Vet. Res. 38 (2007) 319–335 319 c INRA, EDP Sciences, 2007 DOI: 10.1051/vetres:2006056 Review article

Feline calicivirus

Alan D. R*, Karen P. C,SusanD,CarolJ.P, Rosalind M. G

University of Liverpool Veterinary Teaching Hospital, Leahurst, Chester High Road, Neston, S. Wirral, CH64 7TE, United Kingdom

(Received 23 June 2006; accepted 25 September 2006)

Abstract – Feline calicivirus (FCV) is an important and highly prevalent pathogen of cats. It be- longs to the family Caliciviridae which includes other significant pathogens of man and animals. As an RNA virus, high polymerase error rates convey upon FCV a high genome plasticity, and allow the virus to respond rapidly to environmental selection pressures. This makes the virus very adaptable and has important implications for clinical disease and its control. Being genetically diverse, FCV is associated with a range of clinical syndromes from inapparent infections to relatively mild oral and upper respiratory tract disease with or without acute lameness. More recently, highly virulent forms of the virus have emerged associated with a systemic infection that is frequently fatal. A pro- portion of FCV infected cats that recover from acute disease, remain persistently infected. In such cats, virus evolution is believed to help the virus to evade the host immune response. Such long- term carriers may only represent a minority of the feline population but are likely to be crucial to the epidemiology of the virus. Vaccination against FCV has been available for many years and has effectively reduced the incidence of clinical disease. However, the vaccines do not prevent infection and vaccinated cats can still become persistently infected. In addition, FCV strain variability means that not all strains are protected against equally. Much progress has been made in understanding the biology and pathogenesis of this important feline virus. Challenges for the future will necessarily focus on how to control the variability of this virus particularly in relation to emerging virulent strains and vaccination.

calicivirus / evolution / feline / vaccination / virulence

Table of contents 1. Aetiology...... 320 2. Clinical signs...... 321 3. Pathogenesis ...... 322 3.1. FCV-associated oral and upper respiratory tract disease ...... 322 3.2. FCV-associated lameness...... 322 3.3. FCV-associated virulent systemic disease...... 322 3.4. Molecular pathogenesis ...... 324 4. The FCV carrier state ...... 325 5. Epidemiology...... 325 6. Prevention, control and vaccination ...... 326 6.1. Vaccines ...... 326

* Corresponding author: [email protected]

Article available at http://www.edpsciences.org/vetres or http://dx.doi.org/10.1051/vetres:2006056 320 A.D. Radford et al.

6.2. Treatment...... 328 6.3. Management of FCV-associated respiratory disease...... 329 6.4. Control of outbreaks of FCV-associated VSD...... 329 7. Conclusion...... 330

1. AETIOLOGY its variability has been used as the basis of sequence-based methods to differenti- Feline calicivirus (FCV) is a highly ate between strains [84, 105]. Region A is infectious pathogen of cats with a cleaved to produce the mature capsid pro- widespread distribution in the feline tein [10, 102]. ORF 3 encodes for a minor population. The virus typically causes structural protein [103]. moderate, self-limiting acute oral and Having an RNA genome, we should upper respiratory tract disease. However, expect FCV to have a high degree of ge- some strains induce lameness and re- nomic plasticity. This is a reflection of cently, more virulent strains have evolved, the lack of proofreading and associated particularly in the USA. low fidelity generally attributable to viral The virus belongs to the Caliciviri- RNA-dependent RNA polymerases [22]. dae, a family of viruses which includes This mechanism for error-prone replica- important pathogens of man (noroviruses tion should afford FCV great adaptability and sapoviruses; together the common- and allow it to exploit new environmental est causes of infectious gastroenteri- niches. Specific current problems associ- tis in people) and animals including ated with FCV that are a reflection of this the vesiviruses (e.g. FCV – one of include the difficulty of choosing represen- the most consistent clinical signs of tative strains for inclusion in vaccines, the FCV is oral vesicles/ulceration) and the presence of persistently infected cats, and lagoviruses (rabbit haemorrhagic disease the emergence of hypervirulent strains of virus and European brown hare syn- FCV. drome virus) [35]. Feline calicivirus has a The adaptability of FCV is reflected at small single-stranded, positive-sense RNA both genetic and antigenic levels. Phylo- genome of approximately 7.7 kb. The genetic analysis of nucleotide sequences genome is polyadenylated at the 3’ end, mostly from the capsid gene results in a bound by a virally-encoded protein at “star-like” phylogeny with little statistical the 5’-end, and encodes three open read- support for sub-species clusters [31, 33]. ing frames (ORFs). ORF 1 codes for The only exception to this appears to be the non-structural proteins including a in viruses from Japan where there is some viral protease and the RNA-dependent evidence for the presence of two geno- RNA polymerase. This polyprotein is post- types [94], although the significance of this translationally cleaved by the viral pro- is not clear. As a result, it has not proved tease. ORF 2 codes for the major capsid possible to identify groupings of FCV ei- protein which has been divided in to six ther on spatial (except possibly Japan), regions A-F based largely on sequence temporal or clinical grounds, and the virus conservation [99]. Region B, D and F are is generally considered to exist as multiple relatively conserved between FCV isolates, strains that are all members of a single di- whilst regions C and E are variable. Vari- verse genotype. The definition of “strain” able region E is known to contain the is perhaps somewhat arbitrary, but has been major B-cell epitopes [32, 86, 110] and defined by some as FCV isolates that are Feline calicivirus 321

> 20% different based on nucleotide se- 95]. This is reminiscent of rabbit haemor- quence of capsid region E [84, 87, 88]. rhagic disease virus (RHDV). Retrospec- Observed genetic variability correlates tive studies have shown that RHDV existed with earlier serological studies. Most FCV in rabbit populations for many years in a isolates can be distinguished antigenically. seemingly non-pathogenic form [9,11,70]. However, there appears to be sufficient Then, in the 1980s, highly lethal forms antigenic overlap between isolates to de- were first reported in China, and have since fine the viruses as belonging to a single appeared worldwide [58, 72]. diverse serotype [81, 82]. As well as upper respiratory tract dis- Antigenic and genetic variability is also ease, cats affected by FCV-associated a feature of other caliciviruses, especially VSD show to varying degrees pyrexia, the human noroviruses, where highly vari- cutaneous oedema, ulcerative dermatitis, able genogroups containing multiple geno- anorexia and jaundice, with up to 50% types are described [2, 34]. The origins of of cats dying or being euthanased in ex- this diversity are poorly understood. As a tremis. Adult cats are frequently affected result, studies of the evolution of FCV may more severely than kittens, and worryingly, shed new light on the diversification of field vaccination does not appear to be pro- other caliciviruses. tective. Outbreaks start quickly, generally effect less than 100 animals and disap- pear rapidly. FCV can be isolated from oral 2. CLINICAL SIGNS or conjunctival swabs of affected cats. So far, FCV-associated VSD has mainly been Due to the large number of different reported in the USA. In the UK, one out- strains of FCV, a range of clinical signs break in 2003 has been described affecting may be seen. The most characteristic le- a group of five cats in two households [15]. sion is oral ulceration, which may often In addition, the authors are aware of two go unreported. Ocular and nasal discharge outbreaks in France1 and it is possible that also frequently occur [8]. Occasionally, in- considerably more outbreaks occur than apparent infections or pneumonia may also have been reported. VSD has been repro- be seen. Rarely, and usually in young kit- duced experimentally, strongly supporting tens, the more severe respiratory infections a role for FCV in this disease [77]. can be fatal [49, 60]. Calicivirus strains Feline calicivirus has also been as- can also cause an acute febrile lameness sociated with other clinical syndromes syndrome which has been recreated exper- although these have not been recreated imentally [20, 75]. It has been suggested experimentally. The most striking associ- that lameness and oral/respiratory disease ation is with the severe chronic oral dis- represent two extremes of a clinical con- ease, lymphoplasmacytic gingivitis stom- tinuum, with some individual strains tend- atitis (LPGS) complex. In some studies, ing to either extreme, and the majority of approximately 80% of cats with LPGS strains being able to induce both of these have been shedding FCV compared to 20% clinical signs [108]. of controls [52, 59, 109]. Although acute More recently, and more worryingly, faucitis has been reproduced experimen- highly virulent strains of FCV have tally [91], the chronic disease has not been emerged that are associated with outbreaks induced in experimental cats [53, 79]. It is of disease with high mortality and a new therefore likely that factors not associated range of clinical features (FCV-associated with FCV, including other pathogens [52, virulent systemic disease (VSD) – previ- ously haemorrhagic-like fever) [42, 43, 77, 1 Poulet H., personal communication. 322 A.D. Radford et al.

59, 116] and host factors [37], may also necrosis of the overlying epithelium and play a role in this complex and serious syn- infiltration of neutrophils at the periph- drome. There have been several attempts ery and base [30]. Healing generally takes to identify consistent genetic and antigenic place over a period of two to three weeks. differences between FCV isolates from Pulmonary lesions occur more rarely and cats with LPGS and those from cats with appear to result from an initial focal alve- other FCV-associated diseases, and these olitis, leading to areas of acute exudative have met with variable results. Those based pneumonia and then to the development of on sequencing and monoclonal antibodies a proliferative, interstitial pneumonia. Al- have failed to identify consistent differ- though primary interstitial pneumonia may ences [31,33,65]. However, those based on occur with FCV, it is possible that its im- polyclonal antisera reactivity have shown portance in natural cases of disease has some differences between those isolates been over emphasised in the past. This is associated with chronic stomatitis and because many early experimental studies those associated with other diseases, which used aerosol challenge to infect cats, rather has been attributed to evolution of these than the more natural oronasal route of in- FCV isolates in such chronically infected fection. cats [19, 79]. There has also been some debate about the role of FCV in feline urinary tract dis- 3.2. FCV-associated lameness ease [27,92]. Although virus can be visual- ized in, and isolated from, urine, there are Lesions seen in joints of cats with FCV- currently no studies demonstrating a clear associated lameness consist of an acute association between infection and disease. synovitis with thickening of the synovial membrane and an increase in quantity of synovial fluid within the joint [20]. Viral 3. PATHOGENESIS antigen has been identified in macrophage- like cells in the synovial membrane of Cats can be infected with FCV via the joints from affected cats [20]. nasal, oral or conjunctival routes. The virus replicates mainly in the oral and respira- tory tissues, although some strains vary 3.3. FCV-associated virulent systemic in their tissue tropisms and pathogenic- disease ity, such that virus has also been found in visceral tissues, faeces and occasionally How the pathogenesis of virulent sys- in urine. The significance of this to trans- ff mission is unknown but is thought to be temic disease (VSD) di ers from more minimal. typical disease is unknown. However, it is clear that in cases of VSD, virus gains access to cellular compartments not 3.1. FCV-associated oral and upper normally associated with FCV. Lesions respiratory tract disease are widespread and include subcutaneous oedema, ulceration of the mouth, and vari- Oral ulceration is the most consistent able levels of ulceration of the skin par- pathological feature of FCV-induced oral ticularly on the pinnae and pawpads and and upper respiratory tract disease. Ul- nares [77]. Other lesions are more variable cers begin as vesicles, typically on the and include bronchointerstitial pneumonia margin of the tongue but also in other lo- and necrosis in the liver, spleen and pan- cations. These subsequently rupture, with creas. In the most detailed study, viral Feline calicivirus 323 antigen has been detected in the skin, nasal quenced to date, or indeed a combination mucosa, lung, pancreas and endothelial of the two. In addition, it may be possible cells of the dermis associated with necro- to evolve virulence by different mutation sis [78]. Virus particles were also identified pathways. This may explain slight differ- by electron microscopy in the cytoplasm ences in the clinical signs and pathology and nuclei of lytic epithelial cells undergo- observed in the individual outbreaks. ing vacuolar degeneration in these lesions. Most outbreaks of FCV-associated VSD In this study, viral antigen was not detected have been associated with the introduction in the liver of cats despite the presence of of cats from large rescue colonies into an- pathological lesions. This is in contrast to other population [43]. It is possible that one study in the UK, in which viral anti- the high levels of replication of normal gen was found in the liver of jaundiced FCV strains in large groups of cats such cats [15]. This significance of this discrep- as rescue shelters may provide the required ancy remains unclear. conditions necessary for the independent It is interesting to speculate on the emergence of these hypervirulent strains. mechanism of FCV-associated VSD in This is consistent with theories for the evo- cats. It is clear that the virus alone is suf- lution of increased virulence in host popu- ficient to cause the disease as the disease lations with high levels of non-neutralising has now been re-created experimentally at immunity [29,61]. Under these conditions, least twice to the authors’ knowledge. This viral variants that are capable of replicat- suggests that mutations within the viral ing faster and to higher titres will be more genome may be responsible for the highly likely to be transmitted and therefore posi- virulent phenotype. So far, the FCV strains tively selected for. Within the originating from each reported outbreak of VSD have colony the matched immune response to been genetically distinct from each other. the virus may damp down these high lev- Therefore, if viral mutations are required els of virus replication in individual cats to cause the hyper-virulent phenotype, then and therefore the more virulent forms of they must evolve independently in each disease are not seen. However, when these outbreak. Attempts are now being made to virus strains gain access to naïve popula- identify mutations that are markers of the tions that have not been exposed to that virulent phenotype. To date, no consistent particular strain before, extreme levels of genetic motif has been reported within the virus replication lead to the clinical man- available capsid sequences to differentiate ifestation that is VSD. We have recently FCV isolates associated with VSD from shown that virus replication in endemi- those associated with more typical FCV- cally infected colonies of cats is associated associated disease. However, interestingly, with markedly higher levels of biodiversity for the two VSD isolates so far sequenced, than those normally seen within a single there is some suggestion that sequence dif- strain of FCV [14, 90]. This diversity ap- ferences lead to the acquisition of an extra pears to be driven by immune-mediated glycosylation site in both cases [1, 28]. positive selection both within individual This difficulty of identifying clear genomic cats (see carriers below) and associated markers for VSD is not without precedent with transmission between cats. In addi- for FCV, in that attempts to identify mark- tion, the high prevalence of FCV in such ers associated with lameness have also met colonies provides an ideal environment for with failure [31, 33]. It therefore seems mixed infections. As a result recombina- likely that any viral mutations associated tion events between strains, similar to those with VSD are either subtle, or located in a reported for other caliciviruses [7, 46, 50, different region of the genome to that se- 73], have been identified in such colonies, 324 A.D. Radford et al. and provide a further mechanism for the di- 3.4. Molecular pathogenesis versification of viruses [16]. Whether these evolutionary events are associated with the The study of the molecular mechanism selection of more virulent, faster replicat- by which FCV induces disease has bene- ing viral variants remains to be determined. fited considerably from the fact that FCV As stated previously, each outbreak for grows well in cell culture, and because an which sequence data is available has been infectious clone is available [101]. This caused by a distinct strain of FCV. Suc- is in contrast to other members of the cessive outbreaks are not started by a sin- Caliciviridae such as human noro- and gle virulent strain of FCV that is being sapoviruses which do not grow in cell cul- widely transmitted. The reasons why each ture, and where infectious clones are not outbreak seems to “burn out” as quickly available. This has led to the use of FCV as it started are unknown but may in- infection as a model of calicivirus molecu- clude, behavioural mechanisms (dying cats lar biology. are less likely to transmit virus), disease In cell culture, infected cells show a control measures instigated during each characteristic cytopathic effect associated outbreak, and evolved attenuation. These with cell rounding and membrane bleb- virulent FCV outbreaks represent a clear bing [51]. Under these conditions, infec- opportunity to explore the mechanisms that tion with FCV leads to an inhibition of cel- underlie both the evolution of virulence lular protein synthesis (shut-off) associated and mechanisms of attenuation. One ob- with cleavage of the host translation initia- vious concern is that the virus will evolve tion factors [117]. Such a mechanism may to be efficiently transmitted among the cat allow the virus to divert the cellular trans- population. How likely this is to occur is lation machinery from cap dependant to unknown, but if it does, the consequences cap-independent translation thereby stop- would be severe, particularly as current ping translation of cellular mRNAs and vaccines seem to offer little protection. allowing translation to focus on the viral VpG-bound RNA. A similar system is also As well as viral mutations, it is also used by the closely related picornaviruses. possible that host and immune factors Molecular studies have now shown that play a role in this disease. It is certainly virus infection in cell culture triggers the true that not all cats die in each out- mitochondrial pathway, leading to caspase break. Some have suggested an immune- activation and apoptosis [71,104]. Whether mediated contribution to the pathogenesis this is what happens in the entire animal for FCV-associated VSD [15, 28], partly remains unknown. based on the fact that adult cats seem to A big break through for FCV research develop more severe disease than young was recently reported when the junctional animals [43]. A possible immune-mediated adhesion molecule-1 (JAM-1) was iden- pathogenesis has been shown for other tified as a cellular receptor for FCV in FCV infections such as lameness [4], and cell culture [62]. Transfection of non- in some cases, vaccination appears to po- permissive cells with a JAM-1 expression tentiate FCV infection [17]. system rendered the cell line permissive Although outbreaks of VSD have only for FCV and anti-feline JAM-1 antibodies recently been described it is interesting to reduced replication of FCV in permissive note that several case reports in the past cells. Whether strains of FCV associated have described similar clinical findings in with different types of disease use different FCV infected cats including jaundice [26] receptors remains to be determined. In hu- and sudden death [60]. man noroviruses, different host expression Feline calicivirus 325 of viral receptors belonging to the ABH likely to represent a constant source of histo-blood group family is associated with infection to susceptible cats. In addition, resistant to infection in some individu- some carrier cats appear to shed higher lev- als [38, 44, 57]. Whether a similar mech- els of virus than others, and these cats are anism operates for FCV is unknown al- likely to be of greater epidemiological sig- though interestingly in the field, some cats nificance [14, 114]. do appear to be relatively resistant to in- The mechanism of persistence for FCV fection despite between heavily exposed to is not fully elucidated. Virus has been challenge virus [14]. found in tonsils of carrier cats, suggesting the virus may replicate within immune- 4. THE FCV CARRIER STATE privileged sites. However, tonsilectomy does not eliminate the carrier state, and Most cats shed FCV in oropharyngeal therefore it is clear that the virus persists in secretions for 30 days after infection. Car- other as yet undefined extra-tonsillar sites. riers are somewhat arbitrarily defined as Several studies have looked at virus evolu- those cats that shed virus beyond this pe- tion in progressively-evolving carrier cats riod. Some individual FCV carriers may and suggested that, as for other persistent shed virus for life, although most cats ap- RNA viruses, viral evolution, particularly pear to spontaneously eliminate the virus. in immunodominant regions of the capsid In one experimental study, the duration of protein, lead to antigenic variation, and al- FCV shedding by carrier cats was shown to low the virus to evade the developing host broadly conform to a half-life such that ev- immune response [48, 54, 85]. It is likely ery 75 days, half of a group of positive cats that a combination of both viral and host cease to shed the virus [115]. Although factors will ultimately determine the out- an oversimplification, with many factors come and duration of infection. likelytoaffect the duration of shedding, this half-life model of the FCV carrier state remains a useful one. 5. EPIDEMIOLOGY Studies of endemically infected colonies seem to confirm these experimen- Feline calicivirus infection is wides- tal observations, that long-term persistence pread in the general cat population [5, is indeed a relatively rare event [14]. In 36, 68, 107]. The prevalence is gener- such colonies, only a minority of cats ally broadly proportional to the number that are continuously shedding FCV are of cats in the household, with the high- actually infected with the same lineage of est prevalence usually seen where large virus over the course of this infection. We groups of cats are housed together. As a refer to these cats as progressive evolvers. result, privately owned pet cats kept in These cats are likely to provide a reservoir small numbers generally have relatively of virus to colonies, allowing the virus to low prevalence (∼ 10%) [113]. In contrast, persist in what is otherwise a very small random cats living in colonies or shelters population. By contrast, the majority of usually have a higher chance of being in- cats that shed virus over prolonged periods fected (∼ 25%–40%) [3, 13, 40, 88, 113]. of time seem to do so by being reinfected The prevalence within individual colonies either with diverse viral variants of the is very variable. In some circumstances the same strain or with distinct strains that are prevalence appears to be low [14, 41, 89], co-circulating within the household [14]. whereas in other colonies we have found Progressive evolver carrier cats shed prevalence values of 50–90% over pro- virus more-or-less continuously and so are longed periods of time [14, 90]. 326 A.D. Radford et al.

Within the cat population, FCV is cination. In pet cats living in small pop- present in acutely infected cats and in ulations, this is likely to be sufficient. In clinically-recovered carrier cats. The virus larger groups of cats, where the prevalence can also persist in the environment for and amount of virus shed is likely to be several days to several weeks on dried higher, vaccination needs to be accompa- surfaces at room temperature, and longer nied by careful management procedures. in colder wetter conditions [12, 23, 24]. Treatment is non-specific. The control of Indirect transmission can therefore occur, outbreaks of FCV-associated VSD will be especially within the close confines of a considered separately. cattery where secretions may contaminate cages, feeding and cleaning utensils or per- 6.1. Vaccines sonnel. It is generally accepted that there are no known reservoirs or alternative hosts Several types of vaccines are now avail- for FCV, and in utero transmission does able for FCV. They are generally consid- not seem to occur. However interestingly, ered to be safe and effective at reduc- as well as having there own specific ca- ing or preventing classical oral/respiratory nine calicivirus, FCV-like viruses have also disease, but do not protect against infec- been isolated from dogs [39, 64, 93]. The tion or the development of the carrier role of these viruses in the epidemiology state. Evidence from the field suggests that of FCV in the cat (and dog) is uncertain. the current vaccines do not prevent FCV- In one study, an association was shown associated VSD with outbreaks occurring between the presence of dogs and FCV in- in vaccinated cats [15,42,77,95]. However, fection in cats [5], whilst a second study there is some experimental data to support has suggested cat households with dogs their use [6, 77]. The impact of vaccina- have a lower prevalence of FCV infec- tion on LPGS is unclear. Vaccinated cats tion [40]. certainly develop LPGS and no vaccine The immune response has a somewhat carries a data sheet claim for preventing limited impact on FCV infection. It is clear this disease. This is consistent with the un- that pre-existing immunity, acquired either certain role of FCV in this syndrome. naturally as maternal-derived antibodies All licensed FCV vaccines are based (MDA) or artificially following vaccina- on whole viral antigens grown in cell tion, can reduce or eliminate the clinical culture. Most are monovalent (based on signs of subsequent FCV challenge. How- a single strain), although recently a bi- ever, such pre-existing immunity does not valent vaccine has been licensed [80]. prevent infection and these animals may Live-attenuated and inactivated (both ad- become carriers following sub-clinical in- juvanted and non-adjuvanted) vaccines are fection with field virus. As with other sig- available in most countries, and are given nificant pathogens, these “silent-carriers” parenterally. However, in some parts of are likely to play a crucial role in the the world, live-attenuated vaccines are li- epidemiology of this disease. There is no censed for intranasal use. evidence that vaccination will ‘cure’ an ex- Live intranasal vaccines induce local isting carrier state. mucosal immunity, and this is probably more effective than immunity induced by 6. PREVENTION, CONTROL parenteral vaccines. However, because the AND VACCINATION virus replicates at the site of inoculation, clinical signs such as mild sneezing may The main-stay of FCV-associated dis- be seen after several days in some individ- ease control in the cat population is vac- uals [55, 74]. Where available, intranasal Feline calicivirus 327 vaccines are particularly useful when a which is the USDA-approved FCV chal- rapid onset of protection is required e.g. for lenge in the USA. It is therefore likely that a cat going into a boarding cattery or in the shorter durations of immunity/protection face of an outbreak of disease. In contrast would have been seen with a heterologous to parenteral vaccines, only a single dose challenge, although how much shorter is of intranasal vaccine is generally required unknown. to induce immunity following primary vac- As with most vaccines, there are well cination. Most published studies have used documented adverse reactions in a minor- a feline herpesvirus challenge where high ity of cases. Along with other injections, levels of protection have been shown four adjuvanted vaccines have been associated days after intranasal vaccination and par- with injection-site reactions and sarco- tial protection after two [55, 74]. These mas [69]. Parenteral modified-live FCV vaccines may also overcome MDA better vaccines have been associated with clin- than parenteral vaccines, although in gen- ical signs in the immediate period post- eral their use is only licensed in kittens vaccination. Most of these appear to be due from 12 weeks of age. Live intranasal vac- to coincidental infection with field virus cines have shown an increase in popularity although in some cases, sequence analy- amongst some veterinarians, in part due to sis has shown that vaccine virus may be public concerns about the role of inacti- involved [84, 87]. Vaccine virus has also vated vaccines in injection site reactions occasionally been detected circulating in and sarcomas. the cat population, though the significance Recommended vaccination schedules of this is not yet known [77,88,89]. A third tend to be of the “traditional” type with potential problem for current vaccines is a primary course at 8–9 and 12 weeks the antigenic variability of FCV strains, followed by annual boosters. Some are li- which means that no vaccine is likely to censed for earlier use [21]. There is now be able to neutralise all field isolates of evidence to suggest that not all kittens are virus such that occasional vaccine break- able to respond to vaccination at 12 weeks downs can occur [18]. In order to try and of age, such that under some circum- circumvent some of these problems, a bi- stances, later kitten vaccinations may be valent inactivated, non-adjuvanted vaccine needed to overcome persistent MDA [21, has recently been marketed in Europe [80]. 47]. The success of this in controlling disease As with other small animal vaccines, and in the market place remains to be de- the requirement for annual booster vacci- termined. nations is currently being debated. It will The areas where vaccines could be im- be important to consider the antigenic di- proved seem clear, and pose a considerable versity of FCV as this debate is developed. challenge. Firstly, it will be important to Moderate levels of virus neutralizing anti- increase the cross-reactivity of vaccines to body have been shown to persist in a group maximise the chances of cross-protection, of vaccinated cats for at least four years, minimise the number of vaccine break- although after 7.5 years, titers had de- downs, and minimise the possibilities of clined to low or non-detectable levels [97, evolving vaccine resistant strains [56]. 98]. Protection against FCV challenge de- This approach will hopefully help with the creased from 85% three weeks after vac- control of both typical and more virulent cination to 63% after 7.5 years. However, forms of disease. The success of specifi- this study represented a homologous chal- cally including antigens from outbreaks of lenge, with both the vaccine and the chal- VSD in vaccines to protect against these lenge virus being based on strain 255, more severe forms of disease is uncertain 328 A.D. Radford et al. since to date, each strain of FCV associ- to vaccine development, especially as we ated with VSD appears to be different [15]. seek to rationally improve the repertoire A second approach to improving ex- of field strains covered by individual vac- isting vaccines is to develop immune re- cines. Therefore, in the short–medium sponses that reduce or eliminate challenge term, challenge experiments will remain a virus shedding and prevent or reduce the gold-standard for measuring FCV vaccine likelihood of vaccinated cats becoming efficacy. However, the antigenic variabil- persistently infected. It is certainly true ity of FCV complicates both the rationale that existing vaccines do not prevent in- choice of challenge virus, and the inter- fection. Indeed there is a small amount pretation of challenge experiments based of experimental data to suggest that under on single strains. The most sensible ap- some circumstances, challenge virus may proach will be to test vaccines against a be shed for longer and at a higher titre by panel of representative FCV challenge iso- cats with some previous immunity when lates. However, this rigorous experimental compared to naïve cats [17]. Whether this approach will be rendered impractical by can also occur with commercial vaccines is the commercial and welfare implications not known. Whilst one vaccine licensed in of what would become very large experi- the EU has a claim to reduce FCV shed- ments. Perhaps in the future, the ultimate ding, the effect of most vaccines on viral testing of the efficacy of FCV vaccination shedding is generally not publicly avail- may need to take place in rigorous phased able. Reducing or eliminating challenge clinical trials as occurs in human medicine. virus shedding in vaccinated cats is likely There are some published reports to be a “holy-grail” of vaccination, not of novel vaccine technologies including just for FCV but for many other impor- DNA vaccination [100], myxoma recom- tant pathogens. Whilst this is an immense binants [66, 67], and herpesvirus recom- challenge, we will only begin to address binants [118] for FCV. Such vaccines it when the monitoring of FCV shedding could offer several potential advantages patterns in vaccinated and challenged cats over those based on conventional tech- becomes more routine. nologies including inability to induce FCV The mechanisms by which cats are pro- infection, and induction of a local mucosal tected against clinical disease are still un- immune response. However, to date, none clear. Antibody is considered to be most are available commercially. important for protection, and is routinely measured in cell culture by virus neutral- 6.2. Treatment isation tests. Such tests have been used to identify those strains that induce the Broad-spectrum antibiotic treatment is most broadly cross-reactive immune re- generally recommended in cases of more sponse for use as vaccine antigens [19, severe FCV-associated oral and respiratory 76, 80]. Available cross-protection studies disease to minimize potential complica- suggest that the correlation between titre tions associated with secondary bacterial and protection is reasonable [81]. How- infection. As swallowing may be painful, ever, in challenge studies, some cats with antibiotics can be given either as syrups no measurable antibody were also pro- (if available) or parenterally. Good nursing tected against clinical disease [53]. This care, with regular cleansing of discharges, suggests that cell mediated and innate im- is essential. The cat should be encouraged mune responses also play an important to eat by offering strongly-flavoured aro- part in protection. Lack of clear biomark- matic foods. If eating is painful, liquidized ers for protection represent a bottleneck or specialized proprietary foods may be Feline calicivirus 329 of some help. In some cases, the use of colonies that are known to be free of appetite stimulants such as diazepam or virus (e.g. research colonies), inactivated cyproheptadine may also be of some ben- vaccines may be used and animals com- efit. Some severely affected cases may re- ing into the colony (stud cats, replace- quire fluid therapy, and where anorexia is ments) should ideally be sourced from prolonged, an oesophagostomy or gastro- similar FCV-negative colonies, and should tomy tube may be indicated. be quarantined and tested on several oc- For some viral diseases of humans, both casions to determine if they are free of specific and more broad-spectrum thera- the virus. In endemically infected breed- pies have made it to clinical practice. Spe- ing colonies control is generally aimed cific antivirals for veterinary pathogens are at reducing clinical disease. Specific mea- unlikely to be developed in the near fu- sures include reducing stocking density, ture due to the prohibitive costs. Although early weaning kittens into isolation, and some broad-spectrum antivirals are effec- early vaccination of kittens. Vaccinating tive against FCV in cell culture, they are pregnant queens may reduce disease in too toxic for use in the cat [83]. Interferon young kittens by boosting their MDA [45]. is used by some, although to the authors’ However, the safety of vaccines in preg- knowledge, published evidence for its ef- nant queens is largely unknown and clin- fectiveness remains limited to in vitro stud- icians should consult data sheets. Live vac- ies [106], and it is not licensed for control cines should be avoided, particularly those of FCV-disease in Europe. Experimental containing live feline parvovirus. It may trials of chimeric mouse-cat monoclonal be possible to eradicate virus from such antibodies have shown some promise in colonies by a test and remove strategy. treatment [111, 112]. However, in practice, this is likely to be ex- tremely difficult. 6.3. Management of FCV-associated respiratory disease 6.4. Control of outbreaks of FCV-associated VSD In practice, controlling FCV is usually associated with a similar need to control Diagnosing FCV-associated VSD in the feline herpesvirus. A more detailed de- cat remains somewhat of a conundrum scription of the control measures for these since there are no unique clinical or lab- two pathogens is given elsewhere [30]. oratory markers for the disease. Although Briefly, the control measures for FCV- the clinical features can be quite striking associated respiratory disease depend en- with relatively few differential diagnoses, tirely on the population of cats. For indi- FCV strain variability means that each vidual household cats where prevalence is outbreak can be associated with slightly low, vaccination is likely to be sufficient. different clinical signs. The authors are fre- In boarding and rescue catteries, vacci- quently asked about individual cats with nation, quarantine facilities, batching of suspicious signs, some of which are also arrivals, good husbandry/hygiene, well de- FCV positive. Such individual cats must signed pens which prevent direct contact be treated carefully, but whether these rep- between cats, and avoiding overcrowding resent actual sporadic cases of VSD is are critical to minimising viral loads and unknown. The index of suspicion for VSD the spread of virus through the popula- increases dramatically when two or more tion. Molecular studies on FCV suggest cats present with the same clinical signs. that if this is done well, FCV transmis- However, ultimately as we seek to un- sion can be minimal [88]. In breeding derstand the mechanism of this disease, 330 A.D. Radford et al. experimental infections with viruses iso- to disease control measures or includes a lated from such cats will be required to cat- cat behavioural and/or virus evolutionary egorically identify true outbreaks of FCV- component, remains to be determined. associated VSD. Crucial to the control of suspect out- 7. CONCLUSION breaks of this severe disease is early recognition/suspicion and prompt rigorous Feline calicivirus has been recognised biosecurity. Early in the outbreak, it is as an important pathogen of cats for over very important that owners and staff are all 40 years now. As an RNA pathogen, aware of the disease and what it looks like. it seems to rely on evolution to main- This includes veterinary surgeons at neigh- tain itself in the population. Where the bouring practices who may see other cases virus came from we do not know. Today from the same outbreak. Specific measures we struggle with newly emerged virulent must include contact tracing and quarantin- strains and have a clear need to improve ing of all suspect cats. Actual and suspect the cross-protection offered by our vac- cases are perhaps best managed away from cines. What is certainly true is that FCV the veterinary hospital. However, where is still changing. We must expect the clin- cases must be hospitalised, they must be ical features of this virus to change and kept in strict isolation and barrier nursed. accordingly, our attempts to control it will All staff should be made aware of the case, need to be continually updated. Because of and those who do not own cats should its high prevalence, FCV also represents a preferably be involved in the treatment of good model system in which to explore the the affected animal. consequences of virus evolution in its nat- The virus is generally considered to ural host. 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