GUIDELINE for Feline rabies

The feline rabies guidelines were first published in J Feline Med Surg 2009, 11: 585-593 and updated in J Feline Med Surg 2013, 15: 535-536 and in J Feline Med Surg 2015, 17: 570-582; this update has been authored by Tadeusz Frymus and ABCD colleagues.

Introduction

Rabies is one of the oldest and most feared diseases of humans and animals – it was recognized in Egypt before 2300 BC and in ancient Greece, where it was well described by Aristotle. Perhaps the most lethal of all infectious diseases, rabies also has the distinction of having stimulated one of the great early discoveries in biomedical science. In 1885, before the nature of viruses was comprehended, Louis Pasteur developed, tested, and applied a rabies vaccine, thereby opening the modern era of infectious disease prevention by vaccination.

Rabies is also an example of a highly successful eradication of a virus disease by vaccination.  All Western and Central Europe countries are declared Rabies free after WHO standards since 1999 (Switzerland) to 2008 (Germany).  This was achieved by oral vaccination of foxes, the main reservoir host of rabies virus in Europe.

Agent properties

Rabies virus (RABV) is a member of the Rhabdoviridae family. The genus Lyssavirus contains 17 distinct species (ICTV, 2024). According to antigenic properties and phylogenetic relationships, viruses in the genus have been divided into ­phylogroups. Phylogroup I includes RABV, Australian bat lyssavirus (ABLV), Duvenhage virus (DUVV), European bat lyssavirus 1 (EBLV-1), European bat lyssavirus 2 (EBLV-2), Aravan virus (ARAV), Khujand virus (KHUV), Bokeloh bat lyssavirus (BBLV) and Irkut virus (IRKV); phylogroup II includes Lagos bat virus (LBV), Mokola virus (MOKV) and Shimoni bat virus (SHIBV) (Badrane et al., 2001; Fooks et al., 2004). The most divergent viruses in the genus, West Caucasian bat lyssavirus (WCBV) and Ikoma virus (IKOV), are not members of either of these phylogroups. RABV is the virus that causes rabies in a wide variety of species including dogs and cats. All lyssaviruses are generally considered to be capable of causing rabies-like disease in animals and humans, although infections of hosts other than bats have not been reported for all these viruses.

With the exception of RABV, lyssaviruses are highly adapted and generally confined to bat hosts. Spill-over infections to other mammalian hosts are very rare incidences.

Antigenic cross-reactivity between lyssaviruses­­ correlates with the genetic distances between them. Nucleoprotein antigens, which are most abundant in infected cells, cross-react between all members of the genus described to date. This facilitates the use of the same reagents for immunological detection of all lyssaviruses. In contrast, glycoprotein antigens are relatively conserved within phylogroups (ectodomain conservation >75%) but not between phylogroups (ectodomain conservation <65%). Therefore, commercially available rabies vaccines, inducing neutralizing antibodies against the RABV glycoprotein, partially protect against other phylogroup I lyssaviruses but not against other lyssaviruses of other phylogroups (Lefkowitz et al., 2017; Nokireki et al., 2017; Echevarría et al., 2019; Servat et al., 2019).Rhabdoviruses can be stable in the environment especially at alkaline pH but are thermolabile and sensitive to the UV irradiation of sunlight. In clinical practice, rabies virus is easily inactivated by detergent-based disinfectants. Virions are formed almost exclusively in salivary gland epithelial cells. The replication of rabies viruses is slow and usually non-cytopathic. Rabies virus produces prominent cytoplasmic inclusion bodies (Negri bodies) in infected cells.Laboratory-adapted (“fixed”) rabies virus replicates well in Vero (African green monkey kidney) cells and BHK-21 (baby hamster kidney) cells, which are the most common substrates for growing animal rabies viruses for vaccine production. Rabies virus also replicates to high titer in suckling mouse and suckling hamster brain.

Epidemiology

The disease occurs worldwide, with certain exceptions. The rabies situation and the regulations are continuously updated on the web sites of the WOAH and WHO. The number of annual human deaths is estimated at approximately 40,000 to 100,000 worldwide, and more than 15 million people receive post-exposure treatments after being exposed to suspected rabid animals.

In many countries of Asia, Latin America and Africa, endemic dog rabies is a serious problem, causing significant domestic animal and human mortality. In these countries, human vaccines are used in large numbers of doses, and there is a continuing need for comprehensive, professionally organized and publicly supported rabies control agencies. That such agencies are not in place in many developing countries is a reflection of their high cost; nevertheless, progress is being made. For example, a substantial decrease in rabies incidence has been reported in China, Thailand and Sri Lanka, following implementation of dog vaccination programs and improved post-exposure prophylaxis of humans. Similarly, the number of rabies cases in Latin America is declining significantly. Strictly enforced quarantine of dogs and cats for various periods before entry has been used to effectively eliminate terrestrial (i.e. not bat-transmitted) rabies from Japan, the United Kingdom (UK), New Zealand and several other islands. In contrast, rabies was not recognized in Australia until recently, when the Australian bat lyssavirus was discovered, and subsequently found to be endemic in south-east Australia.

In most industrialized countries, even those with a modest disease burden, publicly supported rabies control agencies operate in the following areas: (1) programs of oral vaccination of wildlife, in Europe of the red fox; (2) stray dog and cat removal and control of the movement of pets (quarantine is used in epidemic circumstances, but rarely); (3) immunization of dogs and cats, so as to break the chain of virus transmission; (4) laboratory diagnosis, to confirm clinical observations and obtain accurate incidence data; (5) surveillance, to measure the effectiveness of all control measures; and (6) public education programs to assure cooperation.

In Europe, the red fox is the main reservoir species of rabies. As a result of wildlife vaccination programs large regions in Europe became free of terrestrial rabies (Fig. 1). The incidence of rabies in Europe 2023 is presented in table 1.

Distribution map for animal terrestrial rabies in Europe, 1990

Distribution map for animal terrestrial rabies in Europe, 2000

Distribution map for animal terrestrial rabies in Europe, 2010

2020

Distribution map for animal terrestrial rabies in Europe, 2020

Fig. 1. The success of rabies control in Europe. Source: World Health Organization (www.who-rabies-bulletin.org)

Tab. 1. Rabies cases in Europe 2023. Source: World Health Organization (www.who-rabies-bulletin.org)

As a result of the mass vaccination of dogs, cats have become the companion animal species most commonly reported as rabid in many areas affected by wildlife rabies, as is the case in many states of the USA (Gerhold and Jessup, 2013). In a report from Pennsylvania, among 2755 rabid animals with reported human exposure, as many as 799 (29.0 %) were free-ranging cats, whereas only 57 (2.1 %) were dogs (Campagnolo et al., 2014). Also, in Europe the cat has been considered in endemic areas to be a high-risk species for transmission of rabies from wildlife to human beings. For example, in the past of more than 20,000 inhabitants in Switzerland that had to be vaccinated after exposure to rabies, around 70% had been either bitten or in close contact with cats (Hohl et al., 1978). Even if feline rabies is considered to be a by-product of canine or wild rabies (Blancou and Pastoret, 1990), behavioural characteristics of cats and clinical aspects of the disease in this species render it important for public health reasons. In fact, despite a lower number of post-exposure prophylaxis treatment for people following cat bites compared to dog bites, treatment was justified more often (Blancou and Pastoret, 1990).

There is increasing evidence that lyssaviruses are able to circulate within bat populations in the absence of disease (Banyard et al., 2011). Five distinct from the RABV lyssaviruses have been found sporadically or in a single case, respectively, in European bats: EBLV-2, BBLV (Eggerbauer et al., 2017), Lleida bat lyssavirus (LLEBV) (Picard-Meyer et al., 2019), Kotalahti bat lyssavirus (Nokireki et al., 2018), and WCBV (Leopardi et al., 2021). However, another lyssavirus, EBLV-1, seems to be endemic in various species of European bats. Fig. 2 shows a map of EBLV-1 and EBLV-2 infections in Europe 2014-2023. EBLV-1 is associated with more than 95% of the infected bats diagnosed in Europe (Echevarría et al., 2019). In France, 2 cats died as a result of infection with EBLV-1 (Dacheux et al., 2009). These are the only cases ever known of cats infected with EBLV. However, although lyssavirus-infected bats have been reported in the UK (Johnson et al., 2003; Fooks et al., 2004) and the Mammal Society estimates that British cats could be killing 230,000 bats a year (Woods et al., 2003), no cases of EBLV infections or cat rabies have ever been documented in the UK, or anywhere else in Europe beside the two cases mentioned above. These findings indicate that the risk of cats becoming infected with rabies from bats might be very low or even neglectable. Nevertheless, due to public health reasons, if a cat has caught a bat, it is reasonable to  keep the cat for 3 months in isolation observing for rabies signs.

Fig. 2. Distribution map for bat rabies cases in Europe 2014-2023 (www.who-rabies-bulletin.org)

Another risk for European regions free of terrestrial rabies is cross-border reinfection by foxes from endemic European countries, as happened in Italy 2008, in the Republic of Macedonia 2010, in Greece 2012 and in Slovakia 2013 (Ribadeau-Dumas et al., 2016). Finally, illegal importation of pets from regions where the disease is endemic poses an increasing risk (BBC, 2014). During 2001–2013, a total of 21 animal rabies cases attributed to pets from rabies-enzootic countries were reported in western Europe, introduced mostly from Morocco (Ribadeau-Dumas et al., 2016). Another concern is that inappropriate rabies vaccination in some exporting countries could make rabies a risk connected even with legal importation of pets. Several studies found an extraordinary high proportion of vaccination failures among dogs imported from Eastern Europe (Klevar et al., 2015; Rota Nodari et al., 2017). Recently, among 36 dogs imported into Finland with documents confirming rabies vaccination in the Russian Federation or Romania, 19 had an antibody level < 0.5 IU/mL, whereas in the control group of 36 dogs born, raised and vaccinated in Finland only two had such a level (Kaila et al., 2019). The finding in this study that 39% of the imported dogs had antibody levels < 0.1 IU/mL suggested that at least some of them might not have been vaccinated at all.

Pathogenesis

Rabid animals are the only source of virus. It is shed in the saliva some days before the onset of clinical signs, and the agent is transmitted through a bite (Fig. 3) or a scratch of the skin or mucous membranes (eyes, nose, mouth). The blood of rabid animals is not infectious.

Fig. 3. Rabies transmission from fox and pathogenesis of the infection in the dog – didactic poster

The average incubation period in cats is two months, but can range from two weeks to several months or even years, depending on the dose of virus transmitted and the severity and site of the wound (Charlton et al., 1997; Jackson, 2002). The incubation period is variable because the virus moves along peripheral nerves with the normal axoplasmic flow from the inoculation site to the central nervous system (CNS): hence the greater the distance from the CNS, the longer the incubation period; and the greater the density of innervation of the inoculated tissue, the shorter this duration (Greene and Rupprecht, 2006).
Very long incubation periods have been described in some experimental cases (Murphy et al., 1980), which must be taken into account when evaluating wound history, especially in free-roaming cats exhibiting sudden behavioural change and/or signs of motor neuron dysfunction that can initiate the clinical phase. The virus replicates in striated muscle and connective tissue at the site of inoculation and then enters the peripheral nerves through the neuromuscular junction (Murphy et al., 1973). Alternatively, it can infect peripheral nerves directly, spreading to the CNS via the axonal route.

The virus then travels to the salivary glands by the retrograde axonal route. At this time, the animal becomes infectious, i.e., about 3 days before the first clinical signs appear. By that time, the virus is widely disseminated throughout the organs. In most cases, death occurs within 5 days so that a cat or a dog will be shedding the virus in saliva for about 8 days in total.

Most clinical signs are related to the virus-induced central and peripheral nervous system dysfunction rather than neuronal death, and abnormalities in neurotransmission have been described (Jackson, 2002).

Immunity

Passive immunity

Kittens from vaccinated queens obtain maternally derived antibodies (MDA) via the colostrum. The MDA titer in kittens depends on both the antibody level of the queen and the amount of colostrum ingested during the first day of life. In most kittens, MDA will not persist for longer than 12 weeks. MDA have been demonstrated even in the sera of fox cubs whelped by orally immunized vixens (Vos et al., 2003). Passive immunity can neutralize vaccine virus, thereby inhibiting immunoglobulin production and interfering with immunization during the first weeks of life. Therefore, it is generally recommended to perform the primary vaccination in kittens over 12 weeks of age.

Active immunity

Rabies virus antigens are highly immunogenic and capable of eliciting the full spectrum of protective immune responses. The virus is not cytopathogenic, cells are not destroyed during its replication or maturation, and low levels of antigen are presented to the immune system. Neither humoral nor cell-mediated specific responses can be detected during the early stages of movement of virus from the site of the bite to the CNS (Green, 1997). Hence, infection of naive animals with rabies virus most often results in disease and death. Such sequel can be averted by prompt immunization following exposure, demonstrating that the development of anti-rabies viral immunity prior to extensive infection of neurons is protective.

It is well documented that neutralizing antibodies are crucial in this immunity. Rabies is an example of a “Th-2 healing disease”, where activation of B lymphocytes with the help of CD4 T cells is important for protection. When activated, primarily by the viral nucleoprotein, CD4 T cells produce cytokines (IL-4) that stimulate B cells to produce antibodies. In contrast, rabies-specific CD8 T cells cause neuronal damage when a Th-1 response (IFN-γ and TNF-α) predominates (Lafon, 2002; Hooper, 2005). However, vaccinated animals without detectable virus neutralizing antibodies have survived rabies challenge, indicating that other mechanisms could also protect against this disease (Aubert, 1992; Hooper et al., 1998).

After intramuscular infection, the virus replicates locally for several weeks in the myocytes or nervous tissue. In vaccinated cats with adequate serum antibody titers, the virus is often neutralized during this early incubation period. In contrast, unvaccinated cats exposed to rabies virus can produce an antiviral immune response, usually late in the clinical course, that fails to prevent disease (Johnson et al., 2006). However, protection against the early stages of infection is provided by innate immunity, in which interferon seems to play a critical role. High levels of interferon are detectable in sera of mice inoculated with rabies virus by peripheral or intracerebral routes (Marcovistz et al., 1984, 1994; Johnson et al., 2006).

It is not clear how effective these mechanisms are in naturally exposed naive cats. It is believed that factors determining morbidity include the amount and strain of the virus, the age and immunocompetence of the cat, and the site of the bite; in unvaccinated cats the risk of developing rabies is higher (and the incubation period shorter) in a young animal that has been bitten severely in the head, with a high saliva deposit in the wound, as compared to an adult cat bitten in a limb, especially after extensive bleeding (Pastoret et al., 2004).

If clinical signs are evident, recovery from rabies is exceedingly rare. There have been very few reports of cats, dogs and humans that have recovered following confirmed clinical rabies (Bernard, 1985; Fekadu, 1991; Netravathi et al., 2015). Furthermore, antibodies to lyssaviruses have been detected occasionally in domestic or wild cats with no history of vaccination, suggesting a non-fatal disease or subclinical infection (Tjørnehøj et al., 2004; Deem et al., 2004; Gold et al., 2020). Although rabies is prevalent among lions’ prey and food competitor species, there have only been a few reported deaths in lions (Swanepoel et al., 1993). Lions might be less susceptible to the disease and acquire protective antibodies from natural infection (Berentsen et al., 2013). Also in spotted hyenas (Crocuta crocuta) an antibody prevalence of 37 % was shown, perhaps resulting from the transmission of small infectious doses, e.g. due to the hyenas’ particular behaviour of licking anothers’ muzzles as a greeting behavior (East et al., 2001).

Clinical signs

Aggressive behaviour towards humans is unusual in healthy cats, so any unjustified aggression in cats must be considered highly suspicious. Rabies should be suspected not only when there has been a recent history of a bite by or exposure to a rabid animal but also where an unvaccinated cat might have been in contact with potentially infected wildlife, such as bats.

Fig. 4. Rabid cat, furious syndrome. Courtesy of Andy Sparkes and AFFSA/ERZ (inset)

Two disease forms can be identified in cats: the furious and the dumb form. The furious form (Fig. 4) has three clinical phases (prodromal, furious or psychotic and paralytic) but they are not always distinct. The dumb form (Fig. 5) has two phases: prodromal and paralytic. During the very short prodromal phases (12-48 hours) of both forms, a wide range of quite non-specific clinical signs (fever, anorexia, vomiting, diarrhea) can occur, sometimes accompanied by neurological signs. Behavioural changes can be noticed first, such as an unusually friendly or otherwise shy or irritated behaviour and increased vocalization. Altered behaviour depends on forebrain involvement and can be associated with other neurological signs reflecting the infection site.

Fig. 5. Rabid cats. Courtesy of Artur Borkowski, AFFSA/ERZ, and Merial S.A.S.

If the bite occurs in the face, clinical signs reflect cranial nerve and forebrain involvement: the former can produce depressed or absent reflexes (palpebral, corneal, pupillary etc.), strabismus, dropped jaw, inability to move whiskers forward, dysphagia, laryngeal paralysis, voice change, tongue paralysis. Forebrain involvement is responsible for seizures, muscular twitching or tremors, aimless pacing, exaggerated emotional responses (irritability, rage, fearfulness, photophobia, attacking inanimate objects etc). The tendency to bite can be the consequence of the loss of inhibitory control by cortical neurons over the subcortical bite reflex; dogs and cats then turn and snap at anything that touches them around the mouth (O’Brien and Axlund, 2005), without warning or showing any emotion. Pruritus at the bite site can be observed.

If the infecting bite was on the limbs, neurological signs start from the spinal cord and an ascending lower motor neuron (LMN) paralysis occurs before the brain signs. The inflammation rapidly spreads throughout the CNS producing severe ataxia, disorientation, paralysis, seizures, status epilepticus, eventually followed by coma and death from respiratory arrest. The furious phase is more consistently developed in cats showing behaviour abnormalities (Fogelman et al., 1993). The paralytic phase (incoordination, paraparesis, generalized paralysis, coma and death) usually begins five days after the first clinical signs and death usually occurs after a clinical course of 1-10 days. Cats often die in 3-4 days (Rupprecht and Childs, 1996), whereas dogs mostly succumb within two days (Tepsumethanon et al., 2004).

Atypical forms of chronic rabies in cats have been described after experimental infection (Murphy et al., 1980).

The serious public health risk (particularly for veterinarians) requires a careful differential diagnosis. Any CNS disease characterized by sudden onset and rapidly evolving clinical signs must include rabies for free roaming, unvaccinated cats living in endemic areas or traveling there. The clinical examination must make safety the highest priority, because manipulation and restraint of the patient could provoke biting – at a time when the salivary glands are already infected and rabies virus is shed. Rabies should be included in the differential diagnosis in live cats in endemic areas with suspected encephalitis, based on anamnestic history and observation when the animal is still in the carrier, to reduce the risk of exposure for the veterinary team (see the flow chart below; Fig. 6).

Fig. 6. Assessing the likelihood of rabies, adapted from Tepsumethanon et al., 2003

Clinical signs of rabies in cats 

History and clinical signs observed by the owner:

1. Dramatic behavioural changes, staggering, stumbling
2. Aggressiveness, unprovoked biting

General appearance and clinical signs at observation:

1. Furious form seen in 90 % of rabid cats
2. Deterioration in nutritional status (anorexia)
3. Ruffled and dirty coat (the cat does not clean itself)
4. Mucous membranes, tongue, nose and footpads are reddish pink (high fever)
5. Chin and front legs are wet from salivation
6. Permanent movement and restlessness
7. Imbalanced gait, paresis of the hind legs
8. Pupil dilatation unresponsive to light
9. Abnormal water uptake (water runs from the mouth)
Courtesy Dr Veera Tepsumethanon

Diagnosis

Because clinical diagnosis of rabies is unreliable, a definitive confirmation must be obtained by post-mortem laboratory examination.

Serum antibody tests are used only for surveys and post-vaccinal control in order to test immunity levels in vaccinated animals, especially in the context of international movement.

Routine laboratory diagnosis should be undertaken using only the techniques specified by the WOAH (Terrestrial Manual – WOAH 2023, https://www.woah.org/fileadmin/Home/eng/Health_standards/tahm/3.01.18_RABIES.pdf) and the WHO (Laboratory Techniques in Rabies).

Reference laboratories: The list of reference experts and laboratories can be found on the WOAH web site (http://www.oie.int/our-scientific-expertise/reference-laboratories/list-of-laboratories/).

Detection of the infectious agent

Direct detection

Only direct detection methods are recommended to confirm rabies in human beings and animals.

Samples should be sent according to the national and international shipping regulations and care should be taken in order to avoid potential human contamination. Because rabies virus is rapidly inactivated, the specimen should be shipped (preferably) refrigerated or at room temperature in 50 % glycerol in phosphate buffered saline solution.

Brain tissue (especially thalamus, pons and medulla) is the preferred sample for post-mortem diagnosis but other organs such as salivary glands can also be used.

Primary recommended methods to detect rabies are: direct fluorescent antibody (DFA) test, direct rapid immunohistochemistry test (dRIT), or pan-lyssavirus reverse transcriptase polymerase chain reaction (RT-PCR). These assays provide a reliable diagnosis in 98–100% of cases for all lyssavirus strains if an appropriate antibody conjugate or primer/probe is used. In cases of inconclusive results, virus isolation in cell culture should replace mouse inoculation tests, if possible. Molecular techniques can distinguish between field and vaccine strains and identify the geographical origin of a field virus.

The most widely used test for rabies diagnosis is the DFA test, recommended by both WHO and WOAH for fresh or glycerol samples (Bourhy et al., 1989; Birgham and van der Merwe, 2002); it is less sensitive in formalin-fixed tissues. In addition, formalin fixation inactivates the virus thus preventing virus isolation. The DFA can also be used for rabies virus detection in cell cultures and in the brain tissue of mice that have been inoculated for diagnosis.

Indirect detection (Antibody Tests)

Serological tests should not be used for diagnosis of rabies. For monitoring of the antibody response of vaccinated animals in the framework of rabies control, virus neutralisation (VN) and enzyme-linked immunosorbent assays (ELISA) are suitable. However, for the purposes of measuring antibody responses to vaccination prior to international animal movement or trade, only VN methods i.e. fluorescent antibody virus neutralisation (FAVN) tests and rapid fluorescent focus inhibition tests (RFFIT), are accepted, not ELISA tests. RFFIT and FAVN give equivalent results. Their titer is expressed in international units (IU/ml) and is the reciprocal value of the dilution at which 100% of the virus is neutralised in 50 % of the wells. A value of 0.5 IU/ml of serum antibodies is the internationally accepted threshold titer.

Rabies control in cats

Treatment (post-exposure vaccination)

The allowance to perform post-exposure vaccination of healthy cats depends on the national regulations. In case of clinical suspicion, the animal should be safely confined, and competent authorities should be notified. No supportive or specific treatment has proved to be effective in rabid cats, so treatment is not recommended (Greene and Rupprecht, 2006), and highly contraindicated due to public health risk. Detailed recommendations for animal rabies prevention and control in the USA have been published (Brown et al., 2016).

Prophylaxis (preventive vaccination)

Because of the public health risk associated with susceptible domestic cats becoming infected following exposure to rabid animals, all cats with outdoor access in endemic areas (e.g. Ukraine, Russia, Turkey) should be vaccinated. The vaccine should be administered in accordance with local or state regulations and considering the epidemiological situation. In countries where rabies is absent, vaccination is indicated when the cat moves or travels abroad (see “Rabies vaccination and cat movement within the EU”) or to an area where rabies is endemic.

In the past, when modified-live vaccines were used, vaccine-induced rabies cases were sporadically observed also in cats (Whetstone et al., 1984). Neurological signs occurred several weeks after vaccination and were characterized mostly by progressive upper motor neuron limb paralysis and cranial nerve deficits. Now rabies in cats is usually controlled by traditional inactivated vaccines (OIE, 2019) and several products are available commercially. They are very efficient and generally considered to be safe, even in neonatal kittens. Though differences in the efficacy between some commercial rabies vaccines used in Europe have been demonstrated (Minke et al., 2009; Zanoni et al., 2010; Berndtsson et al., 2011), following a single vaccination these products have been shown to induce in most animals a titer above 0.5 IU/ml what is an internationally accepted threshold antibody level (Fu, 1997; Perez and Paolazzi, 1997; Minke et al., 2009; Van de Zande et al., 2009; Berndtsson et al., 2011). Cats and dogs with such a titer, regardless of the period of time elapsed since vaccination, have a very high probability of survival after a rabies infection (Cliquet, 2006).

Cats respond better to rabies vaccination than dogs and only 2.6% of cats develop titers below 0.5 IU/ml after the first vaccination (Cliquet, 2006). As tested 6 to 12 months post vaccination this proportion was about 8 % (Zanoni et al., 2010). After the first vaccination many cats develop titers even above 5 IU/ml (Cliquet, 2006). In cats and dogs, the peak of rabies neutralizing antibodies is generally reached between 4 to 8 weeks after the first immunization (Cliquet, 2006; Minke et al., 2009).

A very small proportion of cats identified with rabies have had at least one rabies vaccination during their lifetime (Greene and Rupprecht, 2006). Since the new EU regulations in pet movement were put in place in 1993, no single case of rabies in a vaccinated cat has been documented (Cliquet, 2006).

Nevertheless, the titer decreases with time. In an epidemiological study among thousands of dogs tested 120 to 360 days post vaccination the proportion of animals with a titer below 0.5 IU/ml was 12.6 %, or 3.1 %, depending on the vaccine brand used (Berndtsson et al., 2011). There is increasing evidence that the persistence of antibodies after the first rabies vaccination might be much shorter than generally believed, especially in dogs. It has been demonstrated that antibody titers fall below 0.5 IU/ml in almost 21 % of dogs within 4-6 months after a single vaccination (Van de Zande et al., 2009), and in many puppies it happens as early as after 56 or even 28 days (Minke et al., 2009). In another study the proportion of dogs with titers below 0.5 IU/ml reached 6 months after the first vaccination 30 % and then stabilized at above 30 % during the next 6 months (Zanoni et al., 2010). However, even if the titer is below 0.5, it does not mean that the animal is unprotected.

Thus, a regimen for rabies vaccination consisting of double primary vaccination with a short interval of 7 – 10 days and a one-year booster has been postulated (Zanoni et al., 2010). This procedure reduced the proportion of cats developing a titer below 0.5 IU/ml to almost nil as tested within 6 months, and in dogs this proportion was also significantly lower than in animals with single primary vaccination (Zanoni et al., 2010).

All cat and dog sera with a titer above 5 IU/ml neutralise EBL-1 and EBL-2 regardless of vaccine virus strain and among sera with a titer between 0.5 and 5 IU/ml 87 % neutralise EBL-1 and 53 % EBL-2 (Fooks, personal communication). However, against some novel lyssaviruses isolated from bats in Eurasia the protection might be reduced or negligible depending on the genetic distance between the new isolate and the rabies virus (Hanlon et al., 2005; Lefkowitz et al., 2017).

Inactivated vaccines can carry a risk due to the remote possibility of incomplete inactivation of the virus and the inadvertent spread of residual pathogenic particles of rabies virus (Schneider, 1995). Furthermore, inactivated rabies vaccines containing adjuvants can be associated with the development of injection site sarcomas in cats (Dubielzig et al., 1993). Such problems led to continued efforts to develop safer rabies vaccines. New vaccines include recombinant subunit proteins (Wunner et al., 1983), recombinant viral vectors (Paoletti, 1996; Xiang et al., 1996) and DNA-based vaccines (Osorio et al., 1999; Cupillard et al., 2005).

Recombinant live vector vaccines have some advantages over traditional products: they are innocuous, they induce suitable humoral immune responses and they do not require rabies virus to be handled (Paoletti, 1996). They also induce less inflammation at the site of injection (Day et al., 2007). A non-adjuvanted recombinant canarypox rabies vaccine for cats has been approved for use in the European Union in 2011.

Primary vaccination course

In contrast to all other inactivated vaccines, a single rabies vaccination induces in most cats a long lasting immunity due to the immunogenic properties of the vaccinal antigen. Kittens should be vaccinated not earlier than at 12 to 16 weeks of age to avoid interference from maternal antibodies, with revaccination one year later (depending on data sheet recommendations for each brand of vaccine). With this schedule, a single vaccination is sufficient in most cats. However, national or regional legislation regarding vaccination type and interval should be adhered too.

Booster vaccinations

Although some commercial vaccines provide protection against virulent rabies challenge for 3 years or longer (Lakshmanan et al., 2006), national or local legislation sometimes require annual boosters.

Vaccination of immunocompromised cats

See ABCD Guideline “Vaccination of immunocompromised cats”.

Disease control in specific situations

Shelters

In endemic areas, stray cats should be always considered at exposure risk and handling or nursing of rescued animals should be considered dangerous even if they are asymptomatic.

Breeding catteries

Risk of exposure is generally almost nil in breeding catteries because many pedigree cats are kept strictly indoors, but their vaccination is under local or state regulation.

Rabies vaccination and cat movement within the EU

The Directive 998/2003 of the European Community established rules for non-commercial (less than 6 animals) movement of pets between EU countries (dogs, cats and ferrets). According to these rules all such animals should be identified by tattoo and/or microchip and vaccinated against rabies, and a 21-day waiting period in case of primary vaccination is required (the vaccination day is not included in this period). Depending on the vaccine used the veterinarian confirms in the passport how long the vaccination will be valid. Any booster within this time will immediately prolong the validation. However, if the booster is performed after the validation date of the last rabies vaccination, a 21-day waiting period before traveling will be required again. In addition, the above regulation provides that some countries maintain their national provisions for a transitional period. In this case, before entry of the country an individual serological test for rabies neutralizing antibodies is required demonstrating that the titer is at least 0.5 U/ml.

As the national requirements are changing, the actual legislation must be checked and followed in case of international pet movement.

Acknowledgement

ABCD Europe gratefully acknowledges the support of Boehringer Ingelheim (the founding sponsor of the ABCD), Virbac and MSD Animal Health.

References

Aubert MF (1992): Practical significance of rabies antibodies in cats and dogs. Rev Sci Tech 11, 735-760.

Badrane H, Bahloul C, Perrin P, Tordo N (2001): Evidence of two Lyssavirus phylogroups with distinct pathogenicity and immunogenicity. J Virol 75, 3268-3276.

Banyard AC, Hayman D, Johnson N, McElhinney L, Fooks AR (2011): Bats and lyssaviruses. Adv Virus Res 79, 239-289.

Barrat J (1993): ELISA systems for rabies antigen detection. Proceedings of the Southern and Eastern African Rabies Group International Symposium. Pietermaritzburg, South Africa, 29-30 April 1993, 152-155.

Barrat J, Picard-Meyer E, Cliquet, F (2006): Rabies diagnosis. Dev Biol (Basel) 125, 71-77.

BBC (2014): Dog smuggling into UK on increase. http://www.bbc.com/news/uk-25957668.

Berentsen AR, Dunbar MR, Becker MS, M’soka J, Droge E, Sakuya NM, Matandiko W, McRobb R, Hanlon CA. Rabies, canine distemper, and canine parvovirus exposure in large carnivore communities from two Zambian ecosystems (2013): Vector Borne Zoonotic Dis 13(9), 643-649. doi: 10.1089/vbz.2012.1233. Epub 2013 Jun 27. PMID: 23805791.

Bernard KW (1985): Clinical rabies in humans. In Rabies concepts for medical professionals Ed Winkler WG. Merieux Institute, Miami, FL, 45.

Berndtsson LT, Nyman A-KJ, Rivera E, Klingeborn B (2011): Factors associated with the success of rabies vaccination of dogs in Sweden. Acta Vet Scand 53, 22-28.

Birgham J, van der Merwe M (2002): Distribution of rabies antigen in infected brain material: determining the reliability of different regions of the brain for the rabies fluorescent antibody test. J Virol Methods 101, 85-94.

Blancou J, Pastoret P-P (1990): La rage du chat et sa prophylaxie. Ann Med Vet 134, 315-324.

Bourhy H, Rollin PE, Vincent J, Sureau P (1989): Comparative field evaluation of the fluorescent antibody test, virus isolation from tissue culture, and enzymes immunodiagnosis for rapid laboratory diagnosis of rabies. J Clin Microbiol 27, 519-523.

Brown CM, Slavinski S, Ettestad P, Sidwa TJ, Sorhage FE (2016): Compendium of Animal Rabies Prevention and Control. J Am Vet Med Assoc 248, 505-517. doi: 10.2460/javma.248.5.505. Erratum in J Am Vet Med Assoc. 2016 248, 771. doi: 10.2460/javma.248.5.505

Campagnolo ER, Lind LR, Long JM, Moll ME, Rankin JT, Martin KF, Deasy MP, Dato VM, Ostroff SM (2014): Human exposure to rabid free-ranging cats: a continuing public health concern in Pennsylvania. Zoonoses Public Health 61, 346-355. doi: 10.1111/zph.12077.

Charlton KM, Nadin-Davis S, Casey GA, Wandeler AI (1997): The long incubation period in rabies progression of infection in muscle at the site of exposure. Acta Neuropathol 94, 73-77.

Cliquet F (2006): Vaccination of pets against rabies in the context of movements in the EU – Serological testing as a measure to check efficacy of rabies vaccination. Vaccinology Symposium, Prague, October 10th, 2006.

Cupillard L, Juillard V, Latour S, Colombet G, Cachet N, Richard S, Blanchard S, Fischer L (2005): Impact of plasmid supercoiling on the efficacy of a rabies DNA vaccine to protect cats. Vaccine 23, 1910-1916.

Dacheux L, Larrous F, Mailles A, Boisseleau D, Delmas O, Biron C, Bouchier C, Capek I, Muller M, Ilari F, Lefranc T, Raffi F, Goudal M, Bourhy H (2009): European bat Lyssavirus transmission among cats, Europe. Emerg Infect Dis 15(2), 280-284. doi: 10.3201/eid1502.080637. PMID:19193273; PMCID: PMC2657616.

Day MJ, Schoon HA, Magnol JP, Saik J, Devauchelle P, Truyen U, Gruffydd-Jones TJ, Cozette V, Jas D, Poulet H, Pollmeier M, Thibault JC (2007): A kinetic study of histopathological changes in the subcutis of cats injected with non-adjuvanted and adjuvanted multi-component vaccines. Vaccine 25, 4073-4084.

Deem SL, Davis R, Pacheco LF (2004): Serologic evidence of nonfatal rabies exposure in a free-ranging Oncilla (Leopardus tigrinus) in Cotapata National Park, Bolivia. J Wildlife Dis 40, 811-815.

Dubielzig RR, Hawkins KL, Miller PE (1993): Myofibroblastic sarcoma originating at the site of rabies vaccination in a cat. J Vet Diagn Invest 5, 637-638.

East ML, Hofer H, Cox JH, Wulle U, Wiik H, Pitra C (2001): Regular exposure to rabies virus and lack of symptomatic disease in Serengeti spotted hyenas. Proc Natl Acad Sci U S A 98, 15026-15031.

Echevarría JE, Banyard AC, McElhinney LM, Fooks AR (2019): Current Rabies Vaccines Do Not Confer Protective Immunity against Divergent Lyssaviruses Circulating in Europe. Viruses 24;11(10), 892. doi: 10.3390/v11100892. PMID: 31554170; PMCID: PMC6832729.

Eggerbauer E, Troupin C, Passior K, Pfaff F, Höper D, Neubauer-Juric A, Haberl S, Bouchier C, Mettenleiter TC, Bourhy H, Müller T, Dacheux L, Freuling CM (2017): The Recently Discovered Bokeloh Bat Lyssavirus: Insights Into Its Genetic Heterogeneity and Spatial Distribution in Europe and the Population Genetics of Its Primary Host. Adv Virus Res 99, 199-232. doi: 10.1016/bs.aivir.2017.07.004. Epub 2017 Sep 9. PMID: 29029727.

Fekadu M (1991): Latency and aborted rabies. In The natural history of rabies, Ed Baer GM, CRC Press, Boca Raton, Florida, 191-198.

Fogelman V, Fischman HR, Horman JT, Grigor JK (1993): Epidemiologic and clinical characteristics of rabies in cats. J Am Vet Med Assoc 202, 1829-1838.

Fooks AR, McElhinney LM, Marston DA, Selden D, Jolliffe TA, Wakeley PR, Johnson N, Brookes SM (2004): Identification of a European bat lyssavirus type 2 in a Daubenton’s bat found in Staines, Surrey, UK. Vet Rec 155, 434-435.

Fu ZF (1997): Rabies and rabies research: past, present and future. Vaccine, 15 (Suppl), 20-24.

Gerhold RW, Jessup DA (2013): Zoonotic diseases associated with free-roaming cats. Zoonoses Public Health 60, 189-195. doi: 10.1111/j.1863-2378.2012.01522.x.

Gold S, Donnelly CA, Nouvellet P, Woodroffe R (2020): Rabies virus-neutralising antibodies in healthy, unvaccinated individuals: What do they mean for rabies epidemiology? PLoS Negl Trop Dis 13;14(2):e0007933. doi: 10.1371/journal.pntd.0007933. PMID: 32053628; PMCID: PMC7017994.

Green SL (1997): Rabies. Vet Clin North Am: Equine Pract 13, 1-11.

Greene CE, Rupprecht CE (2006): Rabies and other Lyssavirus infections. In Greene CE (Ed): Infectious diseases of the dog and cat. Elsevier Saunders, St Louis, Missouri, 167-183.

Hanlon CA, Kuzmin IV, Blanton JD, Weldon WC, Manangan JS, Rupprecht CE (2005): Efficacy of rabies biologics against new lyssaviruses from Eurasia. Virus Res 111, 44–54.

Hohl P, Burger R, Vorburger C, Steck F (1978): Zum Wiederauftreten der humanen Rabies in der Schweiz. Ein kasuistischr Bericht. Schweiz Med Wochenschr 108, 589-592.

Hooper DC (2005): The role of immune responses in the pathogenesis of rabies. J Neurovirol 11, 88-92.

Hooper DC, Morimoto K, Bette M, Weihe E, Koprowski H, Dietzschold B (1998): Collaboration of antibody and inflammation in clearance of rabies virus from the central nervous system. J Virol 72, 3711-3719.

ICTV. Genus: Lyssavirus. https://ictv.global/report/chapter/rhabdoviridae/rhabdoviridae/lyssavirus [accessed on March 11, 2024]

Jackson AC (2002): Pathogenesis. In Rabies (Eds Jackson AC, Wunner WH). Academic Press, San Diego, 245-282.

Johnson N, McKimmie CS, Mansfield KL, Wakeley PR, Brookes SM, Fazakerley JK, Fooks AR (2006): Lyssavirus infection activates interferon gene expression in the brain. J Gen Virol 87, 2663-2667.

Johnson N, Selden D, Parsons G, Healy D, Brookes SM, McElhinney LM, Hutson AM, Fooks AR (2003): Isolation of a European bat lyssavirus type 2 from a Daubenton’s bat in the United Kingdom. Vet Rec 152, 383-387.

Kaila M, Marjoniemi J, Nokireki T (2019): Comparative study of rabies antibody titers of dogs vaccinated in Finland and imported street dogs vaccinated abroad. Acta Vet Scand 14;61(1):15. doi: 10.1186/s13028-019-0450-8. PMID: 30871641; PMCID: PMC6419415.

Klevar S, Høgåsen HR, Davidson RK, Hamnes IS, Treiberg Berndtsson L, Lund A (2015): Cross-border transport of rescue dogs may spread rabies in Europe. Vet Rec 27;176(26), 672. doi: 10.1136/vr.102909. PMID: 26113337; PMCID: PMC4501168.

Lafon M (2002): Immunology. In Rabies (Eds Jackson AC, Wunner WH), Academic Press, San Diego, CA, 351-371.

Lakshmanan N, Gore TC, Duncan KL, Coyne MJ, Lum MA, Sterner FJ (2006): Three-year rabies duration of immunity in dogs following vaccination with a core combination vaccine against canine distemper virus, canine adenovirus type-1, canine parvovirus, and rabies virus. Vet Therapeutics 7, 223-231.

Leopardi S, Barneschi E, Manna G, Zecchin B, Priori P, Drzewnioková P, Festa F, Lombardo A, Parca F, Scaravelli D, et al (2021): Spillover of West Caucasian Bat Lyssavirus (WCBV) in a Domestic Cat and Westward Expansion in the Palearctic Region. Viruses 13, 2064. https://doi.org/10.3390/ v13102064

Marcovistz R, Hovanessian AG, Tsiang H (1984): Distribution of rabies virus, interferon and interferon-mediated enzymes in the brain of virus-infected rats. J Gen Virol 65, 995-997.

Marcovistz R, Leal EC, Matos DC, Tsiang H (1994): Interferon production and immune response induction in apathogenic rabies virus-infected mice. Acta Virol 38, 193-197.

Minke JM, Bouvet J, Cliquet F, Wasniewski M, Guio AL, Lemaitre L, Cariou C, Cozette V, Vergne L, Guigal PM (2009): Comparison of antibody responses after vaccination with two inactivated rabies vaccines. Vet Microbiol 133, 283-286.

Murphy FA, Bell JF, Bauer SP, Gardner JJ, Moore GJ, Harrison AR, Coe JE (1980): Experimental chronic rabies in the cat. Lab Invest 43, 231-241.

Murphy FA, Harrison AK, Win WC, Bauer SP (1973): Comparative pathogenesis of rabies and rabies-like viruses: infection of the central nervous system and centrifugal spread of virus to peripheral tissues. Lab Invest 29, 1-16.

Netravathi M, Udani V, Mani RS, Gadad V, Ashwini MA, Bhat M, Mehta S, Chowdhary A, Pal PK, Madhusudana SN, et al (2015): Unique clinical and imaging findings in a first ever documented PCR positive rabies survival patient: A case report. J Clin Virol 70, 83–88. doi: 10.1016/j.jcv.2015.07.003.

Nokireki T, Jakava-Viljanen M, Virtala AM, Sihvonen L (2017): Efficacy of rabies vaccines in dogs and cats and protection in a mouse model against European bat lyssavirus type 2. Acta Vet Scand 2;59(1), 64. doi: 10.1186/s13028-017-0332-x. PMID: 28969696; PMCID: PMC5625686.

Nokireki T, Tammiranta N, Kokkonen UM, Kantala T, Gadd T (2018): Tentative novel lyssavirus in a bat in Finland. Transbound Emerg Dis 65(3), 593-596. doi: 10.1111/tbed.12833. Epub 2018 Feb 15. PMID: 29446230.

O’Brien DP, Axlund TW (2005): Brain disease. In Ettinger (Eds SJ and Feldman EC), Textbook of Veterinary Internal Medicine. Diseases of the dog and cat. Elsevier Saunders, St Louis, Missouri, 803-835.

OIE (2019): Rabies. In Manual of Diagnostic Tests and Vaccines for Terrestrial Animals. Chapter3.1.17
https://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/3.01.17_RABIES.pdf

Osorio JE, Tomlinson CC, Frank RS, Haanes EJ, Rushlow K, Haynes JR, Stinchcomb DT (1999): Immunization of dogs and cats with a DNA vaccine against rabies virus. Vaccine 17, 1109-1116.

Paoletti E (1996): Applications of pox virus vectors to vaccination: an update. Proc Natl Acad Sci USA 93, 11349-11353.

Pastoret PP, Brochier B, Gaskell RM (2004): Rabies virus infection. In Feline medicine and therapeutics Eds Chandler EA, Gaskell CJ, Gaskell RM, Blackwell Publishing, 637-650.

Perez O, Paolazzi CC (1997): Production methods for rabies vaccine. J Ind Microbiol Biotechnol 18, 340-347.

Picard-Meyer E, Beven V, Hirchaud E, Guillaume C, Larcher G, Robardet E, Servat A, Blanchard Y, Cliquet F (2019): Lleida Bat Lyssavirus isolation in Miniopterus schreibersii in France. Zoonoses Public Health 66(2), 254-258. doi: 10.1111/zph.12535. Epub 2018 Nov 20. PMID: 30460779.

Ribadeau-Dumas F, Cliquet F, Gautret Ph, Robardet E, Le Pen C, Bourhy H (2016): Traveland Residual Rabies Risk, Western Europe. EID, Volume 22, Number 7 (https://zenodo.org/record/49670/files/Travel_and_residual_rabies_risk_WE_Technical_Appendix_Ribadeau_EID_2016.docx)

Rota Nodari E, Alonso S, Mancin M, De Nardi M, Hudson-Cooke S, Veggiato C, Cattoli G, De Benedictis P (2017): Rabies Vaccination: Higher Failure Rates in Imported Dogs than in those Vaccinated in Italy. Zoonoses Public Health 64(2), 146-155. doi: 10.1111/zph.12268. Epub 2016 May 6. PMID: 27152896.

Rupprecht CE, Childs JE (1996): Feline rabies. Feline Pract 24, 15-19.

Schneider LG (1995): Rabies virus vaccines. Dev Biol Stand 84, 49-54.

Servat A, Feyssaguet M, Morize JL, Schereffer JL, Boue F, Cliquet F (2007): A quantitative indirect ELISA to monitor the effectiveness of rabies vaccination in domestic and wild carnivores. J Immunol Methods 318, 1-10.

Servat A, Wasniewski M, Cliquet F (2006): Tools for rabies serology to monitor the effectiveness of rabies vaccination in domestic and wild carnivores (Review). Dev Biol (Basel) 125, 91-94.

Servat A, Wasniewski M, Cliquet F (2019): Cross-Protection of Inactivated Rabies Vaccines for Veterinary Use against Bat Lyssaviruses Occurring in Europe. Viruses 11;11(10), 936. doi: 10.3390/v11100936. PMID: 31614675; PMCID: PMC6832384.

Swanepoel R, Barnard BJ, Meredith CD, Bishop GC, Bruckner GK, Foggin CM, Hubschle OJ (1993): Rabies in southern Africa. Onderstepoort J Vet Res 60, 325-346.

Tepsumethanon V, Lumlertdacha B, Mitmoonpitak C, Wilde H (2003): Clinical diagnosis for rabies in live dogs. Proceedings of 28th World Congress of WSAVA, October 24-27, 2003 – Bangkok, Thailand.

Tepsumethanon V, Lumlertdacha B, Mitmoonpitak C, Sitprija V, Meslin FX, Wilde H (2004): Survival of naturally infected rabid dogs and cats. Clin Infect Dis 39, 278-280.

Tjørnehøj K, Rønsholt L, Fooks AR (2004): Antibodies to EBLV-1 in a domestic cat in Denmark. Vet Rec 155, 571-572.

Van de Zande S, Kaashoek M, Hesselink W, Sutton D, Nell T (2009): Comments to “Comparison of antibody responses after vaccination with two inactivated rabies vaccines” [Minke JM, et al, 2009. Vet Microbiol 133, 283–286]. Vet Microbiol 138, 202–203.

Vos A, Schaarschmidt U, Muluneh A, Muller T (2003): Origin of maternally transferred antibodies against rabies in foxes. Vet Rec 153, 16-18.

Whetstone CA, Bunn TO, Emmons RW, Wiktor TJ (1984): Use of monoclonal antibodies to confirm vaccine-induced rabies in ten dogs, two cats, and one fox. J Am Vet Med Assoc 1;185(3), 285-288. PMID: 6540768.

WHO – World Health Organisation. Rabies – Bulletin – Europe: www.who-rabies-bulletin.org [accessed on April 13, 2024].

Woods M, McDonald RA, Harris S (2003): Predation of wildlife by domestic cats Felis catus in Great Britain. Mammal Rev 33, 174-188.

Wunner WH, Dietzschold B, Curtis PJ, Wiktor TJ (1983): Rabies sub-unit vaccines. J Gen Virol 64, 1649-1656.

Xiang ZQ, Yang Y, Wilson JM, Ertl HC (1996): A replication-defective human adenovirus recombinant serves as a highly efficacious vaccine carrier. Virology 219, 220-227.

Zanoni RG, Bugnon Ph, Deranleau E, Nguyen TMV, Brügger D (2010): Walking the dog and moving the cat: Rabies serology in the context of international pet travel schemes. Schweiz Arch Tierheilkd 152, 561-568.