Criteria for Selection of Cases

The electronic medical records of all cats visiting Banfield Pet Hospital locations from January 1, 2002, through December 31, 2004, were extracted from the practice database. The practice medical record system^a is computerized and paperless, with veterinarians using standardized coded entries for diagnoses and treatments. Records were included when any record included a code for feline panleukopenia-rhinotracheitis-calicivirus-Chlamydia vaccine,^b Giardia vaccine,^c FeLV vaccine,^d FIP vaccine,^e or rabies vaccine^f (vaccines for which > 5,000 doses had been administered). Vaccine-associated adverse events were identified in cats by searching for the diagnoses: vaccine reaction, allergic reaction, urticaria, anaphylaxis, cardiac arrest, cardiovascular shock, or sudden death within 30 days following vaccine administration.

Procedures

The date of birth, breed, sex, neuter status, weight, and date of vaccination were extracted from each record. The free-text medical note field was reviewed in all cats with the specified diagnoses to ascertain specific clinical signs and whether the clinical signs were associated with vaccine administration. Per practice protocols, veterinarians used standardized anatomic sites for SC vaccine injection, as follows: left shoulder for Giardia vaccine, right shoulder for multivalent distemper vaccine, left thigh for FeLV, and right thigh for rabies. Record review therefore allowed correlation of reactions at described anatomic sites with specific vaccines.

Clinical signs were characterized for the time periods of 0 to 3, 4 to 15, and 16 to 30 days after vaccination. Records for cats with localized vaccination-site reactions were reviewed through December 31, 2005, for the subsequent diagnosis of neoplasia at vaccination sites. This provided a minimum 2-year follow-up period for cats with local VAAEs in 2002-2003 and a minimum 1-year follow-up for cats with VAAEs in 2004. This method did not allow determination of incidence rates for vaccination-site–associated sarcoma because all feline neoplasms diagnosed in this period were not retrospectively evaluated for association with vaccination.

Statistical analysis—Sex and neuter status were analyzed as categoric variables. Cats were grouped on the basis of age at date of vaccination as follows: 2 to 9 months, > 9 months to 1.5 years, > 1.5 to 2.5 years, > 2.5 to 3.5 years, > 3.5 to 5.5 years, > 5.5 to 8.5 years, and > 8.5 years. Cats were grouped by weight at time of vaccination into the following groups: 0 to 2 kg (0 to 4.4 lb), > 2 to 4 kg (> 4.4 to 8.8 lb), > 4 to 6 kg (> 8.8 to 13.2 lb), > 6 to 8 kg (> 13.2 to 17.6 lb), or > 8 kg (> 17.6 lb). Incidence rates with 95% CIs were calculated assuming a binomial distribution for proportions. Tests for trend were performed across ordered groups by use of the Cuzick nonparametric test. All VAAE rates are reported as the number of adverse events/10,000 cats vaccinated. For categoric variables, the χ² test for independence was used to compare rates for affected cats with rates for nonaffected cats.

Bivariate and multivariate unconditional logistic regression was used to evaluate potential risk factors for VAAEs, and multivariate logistic regression included random effect for cats. Estimates of the OR and 95% CIs for each risk factor were obtained by exponentiation of the regression coefficients. Interactions between independent variables in the final multivariate model were assessed for an association with an adverse event, but interactions between vaccines were not included in multivariate analysis because of the large number of vaccine combinations (n = 31). Maximum likelihood estimates of the logistic parameters and final model were assessed for significance by use of the Hosmer-Lemeshow χ² goodness-of-fit test. A P value < 0.05 was considered significant. All calculations were performed with statistical software.^g

Results

In the 3-year study period, 1,258,712 vaccine doses were administered to 496,189 cats at 329 hospitals. Mean number of vaccine doses administered per cat per office visit was 2.5 (range, 1 to 5), and 2,560 cats had a VAAE within 30 days of vaccine administration (51.6 VAAEs/10,000 cats vaccinated; 95% CI, 49.6 to 53.6). Most VAAEs were diagnosed 0 to 3 days after vaccination (92.0% [2,354/2,560]), compared with 4 to 15 days (4.6% [119/2,560]) or 16 to 30 days (3.4% [87/2,560]) after vaccination. The rate of VAAE within the 3 days after vaccination was 47.4/10,000 cats vaccinated (95% CI, 45.5 to 49.4). Of 2,560 VAAEs, 2,142 (83.7%) were coded as vaccine reactions, 394 (15.4%) as allergic reactions, and 17 (0.7%) as anaphylaxis. Death was reported within 48 hours of vaccination in 4 cats (0.081 deaths/10,000 cats vaccinated [8.1/1,000,000]; 95% CI, 0.022 to 0.206).

Description of VAAEs—Clinical signs were further described within records for 1,699 of 2,560 cats with VAAE diagnosis codes. The predominant clinical signs of VAAE within 30 days of vaccine administration were lethargy with or without fever (54.2% [921/1,699]), localized vaccination-site reactions (eg, swelling, inflammation, or soreness; 25.2% [428/1,699]), vomiting (10.3% [175/1,699]), facial or periorbital edema (5.7% [97/1,699]), or generalized pruritus (1.9% [32/1,699]). Most (92.0%) VAAEs were diagnosed within 3 days after vaccination. The distributions of these clinical signs in the 0 to 3, 4 to 15, and 16 to 30 day postvaccinal periods differed significantly (P < 0.001), however, with diagnoses of localized reactions predominating in the latter periods (Figure 1). In multivariate analysis, no single vaccine was significantly associated with localized reactions, but the multivalent panleukopenia-rhinotracheitis-calicivirus-Chlamydia vaccine was significantly (P < 0.001) associated with increased risk of lethargy with or without fever. No localized VAAEs diagnosed within 30 days of vaccination were subsequently diagnosed as neoplasia when followed for 1 to 2 years. In the 4 cats with deaths associated with vaccination, clinical signs consistent with anaphylaxis were described immediately after vaccination in 2 cats—a 5-year-old 5.5-kg (12.1-lb) spayed female domestic shorthair cat that concurrently received distemper, FIP, and rabies vaccines, and a 2-year-old 5.5-kg neutered male domestic shorthair cat that received 5 vaccines concurrently. Clinical signs were not described in a 16-year-old 4.4-kg (9.7-lb) neutered male domestic medium hair cat that received distemper and rabies vaccines, died the same day, and had a veterinary diagnosis of shock. Clinical signs were also not described in a 6-month-old 2.2-kg (4.8-lb) female domestic shorthair cat that received distemper and rabies vaccines, died the next day, and had a veterinary diagnosis of vaccine reaction.

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Distribution of types of VAAEs diagnosed during various periods after vaccination in 496,189 cats administered 1 or more vaccines from January 1, 2002, to December 31, 2004.

Citation: Journal of the American Veterinary Medical Association 231, 1; 10.2460/javma.231.1.94

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Bivariate analysis—The study population included 30,450 (6.1%) sexually intact males, 37,700 (7.6%) sexually intact females, 214,194 (43.2%) neutered males, and 213,845 (43.1%) spayed females. Unadjusted VAAE rates by sex and neuter status were 34.5/10,000 cats vaccinated (95% CI, 28.2 to 41.7) for sexually intact males, 50.7/10,000 cats vaccinated (95% CI, 43.7 to 58.4) for sexually intact females, 51.0/10,000 cats vaccinated (95% CI, 48.0 to 51.4) for neutered males, and 54.8/10,000 cats vaccinated (95% CI, 51.7 to 58.0) for spayed females. Among all cats, the VAAE rates in 2002 (764/138,927 [55.0/10,000] cats vaccinated), 2003 (898/179,316 [50.1/10,000] cats vaccinated), and 2004 (898/177,946 [50.5/10,000] cats vaccinated) were not significantly different (P = 0.11).

Rates of VAAEs for purebreds or mixed-breeds with > 4,000 cats vaccinated did not significantly differ (P = 0.64). Rates for Siamese, Himalayan, Persian, and Maine Coon cats were 58.8, 52.8, 51.1, and 44.1 adverse events/10,000 cats vaccinated, respectively. Rates for cats identified as domestic shorthair, medium hair, and longhair were 52.2, 50.5, and 42.6/10,000 cats vaccinated, respectively.

The VAAE rates significantly (P < 0.001) differed among weight groups, with higher rates in cats that weighed > 2 to 4 kg (71.2/10,000 cats vaccinated; 95% CI, 64.1 to 78.9; Figure 2). The lowest rate was in 151,039 cats that weighed b 2 kg (41.3/10,000 cats vaccinated; 95% CI, 37.5 to 45.5). In 199,057 cats b 9 months of age, the adverse event rate was 55.1/10,000 cats vaccinated (95% CI, 51.9 to 58.4) and increased to 80.6/10,000 cats vaccinated (95% CI, 72.9 to 88.8) in cats 9 months to 1.5 years old (Figure 3). The VAAE rate declined thereafter with age.

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Distribution of rates of VAAEs (± SEM) diagnosed within 30 days of vaccine administration in various weight groups of cats vaccinated from January 1, 2002, to December 31, 2004.

Citation: Journal of the American Veterinary Medical Association 231, 1; 10.2460/javma.231.1.94

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Distribution of VAAE rates (± SEM) in cats of various ages administered 1 or more vaccines from January 1, 2002, to December 31, 2004.

Citation: Journal of the American Veterinary Medical Association 231, 1; 10.2460/javma.231.1.94

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The risk of VAAE significantly increased as the number of vaccines administered per office visit increased (P for trend, < 0.001; Figure 4). Unadjusted VAAE rates increased from 26.5/10,000 cats vaccinated (346/130,595) when a single vaccine was administered to 83.0/10,000 cats vaccinated (441/53,156) when 5 vaccines were simultaneously administered. In all cats, each additional vaccine administered per office visit increased the rate of a VAAE by 27.5%. Significant (P = 0.01) interaction existed between weight and the number of vaccines received, but not between age and number of concurrent vaccinations (P = 0.72). Cats that weighed b 6 kg had greater VAAE rates than cats that weighed > 6 kg when administered only 1 vaccine (31% vs 22%, respectively) or 2 vaccines (55% vs 44%, respectively), but had lower VAAE rates when administered 4 vaccines (66% vs 61%, respectively) or 5 vaccines (71% vs 88%, respectively).

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Distribution of VAAE rates (± SEM) among the number of vaccines administered per office visit in cats vaccinated from January 1, 2002, to December 31, 2004.

Citation: Journal of the American Veterinary Medical Association 231, 1; 10.2460/javma.231.1.94

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The VAAE rates associated with administration of a single dose of different vaccines differed significantly (P < 0.001). The lowest rates were observed with administration of Giardia vaccine (15.3/10,000 cats vaccinated; 26 VAAEs/17,035 cats), FIP vaccine (15.7/10,000 cats vaccinated; 16 VAAEs/10,172 cats), and rabies vaccine (16.5/10,000 cats vaccinated; 76 VAAEs/46,037 cats). Highest rates were observed with multivalent distemper vaccine (36.3/10,000 cats vaccinated; 186 VAAEs/51,205 cats) and FeLV vaccine (37.5/10,000 cats vaccinated; 32 VAAEs/8,531 cats). Five paired combinations of vaccines were administered to at least 5,000 cats. The VAAE rates for these combinations ranged from 18.3/10,000 cats vaccinated for FIP and Giardia vaccines (28 VAAEs/15,314 cats) to 64.5/10,000 cats vaccinated for concurrent administration of distemper and FeLV vaccine (331 VAAEs/51,323 cats).

Multivariate analysis—In the multivariate logistic regression model that included sex, neuter status, age, weight, and number of vaccines received (Table 1), ORs of a VAAE were greatest as the number of vaccines administered at 1 office visit increased (P < 0.001). Compared with the risk of VAAEs associated with a single vaccination, simultaneous administration of 3 vaccines more than doubled the risk (OR, 2.30; 95% CI, 2.02 to 2.62) and with 5 simultaneous vaccinations tripled the risk (OR, 3.17; 95% CI, 2.74 to 3.66). Risk of an adverse event was significantly increased for neutered cats, compared with sexually intact male cats, and was significantly increased for sexually intact female cats, compared with sexually intact male cats. After controlling for other variables, the VAAE risk was approximately 50% greater for cats approximately 1 year old, compared with cats < 9 months of age.

Discussion

This practice-based cohort study characterized the VAAEs diagnosed after vaccination of approximately 500,000 cats. Most VAAEs were diagnosed within 3 days of vaccination, and significant risk factors included age, sex, neuter status, weight, and number of vaccines concurrently administered. The VAAE rate within 3 days of vaccine administration in cats (0.48%) was approximately 25% greater than the VAAE rate (0.38%) in dogs reported by the authors in a similar study.⁹ Passive surveillance has also determined that VAAEs are more commonly reported in cats than dogs.¹⁰

In multivariate analysis, the factor associated with the greatest increase in VAAE risk was the number of concurrently administered vaccines or the total vaccine volume administered during the office visit. The increase in risk associated with each additional vaccination (27.5%) in cats was equivalent to the risk recently reported for dogs that weighed < 10 kg (< 4.5 lb).⁹ When multiple vaccines are simultaneously administered to an animal, the ratio of total volume received per pound of body weight per animal increases, indicating an antigenic dose-response relationship. In a safety profile for a new feline panleukopenia-rhinotracheitis-calicivirus-Chlamydia psittaci vaccine, Starr³ reported that the likelihood of observing short-term lethargy, inappetence, or occasional signs of pain increased as rabies vaccine or especially FeLV vaccine was administered concurrently with the distemper vaccine, and the same day–next day reaction rates were highest when all 3 vaccines (distemper, rabies, and FeLV) were concurrently given.

Nonspecific systemic reactions with clinical signs of anorexia, lethargy, fever, or soreness were the most common VAAEs observed in cats in the present study. These findings are consistent with results of feline vaccine safety studies, although rates for such reactions may exceed 1%.^2,3,10 The causes of these nonspecific reactions may include vaccine organism replication of modified-live vaccines, exposure to endotoxins, adjuvant toxicity, or immune system responsiveness.^2,11 Clinical signs potentially attributable to immediate-type hypersensitivity reactions and mast-cell degranulation (eg, vomiting, facial edema, and pruritus) were less common VAAEs in this cat population than reported in dogs.⁹ Specific causes of vaccine-induced immediate-type hypersensitivity reactions have not been investigated in cats, but heterologous proteins (eg, bovine serum albumin) have been implicated as a cause in dogs.¹²

Local (injection-site) reactions were the second most common VAAE observed in the study, and the frequency of local reactions increased with increasing days postvaccination. Even in the first 3 days after vaccination, however, the local reaction rate was greater in cats than in dogs.⁹ Local reactions in cats occur at 2 to 5 times the rate in dogs according to published summaries of adverse event reports from passive surveillance.^10,13 The cytologic characteristics of subcutaneous postvaccinal reactions in cats have been described as inflammatory infiltrates composed primarily of lymphocytes, consistent with a simple, first-exposure immune nonsuppurative inflammatory reaction.¹⁴ Cellular infiltrates at the vaccination sites increased for 3 weeks, principally because of lymphocytes.¹⁴ Cats have more lymphocytes locally at vaccine injection sites, compared with other species.¹⁵ This nonsuppurative inflammation may be attributable to vaccine adjuvants that enhance the normal immune response.^14,16,17

Although cats with localized VAAEs in this study were followed for up to 2 years, there were no diagnoses of neoplasia at these vaccination sites in these particular cats. The Quality Assurance Section at Banfield, the Pet Hospital, did, however, receive reports from veterinarians of sarcomas associated with vaccination sites. Sarcomas were not subsequently detected at anatomic sites with localized inflammatory reactions in this study, and a direct association between the presence or severity of postvaccinal inflammation and tumor risk has not specifically been established.¹⁸ Also, no specific vaccine was significantly associated with local VAAEs in this study, whereas epidemiologic evidence exists for an association between sarcoma formation and aluminum-adjuvanted rabies virus and FeLV vaccines.¹⁹ The absence of tumorogenesis at sites with local inflammation may indicate a delicate balance between cytokine production and tumor cell recognition. Measurements of mRNA expression in biopsy specimens from cats with inflammatory enteropathy have revealed not only increased gene transcription for proinflammatory cytokines but also increased expression of immunoregulatory cytokines.²⁰

Although feline vaccines have been associated with fibrosarcomas that develop at body locations used for vaccination, the national incidence is estimated to be low (approx 1 to 2 sarcomas/10,000 vaccinated cats).¹⁸ Nevertheless, from 1999 through 2005, the number of voluntarily submitted adverse event reports categorized by the USDA as feline vaccine–associated neoplasia increased even though the total number of reports for feline biologics decreased in that time period.¹³ The time needed for sarcoma development is not established, however, and the 1- to 2-year follow-up time in the present study may not have been sufficiently long. Nevertheless, changes in vaccine manufacturing (eg, adjuvant quantity or composition) and vaccine administration protocols may influence the incidence of vaccine-associated sarcomas in cats,²¹ and these factors may have changed since vaccine-site sarcomas were first recognized.

The risk of VAAEs increased for cats up to 1 year of age, then declined thereafter. Cats 1 year and older had significantly higher VAAE rates, compared with younger cats in 1 study, but all adult cats were analyzed as a single group.³ Changes in VAAE rates with advancing age have not been reported for adult cats. Risk of VAAEs in dogs is greatest in dogs 2 years of age and then declines with age.⁹ In dogs, IgE concentration increases after vaccination at 2 and 3 years of age and then declines,²² but equivalent measurements have not been performed in cats. Declining VAAE rates observed after 1 year of age in the cats in the present study may have been caused by allergen desensitization, reduced sensitization with the use of triennial vaccinations, changes in vaccination protocol in older cats or previous reactors, or owner removal of predisposed cats from the population at risk because they decline further vaccination.

Female cats in this study were at greater risk of VAAEs, compared with male cats of the same neuter status. The influence of sex hormones on the immune system has been reported in other species. Women have stronger immune responses after vaccination or infection than males because of a dimorphic enhancing effect of estrogens and a protective effect of androgens.^23,24 In the present study, however, neutering appeared to be associated with risk of a VAAE as much as sex. Neutering reduces serum estrogen and testosterone concentrations, each acting in the physiologic balance of protective immunity. Although estrogens enhance humoral response, they inhibit cytokine release in human mast cells.²⁵ Testosterone and its metabolites preserve the number of CD4+ CD25+ regulatory T cells, which suppresses autoimmunity.²⁶ The full immunologic impact of alterations in sex hormones remains to be elucidated because the immunomodulatory effects of estrogen and androgens on B-cell function may also be mediated indirectly via gonadotropin-releasing hormone.²⁷

There were no significant breed differences in VAAE rates observed in the present study. In a report based on passive surveillance, it was suggested that some breeds are overrepresented in suspected adverse reactions to vaccines.¹⁰ It is possible that owners of purebred cats are more likely to report VAAEs than owners of mixed-breed cats. A 10-fold difference in rates of postvaccinal immediatetype hypersensitivity reactions was detected among dog breeds,⁹ but much of this is likely correlated with weight differences among breeds. Nevertheless, rate differences exist between dog breeds with similar adult weights, suggesting a genetic factor in the regulation of the immune response.

The VAAEs were more common after administration of either multivalent distemper vaccine or an FeLV vaccine than after administration of rabies, FIP, or Giardia vaccine. In multivariate analyses adjusting for age, weight, sex, and neuter status, risk of postvaccinal lethargy was significantly associated with the multivalent feline distemper-respiratory vaccine. This finding is consistent with results of other studies in which vaccine reactions have been associated with the calicivirus or Chlamydia components of multivalent vaccines.^3,28 No single vaccine type was significantly associated with local injection site reactions.

A limitation of this study, and adverse event surveillance in general, was the difficulty in inferring cause- and-effect relationships between observed clinical signs and vaccination. More than 80% of the adverse events in this study were coded by veterinarians as vaccine reactions—a code that does not specifically describe a clinical sign but rather expresses the veterinarian's professional opinion regarding the etiology of the observed clinical signs. Medical record review was used in this study to verify the temporal association of clinical signs with vaccination and to eliminate records with other probable causes for suspected vaccine reactions. Review of the medical records for all cats was necessary to ascertain the observed clinical signs in each cat with a VAAE diagnosis code. Because the diagnostic codes may have failed to capture all VAAEs, actual rates may have been underestimated. Any underestimation would not be expected to markedly affect relative rates between vaccinated and unvaccinated cats and inferences of relative risk. Conversely, codes for common illnesses (eg, diarrhea, lameness, and alopecia) were not included in analysis in this study because inclusion would have potentially overestimated VAAE rates and erroneously implied association with vaccination.

Although this study is the largest published feline vaccine study to date, it was limited to the evaluation of a single marketed vaccine or combination of vaccines administered concurrently for protection against a specific disease, and most of the vaccines were from 1 manufacturer. These vaccines therefore represent only a small proportion (approx 10%) of all feline vaccines available in the United States during the study period. Variations among vaccines and their composition, including adjuvants, protein concentrations, fermentation conditions, and processing differences, complicate the ability to generalize the findings to all marketed vaccines for cats. Lower VAAE rates (< 20/10,000 cats vaccinated) were observed after administration of modified-live virus vaccine^e or adjuvanted killed organism vaccines^c,f and included vaccines from 2 manufacturers. Higher VAAE rates (> 35/10,000 cats vaccinated) were observed for adjuvanted killed virus vaccines, and those included vaccines considered as core (a multivalent vaccine) and noncore (a single viral agent vaccine).¹⁸ Results of the present study suggested that VAAE rates may be, but are not necessarily, different between adjuvanted killed organism vaccines and modified-live virus vaccines or between multivalent vaccines and single viral agent vaccines and that adverse event rate differences may exist for reasons other than these particular categorizations.

The observed dose-response relationship between the VAAE rate and number of concurrently administered vaccines, as well as the inverse relationship observed between VAAE rate and increasing weight in mature cats, has also been reported in dogs,⁹ suggesting that manufacturers may need to reformulate vaccines to reduce protein and excipient concentrations in vaccines for cats and dogs. This will become increasingly important as new vaccines are introduced for disease prevention and veterinarians must consider additional biologics in vaccination protocols.

Veterinarians should still limit vaccinations to those needed on the basis of individual risk assessments and should limit the number of concurrently administered vaccinations. Results of the present study indicated risk factors for VAAEs in cats and may help veterinarians individualize vaccine protocols for cats, but further studies are needed to evaluate other vaccines or vaccine types. Results of those studies should be interpreted in light of their clinical relevance and statistical validity and thereafter appropriately incorporated into published guidelines. Although the findings of this study can be used in communication with clients regarding risk of adverse events after vaccination, the low rate and mild nature of most VAAEs in cats should not be a deterrent to the routine use of vaccination for the prevention of important infectious diseases.