- Feline rabies
- Rabies-free Countries
- Developing Countries
- Industrialized Countries
- Active immune response
- Clinical signs
- Clinical signs of cats infected by rabies virus
- General appearance and clinical signs at observation
- OIE recommendations
- Virus detection methods
- Fluorescent antibody test
- Immunochemical methods
- Inoculation to laboratory animals and cell cultures
- Histology, immunochemistry
- Other direct methods
- Rabies control in cats
- Treatment (post-exposure vaccination)
- Prophylaxis (preventive vaccination)
- Current rabies vaccines also cross-protect against some other lyssaviruses
- Primary vaccination course
- Booster vaccinations
- Disease control in specific situations
- Breeding catteries
- Vaccination of immunocompromised cats
- FIV-positive cats
- FeLV-positive cats
- Chronic disease
- Cats receiving corticosteroids or other immunosuppressive drugs
- Rabies vaccination and cat movement within the EU
edited July, 2018
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 compiled by Tadeusz Frymus.
Rabies virus (RABV) is the cause of one of the oldest and most feared diseases of humans and animals (Fig. 1) – 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 virus is a member of the Rhabdoviridae family. The genus Lyssavirus contains 14 species (Lefkowitz et al., 2017). According to antigenic properties and phylogenetic relationships, viruses in the genus have been divided into two 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, WCBV and Ikoma virus (IKOV), are not members of either of these phylogroups. Each of these viruses is considered capable of causing rabies-like disease in animals and humans. There is increasing evidence that lyssaviruses may be able to circulate within bat populations in the absence of disease (Banyard et al., 2011). So far only EBLVs have been confirmed in bats in Europe.
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, mainly inducing neutralizing antibodies against the RABV glycoprotein, protect against phylogroup I lyssaviruses but not against other lyssaviruses (Lefkowitz et al., 2017).
Rhabdoviruses may 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. Viral entry into host cells occurs via fusion of the viral envelope with the cell membrane; all replication steps occur in the cytoplasm. Virions are formed by the budding of nucleocapsids through cell membranes. Rabies virus budding takes place mostly upon intracytoplasmic membranes of infected neurons, but almost exclusively upon plasma membranes of salivary gland epithelial cells. The replication of rabies viruses is slow and usually non-cytopathic because it does not shut down host cell protein and nucleic acid synthesis.
Rabies virus produces prominent cytoplasmic inclusion bodies (Negri bodies) in infected cells (Figs 4, 5).
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.
The disease occurs worldwide, with certain exceptions. Large regions in Europe became free of terrestrial (i.e. not bat-transmitted) rabies as a result of wildlife vaccination programs. The rabies situation and the regulations are continuously updated on the web sites of the OIE 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. Dog rabies is important in many parts of the world and the principal cause of human cases.
Distribution map for animal terrestrial rabies in Europe, 2017
Fig. 6. The success of rabies control in Europe. Source: World Health Organisation (www.who-rabies-bulletin.org)
In many countries, wildlife rabies has become an increasingly important threat to domestic animals and humans, especially transmission from vampire bats. The red fox, raccoon, skunk and raccoon-dog are the main reservoir species of terrestrial rabies in Europe and the Americas.
There is increasing evidence that lyssaviruses may circulate within bat populations in the absence of disease. So far only EBLVs have been confirmed in bats in Europe.
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 recent 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).
Strictly enforced quarantine of dogs and cats for various periods before entry has been used to effectively eliminate terrestrial 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 January 2017, the following European countries/localities were free of rabies in terrestrial animals: Albania, Andorra, Austria, Azores, Balearic Islands, Belgium, Cabrera, Channel Islands, Corsica, Czech Republic, Denmark, Estonia, Faroe Islands, Finland, Formentera, France, Germany, Gibraltar, Ibiza, Iceland, Ireland, Isle of Man, Italy, Latvia, Liechtenstein, Luxembourg, Majorca, Malta, Minorca, Monaco, Netherlands, Norway (except Svalbard), Portugal, San Marino, Spain (except Ceuta and Melilla), Sweden, Switzerland, United Kingdom (https://www.cdc.gov/importation/rabies-free-countries.html). However, in many of these regions bat rabies is endemic (Fig. 6a), and on very rare occasions EBLVs were transmitted to terrestrial mammals.
Fig 6a. Distribution map for bat rabies cases in Europe 2008-2017 (www.who-rabies-bulletin.org)
Another risk for these regions are cross-border reinfections by rabid foxes from endemic European countries what 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).
In most 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 recent years 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; the Pan American Health Organization has implemented a vaccination program to eliminate urban dog rabies from the Southern hemisphere.
In most industrialised 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. The cat is considered in some European countries to be a high-risk species for transmission of rabies from wildlife to human beings. For example, 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 is justified more often (Blancou and Pastoret, 1990).
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. 7) or a scratch of the skin or mucous membranes (eyes, nose, mouth). The blood of rabid animals is not infectious.
The average incubation period in cats is two months, but can range from 2 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; EBM grade III), 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 may 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). The rabies virus glycoprotein probably plays a role in the trans-synaptic spread of the virus between neurons and in the topographic distribution of virus infections through the nervous system (Etessami et al., 2000).
Passive immunity acquired via colostrum
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 may 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 immune response
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 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 central nervous system (Green, 1997). Hence, infection of naive animals with rabies virus most often results in disease and death. Such sequel may 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 antibody is 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 N protein, 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 antibody have survived rabies challenge, indicating that other mechanisms may 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).
In natural infections of unvaccinated animals, neutralizing antibody usually appears after the virus has entered the central nervous system. Hence, once clinical signs are evident, recovery from rabies is exceedingly rare. There have been only rare reports of cats, dogs and humans that have recovered following confirmed clinical rabies (Bernard, 1985; Fekadu, 1991). 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). 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 may be less susceptible to the disease and acquire protective antibodies from natural infection (Lutz, 2011; http://www.research-projects.uzh.ch/p14931.htm). 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 behaviour (East et al., 2001).
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 may have been in contact with potentially infected wildlife, such as bats. Indeed, in November 2007, a cat in France died of rabies as a result of infection with bat lyssavirus. However, although rabid 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 cat rabies have been documented in the UK. These findings indicate that the risk of cats becoming infected with rabies from bats might be low.
Two disease forms can be identified in cats: the furious and the dumb form. The furious form (Fig. 8) has three clinical phases (prodromal, furious or psychotic and paralytic) but they are not always distinct in cats. The dumb form (Fig. 9) 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, diarrhoea) may occur, sometimes accompanied by neurological signs. Behavioural changes may be noticed first, such as an unusually friendly or otherwise shy or irritated behaviour and increased vocalization. Altered behaviour depends on forebrain involvement and may be associated with other neurological signs reflecting the infection site.
If the bite occurs in the face, clinical signs reflect cranial nerve and forebrain involvement: the former may 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 may 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 (as in pseudorabies virus infection).
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; EBM grade III). The paralytic phase (paraparesis, incoordination, 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; EBM grade III).
Atypical forms of chronic rabies in cats have been described after experimental infection (Murphy et al., 1980; EBM grade III).
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 may 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 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, adapted from Tepsumethanon et al., 2003).
Vaccine-induced feline rabies was observed in the past when modified-live vaccines were used. Neurological signs occurred several weeks after vaccination and were characterized mostly by progressive upper motor neuron (UMN) limb paralysis and cranial nerve deficits.
Because a clinical diagnosis of rabies is unreliable, a definitive diagnosis must be obtained by post-mortem laboratory examination.
Serological tests are used for surveys and post-vaccinal control in order to test immunity level in vaccinated animals, especially in the context of international movements.
Recommendations from experts of the OIE First International Conference “Rabies in Europe” (Kiev, Ukraine, 15-18 June 2005) are:
i) Routine laboratory diagnosis should be undertaken using only the techniques specified by the OIE (Terrestrial Manual – OIE 2017) and the WHO (Laboratory Techniques in Rabies)
ii) The Fluorescent antibody test (FAT) is the primary method recommended
iii) The confirmation test should use rabbit tissue culture inoculation test (RTCIT). The mouse inoculation test can be used only if rabbit tissue culture is not available
iv) PCR is presently not recommended for routine diagnosis but may be useful for epidemiological studies or for confirmatory diagnosis only in reference laboratories.
Reference laboratories: The list of reference experts and laboratories can be found on the OIE web site (http://www.oie.int/en/our-scientific-expertise/reference-laboratories/list-of-laboratories/).
Virus detection methods
Only direct detection methods are recommended to confirm rabies in human beings and animals.
Samples (animal heads, brain tissues or other organs) 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 % glycerin in phosphate buffered saline solution.
Brain tissue (especially thalamus, pons and medulla) is the preferred sample for postmortem diagnosis but other organs such as salivary glands can also be used.
Fluorescent antibody test
The FAT is the method recommended by WHO and OIE for fresh or glycerol samples (Bourhy et al., 1989; Birgham and van der Merwe, 2002), but is less sensitive in formalin-fixed tissues. It provides a reliable diagnosis in 95 to 99 % of cases for all lyssaviruses in fresh samples. It can also be used for rabies detection in cell cultures and in brain tissue of mice that have been inoculated for diagnosis (Fig. 10).
Other methods available include immunochemical tests (e.g. avidin-biotin peroxydase system, ELISA, direct blot enzyme immunoassay). The rapid rabies enzyme immunodiagnosis (RREID) is an alternative to FAT but detects only the rabies virus. Correlation between FAT and RREID is between 96 and 99 % (Barrat, 1993).
Inoculation to laboratory animals and cell cultures
These tests are used to confirm inconclusive results with FAT in organs or when FAT is negative if human exposure has been reported.
Intracerebral inoculation of mice is performed in newborn or 3 to 4 week-old mice. FAT is used to detect virus 5 days to 11 days post-inoculation. Ideally, these inoculation tests should be replaced by cell culture tests, which are as sensitive, less time-consuming and more ethical. Neuroblastoma cell lines may be used and presence of the rabies virus is revealed by FAT, with results being available within 2 to 4 days.
Since histology and immunohistochemistry to detect Negri bodies are less sensitive than FAT, especially in autolysed tissues, these methods are not recommended for routine diagnosis.
Other direct methods
Reference laboratories may identify rabies virus, especially variants, using monoclonal antibodies, nucleic acid probes or PCR and sequencing. These techniques can distinguish vaccine and field strains and may identify the geographic origin of the isolate.
Seroneutralisation tests in cell cultures, such as fluorescent antibody virus neutralisation (FAVN) or rapid fluorescent focus inhibition test (RFFIT) are widely used to confirm immunity induced by vaccination. The principle of FAVN is neutralisation in vitro of a rabies CVS strain before inoculating BHK-21 C13 cells. The 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. RFFIT and FAVN give equivalent results. A value of 0.5 IU/ml of serum antibodies is the internationally accepted threshold titer.
ELISA is used for testing vaccinated animals (Servat et al., 2007). Commercial kits are available for the detection of antibodies in sera from vaccinated cats and dogs. The tests do not require the culture of live virus, and results can be obtained within 4 hours. Sensitivity and specificity of the ELISA still need to be confirmed before it can be accepted as an official method (Servat et al., 2006). For further details, refer to Barrat et al. (2006) and the OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animals (OIE, 2017).
Rabies control in cats
Treatment (post-exposure vaccination)
The 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 recently (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, Poland, the Baltic and Balkan states) 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, rabies 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.
Rabies in cats is usually controlled by traditional inactivated vaccines (OIE, 2017) and at present, 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; EBM grade III; Van de Zande et al., 2009; EBM grade III; Berndtsson et al., 2011; EBM grade III).
Cats respond better to rabies vaccination than dogs and the proportion of cats developing after the first vaccination a titer below 0.5 IU/ml has been determined as only 2.6 % (Cliquet, 2006) or as tested 6 to 12 months post vaccination as about 8 % (Zanoni et al., 2010; EBM grade III).
Many cats develop after the first vaccination 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; EBM grade III). Cats and dogs with a neutralization titer above 0.5 IU/ml, regardless of the period of time elapsed since vaccination, have a very high probability of survival after a rabies infection (Cliquet, 2006).
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 a recent 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; EBM grade III). There is increasing evidence that the persistence of antibody after the first rabies vaccination may 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; EBM grade III) and in many puppies it happens as early as after 56 or even 28 days (Minke et al., 2009; EBM grade III). 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; EBM grade III).
Thus a new 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 titer below 0.5 IU/ml to almost 0 % 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; EBM grade III).
Current rabies vaccines also cross-protect against some other lyssaviruses
All cat and dog sera with a titer above 5 IU/ml neutralize EBL-1 and EBL-2 regardless of vaccine virus strain and among sera with a titer between 0.5 and 5 IU/ml 87 % neutralize EBL-1 and 53 % EBL-2 (Fooks, personal communication). However, against some novel lyssaviruses isolated from bats in Eurasia the protection may be reduced or negligible depending on the genetic distance between the new isolate and the rabies virus (Hanlon et al., 2005; EBM grade III; Lefkowitz et al., 2017).
Inactivated vaccines may 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 may 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; EBM grade III) and DNA-based vaccines (Osorio et al., 1999; EBM grade III; 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 EBM grade III). 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 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.
Although some commercial vaccines provide protection against virulent rabies challenge for 3 years or longer (Lakshmanan et al., 2006; EBM grade III), national or local legislation may require annual boosters.
Disease control in specific situations
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.
Risk exposure is generally almost nil in breeding catteries because usually pedigree cats are kept strictly indoors, but their vaccination is under local or state regulation.
Vaccination of immunocompromised cats
FIV-positive cats should be kept confined indoors to avoid transmission to other cats, to protect them from other infections and to slower the progression of FIV infection itself. This is an efficient preventive measure for rabies in areas at risk, but national or regional legislation should be adhered too. In outdoor cats with risk of exposure to rabies, vaccination is strongly advised.
In vaccination studies it was demonstrated that FeLV-infected cats may not be able to mount adequate immune response to some rabies vaccines (Franchini, 1990). FeLV infected cats should be confined strictly indoors to prevent spread to other cats in the neighborhood: if cats are allowed to go outside in area at risk for rabies, more frequent vaccination may need to be considered (e.g. every 6 months).
There is general agreement that cats with acute disease should not be vaccinated but cats with chronic illness such as renal disease, diabetes mellitus or hyperthyroidism should be vaccinated regularly if they are at risk of exposure.
Cats receiving corticosteroids or other immunosuppressive drugs
In cats receiving corticosteroids, every vaccination should be considered carefully. Depending on dosage and duration of treatment, corticosteroids may cause functional suppression of immune responses, particularly cell-mediated immunity, but studies exploring rabies vaccine efficacy in cats receiving corticosteroids are lacking. In dogs, corticosteroids do not appear to result in ineffective immunizations if given for short periods of time at low to moderate doses (Nara et al., 1979). However, concurrent use of corticosteroids at the time of vaccination should be avoided if practical.
Rabies vaccination and cat movement within the EU
The Directive 998/2003 of the European Community established new 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 will be 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.
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