what's new in feline flu vaccination?

Presented by Alan Radford, University of Liverpool, at the FAB Breeders Seminar on March 16, 2003

FLU VACCINES FOR CATS have now been around for over 30 years and in that time relatively little has changed. The marketed vaccines remain essentially unaltered as does, to the best of our knowledge, their efficacy.

What exactly do we mean by flu vaccines? Actually, it is nothing to do with real flu, or influenza, in human health terms. As far as we know, cats do not have an influenza virus.

However, the term ‘flu' has been used in cats to describe a group of diseases that produce upper respiratory tract clinical signs similar to those that we are all familiar with in people. The two main infections in cats that cause these symptoms are feline calicivirus and feline herpesvirus. More recently, the bacterial pathogen Bordetella bronchiseptica has also been shown to be a cause of upper respiratory tract disease in cats and will be included, where appropriate, for completeness.

Feline calicivirus (FCV) is a small, highly variable RNA virus that has the ability to change rapidly or evolve. This variability has important implications for designing vaccines (see below). In people, viruses similar to FCV cause vomiting and diarrhoea (Norwalk-like viruses). Another similar virus of rabbits causes a fatal infection of the liver (rabbit haemorrhagic disease virus). In cats, FCV usually causes relatively mild upper respiratory

tract disease including oral and nasal discharges and ulceration of the tongue. Occasionally, particularly in younger kittens, there may also be a short-term lameness. Affected cats tend to recover quickly from the clinical disease but most continue to shed the virus and are still infectious to susceptible cats. These carriers - clinically normal cats shedding FCV - are crucial to maintaining FCV infection in the cat population. While the majority of carriers do seem to eventually clear the infection, some individuals may remain infectious for life.

Feline herpesvirus (FHV) is a large DNA virus that, unlike FCV, shows little variation. The virus tends to cause slightly more severe clinical disease than FCV, with lethargy and ocular and nasal discharges. Many affected cats may also develop ulcers on the surface of the eye - particularly young kittens. Once infected with FHV, it is believed that all cats remain persistently infected for life, the virus going into hiding in the central nervous system (latency). During the time of latency, virus is not shed or detectable and such cats are not infectious. However occasionally, particularly at periods of stress like transport or giving birth, the virus may reactivate itself and be shed from the mouth. At such times, the cats are again infectious and some affected individuals may also show mild clinical disease. This ability to hide in the nervous system and reactivate at times of stress is a feature of all similar herpesviruses and is the cause of shingles and cold sores in humans following infection with chickenpox virus and herpes simplex virus-1 respectively.

B bronchiseptica is a bacterium closely related to B pertussis, which causes whooping cough in people. B bronchiseptica can also cause ‘kennel cough' in dogs, and also results in disease in pigs and rabbits. The disease in cats is associated with enlargement of the lymph nodes under the jaw, sneezing, coughing and nasal discharge. Occasionally severe bronchopneumonia and even death may occur in young kittens. There is some evidence to suggest that bordetella may be transmitted between cats and other animals, particularly dogs. However, more research needs to be done to determine the significance of this transmission to canine and feline health.

Recently Intervet have marketed Nobivac Bb, a live attenuated intranasal vaccine for the control of signs associated with B bronchiseptica infection in cats.

Broadly speaking, the flu vaccines marketed for cats in the UK are essentially very similar. In all cases, FCV and FHV are combined, usually also with feline panleucopaenia virus, in a single vaccine that is licensed to be given subcutaneously or intramuscularly, usually given in the scruff of the neck. Increasingly this triple combination is being added to or combined with other vaccines for example feline leukaemia virus and Chlamydophila felis (previously called Chlamydia psittaci ). Previously live vaccines that went up cats' noses (intranasal) were also marketed in the UK and are widely used in the USA . However, currently there are no intranasal FCV / FHV vaccines marketed for cats in the UK.

Understanding these differences between vaccines is key to understanding much of the debate about their use, and is crucial to making an informed consent about use of flu vaccines in your cats.

‘Live' and ‘killed' are strange terms to use for viral vaccines as ‘life' is not something people normally attribute to viruses. But the idea is clear. Both types of vaccines are initially manufactured by growing the viruses in cell culture. In the case of live vaccines, the viruses have been weakened (attenuated) usually by repeated growth in cell culture, to make them less virulent (less capable of causing disease in the cat). Importantly, because the vaccine still contains live virus, virus can still be grown or cultured from such vaccines and in rare cases, virus from such vaccines may infect and cause disease in cats (see below). In contrast, in the case of killed vaccines, the viruses are inactivated by various treatments, and there is no cultivable virus remaining, and no chance of causing an infection in a vaccinated cat (providing the inactivation process is done correctly!!).

Following injection, the viruses in live vaccines are believed to undergo a small amount of virus replication, and this helps to provoke an immune response. In killed vaccines, there is no virus replication and in order to stimulate an adequate immune response, killed vaccines usually contain an adjuvant. Adjuvants can essentially be thought of as mild irritants that help provoke the immune response to the killed vaccine.

One of the features of FCV is its variability. This makes designing a vaccine that works against all types or strains of virus incredibly difficult. It is the same sort of problem that makes developing good vaccines against foot and mouth disease and human immunodeficiency virus difficult. In the case of FCV, each vaccine contains a single type or strain of virus. The choice of this virus is based upon how cats react to it. It has been shown that strains used in FCV vaccines, when infected / injected into cats, stimulate in the cat a broadly cross-reactive immune response. By this we mean that antibodies in the cat can be shown to neutralise a large proportion (around 80 per cent) of other strains of virus. The most important thing to remember about this is that 80 per cent does not equal 100 per cent and therefore, any current vaccine is unlikely to protect equally against all strains of FCV.

The situation is further confused by different vaccine companies using different FCV strains. While some vaccines do not state what they use, some do. For example Fort Dodge use a strain called 255 whilst Intervet use F9. There is a considerable debate about whether one of these vaccines is better (neutralises more FCV strains) than the other. This is a healthy debate. However, there is currently insufficient evidence on which to make an informed decision. But watch this space, the debate is likely to continue!!

So now we know about the diseases and the vaccines, lets consider some of the common questions and concerns people have about flu vaccination in cats. Firstly, tumours at the site of injection and secondly, flu-like disease in vaccinated cats.

It is now fairly well accepted that some cats may develop very nasty tumours called sarcomas, at the sites used for injection, most commonly the scruff of the neck. These sarcomas are very difficult to treat and in many cases prove to be fatal. The location of these tumours has led to the speculation that vaccines (and other injections) may actually cause this disease. The concerns over this condition in the USA have led to renewed interest in non-injected or intranasal vaccination and in measures to reduce the frequency of vaccination. But what are the facts as far as they are known?

So far injection site sarcomas are believed to be very rare. Early studies from the USA suggested the prevalence was approximately 1-10 cases per 10,000 doses of vaccine given. In the UK, recent evidence suggests the prevalence is lower at around 0.02 per 10,000 doses. Therefore, although this condition is serious if your cat gets it, it is quite rare.

The condition is believed to be caused by irritation at the site of vaccination, particularly, but not exclusively, by inactivated adjuvanted vaccines. This may explain the higher prevalence in the USA, where all pet cats have to be vaccinated against rabies, and many more cats than in the UK are vaccinated against feline leukaemia virus, both of which, until very recently, being inactivated adjuvanted vaccines.

The seriousness of this rare condition has important implications to us as cat owners.

Should I use killed adjuvanted vaccines or should I use a live vaccine? This is a common question without an easy answer. In terms of sarcomas, it seems likely that adjuvanted vaccines are more frequently associated with the disease than nonadjuvanted live vaccines. However, live vaccines also have their problems, in particular they may actually cause the disease you are trying to vaccinate against (see below). Therefore, the debate over whether to use live or killed vaccines essentially comes down to which one are you most concerned about…. flu and enteritis or sarcomas.

Lumps can occasionally form at the site of a vaccine, the vast majority of these are entirely harmless, and disappear over a few weeks. So how do you distinguish these trivial lumps from a sarcoma? Veterinarians are now being recommended to take seriously lumps with any of the following characteristics:

It therefore falls on owners, to monitor the site of a vaccination and report any suspicious lumps back to their vets. Rapid detection and treatment is likely to increase the success rate of surgical removal of these tumours.

There is some evidence to suggest that the more injections given at a site, the greater the risk of sarcoma formation. So in general, the less you have your cats injected the lower the risk of sarcoma development. Unfortunately, all current vaccines are licensed for use annually. The reason for this is that proving vaccines work for longer is very expensive and difficult to do, and has welfare considerations for keeping experimental animals for long periods of time. What the annual booster recommendation means is that experimentally, it has been shown that the minimal duration of immunity is one year. It is therefore likely that in a proportion of cats, the immunity will be longer than this. However, there is no way of telling which cats require annual vaccination and which cats could be less frequently vaccinated. Therefore, the current recommendation is that owners should perform with their vets, a risk benefit analysis of the requirements for vaccinating their cats. In each case the risk and consequences of developing an infectious disease need to be weighed up against the risk of inducing a sarcoma, the cost of vaccination and the risk of other known and unknown complications of vaccination. Remember, the debate over frequency of vaccination also includes rabies and FeLV vaccines which until recently were all inactivated and adjuvanted. In the case of FeLV there is now the option of using a live inactivated vaccine based on canary pox.

A common concern is animals that develop cat flu despite having been vaccinated. This is frustrating for owners and vets alike. There are many possible reasons why a vaccinated cat may develop disease but the scenarios are.

1) Mr Gunn-Moore has a colony of six adult, fully vaccinated, healthy cats. He buys in a new unvaccinated kitten called Lilly from his friend, whose breeding household has never had respiratory disease. After five days in his house, Lilly develops clinical signs consistent with FHV infection. His vet tells him that she probably picked it up from other cats in his household, and when tested, one of Mr Gunn-Moore's cats is FHV positive whilst another two are FCV positive. Mr Gunn-Moore is very surprised and disappointed to find so many of his cats positive for viruses when they are fully vaccinated. Unfortunately, neither FCV nor FHV vaccines protect against infection. Therefore, vaccinated cats may become infected and develop persistent infections without ever showing clinical disease. This is a key feature of these viruses and one that too few people are aware of. It also explains why approximately 20 per cent and 1 per cent of cats attending UK cat shows are positive FCV and FHV respectively. Exactly the same is true of foot and mouth disease, and is one of the reasons why vaccines have not been popular to control the disease in the UK.

2) Nelson, a seven-year-old cat, develops signs of upper respiratory tract disease despite being regularly vaccinated against cat flu. The owner takes Nelson to the vet angry that the vaccines they have paid for have failed. On further investigation by the vet, it was found that Nelson was positive for Bordetella bronchispetica , and negative for FCV and FHV virus. A simple but important point . . . not all respiratory disease is caused by FCV and/or FHV. While we are on the subject of bordetella – what are the recommendations for the use of the new bordetella vaccine? A recent epidemiological survey conducted at Liverpool has shown that bordetella is most frequently associated with larger groups of cats. Therefore, while the vaccine is not being recommended as a core or regular vaccine for individuals, it is being recommended for multi-cat households and other cats perceived to be at particular risk of

3) Murphy, a 10-week old kitten who developed flu-like symptoms on Sunday the 16th March 2003, four days after his first kitten vaccine on Thursday 13th March. The vet used a live attenuated vaccine. The clinical signs were consistent with FCV infection and a mouth swab taken from Murphy tested positive for FCV. This is by far the most common thing we are asked to investigate in vaccinated animals. The first thing to remember is that Murphy is essentially unvaccinated. We do not consider cats to be fully vaccinated until at least one week after their second kitten vaccination. Therefore, in this case, there is no concern about whether the vaccine has worked. However, as a live vaccine has been used, there may be concerns about whether the vaccine caused Murphy's disease and we can now determine this thanks to a technique developed at Liverpool vet school that makes use of the variability between FCV strains (remember FCV is an extremely variable virus) that allows us to identify vaccine viruses.

In our experience, by far the most common cause of Murphy's disease is that he is infected by a field virus. . . that is to say a virus that did not originate from a vaccine. Because the incubation period of FCV is approximately 2-7 days, Murphy may have been infected anytime between the 9th and the 14th of March and it us up to the owner and their vet to consider where the infection may have come from to minimise the chance of it happening again. In colonies where this happens regularly, one option is to consider the use of early vaccination.

Very occasionally in cases like Murphy, we have found cats that are infected with virus that originated from the live vaccine used. The most common reason for this is if some of the vaccine virus gets access to the nose or mouth of Murphy. This can happen if a small amount of vaccine leaks back on to the surface of the skin following vaccination to be subsequently ingested when Murphy (or a fellow littermate) grooms, or if the vaccine is aerosolised at the time of injection. The ability of live vaccines to occasionally cause disease like this is their principal drawback. They are only attenuated. This means they may still cause disease under certain circumstances. It is partly for this reason that vaccines for really serious diseases like rabies tend to be killed vaccines . . you would not want your kitten to develop rabies after receiving a rabies vaccine!!

4) Mr and Mrs Nuttall have a colony of 15 including two breeding queens and one litter of 16-week kittens. Recently, several of the cats have developed clinical signs consistent with FCV infection despite being fully vaccinated.

First things first. . . this situation seems to be relatively rare. The next thing we need to know is what is causing this disease. In this case, the Nuttall's vet took a swab from several of the cats including some apparently healthy individuals, and isolated FCV from all the sick cats and half the normal cats, strongly suggesting that FCV may be involved.

The next question to ask is whether the vaccine dose is functional (stored correctly, etc) and whether there is anything about these cats they make them non-responsive to vaccines.

The latter includes things like general health status and specifically leukaemia virus and immunodeficiency virus infections. But let's assume all that is OK in the Nuttall's household.

So, why are fully vaccinated cats developing FCV-related disease? Well, no vaccine ever made would claim to be perfect. Most vaccinated individuals may still develop disease if the challenge dose of the infection is high enough. The Nuttall colony contains lot of cats and from the results of the swabs the vet took, there are quite a lot of FCV positive individuals in the household. In these cases, it is crucial to minimise infectious challenge to cats by basic measures of hygiene. It may also be necessary to reduce the number of cats in the Nuttall's colony or otherwise seek to segregate the cats.

If everything else seems to be perfect, then it would seem like the vaccine has ‘failed'. In the case of FCV, its variability means that any given vaccine is likely to not protect against some field viruses. Because some vaccines use different FCV strains in their vaccines, it may be worth considering changing to a different vaccine that uses a different FCV vaccine strain. However, this would need to be done in consultation with the vet and with some caution, as it is possible that the new vaccine may protect less against this strain than the current vaccine. Laboratory tests may help inform this decision, but this is an expensive and time-consuming process, that still has some degree of subjectivity.

We have had feline flu vaccination now for many years and it has gone a long way towards reducing the amount of clinical disease we see in our cats. While there are some well

characterised side effects with all the vaccines we use, the frequency of these is very low, and in general, the vaccines we have are very safe to use. We should in general be very proud of this. However, there are certain things to consider when choosing the vaccination strategy that is best for any individual cat. This will help to minimise the potential for vaccineassociated side-effects.

www.avma.org/vafstf/. The home page for the American Vaccine-Associated Feline Sarcoma Task Force. Lots of useful information on this rare, but potentially serious, condition of cats. Gaskell RM, Gettinby G, Graham SJ, and Skilton D, Veterinary Products Committee (VPC) working group report on feline and canine vaccination. Final report to the VPC. 2002, Departmental for Environmental, Food and Rural Affairs.: London.

Binns, SH, Dawson, S, Speakman, AJ, Cuevas, LE, Gaskell, CJ, Hart, CA, Morgan, KL & Gaskell, RM (1999). Prevalence and risk factors for feline Bordetella bronchiseptica infection. Veterinary Record 144, 575-80.