR: Viral diseases: Rhabdoviridae appropriate control measures towards them. This view of rabies has persisted in many countries, and the existence of a sylvatic reservoir of infection is still widely cited as a reason for failure to control dog rabies. In practice, it was observed that 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.167, 623–625 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.389, 391, 572, 573, 623, 625 The major host is not determined simply by the relative prevalence of the species since skunks, for instance, may be as numerous in an area where fox rabies predominates as they are in an area where skunk rabies predominates, and the converse is true for foxes.515, 517 Nor can the phenomenon be ascribed simply to the isolation of vertebrate species from each other in ecological niches since spill-over of infection causes sporadic disease, but only rarely initiates independent spread of the virus in a second species. This suggests that strains of rabies virus become uniquely adapted to circulate in speciﬁc hosts, and indeed it was found, for instance, that skunks are relatively resistant to virus of fox origin, but that foxes are highly susceptible to skunk virus and succumb rapidly without excreting the virus in saliva, i.e. without being able to transmit infection.516, 518, 609 However, it is implicit in these and similar ﬁndings with other species that vertebrates vary inherently in their susceptibility to infection and ability to excrete virus, so that the mechanisms responsible for the compartmentalization of circulation of rabies in species include both host and viral factors.110, 156, 516, 518, 609 Proof that the circulation of rabies virus strains is compartmentalized in vertebrate species came from monoclonal antibody and phylogenetic studies, which in effect resulted in the recognition of virus biotypes.110, 163, 215, 569, 573, 577, 589, 591, 623–626, 629–631, 663, 744, 758, 760, 761 It was found, for instance, that a single biotype of virus occurs in red foxes in western Europe;623 that rabies virus which affects the North American red fox (Vulpes fulva) in hyperendemic areas in south-eastern Canada and northern New York State, USA, corresponds to the Arctic fox virus biotype from which it was ostensibly derived by southwards spread of infection in the 1950s;345, 542, 623, 625, 768 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 biotype from that which occurs in skunks in the south-central states and there is an area of overlap in the distribution of the two biotypes where they converged, with yet another biotype occurring in northern California;95, 165, 516, 623, 625 that virus associated with rabies in the raccoon (Procyon lotor) in the Atlantic states corresponds to the en- demic raccoon biotype of south-eastern USA, from which it was apparently derived through translocation of raccoons by hunters in 1977;342, 462, 501, 623, 625 and that separate biotypes occur in grey foxes (Urocyon cinereoargenteus) in Arizona and Texas.389 There appears to be surprisingly few biotypes of rabies virus in relation to the range of vertebrates which become infected, and those which are known to be in existence appear to have remained unchanged for at least a period of several decades, indicating that the evolution of new biotypes is infrequent and thus most likely to occur where there is large-scale transmission of virus to a second host: it can be said that, in effect, a variant virus is selected only to take advantage of changed circumstances.690 Lyssavirus 1, which affects dogs all over the world, appears to have transferred with facility between canine species, a recent example being the spread of dog virus in coyotes (Canis latrans) in southern Texas.389, 561 More surprisingly, it appears that a bat variant of lyssavirus 1 had become established in skunks in northern Arizona in 2001, when the diagnosis was conﬁrmed in 19 skunks. A control programme of trapping, vaccinating and releasing skunks was instituted, and it remains to be seen whether transmission has been successfully interrupted.414 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 an analogous compartmentalization of circulation of virus in some species with spill-over of infection to others.623 Thus, monoclonal antibody and phylogenetic studies revealed that more than 30 distinct lineages of virus circulate in insectivorous and vampire bats in the Americas, with a tendency for migratory species of bats, either colonial or solitary, to yield the same biotype in different locations, while sedentary species may yield a variety of biotypes.623–625 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 biotypes of virus.390, 623, 624, 625 Indeed, the isolated cases of rabies which occur in humans in the USA each year are almost all caused by virus associated either with the silver-haired bat (Lasionycteris noctivagans) or the eastern pipistrelle (Pipistrellus subfavus), and enigmatically it is usually difﬁcult to obtain a history of exposure to bats, while a limited number of cases of rabies occurs in immigrants exposed to infection with dog virus abroad.390, 624 At the end of the twentieth century, the USA was still experiencing more than 8 000 cases of animal rabies per annum, with over 80 per cent occurring in wildlife.43, 389, 391 By then, 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.43, 132, 608 Control of wildlife rabies 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, as discussed in relation to oral vaccination below. 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 urban rabies in dogs and sylvatic rabies in vampire bats in Central and South America. Vampire bat-associated rabies was apparently ﬁrst encountered by Spanish colonists early in the sixteenth century, and 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 the bats, and roosting sites in otherwise inhospitable grasslands through the digging of wells.45, 46, 60, 62, 149, 306, 416, 442, 524 There are three species of vampire bat, each belonging to a separate genus, but Desmodus rotundus is the most common and the most important transmitter of rabies.45 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.46 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 variously at 100 000 to more than 500 000 cattle per annum, but 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.2, 46, 60, 416 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.207 The results of experimental infections in the 1930s suggested that vampire bats were uniquely capable of acting as true carriers of rabies virus, being able to survive frank disease or to excrete the virus in saliva for extended periods without developing overt disease, but the validity of the experimental methods has been questioned, and it is currently believed that the bats undergo variable incubation periods and disease similar to other animals, excreting virus in saliva for up to eight days before manifesting disease.60, 481 Although a proportion of vampire bats appears to survive infection, as evidenced by the occurrence of antibody in free-living populations, it is thought that salivary gland infection does not occur in the absence of brain infection.60, 481 It has also been suggested that insectivorous bats and hibernating rodents could serve as reservoirs of rabies virus through the persistence of infection in brown fat during hibernation. Virus replication is suppressed by the lowering of the body temperature and metabolic activity in hibernating animals, and the disease runs its normal 1129 course on the emergence of the host from hibernation.119, 120, 655 However, the relevance of the persistence of infection in brown fat to the pathogenesis of the nervous disease has been questioned and, as with vampire bats, it is now believed that salivary gland infection does not occur in the absence of brain infection.62, 119, 120 Urban 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, but concerted urban vaccination campaigns have improved the situation markedly since 1980.2, 167 A peculiar feature of the disease in Latin America is the tendency for greater numbers of domestic cats to be involved than elsewhere in the world.2 Caribbean countries During the 1860s and 1870s, the grey mongoose (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.2, 233, 625 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, with the mongoose being the dominant host of the virus in most instances, although dogs are also important hosts on some of the islands.2, 95, 233, 625 A disturbing feature is that antibody prevalence rates in excess of 50 per cent have been recorded on occasion, indicating that a high proportion of the mongooses survives rabies, and it appears that such high immune rates suppress circulation of virus, so that there are cyclical epidemics as the proportion of susceptible individuals in the population waxes and wanes.232, 233 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 results of feasibility studies suggest that oral vaccination could be used on mongooses.189, 419 Africa Rabies is least well monitored in Africa. For instance, the 2 081 conﬁrmed cases of the disease in domestic and wild animals reported for the continent as a whole in 1988 constituted less than 5 per cent of the total for the world.37 Virtually all African countries have the requisite veterinary and medical infrastructures, but many have been unable to devote adequate resources to monitoring and controlling rabies in the face of poverty, prolonged droughts, other priorities, or armed conﬂict.4, 54, 211, 265, 329, 359, 370, 408, 429, 433, 441, 453, 483, 510, 616, 693, 707, 790 North Africa Rabies has been present in North Africa since antiquity. It occurs principally as an urban disease in the countries of the 1130 SECTION FOUR: Viral diseases: Rhabdoviridae Mediterranean littoral such as Morocco, Algeria and Egypt with each recording up to several hundred cases in dogs annually, with lesser numbers of domestic cats, herbivores and humans being affected, but it is under control in Tunisia and Libya.74, 111, 153 The belt of countries lying immediately to the south, including the northern part of Senegal, Mauritania, Mali, Niger, Chad, Sudan, Ethiopia, Djibouti and Somalia, span the Sahara Desert and are largely arid and sparsely populated. Here rabies occurs in scattered urban foci, but is translocated with the dogs of nomads or refugees ﬂeeing drought or war. Camels are sometimes victims of the disease following outbreaks in dogs, and occasionally infection is recognized in jackals and hyenas.111 The occurrence of rabies in the Ethiopian wolf (Canis simensis),613, 749 is a matter for concern since this species, plus Blanford’s fox of Asia (Vulpes cana), and the African wild dog (Lycaon pictus) are considered to be the only carnivores which are sufﬁciently rare so as to be threatened with extinction by rabies.437 Sub-Saharan Africa In sub-Saharan Africa, where humans and other animals are more widely distributed than in northern Africa, there has been a greater tendency for epidemics of dog rabies to spread over large areas and for the disease to be observed in domestic herbivores and wild vertebrates.111 This trend is most noticeable in the more developed countries of southernmost Africa, where the high proportions of cases recorded in wild animals must to some extent reﬂect more intensive monitoring of the disease, but where speciﬁc problems with sylvatic rabies are nevertheless encountered.667 West Africa In West Africa, rabies was ﬁrst diagnosed in Nigeria, Senegal and Niger in 1912, and the general pattern in the region has been for the disease to affect mainly dogs and to a lesser extent cattle, other livestock and humans.4, 10, 80, 121, 228, 510, 512, 693 It is notable that the region yielded the ﬁrst isolates of Lagos bat and Mokola viruses, plus ﬁve other rhabdoviruses, and that strains of rabies virus with reduced virulence for dogs have been isolated at intervals over many years in the area extending from West Africa across to Ethiopia, suggesting that lyssaviruses have undergone a long period of evolution and dissemination in the region, and fuelling speculation that Africa may be the cradle of rabies.146 A non-fatal form of rabies in dogs, known colloquially as oulou fato (mad dog disease), was ﬁrst recognized in Senegal and Niger in 1912, and its distribution apparently extended across Zaire, Cameroon, Ivory Coast, Ghana, Nigeria and the Sudan.121, 558, 639, 682 There have been no recent reports of a disease by the name of oulou fato, a term which appears to have fallen into disuse, but strains of virus capable of producing non-fatal and chronic infection of dogs were isolated in Ethiopia in the 1950s and 1970s, and similar ﬁndings were reported in India.18, 240, 241, 721 Naturally affected dogs were capable of transmitting fatal disease to humans, in some instances over a period of years. The site of chronic infection may be the tonsil.245 In a recent investigation of the phenomenon, four isolations of rabies virus were made from the saliva of healthy dogs presented for vaccination over a period of ﬁve years in Nigeria, and only one of these isolates produced fatal disease in puppies.6 At about the same time, 1989, six cases of symptomatic rabies in dogs were linked to the use of the Flury strain of attenuated virus vaccine in Nigeria,511 a phenomenon more commonly seen in cats. It was demonstrated in Russia that a proportion of dogs can survive intracerebral inoculation with rabies strains associated with both the convulsive and paralytic forms of the disease.290 East Africa In East Africa, the presence of endemic rabies of dogs and jackals was recognized in Kenya from 1900 onwards and the diagnosis was ﬁrst conﬁrmed in a dog bitten by a jackal in the Nairobi district in 1912, but the disease had been known to the indigenous inhabitants of the country before the arrival of European colonists.321, 359 Endemic rabies of dogs was recognized in north-western Tanzania on the Kenya border in 1932 and was ﬁrst conﬁrmed in 1936.562, 575 In 1956, an outbreak of more serious proportions occurred in Mbeya district in the south-west of the country, adjacent to the borders with Zambia and Malawi, spread north-eastwards across the country during the 1960s, and swung north-westwards in the 1970s to produce a severe epidemic in the extreme north-west of Tanzania at the end of the decade.447, 575 Spread of the epidemic continued into Kenya and by the mid-1980s had engulfed most of that country.359, 616 Dog rabies remains a problem in Kenya and Tanzania. During the 1990s, rabies devastated populations of the wild dog (Lycaon pictus) on the Serengeti plains of Tanzania and Kenya, with infection apparently spreading from the domestic dogs of nomadic herdsman.11, 12, 141, 142, 224, 277, 360, 361, 436, 480 Contentions that the wild dog had been predisposed to rabies through stress induced by handling in ongoing ecological studies, could not be supported on the basis of experiences elsewhere in Africa.204 The wild dog in the Selous Game Reserve in the south of Tanzania appeared to have been spared, but rabies was also recorded in bateared foxes (Otocyon megalotis) (Figure 99.1) in the north.190, 435 In Uganda, sporadic outbreaks of dog rabies were recognized from 1935 onwards, but from 1971 monitoring and control of the disease deteriorated as a result of political instability, and it is believed that the mere 12 cases conﬁrmed in the decade from 1981 to 1990 do not reﬂect the seriousness of the problem which has developed in that country.330, 562 Rabies 1131 Figure 99.1 Bat-eared foxes (Otocyon megalotis). (By courtesy of the National Parks Board, P O Box 787, Pretoria 0001, South Africa) Malawi, Zambia and Angola Namibia Rabies is endemic throughout Malawi, where the occurrence of the disease was suspected in 1916 and conﬁrmed in 1926.639 At least 1 656 cases of rabies were conﬁrmed from 1977 to 1987, with the vast majority occurring in dogs, although the disease also occurs in jackals and hyenas.483 In Zambia, rabies was apparently present in the nineteenth century, and in 1901 Chief Lewanika of the Barotse in the west of the country ordered the destruction of all dogs in the area in an attempt to control a serious outbreak of the disease.226, 605, 639 The diagnosis of the disease was ﬁrst conﬁrmed in 1913 and it has continued to occur throughout the country.615, 707, 790 The disease mainly affects dogs, but appreciable numbers of cattle fall victim to the disease in the south-central part of the country, particularly in locations where jackal rabies is diagnosed close to nature reserves.790 There appears to be a much higher ratio of dogs to people in rural communities in Zambia than in urban centres, and the rural dogs are less accessible to vaccination.202 Recently virus which cross-reacts with anti-rabies ﬂuorescein conjugate was isolated from the brain of an unidentiﬁed bat found dead in Zambia, but no deﬁnitive characterization of the bat or isolate was performed.7 Lyssavirus 1 has only been identiﬁed in bats from the Americas, so the Zambian isolate is likely to have been a rabies-related virus, possibly Lagos bat or Duvenhage virus. Rabies was ﬁrst conﬁrmed in Angola in 1929 and since then the disease has been diagnosed mainly in dogs, with very few cases being recorded in other domestic or wild animals,223 but the protracted civil war in the country has hampered monitoring and control of the disease over several decades. An outbreak of disease ﬁtting the description of rabies and involving dogs, cattle and small livestock was apparently observed in Namibia in 1887,328, 583 and from 1925 onwards there were sporadic reports of outbreaks of disease involving dogs, humans and, on one occasion a hyena, in the Ovambo, Kavango and Caprivi Strip districts in the north, bordering Angola and Zambia, with an isolated case being recorded further south in a child bitten by a dog in Swakopmund in 1928 and another in a woman bitten by a wild cat in Grootfontein in 1937.727 A diagnosis of rabies was ﬁnally conﬁrmed in a dog from Rundu in Kavango in 1938, but a suspected outbreak of the disease which occurred on farms in the Gibeon and Mariental districts in the south in 1945 could not be conﬁrmed.727 The position changed sharply with the occurrence of the second conﬁrmed case of rabies in 1947, also in a dog in Rundu, which was followed in 1948 by the appearance of the disease south of the Etosha National Park in cattle in Outjou district, whence spread of disease involving black-backed jackals (Canis mesomelas) (Figure 99.2) and cattle continued southwards to reach Otjiwarongo in 1949 and the central districts of Gobabis and Windhoek by 1951.13, 40, 583, 727 Since then, rabies has remained a problem in Namibia, with dog and human cases being recorded mainly in the north where the density of the rural population is greatest, jackal and cattle rabies dominating in the central ranching area, and sporadic disease being associated with felids (the African wild cat, Felis lybica, and caracal, Felis caracal) and vivverids (genets and mongooses) in the sheep-rearing areas of the south.40, 208, 583 Outbreaks of rabies in black-backed jackals have a threeto four-year periodicity in central Namibia, and these 1132 SECTION FOUR: Viral diseases: Rhabdoviridae Figure 99.2 Black-backed jackal (Canis mesomelas) outbreaks are signiﬁcant predictors of disease activity in domestic ruminants and dogs.186 There were two unusual developments in Namibia: epidemic spread of rabies in kudu antelope (Tragelaphus strepsiceros) from 1977 to 1985 in the central ranching area, and the subsequent occurrence of the disease in carnivores ranging from bat-eared foxes and jackals to lions in the Etosha National Park. A localized outbreak of rabies in kudus occurred in Windhoek district in 1975, but the epidemic which followed began in Okahandja district in 1977 and over the next few years spread to Karibib, Omaruru, Windhoek, Otavi, Otjiwarongo, Outjou, Gobabis, Grootfontein and Tsumeb districts, causing an estimated loss of 30 000 to 50 000 antelope, or 20 per cent of the population, by the time the outbreak subsided in 1985.84, 85, 303, 328, 583, 603 It is believed that the kudu population had attained an unprecedented density during the 15 years preceding the epidemic, and this was ascribed to the conservation of kudu and control of predators because of the increasing value of trophy hunting and export of venison; overgrazing of pastures by cattle resulting in encroachment by bushes and trees which favour browsing animals; increased installation of watering points on ranches; and the occurrence of a succession of seasons of above average rainfall. 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 thereafter 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. This possibility was strengthened by the fact that eastward extension of the outbreak was initially checked for two years by a game control fence, which hindered the passage of antelope but not small carnivores. 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. However, individuals sometimes browse in close proximity to each other, so that transmission of infection through contamination of vegetation was possible. It was shown that kudus are highly susceptible to infection by the oral route, and that infected individuals excrete high concentrations of rabies virus in saliva.85 The social behaviour of kudus further facilitated the spread of infection through the dispersal of individuals in winter and re-grouping into matriarchal units in summer, with solitary breeding bulls showing the greatest tendency to range over long distances and to make contact with members of different groups. 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. Cattle and game animals generally congregate separately at places, such as watering points, but rabid kudus do not avoid contact with other species. It is notable that Von Maltitz727 had earlier postulated that oral transmission occurred in cattle, in order to account for the high incidence of the disease which occurred on some ranches when rabies spread southwards in Namibia at the end of the 1940s. He had observed on one ranch that where cattle were being fed bone meal that contained coarse chips capable of causing mouth injuries, a rabid individual had salivated into the feeding trough. Rabies Etosha National Park lies in the pathway of the southwards spread of rabies in 1948, and so the outbreak observed in the park in the early 1980s could have originated from endemic disease, but it is believed that the infection was probably re-introduced from Tsumeb district in the 1980s by jackals which are able to penetrate the game-proof fence of the park.91 The outbreak in the park was unusual because rabies has never become established in major game reserves, such as Hwange National Park in Zimbabwe and the Kruger National Park in South Africa, despite the marginal intrusion of jackal rabies into the former on one occasion in the early 1980s,264 and the known periodic incursion of rabid dogs into the latter.40 Foggin264 postulated that the diversity of carnivores which occurs in large undisturbed areas such as the Hwange and Kruger national parks dictates that no single species becomes so numerous that it exceeds threshold density for spread of the disease, and that there is insufﬁcient interspeciﬁc contact for the maintenance of infection. In contrast, the Etosha National Park supports a lesser species diversity and its arid nature is probably more conducive to the occurrence of intra- and interspeciﬁc confrontation. The same is probably true of the Kgalagadi Transfrontier Park in the South African part of the park where rabies has been recorded in the spotted hyena (Crocuta crocuta).40 Antibody to rabies virus was found in 30 per cent of domestic dogs in Tsumkwe district, north-eastern Namibia, but not in the wild dog.406, 407 Botswana In Botswana, there were unconﬁrmed focal outbreaks of rabies in Lobatse in the south-east in 1919 and 1922, and in 1133 Ngamiland district in the north-west in 1936, where the diagnosis was ﬁrst conﬁrmed in a dog in 1938.40, 173, 309, 449, 639 According to veterinary correspondence cited by Foggin,264 an outbreak of dog rabies of more serious proportions was noted in Ngamiland, adjacent to the Caprivi Strip and Kavango districts of Namibia, at some stage before March 1950, and by September the disease had crossed to Serowe in the east and swept down the eastern border to the south of the country, i.e. infection spread to all areas where the human, and therefore dog population was most dense. Along the way, the infection spread into southwestern Zimbabwe and the northernmost Limpopo Province of South Africa. The disease has remained active in all of the areas of Botswana initially affected, but in addition to the original problem of dog rabies with occasional human cases, there has been a tendency for increasing numbers of jackals, cattle and other livestock to be involved.446, 455, 482 From about 1980 onwards a separate outbreak of rabies involving domestic herbivores and wild animals developed in the Ghanzi district on the western border of Botswana, apparently as an extension of the kudu epidemic in Namibia, and within a few years had spread 1 000 km south-eastwards across the country to Kgatleng district on the North West Province border of South Africa.482 Southward extension occurred into the Kgalagadi district482 and Kgalagadi Transfrontier Park, and in 1986 rabies was diagnosed in spotted hyena in the South African part of the park.40 Sporadic cases of rabies are diagnosed in the yellow mongoose (Cynictis penicillata) (Figure 99.3) and in the small-spotted genet (Genetta genetta) in southern Botswana.446, 455, 482 Figure 99.3 Yellow mongoose (Cynictis penicillata) 1134 SECTION FOUR: Viral diseases: Rhabdoviridae Zimbabwe Zimbabwe was apparently free of rabies in 1890 when European colonists arrived in the country, but some of the older inhabitants could recall that the disease had been present when they were young.226 In 1902, dog rabies appeared in the Bulawayo area in south-western Zimbabwe, and there appears to be little doubt that the disease was introduced from western Zambia which had considerable trafﬁc with Zimbabwe at the time, and where the disease was known to be rampant in the Barotseland area in 1901 (see above).226, 605 Within two years 60 000 dogs were destroyed in an attempt to control the disease in Zimbabwe, and, although this must have represented a considerable proportion of the population at the time, the disease continued to spread throughout most of the country. Control of the disease was ﬁnally achieved in 1913, this being ascribed largely to the imposition of a dog tax, which provoked drastic voluntary reduction of the population on the part of dog owners.226, 605 The infection apparently did not become established in wild hosts, and failure of the outbreak to extend into South Africa was ascribed to preventive action in the form of a radical reduction of the dog population within an 80-kmwide strip along the Limpopo River where it forms the northern borders of the country with Zimbabwe and Botswana.449 After 1913, Zimbabwe remained free of rabies until 1938, when two cases were diagnosed in dogs at Victoria Falls, and, as before, the evidence indicated that the infection had been introduced from Zambia.605 Except for bridges at certain points, the Zambezi River forms an effective natural barrier to the spread of rabies from Zambia, and after 1938 Zimbabwe again remained free of the disease until dog rabies crossed the south-western and southern borders of the country from Botswana and the Limpopo Province of South Africa in 1950 — it is believed that the virus was introduced by dogs which accompanied people who crossed the borders illegally to purchase grain.3, 605 The disease spread rapidly through Zimbabwe, following routes along the more densely populated communal farming areas, and by 1954 had reached the north of the country.3, 605 The growth in the human population since 1913 made it difﬁcult to enforce control measures, such as dog ‘tie-up’ orders and the destruction of strays, and from 1951 onwards mass immunization campaigns were conducted with Flury LEP (low egg passage) vaccine, which had then only recently become available.3, 605, 766 By the early 1960s control of the disease had been achieved over most of Zimbabwe, apart from resistant foci on the eastern and western borders with Mozambique and Botswana, and vaccination campaigns were scaled down.264, 444, 766 From 1965 onwards, however, political unrest culminating in civil war rendered it increasingly difﬁcult to immunize dogs in the communal farming areas, and the prevalence of rabies progressively rose to a record level of 861 conﬁrmed cases in 1981, after the cessation of the war in 1980.264, 266, 408, 665 Following the formal ending of the war, the control of dog rabies was complicated by continued strife in Matabeleland in the south-west, and by an inﬂux of refugees from the civil war in Mozambique in the east, while elsewhere in the country jackal rabies assumed serious proportions.264 Dogs, jackals and cattle comprise 89,9 per cent (6 726/7 483) of all animals in which rabies has been conﬁrmed in Zimbabwe from 1950 to 1991, and no other country has recorded as many cases of jackal rabies. A minor portion of the land in Zimbabwe is devoted to national parks and urban development, while the bulk of the country is divided approximately equally between commercial and communal farming. Commercial farms are generally well wooded, and apart from large wild carnivores and herbivores which have been eliminated, wildlife, including jackals, is generally preserved or tolerated, and few dogs are kept.264 In contrast, communal farming areas are generally overgrazed and deforested, wildlife is scarce, and dogs are kept for hunting. Consequently, dog rabies has occurred mainly in or close to communal farming areas, and jackal rabies has occurred almost exclusively on commercial farms.264 Jackal rabies was ﬁrst diagnosed in Zimbabwe in 1952, some 15 months after the disease had entered the country in 1950, and the ﬁrst outbreaks occurred along the eastern border in Chipinge district from 1952 to 1953 and Odzi district from 1952 to 1955.197, 263, 264 Thereafter, outbreaks of jackal rabies occurred in widely separated districts at irregular intervals of many years, including Chipinge again on two occasions, Harare, Marondera and the Midlands twice each, and Plumtree, Bulawayo and Lomagundi districts once each.197, 264, 368 Since the outbreaks always occurred in proximity to outbreaks of dog rabies and did not recur in the same areas for periods of seven years or more, it was argued that the virus was not adapted for maintenance in jackals but had to be re-introduced by dogs.197 However, several of the outbreaks which have occurred since 1965, and sporadic isolations of rabies virus from jackals, have taken place well away from known centres of infection in other species.264 An alternative explanation given for the failure of rabies to persist in areas where epidemics occurred in jackals was that the disease reduced the density of jackals to below the threshold required for spread of infection.264 Both the black-backed jackal and the side-striped jackal (Canis adustus) occur in Zimbabwe, with partially overlapping distributions, and both are involved in outbreaks of rabies. Although outbreaks of the disease in jackals are invariably accompanied by disease in cattle, the degree of involvement of cattle varies. In one outbreak it was established that 1 200 cattle had died, of which 140 were conﬁrmed to have been rabid.264 It can be concluded that rabies is transmitted by jackals in Zimbabwe, and that infection is freely communicable between dogs and jackals, as appears to be the case in other parts of southern Africa, but that jackal populations are probably too sparse to perpetuate virus in the absence of reintroduction of infection from dogs.98, 100, 559 The results of Rabies laboratory investigations suggest that oral vaccination of jackals is possible, but ﬁeld trials would be necessary.67, 101, 103, 104 The occurrence of rabies in most other species in Zimbabwe appears to represent spill-over of infection from dogs or jackals, but there have been clusters of cases of the disease in the slender mongoose (Galerella sanguinea) in the south-west of the country on occasion, with some indication of progressive spread of the centres of infection.264 Control of dog rabies remains a problem particularly in communal farming areas, and dog population studies are important for planning and assessing vaccination coverage.99, 131, 537 South Africa, Mozambique and Swaziland Historical writings have been cited to the effect that suspected rabies involving dogs and/or humans was observed in the Western Cape Province of South Africa in 1772, 1825, 1826 and 1883, in KwaZulu-Natal Province in 1823 and 1857, and in the Free State Province in 1861, although at least two early travellers remarked on the complete absence of the disease in the country.173, 309, 493, 639 In 1893, an outbreak of the disease in dogs in the Eastern Cape Province was diagnosed by inoculation of rabbits, and this was the ﬁrst occasion on which a diagnosis of rabies was conﬁrmed on the continent of Africa.327 The outbreak was initially recognized in Port Elizabeth in April, 1893, but the results of inquiries suggested that the ﬁrst case had occurred in September 1892 in a dog imported from England, which had become rabid a few weeks after its arrival. The outbreak was believed to have affected about 90 dogs, seven cats and a few cattle, but no wild animals, and had spread to the Uitenhage, Jansenville, Willowmore and Albany districts by the time it was brought under control in August 1894 through the muzzling and restriction of dogs and the destruction of strays.225, 309, 327 After 1894, rabies was not conﬁrmed again in South Africa for 34 years, but there was mounting anecdotal evidence to indicate that an endemic form of the disease associated with viverrids was present. In particular, there was a general belief in the Eastern and Northern Cape provinces that bites from genets (Genetta genetta) caused fatal, rabies-like illness in humans, and speciﬁc reports of such incidents dated back to 1885.173, 259, 639 Cluver173 documented 11 unconﬁrmed cases of human rabies which occurred in what is today southern Gauteng, Free State and Northern Cape from 1916 to 1927, following bites by yellow mongooses, dogs and a genet. The disease was ﬁnally conﬁrmed in 1928 in two children bitten by a yellow mongoose in Wolmaransstad district in the North West Province,310 and since that time rabies has been diagnosed regularly in South Africa. Within a short period after the diagnosis of the disease was conﬁrmed in 1928, rabies was recognized in numerous locations in South Africa in dogs, domestic cats, yellow mongooses, suricates (Suricata suricatta), genets and wild felids, and in humans and farm animals which had been bit- 1135 ten by these carnivores.221, 493–495, 638 The veterinary investigators were well aware that the disease, which occurred principally in the yellow mongoose, differed fundamentally from what they termed classical European-type dog rabies in that there were sporadic cases in dogs, but no real tendency for the infection to spread among them; in essence pre-empting the concept of biotypes by several decades.493 Initial conjecture that the endemic disease might have arisen by extension from the epidemics of dog rabies which had occurred in the Eastern Cape Province from 1892 to 1894 and in Zimbabwe from 1902 to 1913 gave way to the conviction that viverrid rabies had long been present in South Africa, possibly for centuries, but had simply not been recognized.221, 222, 493–495, 638, 639 Subsequently, brief reference was made to the fact that experimentally infected mongooses were unable to transmit infection to dogs by bite, but the strain of virus, species of mongoose and numbers of animals on experiment, were not speciﬁed.13 It was subsequently shown that the yellow mongoose is more susceptible to lethal infection with mongoose virus than with dog virus, and excretes mongoose virus more readily in saliva than dog virus.13, 155 As the area known to be affected by rabies expanded, there was speculation that this was due to both recent spread and the fact that the true distribution of the disease was still being elucidated,639 but later the results of deliberate investigations revealed that the occurrence of endemic rabies was conﬂuent over the greater part of the interior plateau of South Africa west of the Drakensberg mountains.466, 467 The only areas to be excluded were those which fell outside the distribution of the yellow mongoose — Limpopo Province in the north, KwaZulu-Natal apart from the northwestern margin of the province adjoining the Free State, the easternmost Transkei portion of the Eastern Cape Province and a narrow coastal strip extending from Port Elizabeth towards Cape Town.466, 467 The mongoose occurs less abundantly in Botswana, where it is absent in the east, and it is present in Namibia apart from the coastal Namib Desert. The yellow mongoose is diurnal and its role as a maintenance host for rabies virus is facilitated by the fact that it lives in colonies of ten or more individuals. It is most abundant in the north-western Free State Province and in the adjacent North West Province,639 where ﬁgures recorded in a study of population density suggest that there were about 78 078 individuals in an area of 122 551 hectares.785, 788 The mongoose prefers open country, devoid of dense bush cover, and lives in proximity to water courses or vleis where soft soil facilitates burrowing. Over much of its distribution, the mongoose utilizes and adapts warrens pioneered by ground squirrels (Xerus inauris) (Figure 99.4) with which it shares the warrens in apparent harmony. Warrens vary from relatively simple, branched burrows, to complex networks of interconnecting tunnels 0,3 to 1 m below the surface, covering an area 50 m or greater in diameter, and with 90 or more openings.639, 788 Peak mating activity occurs in August 1136 SECTION FOUR: Viral diseases: Rhabdoviridae and September, at which time the progeny of the previous year disperse, and after a gestation period of 42 days unisexual litters of up to four pups are born, of which only one or two are successfully weaned.785, 787, 788 Recent evidence suggests that immature individuals do not disperse, but assist in the rearing of the young of the succeeding litter.550, 745 The lifespan of the mongoose is estimated to be between one and four years under natural conditions, but longevity of 13 years has been recorded in captivity.788 The yellow mongoose is mainly insectivorous, but also preys on small vertebrates and feeds on carrion.639, 786 Individuals forage from 600 to 3 000 m from the warren, and range furthest during the dry winter months and in drought years.639, 785, 788 Comparatively few cases of rabies have been recorded in ground squirrels and suricates, the distributions of which largely coincide with that of the yellow mongoose, but there appear to have been no speciﬁc attempts to determine the relative population densities of the three species. It is possible that rabid ground squirrels and suricates have been misidentiﬁed as yellow mongooses on occasion, or categorized as unidentiﬁed mongooses. In the north of its distribution range, the ground squirrel, and by implication the yellow mongoose, occurs focally on lime outcrops where burrows are easier to keep open than in the intervening Kalahari sands,639 and this may account for the more sporadic occurrence of viverrid rabies in northernmost Northern Cape Province, Botswana and Namibia, than further to the south. On the other hand, there is marked genetic variation in populations of the mongoose and this could theoretically be associated with differences in susceptibility to rabies.677, 678 Ground squirrels, which are rodents, occur in Figure 99.4 Ground squirrel (Xerus inauris). (By courtesy of the National Parks Board, PO Box 787, Pretoria 0001, South Africa) colonies of 8 to 30 individuals and are largely vegetarian, feeding on plant bulbs, roots, stems and seeds, but also take insects.637, 639, 786 Suricates, which are viverrids, occur in migratory groups of up to 30 individuals, and are insectivorous but also feed on plant material. Itinerant groups of suricates677 periodically evict yellow mongooses and ground squirrels from warrens, which they then occupy temporarily, usually for a matter of days.639, 785 As early as 1930 efforts were made to control viverrid rabies through the eradication of the yellow mongoose by trapping, poisoning, gassing, or destroying warrens with explosives.639 Carbon monoxide, sulphurous gases, cyanide gas and phosphine were tested, and from 1939 onwards the standard method used to eradicate colonies of the mongoose was to pump cyanogas (later phosphine) into warrens, and to follow this with the setting of gin traps to catch individuals that escaped gassing.639, 789 The method was applied on farms or town commonages where mongoose rabies was diagnosed, and about 50 000 to 160 000 hectares were treated annually until exceptionally heavy rains in 1974 to 1976 restricted the access of control teams to affected locations.40, 639 From that time onwards mongoose control, which had become prohibitively expensive, has been applied more selectively to about 5 000 hectares each year in strategic locations where mongoose rabies occurs in proximity to urban centres, and in addition, chemicals for gassing have been made available to farmers. Furthermore, in the past dogs were immunized within a radius varying from 15 to 25 km from outbreaks of mongoose rabies, while at present dogs are immunized only as deemed necessary by state veterinary ofﬁcials. Rabies It was realized from an early stage that focal eradication of the mongoose provided only temporary control of rabies, that re-colonization of gassed warrens began almost immediately and that there was a compensatory increase in litter sizes, with populations being restored to initial levels within three years.639, 785 It was noted that rabies recurred from 1932 to 1936 on several of the farms where mongooses had been eradicated in the initial experiments of 1930 and 1931.639 The prevalence of mongoose rabies rose progressively in each decade from 1950 onwards to reach epidemic proportions by the early 1970s, despite the application of the control measures, and continued to ﬂuctuate at high levels in the 1970s and 1980s following the abandonment of systematic mongoose control. In retrospect, it is difﬁcult to discern whether or not mongoose control had any signiﬁcant suppressive effect on the occurrence of rabies, or whether it merely created disturbances in population dynamics which ultimately favoured epidemic spread of infection,785 but at least it is clear that control of the disease was not attained. Veterinary ofﬁcials in South Africa were conscious of the threat posed by the invasive canid form of rabies which had appeared in Namibia and Botswana at the end of the 1940s, and spread of the disease from Botswana into the Limpopo Province was duly recognized in June 1950, and thence into southern Zimbabwe by August, but enquiries revealed that the virus had probably entered both countries some months earlier.3, 13, 203, 449, 640 The disease did not extend southwards in the relatively dry and sparsely inhabited western part of Limpopo Province and adjoining North West Province, but spread to the more densely populated areas to the east and entered Mozambique in 1952 via the extreme north-eastern corner of South Africa, which at that time had not been incorporated into the Kruger National Park.13, 449, 712 Some 22 000 dogs were destroyed within two years in an attempt to control the disease in the Limpopo Province, and from 1952 onwards Flury LEP vaccine was used to immunize dogs in the area.3, 13, 449, 640 The outbreak had subsided to a few sporadic cases by 1954, and although 181 414 dogs had been vaccinated in north-eastern Limpopo Province by 1962, dog rabies has remained present in the area.40, 449, 450 Cases of rabies in black-backed jackals and cattle were recorded on bushveld ranches during the initial outbreak of the disease in the Limpopo Province in 1950, and attempts were made to control jackals by trapping or poisoning them with meat baits laced with strychnine.449 The jackal is mainly nocturnal and solitary, but females attract a following of several males during the mating season from May to July, at which time dispersal of the previous year’s progeny occurs, and litters of one to ﬁve pups are born from August to October. Individuals forage over distances of up to 40 km a night, preferring to travel along roads or open pathways.134, 449 There is evidence that individual jackals are loosely associated in cryptic packs, with the implication that disruption of the hierarchy through persecution may increase agonistic encounters and hence the prevalence of ra- 1137 bies.461 Nevertheless, the system which apparently proved to be most effective for the control of jackals consisted of laying a scent trail by dragging fresh or decomposed carcasses, meat or entrails of domestic or wild ungulates along roads or paths, and placing poisoned baits at set intervals along the trail. Comparisons of relative population densities could be made from the numbers of jackal tracks observed on roadways, and the numbers killed could be estimated from the number of baits taken and the fact that dead jackals were found to have consumed an average of two baits.449 Attempts to control jackals were also made in Namibia, Botswana and Zimbabwe, and in the 1960s the explosive coyote-getter device was brought into use.264, 715 An estimated 3 900 jackals were poisoned from 1951 to 1956 in Limpopo Province,449 and although the campaigns provided only temporary and localized control of rabies, the impression had been gained by the mid-1960s that the disease had not become permanently established in wild animals in the region.451 Jackal and cattle rabies became a serious problem again in the mid-1970s, and it was thought that a further introduction of jackal rabies had occurred in the vicinity of Messina (now known as Mussina) in 1974, from Zimbabwe across the Limpopo river.134 Immunization of cattle with Flury HEP (high egg passage) vaccine was introduced in 1976,134 but the disease in jackals and cattle remains a problem in the Limpopo Province. Barnard82 drew attention to the fact that where jackal rabies occurs in Limpopo Province and Namibia, the number of cases of the disease recorded in domestic herbivores, particularly cattle, exceeds that in all vector species by up to three-fold or more, and that this ratio is reversed in areas where viverrid rabies predominates. It is a common ﬁnding in all areas where jackal rabies occurs in Botswana, Zimbabwe and Zambia that laboratory conﬁrmation of the diagnosis is sought only in a minor proportion of the cases of the disease actually observed in cattle.134, 263, 264, 446, 482, 727, 790 Over the years, sporadic cases of rabies have also been recorded in civets (Civettictis civetta), honey badgers (Mellivora capensis), and antelope in Limpopo Province, and isolated cases have been conﬁrmed in genets, bat-eared foxes, hyraxes (Procavia capensis), the brown hyena (Hyaena brunnea) and Selous’ mongoose (Paracynictis selousi), which is nocturnal and solitary.40, 134, 449 In the 1990s, the canid biotype of rabies virus extended to North West Province, and affected wild dogs in the Madikwe Game Reserve.313 Rabies was thought to be endemic in central Mozambique from at least 1908 onwards, and was ﬁrst conﬁrmed in Tete district in 1950.712 In 1952, the epidemic of dog rabies which was raging in the north-eastern Limpopo Province of South Africa extended into Mozambique and spread rapidly throughout the central and southern districts of the country, where the disease has remained prevalent since that time.712 Rabies has been diagnosed predominantly in dogs in Mozambique, and it is hyperendemic in the southernmost Maputo district where the population is densest, but 1138 SECTION FOUR: Viral diseases: Rhabdoviridae monitoring and control of the disease was hampered by prolonged civil war.210, 211, 429, 712 In 1954, dog rabies spread from Maputo district into Swaziland, where the occurrence of the disease was conﬁrmed for the ﬁrst time, and since then there have been periodic incursions of rabies from Mozambique into Swaziland and the adjoining portion of the Mpumalanga Province of South Africa which lies between Swaziland and the southern boundary of the Kruger National Park.40, 312 In mid-1961, dog rabies spread from Maputo district in southern Mozambique into northern KwaZulu-Natal in South Africa.40, 450, 452, 672 Apart from the fact that there had been unconﬁrmed reports of the disease in the nineteenth century,309 KwaZulu-Natal had hitherto been free of rabies, and the epidemic which followed the introduction of the virus in 1961 was of an intensity unprecedented in South Africa. The density of the rural population in the coastal and many of the midlands districts of KwaZulu-Natal favoured the spread of the disease in dogs, and the epidemic extended progressively down the length of the province. Vigorous efforts were made to control the disease through the vaccination of dogs and the prohibition of translocation of unvaccinated individuals,450 and these led to the outbreak in KwaZulu-Natal being ﬁnally brought to an end late in 1968.40 The numbers of dogs immunized annually from 1961 to 1968 never exceeded 41 per cent of the estimated total population, but higher degrees of vaccination coverage were attained in the most severely affected areas, which received the most attention. Rabies reappeared in the northern districts of KwaZuluNatal, adjacent to the Maputo district of Mozambique, in mid-1976,40 at a time when there was an inﬂux of refugees ﬂeeing the unsettled conditions which followed the assumption of independence by Mozambique from Portugal. During the eight years since rabies had last been diagnosed the population of KwaZulu-Natal had continued to burgeon, and since many rural inhabitants sought livelihoods in urban centres, informal settlements ﬂourished, where uncontrolled dog populations provided fertile ground for epidemic spread of the disease. Moreover, the increased mobility of the human population is thought to account for the fact that the disease spread rapidly, appearing per saltum in widely separated locations, and also extending inland towards the borders of Lesotho and the Free State. Dog rabies spread from KwaZulu-Natal to the Transkei area of the Eastern Cape Province in 1987, and by the early 1990s had reached the Ciskei area.40, 42 Like KwaZulu-Natal, the Transkei and Ciskei areas in the Eastern Cape have dense rural and peri-urban populations. After its re-introduction into KwaZulu-Natal in 1976, dog rabies proved to be intractable. Peak numbers of cases were recorded at three- to four-year intervals, each time constituting a new record,363 but resurgence of the disease did not invariably occur in the same locations on each occasion. Peak vaccination coverage of 59 per cent of the estimated total dog population of KwaZulu-Natal was attained in 1980 to 1981, but the immunization of unrestricted dogs in informal settlements constitutes a formidable task which was rendered increasingly difﬁcult by the political unrest which prevailed in the province up to the mid-1990s. Consequently, inadequate vaccination coverage was attained in the strategically important locations where the problem was most severe. The position has improved since then. Most cases of human rabies in South Africa result from dog bites in KwaZulu-Natal (see below) but there has been remarkably little spill-over of infection to domestic cats and herbivores or wild animals in the province, which suggests that the disease could again be eradicated, as in 1968, by obtaining effective vaccination coverage of dogs. Elsewhere in South Africa rabies transmitted by jackals and dogs remains endemic in Limpopo Province, while rabies which is transmitted by the yellow mongoose is hyperendemic in North West Province, across southern Gauteng Province to the Ermelo and Carolina districts of Mpumalanga Province, and extends northwards in a narrow central strip that passes through the Soutpansberg district of Limpopo Province. There is spill-over of infection to cattle, dogs, cats and less frequently other domestic animals, and sporadic cases of the disease occur in the striped polecat (Ictonyx striatus) and the slender and water (Atilax paludinosus) mongooses in the south, and also sporadic cases in suricates, genets, bat-eared foxes and wild felids, particularly the African wild cat, in the south-west.40 In the Free State, yellow mongoose rabies is hyperendemic in the north-west, but occurs throughout the province and the mongoose constitutes about 60 per cent of all animals in which rabies is conﬁrmed.40 Rabies in all other species appears to represent spill-over of infection from the yellow mongoose, and involves mainly cattle, less frequently dogs, cats and other domestic animals, sporadically suricates, ground squirrels and striped polecats, and on rare occasions black-backed jackals, and slender and water mongooses. Sporadic cases of rabies are also recorded in wild felids and genets, mainly in the west, and on isolated occasions in small antelope, bat-eared foxes and the aardwolf (Proteles cristatus).40 The striped polecat is a mustelid which is predominantly insectivorous, and it is considered possible that at least some of the cases of rabies recorded in this species are the result of misidentiﬁcation of its carnivorous relative, the striped weasel (Poecilogale albinucha). The distribution of yellow mongoose does not extend into the easternmost part of the Eastern Cape Province, but in the 1980s dog rabies extended from KwaZulu-Natal to the Transkei and Ciskei areas in the east, where it remains a serious problem. Elsewhere in the Eastern and Western Cape provinces the occurrence of the disease in dogs remains sporadic. Yellow mongooses constitute less than 30 per cent of rabid animals, and positive diagnoses are made in signiﬁcant numbers of several other species of carnivore, with deﬁnite indications that at least some of these have been involved in independent Rabies transmission of the virus. Suricates, striped polecats and ground squirrels appear to acquire the infection only where the disease occurs in the yellow mongoose. In contrast, there have been comparatively few conﬁrmed cases of rabies in the banded and water mongooses, and the small grey mongoose (Galerella purverulenta) which occurs mainly south of the Gariep (formerly Orange) River, but there have been clusters of cases in the water and small grey mongooses in circumscribed foci, suggesting that there has been localized spread of infection in these two species.40 It is clear that there is independent spread of rabies in the bat-eared fox, a small canid which occurs in the drier parts of the country, including Limpopo, North West, western Free State, Northern and Western Cape provinces, as well as in Botswana and Namibia.496, 683 The fox is diurnal where it is not disturbed, otherwise nocturnal, occurs singly or in pairs, and is mainly insectivorous, preferring termites, but it also takes small rodents, reptiles and birds. A few cases of rabies in the bat-eared fox, less than ten, were recorded regularly each year in Namibia from 1967 onwards, and sporadic cases have been recorded in Botswana.40 In South Africa, sporadic cases of rabies were recorded in the bat-eared fox from 1955 onwards, but an increase in the prevalence of the disease was noted in the Northern and Western Cape provinces during the 1970s, and from 1980 onwards there have been up to 24 conﬁrmed cases each year, with progressive spread of the disease to the west coast.40 The bat-eared fox is clearly the dominant host of rabies in the Western Cape Province at present, but during the evolution and spread of the outbreak lesser numbers of cases of the disease were recorded in the black-backed jackal and in the aardwolf, which is a solitary and nocturnal hyenid that subsists almost entirely on termites. Isolated cases of rabies have also been recorded in the Cape fox (Vulpes chama). It is not clear whether the sporadic cases of rabies recorded in bat-eared foxes in the North West and western Free State provinces represents spread of infection from the Northern Cape Province, or are the result of spill-over of infection from other hosts. Rabies has been diagnosed more frequently in antelope in the Western and Eastern Cape provinces than elsewhere in the country, particularly in small species such as the duiker (Sylvicapra grimmia) and this trend has been more marked since the increase in the incidence of the disease occurred in bat-eared foxes, jackals and aardwolves. Over the years, rabies of genets and wild felids has been diagnosed most commonly in the Northern Cape Province, where the disease was anecdotally associated with genets as far back as the nineteenth century. Among the felids, the disease has been conﬁrmed most frequently in the African wild cat and the caracal and on isolated occasions in the small-spotted cat (Felis nigripes). It is believed that the majority of the unspeciﬁed felids in which the disease has been conﬁrmed (Table 99.1), are African wild cat,40 animals which are somewhat larger than the domestic cat, but 1139 which have interbred to a large extent with domestic cats which have become feral. The African wild cat and the small-spotted cat prey on birds, reptiles and small mammals, but the larger caracal preys on animals up to the size of lambs or small antelope. Although the genet is a viverrid, its behaviour is more like that of a cat than a mongoose. It is solitary, nocturnal, largely arboreal and preys on rodents, reptiles and birds, but also takes insects and fruits. The area where felid-genet rabies is most prevalent extends from the Northern Cape Province into southern Namibia, but sporadic cases also occur in North West and Free State provinces, and in southern Botswana. It is not clear whether the circulation of virus in felids and genets is independent of other hosts, or whether these animals acquire infection from mongooses, possibly in their role as predators. However, Barnard drew attention to the fact that there is a much higher prevalence of rabies in the domestic cat in the area where felid-genet rabies occurs than elsewhere.82 This could indicate that there is spread of infection among felids, with the African wild cat serving as a link to domestic cats. The ﬁnal example of possible compartmentalized circulation of rabies virus in South Africa concerns the occurrence during the mid-1980s of the disease in spotted hyenas in the Kgalagadi Transfrontier Park which straddles the boundary between the north-western part of the Northern Cape Province of South Africa and the south-western part of Botswana, where the infection may have resulted from the spread of the kudu virus from Namibia through carnivores in western Botswana (see above). Attention has been drawn to the fact that rabies is much more likely to spread rapidly through wild dog packs than through the more loosely associated hyena clans.476 There are approximately three times as many sheep as cattle in South Africa, and the disparity is even greater in the sheep-rearing areas of the southern Gauteng, Free State and Eastern and Western Cape provinces where mongoose rabies predominates, yet the ratio of cattle to sheep in which the disease has been diagnosed since 1928, exceeds 18:1. It is known that both species on occasion predispose themselves to facial bites by displaying curiosity towards rabid mongooses,13, 40, 221, 451, 452 and it must be concluded either that sheep are fairly resistant to infection,20 or that the disease in sheep is frequently not recognized.644 Prior to 1950, approximately half the cases of human rabies in South Africa resulted from mongoose bites in the southern Gauteng, North West, Free State and Northern, Eastern and Western Cape provinces, but following the incursion of the canid virus into the Limpopo Province, and later KwaZulu-Natal, dogs became the most important source of human infection.41, 666 Currently, 10 to 20 cases of human disease are recorded each year in South Africa, mainly in association with dog bites in KwaZulu-Natal and to a lesser extent Eastern Cape Province. Most victims are under 15 years of age and many are less than ten years old. 1140 SECTION FOUR: Viral diseases: Rhabdoviridae Table 99.1 Total numbers of confirmed cases of infection with rabies and rabies-related viruses recorded in South Africa, 1928– 2000. The information was obtained from references 40, 41, 42 and 496 DOMESTIC ANIMALS NUMBER Dogs 5 755 Cats 583 Cattle 3 029 Sheep 158 Goats 134 Horses and donkeys 81 Pigs 36 Guinea pigs 1 Total domestic animals 9 777 WILD ANIMALS COMMON NAME NUMBER Cynictis penicillata Yellow mongoose 2 587 1 314a Unspecified mongooses Galerella sanguinea Slender mongoose 62 G. purverulenta Small grey mongoose 51 Herpestes ichneumon Large grey mongoose 1 Mungos mungo Banded mongoose 5 Atilax paludinosus Water mongoose 28 Paracynictis selousi Selous’ mongoose 1 Helogale parvula Dwarf mongoose 1 Ichneumia albicauda White-tailed mongoose 2 Suricata suricatta Suricate Civettictis civetta Civet Genetta genetta Small-spotted genet Mellivora capensis Honey badger 27 Ictonyx striatus Striped polecat 71b Poecilogale albinucha Striped weasel 2 Unspecified otter species 198 6 192 1 Panthera leo Lion Felis lybica African wildcat 37 F. caracal Caracal 17 F. serval Serval 3 F. nigripes Small-spotted cat 5 Unspecified felids Canis mesomelas 1 185 Black-backed jackal Unidentified jackal 386c 5 Rabies Table 99.1 (continued ) WILD ANIMALS COMMON NAME Otocyon megalotis Bat-eared fox Lycaon pictus Wild dog 7 Vulpes chama Cape fox 18 Proteles cristatus Aardwolf 53 Hyaena brunnea Brown hyaena 1 Crocuta crocuta Spotted hyaena 1 Xerus inauris Ground squirrel 43 Paraxerus cepapi Tree squirrel 2 Thryonomys swinderianus Greater canerat 2 Procavia capensis Cape hyrax Papio ursinus Chacma baboon 1 Phacochoerus aethiopicus Warthog 1 Sylvicapra grimmia Duiker Raphicerus campestris Steenbok 4 Tragelaphus strepsiceros Kudu 7 Tragelaphus scriptus Bushbuck 1 Taurotragus oryx Eland 3 Aepyceros melampus Impala 1 Damaliscus dorcas phillipsi Blesbuck 1 Redunca arundinum Reedbuck 1 Antidorcus marsupialis Springbok 3 Equus burchelli Burchell’s zebra 2 Unspecified herbivores NUMBER 423 11 20 6 14d Epomophorus wahlbergi Epauletted fruit bat Nycteris thebaica Slit-faced bat 1 Miniopterus schreibersii Long-fingered bat 1e L. saxatilis Scrub hare 1 Unspecified/unidentified TOTAL WILD ANIMALS TOTAL ANIMALS (WILD & DOMESTIC) HUMANS a b c d e 36 5 853 15 630 441 Believed to be mainly C. penicillata Probably includes some P. albinucha Possibly includes a few C. adustus in north-eastern Transvaal (now Limpopo Province) Only two bats positively identified as E. wahlbergi Identification of species based on circumstantial evidence 1141 1142 SECTION FOUR: Viral diseases: Rhabdoviridae In a unique incident in the 1930s, a person became infected after being bitten by an ox, but the widely publicized death of a patient in the 1970s after exposure to the regurgitated ingesta of a rabid cow is believed to have resulted from an encephalitic reaction to mouse brain vaccine, rather than from rabies.40, 468 Despite reports that many people on farms in southern Africa and South America have butchered and consumed rabid cattle, and that rabies has been diagnosed in cattle at abattoirs in Mexico and South Africa, it has never been recorded that humans have acquired the infection by ingesting the tissues of infected livestock.40, 41, 60, 288 It was reported that a butcher in India developed rabies after skinning a calf which had ostensibly died of the disease, and that two people in China acquired infection from preparing dog meat for human consumption.395, 671 In another noteworthy incident, a person developed rabies after being bitten by a baboon (Papio ursinus) in the Pietersburg (now called Polokwane) district in Limpopo Province in 1961, but the virus has only once been isolated from a baboon, from the Middelburg district in the Eastern Cape Province in 1964, and there has been no further evidence of infection of non-human primates in South Africa.40, 41, 500 At an early stage in the investigation of rabies in South Africa, the impression was gained that the occurrence of the disease increased in times of drought and during the dry months of late winter. It was concluded that the scant vegetation cover at such times increased confrontation by forcing mongooses to range further aﬁeld or to migrate in search of food, and rendered rabid individuals more readily visible to susceptible livestock and to humans,452, 495, 638 and later also that stress activated latent rabies in the mongoose population.785, 788 It is now well known that there is seasonal variation in the occurrence of rabies, and although changes in vegetation and foraging activity are contributory factors, it is believed that the major determinant is increased intraspeciﬁc confrontation in the dominant host brought about by mating activities and the probing for unoccupied territories by progeny at the time of dispersal.438, 690 Analysis of the cases of rabies recorded in South Africa on the basis of species, province involved, and month of occurrence, conﬁrms that there is a strong seasonal bias to the disease, with the incidence being highest in the late winter and early spring months of July to September.666 This tendency is most readily apparent in dog rabies in KwaZuluNatal, where a large segment of the dog population in informal settlements and densely inhabited rural areas is unrestricted and breeding is uncontrolled. Seasonal bias is less apparent for the disease in individual species in the other provinces, largely because the exact timing of peak rabies activity varies each year with the effects of the vagaries of climate on animals which are directly dependent on natural resources and food chains. Data for individual years clearly indicate that there is a peak in the incidence of rabies in most species in later winter, but in some instances, such as in bat-eared foxes, it appears that the seasonal increase in incidence may be bimodal. A greater understanding of the mechanisms responsible for seasonal exacerbation of rabies in South Africa would be beneﬁcial in the planning of control measures. The total range of species and numbers of cases in which rabies has been conﬁrmed since regular monitoring was instituted in South Africa in 1928, up until 2000, are shown in Table 99.1.36, 40–42, 493, 667 The results of monoclonal antibody and phylogenetic studies conﬁrm the presence of canid and mongoose rabies virus lineages in southern Africa, and indicate that spill-over of infection between hosts occurs on occasion.376, 377, 499, 591, 729 Lesotho Dog rabies spread from KwaZulu-Natal Province of South Africa into the north-eastern corner of Lesotho in 1982, when the disease was recorded there for the ﬁrst time, and within two years it had spread throughout the country.370, 371 Rabies has been recorded in dogs, cats, cattle, sheep, goats, horses and donkeys in Lesotho, but monitoring of the disease has proved to be difﬁcult in the mountainous terrain of the country and human disease has been recorded with disproportionate frequency. There are few feral carnivores in the country and the disease has not been recorded in wild animals. Dog rabies reached the western border of Lesotho in the mid-1980s, but did not penetrate deeply into the Free State Province of South Africa where preventive vaccination had been undertaken, and where the dog population is less dense.373 Transmission and susceptibility Factors that determine the successful transmission of rabies include the dose, route of administration and biotype of the virus, and the susceptibility of the recipient. Rabies is ordinarily transmitted by bite, and the occurrence and concentration of virus in saliva varies with virus biotype and host species.110, 156 Salivary gland infection rates in excess of 80 per cent have been recorded in naturally infected cattle, kudus and black-backed jackals; infection rates of 20 to 74 per cent have been recorded in the salivary glands of naturally and experimentally infected dogs, and 70 to 80 per cent in cats.85, 110, 156, 227, 264, 718, 719 Virus is usually present in saliva from the time of onset of discernible illness and its presence may be intermittent and may terminate one or two days before death, but it has been demonstrated in salivary glands or saliva up to 13 days before the onset of illness in dogs and three days in cats.244, 719 Titres of virus detected in the salivary glands of experimentally infected dogs ranged from 101 to 107,3 mouse intracerebral 50 per cent lethal doses (MICLD50) per gram of tissue, and titres were slightly higher in cats than in dogs.244, 718, 719 The actual amount of virus transferred by bite presumably varies markedly and would be difﬁcult to determine, but it has been suggested that a dose of 5 000 MICLD50 is involved in fox-to-fox transmission, although the LD50 dose for foxes is much lower.108, 109, 148, 156 Rabies For comparative purposes, the susceptibility of vertebrate species to rabies should be determined by a standard method that involves the inoculation of salivary gland virus from a naturally infected host into the masseter muscle, but in the absence of experimental data for many species, estimates have been based on cumulative epidemiological data.20 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 rabies virus.20, 264 In extension of this classiﬁcation it can be noted, for example, that the LD50 dose of virus was 100,5MICLD50 for foxes, 103,5 for cattle and 106,0 for dogs when a fox biotype of virus was used to produce experimental infections.110 Generalizations are misleading, however, and susceptibility to a particular biotype of rabies virus is not invariably predictable on the basis of either the size of an animal or its phylogenetic relationships.110 It has been suggested that one factor determining differences in susceptibility between species could be differences in density of acetylcholine receptors in muscle, although some investigators doubt the importance of these receptors in uptake of infection by nerve cells.69, 157 The severity, location and multiplicity of bites inﬂicted on the victim also inﬂuence the outcome of potential exposure to infection, and bites on the head and neck are generally associated with the shortest incubation periods and the highest mortality rates. The severity and location of bites are in turn inﬂuenced by the relative sizes of the vector and the victim, and it was found in South America that 25,6 per cent of dog bites in children under 15 years of age occurred on the head and neck, as compared to 11,7 per cent in adults.2 In an early treatise on rabies55 it was recorded that death rates in non-immunized persons bitten by presumed rabid animals ranged from 80 to 100 per cent for severe multiple bites on the face by wolves, through 15 per cent for severe bites on the hands and ﬁngers by dogs to 0,5 per cent for bleeding, superﬁcial bites through clothing by wolves, cats or dogs. The death rate was 0,1 per cent in instances where the saliva of wolves, cats or dogs came into contact with fresh, pre-existing wounds, and no deaths occurred if the wounds were older than 24 hours. More recent estimates of human death rates following bites by proven rabid animals include 4,7 per cent for bites by various species, 32 per cent for severe bites by dogs and jackals, and approximately 60 per cent for bites by wolves.289, 506, 596, 720 Similar data do not exist for lower animals, but it can be concluded that rates of transmission by bite are generally below 50 per cent, and may be as low as 15 per cent on average for humans bitten by dogs.64 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, and 1143 may occur in bats since virus has been found in their milk.5, 62, 584 The occurrence of infection through scavenging, cannibalism or predation is potentially of epidemiological importance and may be a factor in the transmission of Arctic rabies, and in the occasional cases of infection ostensibly recorded in birds of prey in Europe.156, 333 Although birds are susceptible to experimental infection, virus is restricted to the central nervous system and cannot be transmitted to other animals. Early reports of disease have not been conﬁrmed, and there are no recent records of disease in birds.505 Oral transmission of rabies virus 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.85, 333 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,55 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 aerosol infection, and subsequently virus was isolated from the atmosphere of the cave.175, 176, 325, 332, 767 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.767 The ﬁndings suggested that aerosol transmission was a likely mode of spread of infection in colonial bats, but higher infection rates have been found in solitary bat species, probably because solitary bats are most readily encountered when rabid.62, 767 Non-contact transmission was subsequently observed in a poorly ventilated laboratory animal colony where experiments were being conducted with bat isolates.770 In 1972 and 1977, infection occurred in two persons who worked with rabies virus in laboratory equipment which generated aerosols.19, 22, 23 Transplacental transmission of infection has been demonstrated in the foetus of a pregnant cow which had died of the disease,454 and it has been recorded in dogs, and once in a human patient.5, 738 Although there are anecdotal reports of human-to-human transmission dating back many years,738 the only documented recent instances concern the transmission by breastmilk and the transplacental transmission referred to above, an incident in Pakistan where saliva was applied to circumcision wounds of several young boys by a surgeon-barber who was in the early stages of rabies, and a 41-year-old woman and a ﬁve-year-old child who ostensibly became infected in separate incidents from contact with relatives suffering from rabies in Ethiopia.242, 502 In addition, there have been eight 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.24, 25, 26, 279, 318, 341, 661 1144 SECTION FOUR: Viral diseases: Rhabdoviridae Sylvatic rabies Much of our present understanding of the epidemiology of rabies derives from the study of fox rabies in Europe and North America.110, 438, 690 The front wave of the epidemic of fox rabies which swept over much of Europe during the second half of the twentieth century advanced at 20 to 60 km per annum, generally at a steady rate, but with occasional leaps of greater magnitude. Since the average home range of foxes in Europe has a diameter of 1,6 km, and the average interval between successful serial transmissions of infection (incubation plus morbid periods) is one month, it was surmised that the disease was generally propagated from one resident social group to the next, with the occasional leap of infection ahead of the wave front being associated with the long-range dispersal of sub-adults seeking new territories. In Ontario, Canada, fox home ranges or territories are larger than in Europe, and accordingly epidemic wave fronts travel at rates of over 100 km per year, which also appears to be the case with jackal rabies in southern Africa. Interestingly, radio-tracked foxes in Europe and Canada which developed rabies did not necessarily travel beyond their normal home ranges.17, 438 As in most vectors in southern Africa, seasonal peaks in the incidence of fox rabies occur in late winter, one month after the dispersal of young foxes and mating, and the velocity of the front wave of the epidemic increases at this time. Apart from the increased encounters between individuals which mating and dispersal activities entail, it is believed that dispersing sub-adults are predisposed to rabies by stress, and that females are similarly predisposed by pregnancy. Male cubs disperse over longer distances than females, and there is seasonal disparity in the sex and age of foxes which develop rabies, a feature noted in jackal rabies in Zimbabwe.264 Epidemic wave fronts of fox rabies falter temporarily, or are deﬂected into new directions at major physiographic barriers such as mountain ranges or large rivers, with the result that the barriers delimit epidemiological units within which the occurrence of rabies is out of synchronization with neighbouring units. However, barriers do not necessarily act by debarring the passage of animals, but may simply lack suitable habitats to support populations of threshold density for spread of the disease. Thus, areas with loose, sandy soils may not suit burrowing animals in parts of southern Africa. Epidemiological units have also been termed geographical cells.443 In epidemiological units, which meet threshold requirements for endemicity, epidemic peaks are followed by silent phases of two to four years during which rabies activity is minimal or undetectable, and during which the population is restored. Restoration periods are followed by secondary epidemic peaks of rabies, which recur regularly at four- to ﬁve-year intervals. Endemicity is not determined simply by the size of an epidemiological unit or the density of the host population, since high morbidity may reduce the popula- tion to below threshold density for transmission in an area which is uniformly favourable for the host. Carrying capacity is more important than size, and the disease is more likely to become endemic in areas which contain an admixture of less favourable habitats where transmission is retarded and infection can smoulder. In epidemiological units which do not meet requirements for endemicity, transmission stops after the initial epidemic peak has reduced the population to below threshold density. In such areas, the virus spreads again only if it is re-introduced after the host population has been restored, and so epidemic peaks tend to recur at irregular intervals of many years. The occurrence of periodic epidemic cycles in individual epidemiological units is likely to be masked in instances where data on the incidence of rabies are pooled for large regions or countries. Nevertheless, it can be discerned that endemic rabies with periodic epidemic cycles appears to occur in at least some of the areas where rabies affects unrestricted dog populations in KwaZulu-Natal in South Africa, and that blocks of commercial farmland in which epidemics of jackal rabies occur at irregular intervals in Zimbabwe do not meet requirements for endemicity. The recovery of fox populations after the devastation of rabies epidemics is brought about partly by increased reproductive efﬁciency resulting from decreased competition for food resources, and partly by re-colonization of vacated territories by neighbouring foxes. Apart from the fact that dispersing sub-adults seek territories, foxes and many other wild animals generally carry out spacing activity at the periphery of their territories and hence are drawn into vacant niches by the so-called vacuum effect. Competition for and re-establishment of territories may initially increase confrontation and thereby exacerbate outbreaks. Generally, populations recover rapidly, which is why the culling of vectors has succeeded as a means of controlling rabies in exceptional circumstances only, usually where it has been applied ahead of advancing outbreaks and the additional protective effects of natural barriers have been utilized. Even then, the beneﬁts of culling are temporary and, in an epidemiological model devised for coyotes, it was projected that with the killing of 75 per cent of individuals annually, it would have taken more than 50 years to exterminate coyotes and that the population would recover rapidly if culling were discontinued at any stage.174 Urban rabies Urban rabies occurs particularly where there are large populations of unrestricted dogs. Although appreciable numbers of dogs may be abandoned under certain circumstances, as occurred during the civil war in Zimbabwe,264, 408 there are only a few places in the world, such as India, where there are truly feral packs of dogs. However, in much of the world the concept of dog ownership varies with socioeconomic class and ethnicity of people. Ownership may be Rabies vested in individuals or families, or loosely in neighbourhood, village or tribal groupings. The dogs are kept as pets, guard dogs, hunting dogs or even as food animals, and the extent to which they are supervised, sheltered and fed varies.734, 736 Consequently, 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.96 The epidemiology of urban rabies has been studied most intensively in Latin American cities where there has been rapid growth of large informal settlements in which lack of sanitation and proper refuse disposal has created conditions that favour marked increases in populations of rats, cats and dogs.170,404 It was found in Guayaquil, Ecuador, that no dogs were regarded by community residents as being unowned, but that the dog population was made up of three segments.96 Dogs of upper-income households were relatively restricted at all times and were commonly vaccinated at their owner’s initiative. In middle-income households where both spouses were in employment, dogs were frequently conﬁned during working hours, but were allowed to roam at other times of the day. In low-income households, dogs were commonly conﬁned to guard homes at night, but were free to roam and scavenge during the day. Unrestricted dogs formed territories within which there was an order of dominance. The mobility of males and the confrontations between them were increased when females were in oestrus. Elimination of more than 25 per cent of the estimated dog population of Guayaquil in each of 9 out of 18 years during which campaigns were conducted did not lead to an appreciable long-term reduction in the number of dogs. Instead, control campaigns alienated community residents and increased confrontation between dogs competing for vacated territories and re-establishing orders of dominance. Where the area of dog elimination was large, the relative increase in the supply of food available to the remaining scavengers led to increased fecundity of bitches and improved survival of pups. Dogs that had been eliminated, including vaccinated individuals, were thus replaced with younger, susceptible dogs. The inference is that inadequate or inappropriate dog control measures actually increase the risk of transmission of rabies.96 It can be concluded that, although there are fundamental differences between urban and sylvatic rabies, there are also some striking parallels between the two. Many of the complex interactions of the spatial and/or temporal processes which determine the occurrence of the disease can be simulated in computerized models, such as those devised for sylvatic rabies in the northern hemisphere.56, 57, 75, 76, 477, 478, 580, 619, 726 The models can be used to assess the potential impact of intervention strategies, but are not necessarily applicable to problems in southern Africa without adaptation to take account, for instance, of the social behaviour and ecology of jackals or mongooses. 1145 Rabies-related viruses The large number of isolations of rabies virus made from non-haematophagous bats in the Americas during the 1950s prompted investigations elsewhere in the world, and, as a consequence, Lagos bat virus was isolated from strawcoloured fruit bats (Eidolon helvum) in Nigeria in 1956,122 but it was not until 1970 that the virus was identiﬁed as a rhabdovirus antigenically related to, but distinct from, rabies virus.607 In 1968, a virus was isolated from three Crocidura sp. shrews trapped in Mokola Forest near Ibadan, Nigeria, in a survey of arthropod-borne viruses, and from a fourth shrew found dead in Ibadan.365, 366 Identiﬁcation of the Mokola virus as a rhabdovirus related to rabies virus was reported in the same publication as the identiﬁcation of Lagos bat virus, and hence the concept of a rabies-related subgroup of rhabdoviruses was established.607 In 1970, an adult man living in the Bela-Bela (formerly Warmbaths) district about 100 km north of Pretoria, South Africa, died of rabies-like disease ﬁve weeks after being bitten by an insectivorous bat, possibly Miniopterus schreibersii.714 A virus isolated from his brain was found to be yet another rabiesrelated virus; named Duvenhage after the victim.470, 687 These three rabies-related viruses have been encountered in only a few countries of western and southern Africa.666 In general, isolates obtained from ostensibly healthy bats, shrews or rodents in surveys were deliberately subjected to tests appropriate for the identiﬁcation of rabies-related viruses, whereas isolates obtained from specimens submitted from humans and lower animals for the investigation of suspected rabies, were only recognized as rabiesrelated viruses because the investigators concerned were alert to non-speciﬁc features which distinguished the infections from rabies: routine diagnostic procedures do not allow rabies and rabies-related viruses to be differentiated with certainty. Thus, Lagos bat virus was isolated in surveys from a fruit bat in the Central African Republic in 1974, and from a fruit and an insectivorous bat in Senegal in 1985.28, 660, 664 Immunoﬂuorescence was detected with anti-rabies conjugate in the brains of 13 Epomophorus wahlbergi fruit bats which had behaved abnormally in KwaZulu-Natal, South Africa, in 1980 to 1981, but only three isolations of virus were made and identiﬁed as Lagos bat virus, with a further isolation being made in 1990, although two of the isolates were at one stage mistakenly reported to be Mokola virus.105, 196, 374, 471, 591 Lagos bat virus was isolated from two cats, one in South Africa in 1982 and one in Zimbabwe in 1986, which had been vaccinated against rabies and exhibited atypical signs of the disease, plus a dog which behaved abnormally in Ethiopia in 1990.264, 374, 463, 464 The virus has also reportedly been imported into France in an infected Roussettus aegyptiacus fruit bat.340 Mokola virus was isolated in 1969 from the cerebrospinal ﬂuid of a young girl with fever and seizures in Ibadan, Nigeria, who had no speciﬁc history of exposure to infection and who recovered without sequelae, but the validity of this 1146 SECTION FOUR: Viral diseases: Rhabdoviridae isolation has been questioned.234, 623 Subsequently, the virus was isolated from the brain of a girl who died of paralytic disease in Ibadan in 1971, and again no source of infection could be identiﬁed.235 Mokola virus was isolated from a shrew in a survey in Cameroon in 1974, and a rodent in the Central African Republic in 1983.410, 578 The possibility that the rabies-related viruses were capable of spread among domestic carnivores was raised when Mokola virus was isolated from the brains of six cats and a vaccinated dog from Bulawayo, Zimbabwe, in 1981 and 1982, which had been submitted for the investigation of suspected rabies, but the outbreak possibly resulted from spill-over of infection from rodents or shrews.260–262, 264, 761 The ﬁndings in Zimbabwe prompted retrospective investigation of a virus which had been isolated in 1970 from a cat with atypical rabies in KwaZulu-Natal, South Africa, and the isolate was identiﬁed as Mokola virus,373, 468, 591 but has also been reported as Lagos bat virus.623 In 1995 and 1996 three isolations of Mokola virus was made from cats with suspected rabies in the Eastern Cape Province of South Africa, and in 1997 and 1998 from a further three cats in KwaZulu-Natal Province; four of the cats had been vaccinated against rabies.469, 728 The virus has also been isolated from a cat which behaved abnormally in Ethiopia in 1990.463, 464 Mokola virus has never been isolated from bats, and it is thought that it may be harboured in shrews or myomorph rodents. Antibody to the virus was found in rodents in Zimbabwe, particularly bushveld gerbils (Tatera leucogaster),264 and it is notable that virus isolation and characterization was not attempted on the brains of two greater cane rats (Thryonomys swinderianus) from Limpopo Province, South Africa, which ﬂuoresced in diagnostic tests with anti-rabies conjugate in 1985 and 1987.668 Following its initial isolation from a human patient, Duvenhage virus was isolated in 1981 from a bat, thought to be M. schreibersii,714 caught in daylight by a cat in Louis Trichardt (now called Makhado) in Limpopo Province, South Africa,591 and in 1986 from a common slit-faced bat (Nycteris thebaica) caught in a survey in south-eastern Zimbabwe.264 In 1963, prior to the recognition of the rabies-related viruses, virus was isolated from a N. thebaica bat collected in a survey from a cave in Mpumalanga Province, South Africa, but the isolate was simply described as rabies virus, presumably on the basis of histopathological lesions observed in mice.451 Numerous viruses isolated in southern Africa from the brains of humans and lower animals which ﬂuoresced in diagnostic tests with anti-rabies conjugate, have been screened with monoclonal antibodies and in phylogenetic studies, and, apart from the cases mentioned above, no evidence of infection with rabies-related viruses has been found.376, 377, 497, 499, 591, 729 The implication is that the rabies-related viruses have not adapted to spread in carnivores, but that sporadic infections may be encountered in humans and domestic animals, particularly cats, which are predators of small mammals such as shrews, myomorph rodents and bats. Only insectivorous bats occur in Europe, and prior to 1985 there were 12 isolations of lyssaviruses from bats in Yugoslavia, Turkey, Germany and Poland, and one from a human who died in the former USSR in 1977 after having been bitten by a bat.374 Many of these isolates were obtained prior to the recognition of the rabies-related viruses, and most were thought to be rabies virus at the time of isolation and have not remained available for deﬁnitive characterization.374 However, three of the viruses obtained from unidentiﬁed, apparently sick bats in Germany in 1968, 1970 and 1982 were preserved and later found to be antigenically close to Duvenhage virus from Africa, and at that stage it was speculated that the virus may have been introduced into Europe from Africa, possibly in bats carried by boat.591 In 1985, a lyssavirus was isolated from an Eptesicus serotinus bat which attacked a person in Denmark, another from a bat zoologist who died in Finland, and one from a person who died after being bitten by a bat in the former USSR. In the ensuing investigations more than 450 isolations of virus were made from bats in Denmark, USSR, Poland, Netherlands, Germany, Spain, France and Czechoslovakia.29, 32, 35, 287, 373, 374, 432, 592 The isolates were obtained mainly from E. serotinus bats, but also from Myotis dasycneme and a few other species. Many of the bats had behaved abnormally or were found dead, and it appears that an epidemic situation existed among bats in Europe from about 1985 onwards. Isolations from bats in Europe subsequently declined to about 40 per annum.373 Various terms were applied to the isolates, such as Duvenhage, Duvenhage-like and Denmark bat virus, but it is now clear that European bat lyssaviruses differ from the Duvenhage virus of Africa, and that distinct subtypes are associated with serotine and myotine bats: European bat lyssavirus 1 (= lyssavirus genotype 5) is associated almost exclusively with E. serotinus, while European bat lyssavirus 2 (= lyssavirus genotype 6) is associated mainly with M. dasycneme and Myotis daubentonii.106, 123, 375, 376, 488, 592, 624, 694, 732 As in Africa, the monoclonal antibody and molecular studies failed to reveal evidence that rabies-related viruses have adapted to spread in carnivores. Recently, European bat lyssavirus 2 was isolated for the ﬁrst time from a M. dasycneme bat in Britain, presumed to be a migrant from mainland Europe.747 Reference has been made above to the recent discovery of an Australian bat lyssavirus (= lyssavirus genotype 7), which occurs in both fruit and insectivorous bats, and which has been associated with fatal infection in two humans.253, 270, 301, 317, 579, 617, 645 Genetic divergence between fruit and insectivorous bat isolates suggests that bat lyssaviruses have long been present in Australia.739 Since rabies virus, genotype 1, has been isolated from bats only in the Americas, it seems likely that incompletely characterized lyssaviruses isolated from bats in Thailand, Rabies India and Zambia may have been rabies-related viruses,7, 513, 635 with the implication that these viruses may be more widely distributed than realized at present. Pathogenesis The most superﬁcial portals for entry of rabies virus into the nervous system are sensory nerve endings of the epithelial and subepithelial tissues of the skin and mucous membranes, and this route is involved when transmission results from superﬁcial bites, licking of mucous membranes or shallow skin wounds and abrasions, and ingestion or inhalation of infected material. It has been shown that rodents, other laboratory animals, foxes, skunks and kudus are susceptible to oral infection, that infection occurs with greater efﬁciency when there are mouth lesions, and that virus replication, as indicated by immunoﬂuorescence, occurs ﬁrst in epithelial cells or tonsils and sensory organs, such as taste buds, and later in nerve bundles of the submucosa of the oral cavity and tongue.85, 92, 107, 115, 179, 256, 258, 487, 549, 555, 641 Rabies virus is inactivated in vitro by the digestive enzymes and low pH of stomach contents, but laboratory animals can be infected by stomach tube, as well as by rectal instillation of virus.5, 258, 553 Nerve tissue is particularly exposed in the nasal cavity. Experimental infection with rabies virus by the intranasal route has been demonstrated in laboratory rodents, rabbits, bats and skunks.49, 66, 159, 161, 257, 319, 320, 343, 487, 557, 576 Infection appears to involve both the olfactory end organ in the nares, neuroepithelial cells which are in contact with the surface of the body and extend directly into the olfactory bulb of the brain via the olfactory nerve, and terminations of trigeminal nerve ﬁbres which ramify in the nasal mucosa.156, 256, 320, 486 Aerosol transmission of rabies virus has been recorded in nature only in exceptional circumstances (see above), but intranasal infection may also occur when infected material is eaten.156 The eye is also an extension of the central nervous system, but following inoculation of rabies virus into the anterior chamber of the eye of rats it was found that the virus is taken up by parasympathetic oculomotor nerve ﬁbres, retinopetal ﬁbres of pretectal origin and ﬁbres of the ophthalmic branch of the trigeminal nerve; not by the optic nerve, although ultimately infection extends back from the brain to the optic nerve and retina.393 The cornea has only sensory innervation and ocular infection has been recorded after transplantation of infected corneas in humans (see above). Following deep introduction by bite, rabies virus enters the 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).486, 740 There is no evidence that virus is taken up directly by severed nerve endings.156 1147 After a variable period of hours following inoculation, rabies virus 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.61 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.181, 205, 740 On the other hand, 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 nonneural tissue at the site of inoculation.68 Such replication has been demonstrated in myocytes within 36 hours of inoculation of 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.119, 160, 162, 487 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 virus in muscle occurs as a preliminary to the infection of nerves, and this may account for the delay in pathogenesis which occurs in incubation periods of intermediate length.68, 156, 160, 162, 487, 704 However, it is not universally accepted that infection of myocytes is a link in the pathogenesis of the disease.157 The site of sequestration of virus during long to extreme incubation periods remains undetermined, but on the basis of the low intensity of replication seen in cultures of sensory neurons of dorsal root ganglia infected in vitro, it has been suggested that these cells are poorly permissive for the virus and could harbour infection for prolonged periods.434 Once virus has entered nerves, there is passive centripetal transport of subviral genome-containing particles, presumably ribonucleocapsids, by retrograde axoplasmic ﬂow to the central nervous system.486 Proof that virus is transported within axons includes the facts that neurectomy or the administration of drugs that impair nerve function can spare life in experimental infections; localized early paralysis and lesions in the central nervous system are associated with the entrance of nerves from the inoculation site; the paraesthesias which occur in humans and the self mutilation sometimes seen in rabid animals are frequently referable to the infection site, and furthermore, it is notable that the lymphatic drainage system of the epineural spaces does not constitute a direct pathway to the central nervous 1148 SECTION FOUR: Viral diseases: Rhabdoviridae system.68, 70, 156, 205, 355, 700 More speciﬁcally, virus antigen and infectivity are ﬁrst demonstrable ipsilateral to the site of infection in segments of the spinal cord which have nerve connections to the inoculation site, and axonal transport of rabies virus has been demonstrated in in vitro cultures of neurons.71, 181, 434, 586 The presence of viral matrix and virions in axons has been demonstrated in vivo, but this could have represented centrifugal spread following virus replication in neurons.181, 343, 487, 489 Estimates of the rate of passage of virus along nerves, ranging from 0,5 to 3 mm/hour, are too fast to allow for cycles of replication and cell-to-cell transfer of virus en route, and in any event there is little evidence of infection of Schwann cells or endoneural ﬁbrocytes even late in infection.156, 181, 205, 393, 434, 701 The axoplasm lacks free ribosomes and granular endoplasmic reticulum, so the ﬁrst possible location for replication of virus which has gained direct entry into peripheral nerves would be the perikaryon of either sensory neurons in dorsal root or cranial ganglia, or motor neurons of the ventral horn of the spinal cord or autonomic ganglia.156 Neurons of the dorsal root ganglia are unipolar, with the single axon bifurcating a short distance from the cell body into a peripheral and a central process, so it has been speculated that virus ascending the axon following peripheral infection could by-pass the perikaryon of the neuron and proceed directly to the spinal cord.156 Evidence that infection can occur via either sensory or motor nerves includes the results of experiments in which either sensory or motor nerve roots were severed, demonstration of sensory spread following ocular infection, the accumulation of inoculated virus at motor end plates, and the demonstration of early virus replication in both sensory neurons of the dorsal root ganglia and ventral motor neurons of the spinal cord.156, 181, 205, 393 Although peripheral nerves are considered to constitute the main pathway for infection, it has been known since the time of Pasteur that the disease can be produced by intravenous administration of rabies virus, and it has since been shown that neurectomy may fail to protect immature laboratory animals or those given large doses of virus peripherally.205 On this basis it was postulated that haematogenous spread of inoculated virus to the nervous system can occur in very young animals, animals of exceptionally susceptible species and those in which resistance has been lowered as, for instance, by trauma or shock.205 It is believed that the immunosuppressive effects of pregnancy can also facilitate the occurrence of viraemia and thus account for the transplacental transmission of infection which has been demonstrated experimentally in a variety of animals,5, 178, 258, 383, 384, 556, 582, 584, 595, 614 but which has only been recorded in nature on rare occasions (see above). 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.335, 486, 659 Hence, 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.181 The initial cycle of virus replication in the spinal cord is followed by further cycles at intervals of several hours with exponential increase in the number of infected neurons.181 Spread does not proceed in a strictly progressive fashion: 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.181 Occasionally, infection may be limited to the spinal cord.473 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,156, 588 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. It has been suggested that the cerebrospinal ﬂuid may act as a vehicle for the rapid dissemination of rabies virus in the brain, but the virus can seldom be isolated from cerebrospinal ﬂuid.227, 335, 588 Moreover, there appears to be selective involvement of neurons with little evidence of infection of pial, ependymal or endothelial cells, and relative sparing of glial cells.156, 349, 489, 588 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.156, 347, 348, 700 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 manifestation of aggressiveness, sexual arousement and loss of fear which often characterizes the disease.348, 486 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.702, 738 Electroencephalograph studies indicate that there is progressive extinction and ﬁnal cessation of electrical activity of the brain before cardiac arrest.285 From the time that the infection reaches the central nervous system, passive centrifugal spread of 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, infection may become demonstrable in contralateral dorsal root ganglia and nerves.181 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 Rabies hair follicles, the interscapular brown fat in bats, myocardium, lungs, pancreas, adrenal medulla, kidneys and bladder, as well as in milk, tears and urine.156 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.212, 213 It is well documented that rabid animals may exhibit wasting, emaciation or cachexia and dehydration, or failure to thrive in the young, and in the past these phenomena have tended to be regarded merely as the consequences of impaired uptake of food and water resulting from paralysis. However, the onset of wasting precedes changes in consumption of food and water and is not initially accompanied by the marked changes in plasma glucose levels which are to be expected in fasting.699 It was established in mice, rats, cattle and cats that there is regular infection of the hypothalamus and/or adenohypophysis in rabies, with dysfunction of growth hormone production.699 Suppression of cellmediated immunity is also well documented in rabies,752, 755, 756, 762 and it is postulated that this, together with the wasting syndrome, results from the effects of the virus on the hypothalamic-pituitary-adrenergic axis, with impaired production of growth hormone and excess corticosteroids leading inter alia to atrophy of the thymus and suppression of T lymphocyte cell-mediated immunity.699 Terminally, the virus-induced wasting is augmented by the secondary wasting resulting from food and water deprivation. Contradictory evidence indicates that adrenalectomy does not modify immunosuppression in rabies infection, and it is proposed that in rabies encephalitis there is direct neural delivery of catecholamine neurotransmitters to peripheral immune organs, stimulating immune cells to secrete cytokines such as IL-6, TNF-α or IL-10 that impair peripheral immune response.401, 654 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.73, 79, 708 The response to the administration of inactivated virus or attenuated live virus is three-fold: there is production of interferon and circulating antibody, and induction of cell-mediated immunity, with antibody becoming demonstrable and interferon and cellmediated responses being maximal six to ten days after inoculation of virus.752, 755, 756 Attenuated strains of virus used as veterinary vaccines produce abortive infection of the central nervous system, and all three components of the response to infection contribute to the clearance of virus; immunosuppression renders infection of adult mice with the attenuated viruses fatal.257, 622, 627 1149 Proof that humoral immunity plays a protective role in rabies stems from the fact that neutralizing antibody titres induced by pre-exposure immunization correlate well with resistance to infection with virulent virus, although no such correlation can be made for post-exposure immunization.194, 752 Furthermore, passively acquired antibody can be protective if adequate amounts are administered prior to infection, but antibody administered at the time of, or soon after, infection may only prolong survival.145, 610 Deﬁciency of B lymphocytes responsible for the humoral response, induced by the administration of anti-µ chain antiserum, increases susceptibility to fatal intracerebral infection with attenuated virus.475 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 central nervous system.93, 156, 335, 392 The blood–brain barrier is only breached late in symptomatic or fatal infection.439 The intracellular location of rabies virus in nerve tissue and its direct manner of spread from cell to cell renders it inaccessible to antibody, as evidenced by the inability of an antibody overlay to prevent spread of infection in in vitro cell cultures.218 Apart from the possible direct action of antibody on extracellular virus in the infective inoculum, therefore, 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.439 Mice that have been rendered T cell-deﬁcient are more susceptible to infection with attenuated or virulent virus than are B cell-deﬁcient mice, conﬁrming that both humoral and cell-mediated immunity are required for optimum clearance of infection, and survival correlates better with cytotoxic T cell response than with interferon or antibody responses.357, 474, 475, 622, 752, 755, 756 Cell-mediated immunity acts through cytotoxic lysis of infected cells, but it also appears that the induction of antibody response is dependent on T-helper cells since athymic nude mice succumb to infection without producing antibody.357, 752, 755, 756 Furthermore, T cells, including helper, suppressor and cytotoxic cells, are responsible for the release of interferon.439 It has been shown that timely administration of exogenous interferon or interferon inducers is beneﬁcial in rabies infection.302, 752 Interferon counteracts spread of the virus by conferring resistance to infection on susceptible cells, and also promotes expression of histocompatibility antigens which are recognized as a complex with rabies antigen on infected cells by T-effector cells.439 In contrast to killed or attenuated virus, infection with street virus does not induce cell-mediated immune response, although antibody response becomes demonstrable in seven 1150 SECTION FOUR: Viral diseases: Rhabdoviridae to ten days if a high dose of virus is inoculated.164, 752, 755, 756 Following inoculation of low doses of street virus or occurrence of natural infection, however, 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.16, 164, 304, 752, 755, 756 It appears that little or inadequate antigen is presented to immunocompetent cells in the inoculum in natural transmission and once nervous infection occurs, virus is ensconced intracellularly and is further protected from host immune surveillance by myelin sheaths and the blood–brain barrier, and by the paucity of lymphatic drainage and lymphocyte trafﬁcking in nerve tissue.439, 486, 706 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 priviliged position when the blood barrier is breached during spread of infection in the brain, and when non-neural tissues, such as salivary glands, become infected as a result of centrifugal spread of virus.439 The relative lack of inﬂammatory response in the central nervous system of non-immunized animals which develop rabies,486, 489, 528 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 has been found in mice, for instance, that there is atrophy and loss of cellularity of lymphoid organs, including the thymus and spleen, and abolition of the ability to mount cytotoxic T cell response not only to rabies virus, but also to other antigens such as inﬂuenza virus or skin grafts.439, 755, 756 More speciﬁcally, 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.762 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 socalled blood–brain barrier not only restrict lymphocyte migration, but also passage of antibodies and complement.400, 401 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 inactivate T cells. In injury, infection or stress, such as late in rabies infection, glial cells can act as antigen presenting cells, but they cannot migrate from the central nervous system 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,762 including tumour growth factor-beta and alpha-melanocyte stimulating hormone.401 From the foregoing 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.63, 71, 156, 439 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.622, 627 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 effect.546, 622, 627 In infected mice in which immunosuppression is discontinued, deaths tend to coincide with the return to immunoresponsiveness as marked by the appearance of antibody in serum.627 The early death phenomenon is observed when infection occurs in partially immune or inadequately immunized animals.112, 113, 610, 722 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.156, 164, 609 Antibody limits extracellular spread of infection in non-neural tissue and neutralizes virus present in saliva.156 It is implicit in the above discussion that there are many variations to the pattern of rabies pathogenesis, and that these 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. The structure of the G protein is at least one of the factors which determines the pathogenicity of strains of rabies virus.184, 185, 547 Although the exact mechanism of attenuation is poorly understood, it has been shown that virulent virus in which a single substitution is made at amino acid position 333 in the G protein, can reach the spinal cord following peripheral inoculation in mice, but has a reduced capacity for spread in the cord after an initial cycle of replication.181, 183 This site of mutation appears to be involved in certain well-known veterinary vaccine strains of rabies virus.219 From the results of studies in inbred mice, it can be concluded that there is genetic control of resistance to rabies, and that in mice this is controlled by one or two dominant Rabies genes not linked to the H-2 locus or to the neutralizing antibody response gene, although it is expressed in collaboration with immune response since immunosuppression of a resistant animal can convert asymptomatic into lethal infection.422, 679 Johnson348 and Murphy486 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 behavioural 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. In other virus infections of the central nervous system, the occurrence of encephalitis does not play a similar essential role in promoting transmission of infection. The sequence of events observed following peripheral inoculation of Mokola and Lagos bat viruses in hamsters is essentially similar to that seen in the pathogenesis of rabies: replication of virus in muscle cells at the site of inoculation, centripetal spread of infection along nerves and dissemination of virus in the central nervous system.487, 489 However, the rabies-related viruses tend to replicate to a greater extent in non-neural tissues and organs and may produce demonstrable viraemia.264, 367, 527, 595, 687, 689 Clinical signs Humans More detailed observations have been made on the clinical course of rabies in human patients than in other species. 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 apparently suspected to have occurred in one patient.305 It was demonstrated recently 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.626 However, only about 14 per cent of incubation periods in humans are longer than 90 days, and in South Africa most fall between 20 and 60 days, with a mode of 34 days.41, 304 At the end of the incubation period there may be a prodromal phase of one to four days during which patients develop non-speciﬁc signs and 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 1151 the affected extremity, and in some there is intense itching leading to frenzied scratching of the wound site.304, 738 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.304, 738 Aerophobia is an analagous reaction which occurs when patients are exposed to a draught of air.354 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 in southern Africa they are generally brought to medical attention at a late stage and 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 maximal in the extremity where the infection occurred, or be of the ascending Landry type, but progresses and spreads until ultimately there is respiratory paralysis.304 Only four instances of human survival of rabies have been well documented.206, 338 One 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 (see above) and recovered with severe neurological sequelae.22, 23, 305, 543 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.15 These reported recoveries have inspired intense efforts to treat patients, but at most prolongation of the morbid period has been achieved.338 It is also claimed that a prominent research scientist became infected while working on vampire bat-associated rabies of cattle in Mexico and made a protracted recovery from paralytic disease.649 1152 SECTION FOUR: Viral diseases: Rhabdoviridae Domestic animals Incubation periods in dogs commonly range from two to eight weeks, and, although Henning309 cites an instance in India where an incubation period of three years was recorded, the longest incubation period observed in a dog imported into Britain was just under eight months.95, 505, 686 Nevertheless, by analogy with humans it may be expected that lower animals occasionally undergo protracted incubation periods. In South Africa and Zimbabwe, most incubation periods recorded in dogs fall between two and four weeks.81, 264 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 KwaZulu-Natal Province in South Africa in 1961.672 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.95, 686 Within two to three days of 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. They 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.95, 686 Dogs that develop so-called dumb 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 paralysed 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 become comatose and die.95, 686 It appears that in excess of 70 per cent of rabid dogs in South Africa and Zimbabwe develop the furious form of the disease, many of the remainder develop dumb rabies, but in some instances little or no information on the nature of the illness is received with specimens submitted for laboratory investigation.81, 264 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.264 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. Apart from the few instances of dogs surviving rabies or developing chronic infection in West Africa, Ethiopia and India (see Epidemiology), there have been isolated reports, mostly unconﬁrmed, of similar incidents occurring elsewhere in the world, but until further evidence is produced it can be assumed that the carrier state in dogs is extremely rare.95 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.95 Incubation periods of two to six weeks have been recorded in southern Africa.40, 264 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.95, 717 Similarly, cats are more likely than dogs to acquire infection with rabies-related viruses in southern Africa. Cats are also more likely than dogs to develop the furious form of the disease, and are generally more aggressive than rabid dogs.81, 95, 264, 717 Foggin264 noted that 89 per cent of unvaccinated cats which developed rabies in Zimbabwe manifested the furious form of the disease. 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 which 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.81, 95, 264, 717 Rabies Incubation periods of 2 to 12 weeks have been recorded in cattle in South Africa and Zimbabwe, but longer periods have been recorded elsewhere, including 87 weeks in experimental infection.81, 95, 264 About half of the rabid cattle for which information is available in South Africa, and a higher proportion in Zimbabwe, manifested aggressive behaviour.81, 264 Often several animals in a herd develop the disease within a short space of time in areas where jackal or mongoose rabies is prevalent. Early signs of illness observed in southern Africa 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 99.5), and 1153 cattle often develop a characteristic hoarse bellow (Figure 99.6) which is recognized by stockmen. 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 paralysed, 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.81, 95, 264, 322 Figure 99.5 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 99.6 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) 1154 SECTION FOUR: Viral diseases: Rhabdoviridae 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.81, 95 The disease in these animals generally resembles that in cattle, but sexual excitability is more common in sheep, while goats have a tendency to bleat incessantly and are more frequently aggressive than cattle.81, 322, 644 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.95 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 South Africa.81, 95 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.95, 323 Rabies is seldom diagnosed in pigs in southern Africa (Table 99.1). Rabid pigs may attempt to hide in corners of their pen, but often display aggressive behaviour and attempt to bite humans if approached, and sows may kill their offspring.95 Wild animals Rabid yellow mongooses in South Africa tend to lose their fear of humans and other animals and are often found in or close to farm homesteads, outbuildings or stables. Only about 38 per cent of rabid mongooses are overtly aggressive and humans are usually bitten when they attempt to handle what are perceived to be tame animals.82 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 in a similar manner to yellow mongooses, except that nocturnal species may become active in daylight.82, 264 Aggressive and non-aggressive patterns of behaviour appear to have been observed with almost equal frequency in rabid jackals in Zimbabwe, South Africa and Namibia.82, 263, 264 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 in a similar manner 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.82 Honey badgers are ordinarily vicious and ﬁerce ﬁghters, and although they seldom approach human dwellings they can be formidable opponents for humans or dogs when rabid.82 In one instance a rabid badger was apparently responsible for the deaths of 47 sheep in a ﬂock in Zimbabwe.198 The most frequently observed signs of disease in rabid kudus in the 1977 to 1985 epidemic in Namibia were salivation, docility and paresis or paralysis.84, 85, 303, 328, 583, 603 The antelope approached and even attempted to enter farm buildings (Figure 99.7), 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 in South Africa, such as duikers, were sometimes found to be very aggressive towards humans and livestock and capable of inﬂicting severe wounds with their sharp horns.40 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.167, 505 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. 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 central nervous system, and cranial and spinal ganglia, and were ﬁrst described in the 1870s.529 They consist of perivascular cufﬁng, focal and diffuse gliosis, neuronal degeneration, and intracytoplasmic inclusions, or Negri bodies (Figure 99.8), in neurons.156, 331, 403, 337, 529, 656 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 Rabies 1155 Figure 99.7 Rabid kudu that entered a farm building. (By courtesy of Dr B.J.H. Barnard, Section of Virology, OVI, Onderstepoort 0110, South Africa) Figure 99.8 Negri bodies in a neuron. Acid fuchsin-methylene blue staining method 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.331, 656, 710 Negri bodies must be distinguished from lyssa bodies, which are small, homogeneous, eosinophilic neuronal inclusions found in normal cats, and to a lesser extent in dogs and other animals.331, 669 Small, angulated, dust-like, non-speciﬁc inclusions may be found in the neurons of healthy, aged sheep and cattle.656 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.156, 656 It has been suggested, but not demonstrated conclusively, that the intensity and distribution of the lesions in the central nervous system are related to the anatomic location of the infecting wound site.529 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 1156 SECTION FOUR: Viral diseases: Rhabdoviridae and grey matter, as does diffuse gliosis, and there is a variable degree of meningitis.529 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.156 Electron microscopic examination reveals that viral infection is usually widespread in the brain at the time that death supervenes, despite the fact that demonstrable viral antigen and the lesions seen by light microscopy, may have a limited distribution.487 However, the use of immunoﬂuorescence or immunohistochemistry reveals that rabies virus antigen is far more widely distributed in nerve tissue than are the Negri bodies visible by ordinary microscopy.489 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.331, 403, 529, 656 Lesions in salivary glands consist of degeneration and necrosis of acinar epithelial cells, with inﬁltration of lymphocytes, neutrophils and plasma cells.264, 656 Diagnosis It is more important to be aware that rabies induces abnormal behaviour than to suspect the disease only when animals exhibit the furious behaviour classically associated with it. 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. 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 only 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; the severity of the lesions theoretically increases as the disease progresses, but it has not invariably been found that the chances of establishing a laboratory diagnosis are better in animals that die naturally than in those that are killed for examination.710 Animals should be killed in such a manner as to avoid damaging the cranium. Protective clothing to be worn while collecting specimens should include gloves, an impermeable apron and a face mask or visor, and personnel 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.743 Brain specimens to be submitted for laboratory examination include 10 to 20 mm3 blocks of cerebrum, cerebellum, hippocampus, medulla, thalamus and brain stem preserved in duplicate in 50 per cent glycerol-saline solution for virological examination and in 10 per cent buffered formalin for histopathological examination. Where small animals are involved, half of the brain (sectioned sagittaly) may simply be placed in the glycerol-saline preservative and the other half in the formalin. Adequate samples for making an accurate diagnosis may also be collected in wide-bore, plastic drinking straws by a method which obviates the need to skin the head and saw the cranium open: the occipital foramen is exposed with a knife and the sample is collected by inserting the straw through the foramen and pushing it with a slight twisting motion towards one of the eyes.87, 88, 311 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. Occasionally, virus antigen or infectivity may be demonstrated in salivary glands and not brain, and it is recommended that samples of submaxillary salivary gland should also be submitted in glycerol-saline and formalin preservatives. Examination of salivary glands also provides valuable epidemiological information on the excretion of virus by different vertebrates. Specimen containers are 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. Formalin-ﬁxed tissue is used for making a diagnosis by examining histological sections stained with acid fuchsin and methylene blue713 or similar stains, for the presence of Negri bodies (Figure 99.8). Preparing and examining the sections may take two days or more and the method lacks sensitivity: in southern Africa, positive histological diagnoses were made in 66 to 87,7 per cent of cases in which virus was isolated in mice or antigen demonstrated by immunoﬂuorescence.264, 710 It was found in Zimbabwe that histopathological diagnoses were made signiﬁcantly less frequently in dogs with the paralytic form of the disease than in those with furious rabies,264 and it should be borne in mind that occasionally the presence of virus and lesions may be limited to the spinal cord.473 Nevertheless, histopathological examination of specimens has the merit that it sometimes allows an alternative diagnosis to be established in cases of nervous disease which are not due to rabies, such Rabies as distemper in dogs, or cerebral theileriosis and babesiosis in cattle.264, 618 Negri bodies can also be demonstrated in impression smears prepared from fresh (glycerol-saline preserved) brain tissue and stained by the method of Sellers.600 The technique is of similar sensitivity to histopathological examination of brain sections, and takes only one hour, but is less useful for establishing alternative diagnoses and is rarely used. The standard method of making a diagnosis is to demonstrate rabies virus antigen in impression smears of fresh brain by immunoﬂuorescence.281 The test takes only one to three hours to perform, and is of comparable sensitivity to mouse inoculation, with a concordance of 95 to 99 per cent between the two methods when the immunoﬂuorescence test is performed by experienced investigators.124, 731, 743 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 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. Microwave ﬁxation has been used successfully as an alternative to acetone ﬁxation of tissues for examination by immunoﬂuorescence.201 Most laboratories use immunoﬂuorescence as the sole diagnostic test and resort to mouse inoculation as a conﬁrmatory test only in instances where a negative result is recorded in an animal which has potentially been involved in the exposure of a human to infection. However, it has been argued that the chances of virus being present in infective concentrations in saliva are negligible when the immunoﬂuorescence test on brain is negative, and that mouse inoculation is therefore not strictly necessary.27 It is nevertheless recommended that the immunoﬂuorescence test should be repeated in such instances. Formalin-ﬁxed brain tissue has been used successfully in immunoﬂuorescence tests.750 However, formalin ﬁxation may mask virus antigen, and when only ﬁxed tissue is available for examination, the tissue can be treated with trypsin to unmask antigen prior to performing the immunoﬂuorescence test.86, 346, 711 Virus antigen may also be demonstrated by enzymelinked immunoassay,50 and kits for performing the test in microplates are available commercially.535, 536 The test can be performed in the course of a working day and there is 95 per cent concordance with results obtained by immunoﬂuorescence.124 The results can be read accurately by the naked eye, without need for a colorimeter, so that the test is suitable for use in laboratories which lack facilities for performing immunoﬂuorescence tests.124, 535, 536 Modiﬁed antigen detection kits are available to increase sensitivity for 1157 the detection of rabies-related viruses in addition to rabies virus.530 The isolation of virus by intracerebral inoculation of brain suspension into weaned mice was the standard diagnostic method prior to the widespread adoption of the immunoﬂuorescence test. Isolation of virus is conﬁrmed by histopathological examination of the mouse brain, or preferably by performing an immunoﬂuorescence test on it. The method is sensitive, yielding isolates from virtually all infected specimens received at the laboratory in a wellpreserved state, but it may take up to four weeks or longer to obtain a result. Quicker results may be obtained by using suckling mice and sacriﬁcing individuals for examination by immunoﬂuorescence from the third or fourth day postinoculation onwards.280, 508, 731 Virus may be isolated in a variety of line cell cultures in place of mice, and greatest sensitivity is claimed for neuroblastoma cells of murine and human origin.124, 171, 336, 566, 567, 568, 620, 621, 783 Brain or other tissue suspensions may be toxic to cells, and it is usually necessary to subculture cells in order to isolate virus. Since rabies virus is poorly cytopathic, its isolation has to be demonstrated by performing immunoﬂuorescence tests on the cultures. Under optimum conditions, isolation of virus can be achieved in two to four days with a sensitivity similar to the detection of virus by enzymelinked immunoassay.124 The demonstration of virus antigen by immunoﬂuorescence in corneal impression smears, or in nerve ﬁbres surrounding hair follicles in frozen sections of nuchal skin biopsies, were developed as tests for making a diagnosis in live animals or in instances where the brain has been destroyed, and have also been applied to intra vitam diagnosis of the disease in human patients, but the results obtained have been inconsistent.102, 117, 118, 135, 405, 587, 636, 781 Isolation of virus from saliva can also be used to make a diagnosis in live human patients or lower animals.743 Monoclonal antibodies can be used in indirect immunoﬂuorescence tests to identify rabies-related viruses directly in ﬁeld specimens,731 but in view of the apparently rare occurrence of infection with these viruses it is doubtful whether the extra labour and expense involved in routine use of monoclonal antibodies in diagnostic laboratories is justiﬁed. It is probably better to perform tests for the identiﬁcation of the rabies-related viruses only when there are indications that they may be involved (see above). Otherwise, monoclonal antibodies can be used to identify rabies virus biotypes or rabies-related viruses in speciﬁc surveys. Reverse transcription polymerase chain reaction can be used to detect viral nucleic acid in brain tissue, saliva, and cerebrospinal ﬂuid.292, 334, 577, 626, 730, 748 The technique has been used successfully on decomposed and formalin-ﬁxed brain tissue,199, 394, 749 and can be combined with nucleotide sequencing, or the use of selective primers to identify the genotype of lyssavirus involved.307, 490, 498, 626 1158 SECTION FOUR: Viral diseases: Rhabdoviridae Antibody to rabies virus may be demonstrated by a variety of methods including indirect immunoﬂuorescence, complement ﬁxation, haemagglutination-inhibition, radioimmunoassay, enzyme-linked immunoassay and neutralization tests.147, 172, 238 The tests can be used to establish a diagnosis of rabies in live human patients, who develop an antibody response ﬁve days or more after the onset of the illness, but this approach is less applicable in animals since antibody only becomes demonstrable in terminal illness or not at all.147 Serological tests are also performed to assess response to vaccine, or to identify virus isolates. Differential diagnosis Diseases which may be, or have been, confused with rabies in southern Africa include distemper, infectious canine hepatitis, ehrlichiosis, cerebral babesiosis, toxoplasmosis, cerebral cysticercosis (caused by Taenia solium), tetanus, diminazine toxicity, pesticide (such as metaldehyde) and strychnine poisonings in dogs; cerebral theileriosis and babesiosis, thrombotic meningoencephalitis (caused by Haemophilus somnus), sporadic bovine encephalomyelitis (caused by Chlamydophila pecorum), botulism, lead, urea, chlorinated hydrocarbon and organophosphate poisonings, and cerebrocortical necrosis (caused by thiamine deﬁciency) in cattle; coenurus cerebralis (Taenia multiceps coenurosis) in sheep; heartwater and a variety of plant poisonings (such as those caused by Homeria and Morea spp., Matricaria nigellifolia, Cestrum spp., Cynanchum spp., and Dipcadi glauca) and the mycotoxicosis, diplodiosis, caused by the fungus Diplodia maydis in domestic ruminants; encephalomyelitis caused by equid herpesvirus 1 infection, tetanus, leukoencephalomalacia (caused by fumonisin B1 produced by the fungus Fusarium moniliforme) and poisoning by Senecio spp. in horses; and pesticide poisonings in all animals.264, 364, 727 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. Many of these same conditions occur elsewhere in the world,505 and as a generalization it can be added that local viral encephalitides and plant poisons should be borne in mind. Control Control programmes The existence of appropriate enabling legislation is a prerequisite to the control of rabies.30, 734 In addition, there is a need for surveillance and the compilation of information on the distribution and occurrence of the disease, which implies the existence of an adequate veterinary ﬁeld service infrastructure with diagnostic laboratory support. For the control of urban rabies, information is needed on the number of dogs in the area where the disease is to be controlled, and this can be assessed by establishing the dog to human ratio in a random survey of households, or by a variety of methods for estimating populations of free roaming dogs.30, 44, 131 It is also desirable to determine the age and sex structure of the dog population, and to derive estimates for longevity and the reproduction rate, since this will inﬂuence decisions on the frequency with which vaccination campaigns need to be conducted. It should be determined whether or not there are wild reservoirs of infection or whether, as in Europe and North America, dog rabies can be controlled independently of sylvatic rabies. The assembled information is used to plan and budget for control campaigns, and this could include cost-beneﬁt analysis in which the expense of controlling rabies is weighed against the cost of vaccinating and treating humans, and the other losses incurred in continuing to cope with the disease. Cumulative experience suggests that it takes six to ten years to eradicate dog rabies from a large country and currently dog vaccination campaigns cost in the order of US $100 000 per million human residents, assuming a ratio of one dog to ten humans.472 The ﬁrst step in controlling the disease is generally to declare the area where it occurs to be an affected area in terms of the legislation, thus permitting the enforcement of control measures. Vaccination of dogs in the affected area then becomes compulsory, and dogs may not be removed from the area without a movement permit and proof of vaccination at least one month prior to movement. The importance of educating members of the public and obtaining their support for rabies control campaigns cannot be overemphasized.30, 734 In afﬂuent countries, control campaigns consist of three elements: restriction of the movement of dogs, removal of unrestricted dogs and vaccination of restricted dogs. Members of the public in such countries generally accept and fulﬁl their obligations, and neither the state nor the public lack the resources for complying with the requirements for control of the disease.96 Even in developing nations, it is relatively easy to obtain restriction of the movement of dogs of the higher-income segment of the population, and to a variable extent the vaccination of such dogs may be catered for by private veterinary practitioners, but it is necessary for the state to conduct speciﬁc vaccination campaigns for the dogs of the lower-income segments of the population, preferably at no cost to dog owners. Depending on local circumstances, it may be preferable to arrange for dogs to be vaccinated at pre-selected sites and dates, or to conduct house to house vaccinations. It is preferable to use one of the current generation of inactivated cell culture vaccines incorporating an adjuvant, which provides protection for up to three years, and it is important to obtain maximum coverage of the dogs within a given epidemiological unit (geographic cell) in as short a time as possible: the high turnover rate in populations of unrestricted dogs renders it ineffective to perform piecemeal or protracted campaigns.404 Rabies It is generally impractical or inconvenient to issue vaccination certiﬁcates during campaigns, but dogs may be given neckbands with tags, or tattooed on the inner surface of the ear.766 An alternative is to issue certiﬁcates only on request or payment of a fee. At the least, a count should be kept of the numbers of dogs vaccinated, and dogs should be marked at some of the locations where vaccination is performed, even temporarily by daubing them with paint, to allow subsequent assessment of vaccination coverage. The degree of vaccination coverage attained is assessed by comparing estimates of dog populations with numbers vaccinated, or by determining the ratio of marked (vaccinated) to unvaccinated dogs after campaigns, or by conducting antibody surveys. 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, and, for instance, Foggin264 calculated from ﬁgures recorded in Zimbabwe that control could be achieved by sustained 50 per cent vaccination coverage of dogs in the communal farming areas of that country. 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.30, 404, 734 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. Current immunization regulations in force in some African countries are still based on the immunity induced by modiﬁed live vaccines, in particular Flury LEP or HEP vaccines, and require the vaccination of dogs to be performed at three months of age, again at one year of age, and every three years thereafter, but 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 proof of immunization status can be produced by the owner. 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. Cats generally play a lesser role in the propagation of urban rabies and their vaccination is usually recommended, but left to the discretion of the owner. They can be included in vaccination campaigns where cat rabies is a particular problem, but they are more prone to lead a semi-feral existence than dogs, and it is neither necessary nor feasible to obtain the same degree of vaccination coverage as in dogs. It is recommended that 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 may be given a booster and kept 1159 under observation for a period of three months.27 Immunization of feral animals in captivity is 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 feral animals which 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 (see Epidemiology). Owing to the recuperative reproductive capacity of populations of unrestricted dogs, it is estimated that 50 to 80 per 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.734 Alternatives include offering and promoting a service to sterilize dogs. The same principles apply to populations of feral animals, and rather than applying ineffective or indiscriminate methods for removing individuals it is better to use methods which leave existing social structures and hierarchies intact, such as the use of drugs to control breeding,255 or to develop a method for oral immunization analagous to that which has recently been applied with great success to foxes in Europe (see below). Import and quarantine regulations constitute another important facet of rabies control. Some countries which are free of rabies in terrestrial species, such as Britain, require imported dogs to be vaccinated and subjected to six months quarantine, and have nevertheless recorded a few cases of the disease after expiry of the quarantine period.143 Other countries which are free of the terrestrial disease, such as Australia, allow importation only from rabies-free countries, so that Britain is sometimes used as a ‘stepping-stone’ in the movement of animals. South Africa requires that cats and dogs from countries with rabies should be immunized one month prior to importation and be held in quarantine for a month after arrival. Conditions for the importation of other animals, including zoo animals, are determined by the state veterinary services as the occasion arises. In all instances of intended international movement of animals it is necessary to establish the latest requirements of the recipient country prior to the translocation of the animals. Vaccines and immunization of domestic animals The immunogenicity of the inactivated nerve tissue vaccines originally used in humans and lower animals was generally poor,460, 741 but improved after potency assays were introduced in 1940.293, 598 However, the vaccines caused 1160 SECTION FOUR: Viral diseases: Rhabdoviridae 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).291, 326, 352, 398, 560 Consequently, a change was made in the 1950s to the use of immature animals, particularly suckling mice,274 for the preparation of vaccine at a stage before brain tissue is fully myelinated, while vaccine prepared from virus cultured in embryonated duck eggs was introduced for use in humans.545 Neither of these two types of vaccine was entirely free of allergens21, 308 and there were still doubts about their immunogenicity.78, 192 In particular, nerve tissue and duck embryo vaccines were found to have a much higher content of rabies virus N protein than G protein antigen. Nevertheless, inactivated nerve tissue vaccines remain in use for humans and lower animals in many countries,37 while production of duck embryo vaccine was discontinued in 1981.397, 398 From the 1950s onwards there was a trend in the developed nations towards replacing nerve tissue vaccines with attenuated or so-called modiﬁed live virus vaccines for veterinary use. These included the LEP derivative385, 387 of the Flury strain of virus412 for use in dogs, the HEP derivative of the Flury strain for use in cats and cattle,386 the ERA vaccine strain1 derived from the SAD (Street Alabama Dufferin) strain of virus249 for use in dogs and other animals, the Vnukovo-32 vaccine strain derived from the SAD strain in the former USSR,599 the SAD-B19 clone of virus used for oral immunization of foxes in Europe,593 and the Kelev vaccine strain developed from a strain of rabies virus isolated from a dog in Israel.382 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,94, 137, 138, 144, 525, 746 problems which were also encountered in southern Africa.40, 83, 264, 449, 605 Currently, a range of highly effective, safe and thermostable, inactivated veterinary vaccines, prepared from virus grown in a variety of primary and line cell cultures, is available,90, 548, 602, 716 and vaccines of this type have been brought into use in most southern African countries. Some of the vaccines may be used in all domestic carnivores and herbivores, while others are designed for use in speciﬁc species and may be multivalent, incorporating antigens of other infectious disease agents, which affect the species. Some are recommended speciﬁcally for either intramuscular or subcutaneous use, but others may be administered by either route. The duration of the protective immunity to challenge with rabies virus 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 are 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. Recombinant vaccines are becoming commercially available and, for instance, several manufacturers in the USA market canary pox virus expressing the rabies virus glycoprotein gene for use in cats and horses.271, 491, 675, 676 A vaccine strain of the poxvirus causing lumpy skin disease in cattle in Africa, has been used to prepare a recombinant expressing rabies glycoprotein, which has proved to be highly immunogenic in cattle.48 DNA-based vaccines are also being explored for use in immunizing against rabies virus, and have the advantage over recombinant antigens that they can be used to induce cell-mediated immunity as well as humoral immunity.127, 531, 680, 780 Moreover, the DNA vaccines can also be made multivalent to protect against rabies-related viruses.72, 532, 533, 423, 425, 426 However, one problem which is still receiving attention is the relatively slow immune response induced by DNA vaccines.424 Oral vaccination 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 concentraion, stable at high ambient temperatures, and immunogenic for the target species without being pathogenic for non-target species. Baits should be able to be mass produced, attractive to the target species and readily chewed so that the immunizing agent is exposed when the bait is taken.65, 116, 593 The concept of oral vaccination arose from the demonstration of susceptibilty to oral infection in laboratory animals,179, 641 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 rabies virus were known to be pathogenic for foxes.65 It was subsequently shown that foxes could be immunized by enclosing a plastic straw ﬁlled with vaccine in a sausage bait.760 Following successful ﬁeld trials in Switzerland in 1978, in which foxes were immunized with SAD-Berne virus in capsules inserted into chicken head baits,647 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.93, 523, 590, 737 The possibility was raised that SAD virus derivatives could produce disease and become established in nontarget species which took baits, particularly rodents and mustelids,65, 503, 771 but the problem did not materialize in the ﬁeld.116, 735, 737 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.116 The SAG-1 virus was a monoclonal antibody escape Rabies mutant of SAD virus that had a substitution of serine for arginine at amino acid position 333 in the glycoprotein, brought about by a single nucleotide mutation in codon 333, while SAG-2 had a double mutation in the codon, rendering reversion less likely, and substituting116 glutamine for the arginine.182, 183, 399, 409 Subsequently a vaccinia-rabies glycoprotein recombinant (VRG) vaccine was produced to overcome concerns about safety in non-target species,372, 571, 763 and this was found safe and effective for use in racoons in the USA and foxes in Europe.128, 129, 130, 209, 574, 522 Other poxviruses used successfully to produce recombinants expressing rabies virus antigens included racoonpox, fowlpox and canarypox viruses.48, 231, 673, 674 Recombinants were used to demonstrate the protective immunogenicity of rabies nucleoprotein.248, 275, 316 Adenoviruses-vectored recombinants expressing rabies glycoprotein were also developed successfully,158 and there is even the prospect that food plants can be used for the production and delivery of rabies vaccines through the expression of virus-vectored genes, as demonstrated with tomatoes and spinach.459 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.351, 593, 737, 484 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,737 or by the use of automatic cameras. Other markers include Du Pont Oil Blue A, Rhodamine B, and sulphadimethoxine which is a serum marker.298, 300, 350, 419 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.51–53, 521, 652, 782 It was suggested that in order 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.51, 691 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 rabies viruses, vaccinia-rabies glycoprotein recombinant, racoon pox-rabies glycoprotein recombinant, baculovirus-expressed rabies glycoprotein, and canine adenovirus 2-rabies glycoprotein recombinant, in racoons, 1161 skunks, arctic foxes, red foxes, grey foxes, and coyotes.47, 247, 267, 268, 272, 297, 570, 763 A variety of speciﬁc baits were developed and tested for coyotes, grey foxes, and racoons.236, 237, 296, 300, 418, 421, 539, 563, 650, 651 In general, the immunizing agents all performed well, but canine adenovirus 2 recombinant virus proved to be potentially pathogenic for racoons.297 Only VRG has been registered for use in rabies control programmes in wildlife in the USA, and its use is restricted to state authorities.491 The ﬁrst trial release of recombinant oral vaccine, VRG, in the USA was directed at racoons in Virginia, in 1990, and proved to be successful.299 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 racoons, skunks and foxes all being involved as vectors, a programme of capture, vaccination and release of animals plus oral immunization of racoons with the ERA derivative of SAD virus has proved to be effective in controlling the threat of infection to humans.563, 564 Oral vaccination of racoons 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.350 Oral vaccination of grey foxes and coyotes is proving to be effective in different locations in Texas.237, 239, 254 Capture, vaccination and release is being used to combat spread of rabies virus of bat origin in skunks in northern Arizona.414 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.101, 103, 104, 189, 381, 420 It has been mooted that oral immunization could be extended to populations of unrestricted dogs which are inaccessible to vaccination by ordinary means.65, 67, 243, 538, 417, 540 Human immunization and post-exposure treatment It was not until the use of rabies antiserum in conjunction with vaccine was standardized that convincing evidence of post-exposure protection of humans was obtained.77, 294, 295 Antiserum 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 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.397, 398, 757, 764 The vaccine is prepared in France from virus grown in WI38 diploid cells and in Germany from virus grown in MRC5 diploid cells,448, 504 and is highly effective and safe. 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 1162 SECTION FOUR: Viral diseases: Rhabdoviridae observed in a small proportion of patients.397, 398 There were about 20 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.31, 397, 398, 685 Moreover, it is noticeable that several of the patients in whom vaccine failure occurred had short incubation periods, including a South African patient,31, 604 so that it is possible that nerve infection occurred too rapidly in these instances for treatment to be effective. 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,89 or Vero line cells,479 or from virus grown in duck embryos and subjected to a high degree of puriﬁcation and concentration.278 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. An effective aluminium phosphate adsorbed, inactivated vaccine was also developed from virus grown in diploid foetal rhesus monkey kidney cells.139 All of these vaccines are puriﬁed, safe and of similar potency to the human diploid cell culture vaccine. In terms of control legislation, rabies is generally 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. All veterinarians should, moreover, be familiar with current recommendations on pre- and postexposure treatment of humans in order to ensure that they and their assistants are adequately protected. Recommendations on pre- and post-exposure treatment of humans are published periodically in Reports of the World Health Organization Expert Committee on Rabies and the following information is based on the recommendations included in the Eighth Report published in 1992, and a subsidiary report on intradermal immunization published in 1997.33, 38, 39, 685 Reference below to vaccine implies human diploid cell culture vaccine or one of the equivalent puriﬁed and inactivated products with an antigenic potency of >2,5 IU/ml. Full doses of modern cell culture vaccines vary from 0,5 to 1,0 ml in volume, depending on the manufacturer, but all contain the same amount of antigen. It is recommended that persons with an occupational risk of exposure to infection, such as veterinary staff, should be subjected to pre-exposure prophylaxis through the administration of an initial three full doses of vaccine into the deltoid muscle on days 0, 7 and 28; a few days’ variation in the timing of the repeat doses is acceptable. The inactivated vaccines stipulated above may all be used effectively and there is generally no need to monitor antibody response. Single booster doses are administered every two to three years depending on risk, i.e. the frequency with which rabid animals or infected materials are handled. For people at constant risk, such as veterinary and laboratory staff, it is recommended that rabies neutralizing antibody titres are checked, and a booster administered when titres fall below 0,5 IU/ml, although recent ﬁndings suggest that immunity may last ﬁve to ten years.39, 653 Pre-exposure immunization was also achieved with 0,1 ml intradermal doses in place of the full intramuscular doses, but poor response was observed in persons who were taking chloroquine as an antimalarial prophylaxis.97, 514, 678 Persons who are preimmunized receive a single intramuscular dose of vaccine after exposure to infection, followed by a second dose on day 3 or later; the exact timing is not critical. Such persons should not, however, receive rabies antiserum or immunoglobulin if their last immunization occurred during the previous ﬁve years since this interferes with their rapid anamnestic response to vaccine. Preventive pre-exposure immunization is generally performed at the expense of the vaccinee or the employer, but in many countries, including South Africa, post-exposure treatment is performed at state expense. All bite wounds inﬂicted by potentially rabid animals should be cleansed thoroughly with soap and water or a quaternary ammonium compound detergent (never both together since their effects are antagonistic), or water alone, and an antiseptic should be applied, preferably consisting of either tincture of iodine, aqueous iodine or 70 per cent alcohol. Bleeding should be encouraged and suturing of the wound should be avoided if possible, but anti-tetanus treatment and antibiotic therapy should be applied as deemed necessary. If anti-rabies serum or immunoglobulin is to be used (see below), as much as possible of the calculated dose should be inﬁltrated into the tissues around the wound and instilled into the depth of the wound, and the rest administered at a single site into the gluteal muscle. The dosage is 20 IU/kg body weight for human anti-rabies immunoglobulin, or 40 IU/kg for antiserum or immunoglobulin prepared in horses. The indications for speciﬁc anti-rabies therapy vary with the degree of risk attached to the exposure to infection, and three categories are deﬁned. Category I In this category risk of exposure to infection occurs where persons have touched or fed, or have been licked on unbroken skin by, conﬁrmed or suspected rabid domestic or wild animals, or animals which have not remained available for observation, or animals from which specimens suitable for laboratory examination have not been obtained, and no speciﬁc treatment is indicated in such instances if a reliable history has been obtained. Category II In category II risk of exposure to rabies arises where the animals stipulated above have nibbled uncovered Rabies skin, or have inﬂicted minor bites and scratches without drawing blood, or have licked broken skin. In these instances a course of vaccination is started immediately but may be discontinued if the animal remains healthy throughout an observation period of ten days, or has been killed for laboratory examination and found to be negative for rabies. The start of vaccination may be delayed in instances where apparently healthy dogs or cats from a low-risk area are placed under observation. The use of anti-rabies immunoglobulin is not essential in risk Category II exposures. The standard treatment (Essen schedule) to be applied where Category II risk of exposure arises consists of a course of ﬁve full doses of vaccine (0,5 or 1,0 ml according to the manufacturer’s product) delivered into the deltoid muscle, or anterolateral thigh muscle in small infants, on days 0, 3, 7, 14 and 30; day 0 being the day on which the patient ﬁrst presents for treatment. Administration of vaccine into the buttock is contra-indicated since fat deposits may impair uptake of vaccine. Alternative abbreviated courses of vaccination may be applied in risk Category II exposures, and these are of particular advantage in underdeveloped nations since there is a saving in the amount of vaccine used and in the number of visits to clinics which patients have to make for treatment. In the so-called 2-1-1 schedule (Zagreb schedule) two full doses of vaccine are administered bilaterally into the deltoid muscles on day 0, and single doses are administered on days 7 and 21.725 The 2-1-1 schedule should only be used in Category II exposures and should not be combined with the use of immunoglobulin or antiserum. In the Thai Red Cross intradermal schedule, two 0,1-ml intradermal doses are administered bilaterally on the fore or upper arms on days 0, 3 and 7, followed by single 0,1-ml intradermal doses on days 28 and 90, resulting in a total usage of only 0,8 ml of vaccine. The Oxford intradermal schedule involves the use of eight 0,1-ml doses of vaccine at multiple sites on day 0 chosen for proximity to lymph nodes (bilateral deltoids, anterior thighs, lower abdominal quadrants, and suprascapular regions), followed by four 0,1-ml doses on day 7 (bilateral deltoids and thighs), and single 0,1-ml intradermal doses on days 28 and 90.39 The intradermal schedules should only be used where good technique can be guaranteed, and once an ampoule of vaccine has been opened, it should be kept refrigerated and used only on the same day. Category III This category risk of exposure to infection arises where the animals stipulated above inﬂict single or multiple transdermal bites or scratches, and the correct treatment is to administer anti-rabies immunoglobulin (or antiserum) and vaccine on the day that the patient presents for treatment, irrespective of the time elapsed since the exposure to infection occurred (this represents a modiﬁcation of previous recommendations in which the use of immunoglobulin was only advocated if patients presented for treatment within a week of exposure to infection). Moreover, it was formerly advocated that immunoglobulin should only 1163 be given at the time that the ﬁrst dose of vaccine is administered so as not to depress response to vaccine, but it is often difﬁcult to obtain immunoglobulin immediately, and it is now considered acceptable to administer immunoglobulin up to seven days after the ﬁrst post-exposure immunization since it is reasoned that there is still a need for passive immunity until antibody response occurs.369 Vaccination schedules to be used in Category III exposures include the standard intramuscular regime, or the intradermal schedules as described above. Use of immunoglobulin with abbreviated schedules of immunization is controversial, and conﬂicting results have been obtained,169, 658 but the eightsite Oxford schedule of immunization is intended to be effective without immunoglobulin. As with Category II exposures, treatment may be stopped if animals under observation remain normal for ten days or are found to be negative for rabies on laboratory investigation. The ﬁrst dose of vaccine to be administered should be doubled or trebled where: • treatment is delayed for 48 hours or more post-exposure, particularly if immunoglobulin or antiserum is used; • patients incorrectly receive immunoglobulin or antiserum 24 hours or more before vaccine; • there is chronic underlying disease such as cirrhosis; • patients have a congenital or acquired immunodeﬁciency state; • patients are under treatment with immunosuppressive drugs, including antimalarials; or • patients are aged or malnourished. It should be stressed that the guidelines for use of abbreviated schedules of immunization produced by WHO are only recommendations, and that the decision to implement such schedules resides with the government agencies which select policies for their own countries. In South Africa, for instance, there is as yet little experience of intradermal technique in rural clinics, and it is recommended that the abbreviated schedules be applied only after discussion with state authorities in certain situations requiring immunization of large numbers of people with low risk exposure. A low risk of infection occurs in instances where persons have had contact with rabid human patients or have butchered and consumed rabid farm animals (see Epidemiology). It is generally suggested that by careful questioning such persons are classiﬁed as either deﬁnitely being at risk and in need of treatment, or unlikely to be at risk, and that persons in the latter category be given the option of receiving treatment if they are concerned for their own safety. As with other schedules of immunization, there have been vaccine failures with intradermal vaccination, particularly in immunocompromised patients, but the results of one study suggest that good immune responses can be obtained even where intradermal technique is deﬁcient.541, 670 Among the rabies-related viruses, Duvenhage is antigenically closest to rabies virus, and rabies vaccine affords 1164 SECTION FOUR: Viral diseases: Rhabdoviridae the greatest protection against this virus, and least protection against Mokola virus.246, 388, 688 In the absence of speciﬁc vaccines, however, rabies vaccine should be used in all instances where it is deemed that persons have been poten- tially exposed to infection with a rabies-related virus. Persons who have been accidentally inoculated with SAD or Flury vaccine strains of rabies virus should not be considered at risk, and no speciﬁc treatment is indicated.21, 269 References 1 abelseth, m.k., 1964. 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