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| J R Soc Med. 2002 January; 95(1): 9–13. | PMCID: PMC1279140 |
Copyright © 2002, The Royal Society of Medicine Rabies in North America and Europe Christopher J Finnegan, BSc MSc, Sharon M Brookes, BSc PhD, Nicholas Johnson, BSc PhD, Jemma Smith, BSc, Karen L Mansfield, BSc, Victoria L Keene, BSc, Lorraine M McElhinney, MSc PhD, and Anthony R Fooks, BSc PhDRabies Research and Diagnostics Group, Department of Virology, Veterinary
Laboratories Agency (Weybridge), New Haw, Addlestone, Surrey KT15 3NB,
UK |
Rabies is caused by infection with a negative-stranded RNA virus within the
Lyssavirus genus (family Rhabdoviridae, order Mononegavirales),
mainly transmitted via saliva following a bite from an infected animal.
Transmission may also occur through mucous membranes, but not through intact
skin. The main source of infection from domestic reservoir species is dogs and
cats. There are seven rabies virus (RV) genotypes, six of which have similar
effects in man; the exception is genotype 2, which has never been isolated in
human cases. The main genotypes of interest for the purpose of this review are
1, 5 and 6. Genotype 1 viruses have a worldwide distribution and are generally
found in terrestrial animals. Genotypes 5 and 6, commonly known as European
bat lyssaviruses (EBLs), are restricted in distribution to Europe and are
frequently isolated from European bats. Genotype 1 viruses have never been
isolated from European bats. Rabies can probably infect most if not all mammals. The virus enters the
central nervous system of the new host, causing an encephalomyelitis which is
always fatal once symptoms develop. The manifestations in human cases include
spasms, hallucinations, hydrophobia, aerophobia, dysphasia, paralysis and
coma. Extreme agitation and convulsions can be interspersed with periods of
lucidity. World wide, the disease causes many thousands of human deaths each
year. The World Health Organization (WHO) World Survey of Rabies for the year
1997 gave an estimate of between 35 000 and 50 000
annually 1. Gross
under-reporting is likely because many countries lack the necessary diagnostic
facilities; also, the populations most affected tend to be rural (especially
in developing countries) with erratic notification systems. African and Asian
countries are particularly affected because of their animal reservoirs and the
lack of healthcare and control measures. The subject has been thoroughly
reviewed by King and
Turner 2. Here we
focus on human rabies in North America and Europe. |
HUMAN RABIES North America Until recently it was difficult to identify which strains of RV were
causing human disease. This has changed with the advent of molecular
diagnostic tools such as nucleotide analysis, which also provide clues to the
source of the virus. It now seems that a large proportion of human rabies
infections in the United States are transmitted by bat bites. Some people when
bitten ignore the danger and take no action; many are simply unaware of the
bite—perhaps because they are asleep when it happened. Also, parents may
not know that their children have been in contact with bats. Since the 1900s, the number of deaths from rabies in North America has
fallen from 100 or more each year to just one or two cases. Much of the
decline dates from the 1940s, when vaccination and animal control programmes
were set up. In the early 1940s, there were about 40 cases each
year 3. This figure
decreased to a total of 99 for the entire decade in the 1950s, and then
dropped further to 15 in the 1960s, 23 in the 1970s, 10 in the 1980s and 22
from 1990 to 1996 4.
Widespread vaccination of canine pets in the 1950s was partly responsible for
the decrease in human cases in subsequent
years 5. The
vaccination campaigns implemented in the 1940s all but eliminated the
circulation of canine strains of genotype 1 RV by the 1960s. However, the late
1970s and early 1980s witnessed the re-emergence of a variant well adapted to
dogs in south
Texas 6, thereby
increasing the risk to human beings. 4 human cases were reported in 1997 (Montana, Washington, Texas and New
Jersey) and just 1 case in 1998 (Virginia). No human deaths were recorded in
the USA for 1999 but in 2000 there were 5, reported from California, New York,
Georgia, Minnesota and Wisconsin plus 1 from Quebec
(Canada) 7. The case
reported from New York was in a patient who had come from Ghana after being
bitten by a dog; all the others were thought to be associated with bats. Europe Human cases in Europe have been well documented since the late 1970s. In
1997 17 human cases were
reported 8— 12
from the Russian Federation, 3 from Romania, 1 from Lithuania and 1 from
France (imported). In 1998 the total was 7 cases and in 1999 it was 11 (all
reported by the Russian
Federation) 8. In
2000 the total was 9-7 reported by the Russian Federation, 1 by Romania and 1
by Lithuania 8. In June 2001 the UK had 2 human cases—the first being imported from
the Philippines and the second from Nigeria. Both were confirmed in our
laboratory as genotype 1 canine strains by virus sequence analysis. The
previous introductions of rabies into the UK were both in 1996. There was an
imported human case from Nigeria (genotype 1) and a Daubenton's bat case (EBL
2, genotype 6, which may have originated from mainland
Europe 9). The bat
had bitten 2 people, both of whom successfully completed post-exposure
prophylaxis (PEP). Because the human cases had been imported and the bat was
harbouring a EBL, the rabies-free status of the UK remained unaffected. |
RABIES VACCINES FOR HUMAN USE Pre-exposure Safe and potent rabies vaccines are available for use in man. Both
pre-exposure and post-exposure treatments for rabies have been harmonized
across Europe and North America following the guidelines set by the WHO. The
vaccine currently employed in the UK is a rabies human diploid cell vaccine
(HDCV). Easily accessible, it is a freeze-dried suspension of Wistar RV strain
PM/WI 38 1503-3M. Pre-exposure prophylaxis is routinely offered to those whose
occupation may lead to exposure to rabies viruses. These include workers at
animal quarantine centres, at zoos, at research and acclimatization centres
where non-human primates and other imported animals are housed, and certain
customs and excise officers, veterinary and technical staff in the State
Veterinary Services, inspectors appointed by local authorities under the
Animal Health Act 1981, bat handlers and laboratory
workers 1. The
recommended schedule for primary pre-exposure immunization with HDCV is three
doses given by deep subcutaneous or intramuscular injection in the deltoid
region on days 0, 7 and 28. The antibody response may be lower with gluteal
injection. Travellers to rabies endemic areas are offered two doses by deep
subcutaneous or intramuscular injection four weeks apart, and this can be
expected to give immunity in 98% of recipients. This level of protection may
be acceptable if post-exposure treatment is likely to be readily available.
However, for those travellers with continued exposure to rabies viruses a
further dose should be given 6-12 months
later 1. Post-exposure The treatment regimen after exposure depends on several factors. Daily
doses of vaccine in the abdomen are no longer necessary. The strategy
recommended by WHO is essentially as follows. Patients who have had a
pre-exposure course of HDCV should be given two subcutaneous or intramuscular
doses of HDCV in the deltoid region, one on day 0 and one between days 3 and
7. For children, vaccine can be delivered in the anterolateral aspect of the
thigh 1. Previously unimmunized individuals should be given, in addition to vaccine,
rabies immunoglobulin in a dose of 20 IU/kg body weight. Up to half the dose
should be infiltrated in and around the wound after cleansing and the rest by
intramuscular injection. HDCV should be delivered by subcutaneous or
intramuscular injection (not the buttocks), on days 0, 3, 7, 14, and
30 1. |
WILD AND DOMESTIC ANIMALS North America Since the 1950s raccoons have continued to be an important reservoir for
the circulation of rabies in the south-eastern States of North America. In
addition, three strains of RV seem to cause disease in skunks in the north and
south central States and in
California 9. The
disease spread in the 1950s, affecting foxes across Canada and in New England.
Although rabid foxes have declined in Canada as a result of successful baiting
strategies, Alaska still harbours the virus in the red and arctic fox
populations 6. In the United States over the past 40 years, most of the reports of rabies
have been in wild rather than domestic animals. During 1998, wild animals
accounted for 92.4% of all cases reported to the Centers for Disease Control
and Prevention 6.
Raccoons are the species reported most frequently to harbour the disease
(40.6%), followed by skunks and bats (29.4% and 14% respectively). Foxes
accounted for
5.4% 10. Outbreaks
of rabies infections in terrestrial mammals inclusive of skunks, foxes,
raccoons and coyotes are found in broad geographic regions across the
US 10. Hawaii is a
unique State in that it has never reported an indigenously acquired human or
animal case of
rabies 10. Interestingly, from 1998 to 1999, cases of rabies in feline, canine and
equine species decreased by 1.4%, 1.8% and 20.7%, respectively, whereas those
in bovine, ovine and porcine species increased by 16.4%, 12.5% and 200.0%. The
two States reporting the highest number of rabid domestic animals were Iowa
(57) and Texas
(54) 10. For the
first time, a bat-associated RV was isolated from a cat—in
Maryland 11. In North America, bat rabies is caused by genotype 1 viruses. The main
species involved are Eptesicus fuscus, the big brown bat;
Tadarida brasiliensis, the Brazilian (Mexican) free-tailed bat;
Myotis lucifugus, the little brown bat; Lasiurus cinereus,
the hoary bat; Lasionycteris noctivagans, the silver-haired bat,
L. borealis, the red bat; and Pipistrellus hesperus, the
western pipistrelle. Control Although human rabies cases are rare in the US, as many as 16 000-39 000
people receive PEP every
year 12. The
persistence of RV in a broad range of native species continues to present a
public health hazard. Controlling rabies in the US is a complex issue. In contrast to Europe, for
a given area the principal vectors for the disease are multiple rather than a
single wildlife species. Vaccination of domestic pets, observation of suspect
animals and public education have all assisted in controlling rabies in
domestic animals. However, these activities are not sufficient to eliminate
sylvatic rabies. Population reduction techniques have been employed in the past in an
attempt to reduce susceptible animals below the threshold necessary for rabies
to spread through
populations 13. The
programme to control skunks infected with rabies in Alberta, Canada, is a
prime example of this
method 14. Modifications to habitats are simple ways in which human/animal contact is
minimized. Routine rubbish disposal and pick-up (with animal-proof
receptacles, capping chimneys and screening vents) can help to achieve this
objective. All these methods minimize human/animal contact and so reduce the
need for PEP, which is costly and can generate much anxiety. Trap—vaccinate—release (TVR) programmes have also been employed
with success. Such a programme was tested in Toronto in 1984 in an effort to
control skunk rabies before an oral rabies vaccine (ORV) had been developed.
The scheme cost in the region of $450-$1150 per km 2. However, some
of these costs were offset by fewer people needing
PEP 15. Between July and October 1999, an emergency response was implemented to
combat rabies in Ontario. The objective was to contain the first three
confirmed cases of raccoon rabies in Canada. The strategy employed was known
as point infection control and involved the combination of TVR, ORV and
population
reduction 16. Oral
rabies vaccination was implemented in Ontario by the Ministry of Natural
Resources from 26 to 28 June 2000, with a planned drop of 300 000 baits
containing vaccine against the raccoon strain of RV. The target area stretched
from Napanee to Cornwall. To maximize safety and exposure, baits were placed
by hand in urban areas. Currently, field trials are underway in specific States in the USA with a
vaccinia recombinant expressing the RV glycoprotein (VRG). In September 2000,
a 28-year-old pregnant woman was bitten by her pet dog whilst attempting to
remove a VRG bait from the dog's mouth. Material from the woman's wound was
cultured in vitro and demonstrated a virus with a poxvirus
morphology 17.
Although an isolated case, this incident may create difficulties for VRG use
near urban areas and emphasizes the need to prevent accidental human exposure
when using VRG. Europe 8155 cases of animal rabies were reported in Europe in
2000 18. Wild
animals accounted for 72.1%. Of the domestic animals, dogs (34.2%) and cats
(26.1%) ranked highest as hosts to RV. Foxes (83.4%) and raccoon dogs
( Nyctereutes procyonoides) (10.5%) represented most of the wild
animal hosts for classic rabies. Rabies in Europe provides excellent examples of temporal change in the
reservoir species and geographical spread. The reduction of wolves ( Canis
lupus) and stray animals diminished two ancestral reservoirs for rabies
during the 1900s 16,
leaving central Europe rabies-free for many years. It was soon clear, however,
that rabies had not been eliminated since new reservoir species
emerged 19. There
are reports of RV being isolated from wild rodents in many countries,
including the Russian Federation and
Germany 20. However,
there is no evidence of virus adaptation in rodents to date. The epizootic of
rabies in the red fox started in 1939-1940 on the Russian—Polish border
and in northern
Poland 21,22,23.
After a period of adaptation, the disease spread in foxes to the rest of
Europe, moving south and west at 20-60 km/year. The progression of disease was
well documented from
1945 24, reaching
France by
1968 23,25
and Northern Italy in the early
1980s 26,27. The main reservoir host species of classic RV in Europe remains the red fox
and the raccoon dog. Raccoon dogs were introduced into western Russia for fur
farming in the 1920s; they subsequently spread throughout much of Eastern
Europe and north to Finland. The arrival of the omnivorous raccoon dog further
complicates the control of red fox rabies in Eastern Europe. There is evidence
that, during their winter hibernation, raccoon dogs can incubate RV and so
cause the disease to persist from one season to the next in geographical areas
where fox densities are so low that rabies might otherwise die
out 28. EBLs are common in insectivorous bats throughout parts of Europe and hence
are important reservoirs of sylvatic rabies. The importance of bat rabies
(specifically EBLs) as a ‘spill-over’ threat to humans and
terrestrial animals, domestic and wild (including badgers and rodents),
remains unclear. From 1977 to 2000, 630 cases of bat rabies were reported in
Europe, 3 of which were human
cases 8. In Europe, bat rabies isolates are genetically different from those found
in bats in North America. The species involved are Eptesicus
serotinus, the principal reservoir for genotype 5, Myotis
dasycneme and M. daubentonii, the principal reservoirs for
genotype 6. To date, there is no evidence that spill-over infections to other
mammals have resulted in host adaptation. Of the domestic animal species in Europe, ruminants, dogs ( Canis
familiaris), and cats remain important hosts for classic rabies. Rabies
in companion animals within Europe has been largely controlled (except in
Turkey and the Russian Federation) and is being successfully reduced in foxes
by vaccination
programmes 29. Control Countries that have not reported any cases of indigenous rabies in mammals
(excluding EBLs) for at least two years are recognized by the Office
International des Epizooties (OIE) as rabies-free. In addition, countries must
practise active surveillance strategies and have statutory importation
policies in place for rabies. Historically, the destruction of foxes failed to reduce the spread of the
epizootic. More recently, many of the successful control measures undertaken
to combat fox rabies in Europe have employed oral vaccines. The rabies
vaccines for oral immunization are based on the Street Alabama Dufferin (SAD)
strain of rabies virus or VRG. Switzerland hosted the first field trial with
the attenuated strain SAD Berne in
1978 30. In 1986,
some European countries employed SAD B19. In 1991, SAG 1, a mutated version of
SAD Berne was employed and this has since been superseded by a more
genetically stable vaccine, SAG 2. However, there was and still is concern
over safety and stability when using attenuated strains. In the hope of
allaying this safety concern VRG was developed and tested in the field for
oral vaccination of
foxes 31. Since
1989, the increased use of VRG has been instrumental in successfully
eliminating sylvatic rabies from large areas within Europe. However, following
the success of the vaccination campaigns, complacency may result in a partial
or total halt to control programmes and thus allow the reintroduction of
rabies from endemic areas into rabies-free areas. There is also the threat
that genotypes now found in bats may adapt to other species of mammals. An EBL
has been detected in three sheep in
Denmark 32; hence,
there is a risk that EBL may adapt to terrestrial mammals. Adaptation to
carnivorous mammals would obviously pose the greatest risk. Fox rabies control
measures are ineffective against bats and may not be effective against raccoon
dogs. This is because different baits are often necessary for enticing
different mammals to take up the vaccine-containing materials. The UK Government aims to keep rabies out of the country by employing
stringent quarantine and import controls. Controls include compulsory
quarantine for six months unless the animals are exempt under the ‘Balai
Directive’ (set up for commercial trading of cats and dogs), or the Pet
Travel Scheme (PETS). In February 2000, a pilot Pet Travel Scheme was
introduced that allows for the free movement of domestic dogs and cats to the
UK from specific countries in Europe without quarantine. The full scheme was
launched in April 2001. To qualify, each animal is required to be fitted with
a microchip (tattoos are not accepted). In addition, it must be vaccinated
against rabies with inactivated vaccine and shown to have developed RV
neutralizing antibodies by a recognized laboratory. Furthermore, all pet
owners have to testify that the animal has not been outside of the qualifying
countries in the six months before travel. The animal is then issued with a
travel certificate. Pets may not enter the UK under PETS until six months from
the date that a veterinary surgeon took the blood sample that led to a
successful test result. Before re-entering the country the animal must also be
treated against ticks and tapeworms. The Government is considering whether the scheme should be extended to
include North America even though in parts of that continent rabies is endemic
in wildlife. |
CONCLUSIONS In some areas of the US, the control of sylvatic rabies remains
problematic. In Europe, control programmes have been largely successful. The
list of countries now classified as rabies-free is expanding, one of the more
recent additions being France. Rabies infections of terrestrial animals tend to appear in discrete areas
and transmission occurs mainly between members of the same species. In Europe
and the US it is highly unusual to find bat-associated variants of rabies in
other mammals (except when human exposure has occurred). There is concern in
the US over the colonies of different bat species that live in and around
dwellings inhabited by man. Just as the EBLs are not known to have adapted to
mammals in Europe, some bat variants of genotype 1 exist in the US that seem
to be maintained only within unique bat species. Similarly, the Australian bat
lyssavirus appears to be maintained only within indigenous bat
populations 33. The
reported isolation of a EBL1 in sheep in Denmark raises concerns that
lyssavirus adaptation to new hosts may occur. This would be especially
worrying should densities of a new host be high enough to allow rapid
dissemination of an adapted virus. Surveillance must continue. In addition,
experiments to determine the risk of EBL transmission to terrestrial wild and
domestic animals are underway in several European laboratories. Perhaps the biggest concern is the continual threat that rabies may be
reintroduced from a rabies-infected area into a rabies-free zone as a result
of complacency, political instability or lack of funding for control
campaigns. To minimize human contact with rabies, the disease must be
controlled in animals. |
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