Feline vaccination: Guidelines, indications, and risks (Proceedings)

A physical examination, fecal parasite screen, and vaccine needs assessment should be performed at least yearly for all cats. The American Association of Feline Practitioners (AAFP) recently published the third version of the Feline Vaccine Advisory Panel Report (Richards and colleagues 2006; www.aafponline.org). These guidelines are an excellent source of information for veterinarians to use when individualizing vaccination protocols. Vaccine antigens were divided into those that were considered core (FPV, FCV, FHV-1, and rabies), noncore (FeLV, FIV, Bordetellabronchiseptica, and Chlamydophila felis), and not generally recommended (Giardia and FIP). The following recommendations were adapted from the AAFP Panel Report.

Core vaccines

FPV, FCV, FHV-1

All healthy kittens and adult cats without a known vaccination history should be routinely vaccinated with an intranasal or parenteral vaccine that contains FPV, FCV, and FHV-1 (FVRCP). Multiple modified-live products and killed products are available and the products available in the United States were recently reviewed (Richards and colleagues 2006). In general, modified live FVRCP vaccines are recommended for kittens housed in environments at high risk for exposure to FPV. Modified live FVRCP vaccines for intranasal administration can induce protection against FHV-1 as soon as four days after administration (Lappin and colleagues 2006a) and so this route of administration may be preferred for kittens housed in environments at high risk for exposure to FHV-1. Modified live products should not be administered to clinically ill, debilitated, or pregnant animals. Administration of intranasal FVRCP vaccines can induce transient, mild sneezing or coughing and so the owners should be informed.

For kittens thought to have no more than routine risk of exposure to FPV, FCV, or FHV-1, it is currently recommended that FVRCP vaccines should be administered starting no sooner than 6 weeks of age with boosters every 3-4 weeks until 16 weeks of age. Older kittens and adult cats with unknown vaccination history should be administered two killed or two modified-live FVRCP doses 3 to 4 weeks apart.

For kittens thought to have high risk of exposure to FPV, like those housed in animal shelters or pet stores, the AAFP panel currently recommends parenteral administration of modified live FPV containing vaccines as early as 4 weeks of age, particularly during an outbreak. However, intranasal administration of modified live FVRCP vaccines instead of or in addition to parenteral administration of modified live FVRCP vaccines may be superior for protection against FCV and FHV-1 in these environments.

The current AAFP Advisory Panel recommends a booster FVRCP vaccine one year later. However, a recent study showed that while there was no difference in FPV immunity, the relative efficacy of FCV and FHV-1 vaccines were lower at 1 year after initial vaccination than at 4 weeks after initial vaccination (Poulet 2007). The author concluded that the first FCV and FHV-1 booster vaccination after the completion of the initial series should be administered earlier than one year.

Based on several challenge studies, it appears that there is no need to administer FVRCP vaccines any more frequently than every third year after the one year booster vaccine; it is possible the duration of immunity is much longer. As previously discussed, serological test results for antibodies against FPV, FCV, and FHV-1 can be used to aid in the determination of vaccine needs (Lappin and colleagues 2002). Validated serological tests are available at New York State Veterinary Diagnostic Laboratory, Ithaca, New York and Heska Corporation, Loveland, Colorado.

Some variants of FCV induce systemic vasculitis in cats (virulent calicivirus) and clinical signs can be severe in some cats previously vaccinated with FVRCP vaccines (Hurley and colleagues 2004). A killed, virulent FCV containing vaccine line is now available (Fort Dodge Animal Health, Fort Dodge, Iowa). Whether it will be beneficial to administer this strain of FCV to cats is currently unknown. Factors to consider include 1. the prevalence of virulent FCV infections are unknown and currently are thought to be rare; 2. the virulent FCV strains characterized to date have been genetically and antigenically distinct and so it appears unlikely that a vaccine produced from one strain will cross protect against multiple strains; 3. the currently available vaccine line has only been shown to be effective against homologous challenge two weeks after completing the vaccine series; the maximal duration of immunity and whether the vaccine induces cross-protection against other virulent FCV or regular FCV strains is unknown. However, there may be benefit to having multiple FCV in feline vaccines to increase cross-protection against other FCV. The AAFP (www.catvets.com/professionals/guidelines/feline_friendly/?Id=286) has posted an informational brief on the topic

Rabies. All cats should be vaccinated against rabies. Rabies vaccine should be administered SC in the distal right rear limb at the age recommended by the vaccine manufacturer (as early as 8 week depending on brand) in accordance with state and local statutes. Cats should be vaccinated one year later and then either annually or triennially based on state and local statutes and the vaccine product used. The currently available live virus-vectored rabies vaccine (Merial, Duluth, Ga) induces less inflammation than killed rabies vaccines but whether this vaccine is less likely to be associated with soft tissue sarcomas is currently unknown.

Noncore vaccines

Bordetella bronchiseptica

The currently available B. bronchiseptica vaccine for intranasal administration can be administered as early as 4 weeks of age, has an onset of immunity as early as 72 hours, and has a minimum duration of immunity of 1 year. Many cats have antibodies against Bordetella bronchiseptica, the organism is commonly cultured from cats of crowded environments, and there are sporadic reports of severe lower respiratory disease caused by bordetellosis in kittens and cats of crowded environments or other stressful situations. However, the significance of infection in otherwise healthy pet cats appears to be minimal. For example, in client-owned cats in north central Colorado, the organism was rarely cultured from cats with rhinitis or lower respiratory disease (approximately 3%). In addition, because the vaccine is administered by the intranasal route, mild sneezing and coughing can result. Bordetella vaccination should be considered primarily for use in cats at high risk for exposure and disease, such as those with a history of respiratory problems and living in humane shelters with culture proven outbreaks. Since the disease is apparently not life-threatening in adult cats, is uncommon in pet cats, and responds to a variety of antibiotics, routine use of this vaccine in client-owned cats seems unnecessary.

Chlamydophila felis

Killed and modified live C. felis containing vaccines are available. Infection of cats by C. felis generally only results in mild conjunctivitis, is easily treated with antibiotics, has variable prevalence rates, and the organism is of minimal zoonotic risk to people. In addition, use of FVRCP vaccines that also contained C. felis was associated with more vaccine reactions in cats when compared to other products (Moore and colleagues 2007). Thus, whether C. felis vaccination is ever required is controversial. The use of this vaccine should be reserved for cats with a high risk of exposure to other cats and in catteries with endemic disease. Duration of immunity for Chlamydophila vaccines may be short-lived, so high-risk cats should be immunized before a potential exposure.

Feline leukemia virus

Several feline leukemia virus (FeLV) containing vaccines are currently available. Some contain killed FeLV and an adjuvant and others contain recombinant antigens of FeLV without adjuvant. In the United State, the recombinant product is only available for delivery transdermally by use of a special device. Because of difficulties in assessment of efficacy studies it is unclear which vaccine is optimal. The AAFP Panel highly recommended vaccinating kittens for FeLV as they are more susceptible than adult cats and housing status may not have been determined at that time. Feline leukemia virus vaccines are most indicated in cats allowed to go outdoors or that have other exposure to cats of unknown FeLV status. Vaccinated cats should receive two vaccinations initially. Products with adjuvants should be administered SC in the distal left rear limb because of the risk for development of soft tissue sarcomas. While the products without adjuvants are known to induce less inflammation, it is currently unknown whether they are safer than the products containing adjuvants. Because there is little data available concerning duration of immunity after one year, the AAFP Advisory Panel recommended annual boosters. The vaccine is not effective in persistently viremic cats and so is not indicated. However, administration of the vaccine to viremic or latently infected cats does not pose an increased risk of vaccine reaction. FeLV testing should be performed before vaccination because the retrovirus serologic status of all cats should be known so appropriate husbandry can be maintained.

Feline immunodeficiency virus

A killed vaccine containing two FIV subtypes (clades A and D) is currently available for use in the United States (Fel-O-Vax FIV; Fort Dodge Animal Health, Overland Park, Kan). Administration of three doses, three to four weeks apart, starting no sooner than 8 weeks of age with annual boosters is currently recommended in cats to be vaccinated. In pre-licensing studies, 689 cats received 2051 doses of vaccine with side effects detected in less than 1%. In a challenge study performed 375 days after inoculation with three doses (three weeks apart), 84% of the vaccinated cats did not become FIV-infected and 90% of the controls became FIV-infected, giving a preventable fraction of 82%. However, the efficacy and safety of the vaccine have not been assessed under field conditions in large numbers of cats exposed to with multiple FIV subtypes. The primary problem with FIV vaccination at this time is that the vaccine induces antibodies detectable by the currently available antibody test. Thus, after vaccination, the practitioner will be unable to determine whether the cat is infected by FIV. It is recommended that microchips are used so that owners of FIV vaccinated, seropositive cats can easily be found so that euthanasia is not inadvertently performed because of the FIV positive status. Polymerase chain reaction (PCR) for detection of FIV provirus is available in some laboratories, but standardization and external quality control for laboratories providing PCR testing are not currently performed. The AAFPAdvisory Panel recommends vaccinating only high risk cats like those that go outdoors and are known to fight and those housed with FIV infected cats. Serological testing should be performed prior to vaccination; the vaccine is not indicated in seropositive cats.

Not generally recommended vaccines

Feline infectious peritonitis

A relatively safe, intranasal coronavirus vaccine that may protect some cats from developing feline infectious peritonitis (FIP) is currently available for administration after 16 weeks of age. The vaccine may result in mild, transient sneezing since it is administered by the intranasal route. Antibody dependent enhancement of infectivity has not been detected in field studies. Results of the vaccine when used in field studies have been variable. If cats have previously been exposed to coronaviruses, the vaccine is unlikely to be effective (Fehr and colleagues 1997). Because the incidence of disease is low, cats are commonly exposed to coronaviruses before vaccination, and the efficacy is questionable, the AAFP Panel considered this vaccine to be considered not generally recommended. The vaccine may be indicated for seronegative cats entering a known feline infectious peritonitis–infected household or cattery.

Giardia spp

When administered twice the currently available Giardia spp. vaccine lessened numbers of cysts shed and lessened clinical disease after challenge with one heterologous strain one year later. There are currently no published field studies proving efficacy of the vaccine. In addition, it is now known that there are multiple Giardia spp., including a feline-specific strain. It is unknown whether the vaccine is protective against strains other than the one used in challenge studies. In one study of experimentally infected cats, administration of three doses of the vaccine failed to change the course of cyst shedding using one strain of Giardia (Stein and colleagues 2005). Because giardiasis is usually not life-threatening, usually responds to therapy, and vaccine efficacy has not been documented, the AAFP Advisory Panel considered this vaccine to be considered not generally recommended. However, because there are multiple strains of Giardia spp. it is possible that some cases with diarrhea and Giardia that have failed classical drug therapy will respond to administration of the vaccine (2 doses) as an immunotherapy.

FVRCP associated illness

Overall, vaccines for cats are very safe. In my opinion, vaccines for cats undoubtedly have saved many more cats than they have hurt. Core vaccine antigens as defined by the American Association of Feline Practitioners Vaccine Guidelines Committee should be administered to all cats; non-core antigens should be selected based on needs of the individual cat (Richards et al, 2006). The most significant problems associated with feline vaccines have been injection-associated sarcoma. To date, this problem is most apparent in cats administered adjuvanted rabies virus and feline leukemia virus vaccines.

While generally very safe, modified live FVRCP vaccines have been associated with a number of clinical abnormalities including fever, infection of the fetus, induction of a chronic carrier state, polyarthritis, and upper respiratory tract disease. Parenteral administration of FVRCP vaccines occasionally leads to vaccination site sarcomas (Burton et al, 1997). The purpose of this proceedings and lecture is to present new information concerning potential FVRCP vaccine associated side-effects.

We recently reported recombinant antigens of feline herpesvirus 1, calicivirus, and panleukopenia virus for use in serological assays (Lappin et al, 2002). In the same work, we showed that serology could be used to accurately determine need for FVRCP vaccination in cats if validated assays are utilized. While titrating the recombinant antigen based ELISAs by comparing to ELISAs performed using whole viruses, we discovered that vaccinated cats make antibodies against a commonly used cell culture line.

The Crandall-Rees feline kidney (CRFK) cell line has been used to propagate feline viruses for years. While isolated from a kidney, the cell line has characteristics of a fibroblast. During virus purification for vaccine production (FVRCP) or immunoassay development, it is impossible to remove all CRFK proteins or other cell constituents. Thus, CRFK proteins contaminate the viral preparations and commercially available FVRCP vaccines grown on the cell line contain CRFK proteins. As a consequence, during the course of routine immunization, cats are exposed to CRFK proteins and may mount an immune response against those proteins. Since the CRFK cell line is derived from a feline cell line, administration of FVRCP vaccines induces antibodies that also bind to feline tissues. We have now performed several studies to assess the problem.

In the first study (Lappin et al, 2005), our objectives were to determine whether cats inoculated with FVRCP vaccines grown on the CRFK cell line develop antibodies against CRFK lysates or renal cell lysates (FRC), whether cats hypersensitized with CRFK lysate develop antibodies against CRFK cell lysates or FRC lysates, and whether FVRCP vaccination or hypersensitization with CRFK cell lysates induces clinical pathological or histopathological abnormalities over a 56 week period. We assessed three FVRCP vaccines for SQ administration and one FVRCP vaccine for intranasal/intraocular administration. CBC, serum biochemical panel, urinalysis, microalbuminuria assay, and ELISAs to detect antibodies against CRFK lysate or FRC lysate were performed on samples collected at intervals during the study. Renal biopsies were assessed for abnormalities independently by two pathologists. None of the cats was positive for antibodies against CRFK lysate or FRC lysate prior to inoculation. All six cats administered CRFK lysate alone were positive in the CRFK ELISA on multiple sample dates in the CRFK ELISA. Neither of the cats receiving intranasal/intraocular vaccination achieved the positive cutoff value in the CRFK ELISA. Five of the six cats administered a parenteral vaccine were positive in the CRFK ELISA at least once during the study. All six cats administered CRFK lysate were positive on multiple sample dates in the FRC ELISA. All six cats administered a parenteral vaccine were positive on multiple sample dates in the FRC ELISA. Neither of the cats administered the intranasal/intraocular vaccine were positive in the FRC ELISA. Significant CBC, serum biochemical, urinalysis, microalbuminuria, or histopathologic abnormalities were not detected during the study. We concluded that parenteral administration of vaccines grown on the CRFK cell line and SQ inoculation of CRFK lysate alone induced CRFK antibodies and FRC antibodies in most cats in this study. However, the clinical pathological and histopathological results suggest that even hypersensitization with CRFK proteins was not associated with detectable renal dysfunction, renal inflammatory disease, or glomerular disease in the 56-week time period studied.

In the first study, renal biopsies were collected 6 weeks after the last vaccination or hypersensitization (Lappin et al, 2005). It is possible that inflammation of renal tissues occurred but was transient and resolved by the time of biopsy. We have just completed a follow-up study (Lappin et al, 2006) in which we hypothesized that interstitial nephritis would be detected in cats hypersensitized with CRFK lysates, boosted with CRFK lysates, and then biopsied 2 weeks after the booster. We documented interstitial nephritis in 3 of 6 cats hypersensitized with CRFK lysates, but not cats vaccinated with the intranasal FVRCP vaccine. None of these 3 cats had significant inflammation detected 1 year previously. One of the 6 cats recently died of interstitial nephritis. However, it is important to emphasize that the cats in the study have been inoculated multiple times with CRFK proteins over the first year of the study. Whether this occurs after parenteral administration of CRFK contaminated FVRCP vaccines using routine vaccination protocols remains to be proven.

In our first study to determine CRFK antibodies in vaccinated cats, we only had 2 cats per group. Thus, a larger study (Lappin et al, 2004) was performed with 5 groups of cats (1 intranasal vaccine and 4 parenteral vaccines). In that study, we showed that parenteral administration of FVRCP vaccines induces a statistically greater magnitude of antibody response to CRFK proteins than intranasal administration of a FVRCP vaccine. These findings were expected because parenteral inoculation of CRFK lysates to immunocompetent cats would be expected to induce an immune response. The viruses used in the production of the FVRCP vaccine for intranasal administration is also grown on CRFK cells. However, while the viruses in the vaccine are alive, the CRFK cell line components that contaminate the vaccine are not. Thus, we believe the reason cats inoculated with this intranasal vaccine do not develop CRFK antibodies relates to immune exclusion of the CRFK cell line components by the mucosal lining the nose and mouth. We are in the process of determining the immunodominant CRFK antigens recognized by feline antibodies (Whittemore et al, 2005). We have identified 3 immunodominant antigens and will study these antigens further. Antibodies against two of the three antigens have been associated with autoimmune disorders in people.

At this time, we have not directly linked FVRCP vaccination to auto-immune diseases in cats. To further assess for disease associations with administration of CRFK containing FVRCP vaccines, we are currently performing the following studies: 1. Determination of the source and distribution of CRFK proteins in feline tissues; and 2. Correlation of CRFK antibodies with presence of biochemical abnormalities in a group of client-owned cats of the United States. A general recommendation at this time would be to not use parenteral FVRCP vaccine at an interval shorter than every third year. Antigens should also not be split and given yearly as that may lead to increased hypersensitization to the cell line contaminants.

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