Leptospirosis, caused by a bacterial spirochete of the genus Leptospira, is a widespread zoonotic disease with outbreaks reported in the United States and globally.1 Surface antigens differentiate the genus into > 200 different serovars and 9 pathogenic species.2 A variety of wild and domestic animal species such as rodents and cattle can be maintenance hosts of the 2 species most commonly detected in dogs, Leptospira interrogans and Leptospira kirschneri3; such maintenance hosts are commonly subclinically or chronically infected. Clinical hosts such as dogs and humans can develop acute and severe disease. The prevalence of leptospirosis in dogs in North America has increased since 1983, and during this time there have been changes in the prevalence of various serovars as well.4 In the past, infected dogs primarily had seroreactivity against L interrogans serovars Canicola and Icterohemorrhagiae, whereas currently seroreactivity among dogs in North America is predominantly against L interrogans serovars Pomona, Bratislava, and Autumnalis and L kirschneri serovar Grippotyphosa.4–7 Dogs can become infected with Leptospira organisms through exposure to water, grass, or soil that has been contaminated by the urine of infected animals8,9; similarly, among other sources, people can be exposed to Leptospira by contact with urine from infected dogs.10–13 Clinical signs in dogs are nonspecific or relate to particular organs or systems such as the kidneys, liver, or reproductive tract; common signs include fever, joint or muscle pain, vomiting, diarrhea, icterus, and tachypnea secondary to pulmonary hemorrhage.14–17 The severity of clinical signs varies depending on the age, immune status, and vaccination status of the dog, as well as the virulence of the infecting strain of Leptospira.9
Leptospira bacterin vaccines containing L interrogans serovars Canicola and Icterohemorrhagiae have been available for administration to dogs since the 1980s; quadrivalent vaccines now also contain L interrogans serovar Pomona and L kirschneri serovar Grippotyphosa bacterins.9 However, small animal veterinary practitioners have expressed concern about the safety of Leptospira vaccines. Adverse events associated with vaccination range from focal injection-site reactions to death secondary to anaphylactic shock. According to the canine vaccination guidelines published by the American Animal Hospital Association in 2003,18 puppies < 12 weeks of age and small-breed dogs have a high incidence of vaccine-associated reactions following administration of Leptospira vaccine, without reference to the specific vaccine types. More recently, vaccine manufacturers report that their modified, proprietary vaccine components are less likely to induce adverse reactions.9 A large study published in 2005 by Moore et al19 found that small-breed dogs (≤ 10 kg [22 lb]) were at increased risk of vaccine-associated AEs, compared with dogs of larger breeds, although in that series, it was not possible to separate the risk attributable to the multivalent Leptospira vaccine from other core vaccines because a distemperadenovirus-parainfluenza-parvovirus-leptospirosis vaccine was used. In the 2011 American Animal Hospital Association canine vaccination guidelines,20 no mention of a high IR of postvaccination reactions for Leptospira vaccines was made, except to state that they should not be administered to puppies < 12 weeks of age. The paucity of published reports of the true incidence of AEs after vaccination against leptospirosis makes it difficult for veterinary clinicians to make evidence-based decisions regarding use of Leptospira vaccines. Although there are premarketing safety trials21,22 and a postmarketing report system to assess the effectiveness and safety of vaccines, this system has limitations, including variability in report quality, biased reporting, underreporting, and the inability to determine whether a vaccine caused the AE in any individual report.23 Additionally, the incidence of AEs often cannot be determined because the total number of dogs receiving a given vaccine is often unknown.
Vaccination is one of the most common procedures performed by veterinarians. Information about vaccination safety and risk factors for AEs is an essential part of developing an appropriate, individualized vaccination strategy for patients. The objective of the study reported here was to report IRs and identify risk factors for AEs perceived by owners of dogs that received vaccinations that did or did not include prophylaxis against Leptospira and to provide veterinary clinicians with evidence-based information for development of vaccination guidelines against leptospirosis in dogs.
Materials and Methods
Study population and record assessment—Electronic medical records for dogs were collected from the database of a mobile veterinary companya with community veterinary clinics in California, Michigan, Ohio, Pennsylvania, and New York. The main services provided by these clinics were related to preventive veterinary care and included vaccination, microchipping, testing of blood and fecal samples for parasites, flea and tick control, deworming, and heartworm prevention. These clinics had standardized protocols, and a single 4-way Leptospira vaccine (with antigen from L interrogans and L kirschneri serovars Canicola, Icterohemorrhagiae, Pomona, and Grippotyphosa) was used in all study clinics during the study period. This negated the need for analysis of manufacturer-related differences. A central call line was provided for owners to contact veterinarians with questions or concerns about their dogs following the visit, and reports of AEs were recorded in the dogs’ medical records.
The medical records were searched comprehensively to identify dogs that received ≥ 1 vaccination between June 1, 2012, and March 31, 2013. Dogs were eligible for study inclusion if the record indicated administration of Bordetella bronchiseptica vaccine (intranasal or SC route); rabies virus vaccine; Borrelia burgdorferi vaccine; Leptospira vaccine, alone or together with a 5-in-1 (canine distemper virus, canine adenovirus type 1, canine adenovirus type 2, canine parainfluenza virus, and canine parvovirus and canine parvovirus-2c) combination vaccine; or the 5-in-1 vaccine alone. Vaccination against Leptospira was counted independently regardless of whether it was administered with the 5-in-1 combination vaccine. Dogs were excluded if the owners reported that they were currently receiving glucocorticoids, NSAIDs, injectable heartworm prophylactic medication, or antimicrobials, because of the potential for these medications to influence AEs following vaccination. Information extracted from each dog's record included sex, date of birth, body weight, date of visit, neuter status, breed, vaccinations received, as well as date of onset and clinical signs associated with the reported AE.
Owner-reported AEs that developed ≤ 5 days after vaccination were categorized according to the reported clinical signs as lethargy and inappetence, reaction at the injection site (including signs of tenderness or pain, cutaneous swelling or mass, local hair loss, or lameness in a limb close to the injection site), nonspecific vaccine reaction (including cough, nasal discharge, shivering, diarrhea, or vomiting), hypersensitivity reaction (swelling of the face, hives or bumps on the face or body, hyper-salivation, tachypnea, or respiratory distress, or type not specified [used when there was not enough information in the record to classify the reaction into one of the previous categories]). Reported AEs that developed within the predetermined time frame were not screened for plausibility of an association with vaccines. If a dog had multiple owner-reported AEs, only the most medically important reaction was included in the analysis (to avoid pseudoreplication). A described AE was categorized as hypersensitivity if those signs were present, alone or in combination with other reactions, because this is a potentially life-threatening condition.
Statistical analysis—Statistical analysis was performed with commercially available software.b,c Normality assumptions were evaluated with a Shapiro-Wilk test. Data were reported as mean and SD or median and range if the assumption of normality was not met. Sex, neuter status, and breed were analyzed as categorical variables. Inclusion of all breeds in the analysis was anticipated to cause difficulty (where only small numbers of dogs represented some breeds), so breeds were categorized into groups according to American Kennel Club criteria as follows: toy, working, herding, terrier, hound, sporting, nonsporting, and mixed or miscellaneous. Continuous variables of age and body weight were converted into categorical variables since they were not linearly associated with the outcome (determined through visual inspection of the data). Age was calculated at the date of the visit in which vaccinations were administered and categorized as follows: 0 (as early as 6 weeks for some vaccines) to < 6 months, 6 months to < 1 year, 1 year to < 7 years, and ≥ 7 years (categories were selected to represent stages of maturity). Size was determined on the basis of body weight and categorized as very small (< 4.5 kg [< 10 lb]), small (4.5 to < 13.6 kg [10 to < 30 lb]), medium (13.6 to < 22.7 kg [30 to < 50 lb]), large (22.7 to < 45.5 kg [50 to < 100 lb]), and giant (≥ 45.5 kg).
With an assumption of binomial distribution for proportions, IRs and ORs with 95% CIs were calculated by means of the exact method. The IRs were reported as the number of dogs with ≥ 1 AE/10,000 dogs vaccinated. A χ2 likelihood ratio test was used to determine associations between univariate predictors and outcome. Variables with values of P < 0.2 from the univariate analysis were used for selection of a fitted multivariable model. Logistic regression with backward stepwise elimination (with P = 0.10 used for removal of a term) based on a likelihood ratio test was used to construct the final model of risk factors for owner-reported postvaccination AEs. Cases missing data for variables selected for the final model (breed, age, and weight) were excluded from the analysis. The goodness of fit of the final model was evaluated by the Hosmer-Lemeshow test. Values of P ≤ 0.05 were considered significant.
Results
Medical records of 130,658 dogs that received 250,883 vaccines in the 9-month study period were examined. Forty-seven dogs were excluded from the analysis because they had been treated with anti-inflammatory drugs, and 54 dogs were excluded because their owner-reported postvaccination AE did not meet the case definition (either onset of signs > 5 days postvaccination or the record did not contain enough information to determine time of onset). Thus, the medical records of 130,557 dogs representing the administration of 249,880 vaccines remained for the analysis. The study population included 129,545 dogs of known sex (64,018 [49.4%] females and 65,527 [50.6%] males); sex was not recorded for 1,012 (0.8%) dogs. Of 128,564 dogs that had the information recorded, 71,136 (55.3%) were neutered and 57,428 (44.7%) were sexually intact. The median age was 3.0 years (range, 0.12 to 25.00 years; n = 126,910 dogs), and median body weight was 7.73 kg (17.0 lb; range, 0.23 to 118.18 kg [0.51 to 260 lb]; 121,952 dogs).
Of the 249,880 vaccinations, 63,603 (25.5%) were for protection against B bronchiseptica (43,124 SC and 20,479 intranasal vaccinations, representing 17.3% and 8.2% of all vaccinations, respectively), 75,825 (30.3%) were against rabies virus, 925 (0.4%) were against B burgdorferi, and 17,557 (7%) were against Leptospira; 91,970 (36.8%) vaccines were the 5-in-1 combination. The mean ± SD number of vaccines administered per dog per visit was 1.9 ± 0.94 (range, 1 to 5). Of the 17,557 Leptospira vaccines, 15,767 (89.8%) were given in conjunction with the 5-in-1 combination vaccine, and 1,790 (10.2%) were given alone.
Owner-reported clinical signs that developed ≤ 5 days after vaccine administration and were considered to represent a postvaccination AE were found in records of 343 dogs. One hundred nine of 343 (32%) reported AEs developed on day 0 (the same day as vaccination); the percentage declined thereafter, with 80 (23%) developing on day 1, 64 (19%) on day 2, 39 (11%) on day 3, 30 (9%) on day 4, and 21 (6%) on day 5. The IR of owner-reported postvaccination AEs/10,000 dogs for dogs vaccinated against Leptospira (alone or together with other vaccines) was 53.0 (95% CI, 42.8 to 64.9), which was significantly greater (on the basis of nonoverlapping 95% CIs) than that for dogs that did not receive a Leptospira vaccine (IR, 22.1; 95% CI, 19.5 to 25.0) and for dogs that received any vaccination (IR, 26.3; 95% CI, 23.6 to 29.2; Table 1). None of the dogs included in the study died as a result of a hypersensitivity reaction. The IR of hypersensitivity-type reactions/10,000 dogs was 6.2 (95% CI, 4.8 to 7.8) among dogs that did not receive the Leptospira vaccine, compared with 8.5 (95% CI, 4.8 to 14.1) among dogs that did receive the Leptospira vaccine; these values were not significantly different. However, dogs that did receive the Leptospira vaccine had a significantly higher IR of nonspecific-type reactions than did dogs that did not receive the Leptospira vaccine (IR, 20.5 and 11.7, respectively). Among breeds represented by > 100 dogs and for which the IR of owner-reported AEs was > 26.3 (the IR of owner-reported AEs for the study population) with ≥ 2 AEs reported for the group, the highest IRs/10,000 dogs vaccinated were found for American Eskimo Dogs (110.5; n = 181), German Shorthaired Pointers (90.9; 330), Mastiffs (83.0; 241), Bichon Frise (73.5; 952), and Pit Bull Terriers (63.1; 6,180). Data for other breeds meeting these criteria were summarized (Table 2).
Incidence rate/10,000 dogs (95% CI) for various owner-reported AEs following vaccinations that did or did not include prophylaxis against Leptospira (a single injection that included antigen from Leptospira interrogans and Leptospira kirschneri serovars Canicola, Icterohemorrhagiae, Pomona, and Grippotyphosa) in a retrospective cohort study of 130,557 dogs treated between June 1, 2012, and March 31, 2013.
| Reaction | No. of dogs | Received a Leptospira vaccine | Did not receive a Leptospira vaccine | Received any vaccine |
|---|---|---|---|---|
| Lethargy and inappetence | 27 | 4.6 (2.0–9.0) | 1.6 (1.0–2.6) | 2.1 (1.4–3.0) |
| Reaction at injection site | 47 | 7.4 (3.9–12.6) | 3.0 (2.1–4.2) | 3.6 (2.6–4.8) |
| Nonspecific vaccine reaction | 168 | 20.5 (14.4–28.4)a | 11.7 (9.8–13.9) | 12.9 (11.0–15.0) |
| Hypersensitivity | 85 | 8.5 (4.8–14.1) | 6.2 (4.8–7.8) | 6.5 (5.2–8.0) |
| Type of reaction not specified* | 16 | 0 (0–2.1) | 1.4 (0.8–2.3) | 1.2 (0.7–2.0) |
| Total | 343 | 53.0 (42.8–64.9)a,b | 22.1 (19.5–25.0) | 26.3 (23.6–29.2) |
Dogs were included if the medical record indicated administration of Bordetella bronchiseptica vaccine (intranasal or SC route); rabies virus vaccine; Borrelia burgdorferi vaccine; Leptospira vaccine, alone or together with a 5-in-1 (canine distemper virus, canine adenovirus type 1, canine adenovirus type 2, canine parainfluenza virus, and canine parvovirus and canine parvovirus-2c) combination vaccine; or the 5-in-1 vaccine alone. Owner-reported clinical signs that developed ≤ 5 days after vaccination were included in the analysis. Dogs receiving other medical treatments that could potentially influence reported signs (glucocorticoids, NSAIDs, injectable heartworm prophylactic medication, or antimicrobials) were excluded. If multiple AEs were reported for any individual dog, only the most clinically relevant AE was used in the study.
An AE was classified as type of reaction not specified if there was not enough information in the record to categorize it as one of the listed types.
Incidence rate for dogs that received a Leptospira vaccine was significantly higher than that for dogs that did not receive a Leptospira vaccine. bIncidence rate for dogs that received a Leptospira vaccine was significantly higher than that for dogs that received any vaccines. For all comparisons, values with nonoverlapping 95% CIs were considered significantly different.
Incidence rate/10,000 dogs (95% CI) by breed for owner-reported AEs that developed ≤ 5 days after vaccination.
| Breed | No. with AE | No. without AE | IR (95% CI) |
|---|---|---|---|
| American Eskimo Dog | 2 | 179 | 110.5 (13.4–393.4) |
| German Shorthaired Pointer | 3 | 327 | 90.6 (18.8–263.4) |
| Mastiff | 2 | 239 | 83.0 (10.1–296.5) |
| Bichon Frise | 7 | 945 | 73.5 (29.6–150.9) |
| Pit Bull Terrier | 39 | 6,141 | 63.1 (44.9–86.2) |
| Miniature Poodle | 2 | 316 | 62.9 (7.6–225.3) |
| Miniature Pinscher | 5 | 979 | 50.8 (1.7–118.2) |
| Bulldog | 2 | 399 | 49.9 (6.0–179.0) |
| Maltese | 9 | 1,866 | 48.0 (22.0–90.9) |
| Yorkshire Terrier | 14 | 3,633 | 38.4 (21.0–64.3) |
| Miniature Schnauzer | 2 | 702 | 28.4 (3.4–102.2) |
| Toy Poodle | 2 | 710 | 28.1 (3.4–101.1) |
| Mixed breed | 107 | 38,069 | 28.0 (23.0–33.9) |
| Chihuahua | 38 | 13,612 | 27.8 (19.7–38.2) |
| Husky | 2 | 734 | 27.2 (3.3–97.8) |
| Dachshund | 7 | 2,635 | 26.6 (10.7–54.5) |
Breeds were included in the analysis if represented by > 100 dogs, ≥ 2 AEs were reported for the group, and the IR/10,000 dogs for the group was > 26.3 (the IR for all dogs in the study).
In total, 17,557 of 130,557 (13.4%) dogs received a Leptospira vaccine and 113,000 (86.6%) dogs did not. Variables selected in univariate analysis for inclusion in the multivariable model were Leptospira vaccination (yes or no), reproductive (neuter) status, breed group designation, number of vaccines per visit, age group, and weight group (Table 3). After backward stepwise elimination, variables retained in the final multivariable model were Leptospira vaccination, breed group, age group, and weight group (Table 4). These data were available for 111,974 dogs, which were included in the final analysis. The odds of having an owner-reported AE were significantly greater for dogs that received the Leptospira vaccine (adjusted OR, 2.13) than for those that did not. The odds of an AE were significantly lower for dogs that were 1 to < 7 years (adjusted OR, 0.54) or were ≥ 7 years of age (adjusted OR, 0.44), compared with dogs < 6 months years of age. Breed group was a significant predictor, with sporting breeds less likely to have owner-reported AEs, compared with mixed or miscellaneous breeds (adjusted OR, 0.45). Finally, weight group was a significant predictor of an owner-reported AE, with lower risk for medium-sized dogs (13.6 to < 22.7 kg; adjusted OR, 0.48) and large dogs (22.7 to < 45.5 kg; adjusted OR, 0.55) when compared with very small dogs (< 4.5 kg). The final model satisfied the Hosmer-Lemeshow goodness-of-fit test (P = 0.963).
Results (OR [95% CI]) of univariate analysis to identify potential risk factors associated with owner-reported AEs among the 130,557 dogs in Table 1.
| Risk factor | No. with AE | No. without AE | Total | OR (95% CI) | P value |
|---|---|---|---|---|---|
| Leptospirosis vaccination | |||||
| No (reference) | 271 | 112,729 | 113,000 | 1.00 | < 0.001 |
| Yes | 72 | 17,485 | 17,557 | 1.71 (1.32–2.22) | |
| Sex | |||||
| Female (reference) | 174 | 65,844 | 66,018 | 1.00 | 0.516 |
| Male | 166 | 63,361 | 63,537 | 0.93 (0.75–1.15) | |
| Reproductive status | |||||
| Sexually intact (reference) | 206 | 57,222 | 57,428 | 1.00 | < 0.001 |
| Neutered | 131 | 71,005 | 71,136 | 0.51 (0.41–0.64) | |
| Breed group | |||||
| Mixed or miscellaneous (reference) | 154 | 48,468 | 48,622 | 1.00 | 0.001 |
| Toy | 83 | 29,775 | 29,858 | 0.88 (0.67–1.15) | |
| Working | 12 | 6,917 | 6,929 | 0.55 (0.30–0.98) | |
| Herding | 15 | 8,746 | 8,761 | 0.54 (0.32–0.92) | |
| Terrier | 8 | 4,980 | 4,988 | 0.51 (0.25–1.03) | |
| Hound | 10 | 5,091 | 5,101 | 0.62 (0.33–1.17) | |
| Sporting | 15 | 11,328 | 11,343 | 0.42 (0.25–1.03) | |
| Nonsporting | 23 | 7,677 | 7,700 | 0.94 (0.61–1.46) | |
| No. of vaccinations per visit | |||||
| 1 or 2 (reference) | 218 | 91,736 | 91,954 | 1.00 | 0.015 |
| 3 or 4 | 124 | 38,380 | 38,504 | 1.36 (1.09–1.70) | |
| 5 | 1 | 98 | 99 | 4.29 (0.60–30.93) | |
| Age (y) | |||||
| 0 to < 0.5 (reference) | 126 | 29,444 | 29,573 | 1.00 | < 0.001 |
| 0.5 to < 1 | 19 | 6,381 | 6,400 | 0.73 (0.44–1.20) | |
| 1 to < 7 | 123 | 64,572 | 64,695 | 0.42 (0.33–0.57) | |
| ≥ 7 | 36 | 26,206 | 26,242 | 0.32 (0.22–0.47) | |
| Weight group (kg) | |||||
| 0 to < 5 (reference) | 126 | 32,459 | 32,585 | 1.00 | < 0.001 |
| 5 to < 14 | 123 | 44,869 | 44,992 | 0.73 (0.56–0.95) | |
| 14 to < 23 | 23 | 13,935 | 13,958 | 0.42 (0.26–0.69) | |
| 23 to < 45 | 41 | 26,954 | 26,995 | 0.39 (0.26–0.57) | |
| ≥ 45 | 1 | 3,421 | 3,422 | 0.09 (0.01–0.63) | |
| Leptospira vaccine administration | |||||
| Given alone (reference) | 9 | 1,781 | 1,790 | 1.00 | 0.555 |
| Given with 5-in-1 vaccine | 63 | 15,704 | 15,767 | 0.79 (0.39–1.82) | |
Not all data were available for all dogs.
Adjusted ORs (95% CI) determined by multivariable logistic regression modeling for prediction of owner-reported AEs among 111,974 dogs for which all data were available.
| Risk factor | Adjusted OR (95% CI) | P value | Overall P value |
|---|---|---|---|
| Leptospirosis vaccination | |||
| No (reference) | 1.00 | — | < 0.001 |
| Yes | 2.13 (1.58–2.86) | < 0.001 | |
| Breed group | |||
| Mixed or miscellaneous (reference) | 1.00 | — | 0.032 |
| Toy | 0.78 (0.56–1.07) | 0.117 | |
| Working | 0.63 (0.33–1.21) | 0.164 | |
| Herding | 0.59 (0.32–1.07) | 0.084 | |
| Terrier | 0.45 (0.20–1.03) | 0.060 | |
| Hound | 0.74 (0.38–1.47) | 0.393 | |
| Sporting | 0.45 (0.24–0.85) | 0.014 | |
| Nonsporting | 1.04 (0.65–1.66) | 0.868 | |
| Age group (y) | |||
| 0 to < 0.5 (reference) | 1.00 | — | < 0.001 |
| 0.5 to < 1 | 0.86 (0.52–1.42) | 0.551 | |
| 1 to < 7 | 0.54 (0.40–0.73) | < 0.001 | |
| ≥ 7 | 0.44 (0.29–0.67) | < 0.001 | |
| Weight group (kg) | |||
| < 4.5 (reference) | 1.00 | — | 0.006 |
| 4.5 to < 13.6 | 0.84 (0.62–1.13) | 0.242 | |
| 13.6 to < 22.7 | 0.48 (0.28–0.82) | 0.007 | |
| 22.7 to < 45.5 | 0.55 (0.34–0.89) | 0.016 | |
| ≥ 45.5 | 0.14 (0.02–1.04) | 0.054 | |
— = Not applicable.
Discussion
Vaccination against Leptospira spp has the potential to prevent leptospirosis in dogs, and may also prevent possible zoonotic transmission. However, concerns about the safety of Leptospira vaccines have limited their widespread use, even in endemic areas. By assessment of a large population of dogs undergoing routine vaccination in the present study, it was possible to estimate with reasonable confidence the IR of owner-reported AEs that developed ≤ 5 days after vaccine administration. Significant risk factors for owner-reported AEs after vaccination, as compared with referent values, were receiving a Leptospira vaccine, being ≤ 6 months of age, or weighing < 4.5 kg, which was in agreement with clinical experiences reported anecdotally. Appropriate guidelines for safe vaccine use rely on accurate data to allow better protection against serious diseases such as leptospirosis and to concurrently minimize adverse effects.
In some studies, the safety of vaccines has been measured as number of AEs per number of vaccines sold, rather than per dog. By focusing on dogs instead of vaccine doses, we were able to evaluate owner-reported AEs in the context of concurrently administered vaccines. Unfortunately, reliance on information reported by the owners to a veterinarian by telephone was also a major limitation of the study. We did not have complete clinical information about these animals and their clinical signs. Some AEs were nonspecific and may not have been related to the vaccine, and there may have been recall bias against events that happened earlier in the course of a vaccine response. Additionally, some AEs may not have been witnessed by owners; some owners may not have called to report a possible AE, especially if clinical signs were mild; or owners may have taken animals to another veterinarian and not reported the AE.
In some previous companion animal studies,21,24,25 the rate of postvaccination AEs ranged from 0.13 to 0.40/10,000 vaccine doses, although the methods of reporting AEs varied, with some relying on owner observations and others on the owner contacting a referring veterinarian and the patient undergoing medical evaluation before reporting. In the latter scenario, we consider it likely that fewer AEs would ultimately be reported because the information obtained from owners would be interpreted by a veterinarian who evaluated the animal prior to the signs being classified as representing a postvaccination AE. In our study, the IR for owner-reported postvaccination AEs (for any vaccine) was 26.3/10,000 dogs. This rate was considerably higher than those identified in some studies, and we attributed this difference to the manner in which AEs were classified as well as the use of number of dogs, rather than vaccine doses, as a denominator (many dogs in the study received multiple vaccines). Our findings were comparable to those of the cohort study by Moore et al19; in that study, the rate of AEs following vaccination (with any vaccine) was 38.2/10,000 dogs. This suggests that the findings of the 2005 study by Moore et al19 and of the present study should be generalizable to dogs in other general practice settings, if identification and reporting of postvaccination AEs by owners are consistent.
In the present study, the overall IR of owner-reported AEs in dogs administered the Leptospira vaccine (alone or with another vaccine) was 53.0/10,000, compared with 26.3/10,000 dogs that received any vaccine. The adjusted OR of having an owner-reported AE after Leptospira vaccination was 2.13. However, the design of our study could have resulted in underestimation of the incidence of minor AEs, not only because such reactions may have gone unreported by owners, but because when a dog had multiple owner-reported AEs, only 1 was included in the analysis (hypersensitivity [if present] or the event considered the most medically important). This was done to avoid pseudoreplication (as the 2 events would not be independent) while allowing the most severe AE, which is more important for making recommendations regarding vaccination, to be included in the analysis.
Moore et al19 reported that when multiple vaccines were given simultaneously, dogs had a higher risk of developing AEs than did dogs receiving 1 vaccine in a given visit. Although we also found an increased risk in the univariate analysis of owner-reported AEs after administration of 3 or 4 vaccines in a single visit (compared with 1 or 2), when this risk factor was incorporated into a multivariable model that included age and size, it was no longer significant. This should be interpreted as a possibly confounding interaction between age, size, and multiple vaccines. Importantly, smaller and younger dogs may still be at risk of leptospirosis, and strategies to allow them to be safely vaccinated are important. Reducing the antigen mass of vaccines for dogs at greater risk for AEs, such as very small or young dogs, might be warranted. This could potentially be done by not giving all vaccines at a single visit or by development of vaccines with smaller antigen mass designed for administration to small dogs; research to assess these possibilities would be valuable.
The fact that there were no significant differences in the IRs of owner-reported AEs for dogs that received a multivalent vaccine versus a single-antigen vaccine in a previous study19 supported that some AEs may be attributable to adjuvants present in inactivated (killed) vaccines, including Leptospira, B bronchiseptica (formulated for SC administration), rabies virus, and some B burgdorferi vaccines. Immune responses toward vaccine adjuvant have been described previously.26,27 Additionally, postvaccination immediate-type hypersensitivity reactions in dogs have been shown to be associated with fetal calf serum (a common culture medium), as well as gelatin, casein, and bactopeptone (common vaccine stabilizers).26 In the present study, we found no difference in the risk of owner-reported AEs between dogs that received a Leptospira vaccine alone versus those that received the same injection together with a 5-in-1 modified live virus vaccine that contained multiple antigens. Future research on reducing vaccine allergenicity while maintaining immunologic protection, especially for very small or small-breed dogs, should be a priority. Premarketing safety trials, because they are limited in size, will have limited power to detect rare AEs that may develop in animals with particular risk factors.
In the present study, the risk of having an owner-reported postvaccination AE among very small dogs (weighing < 4.5 kg) was > 7 times that for dogs categorized as giant (weighing > 45.5 kg). Similar results were found or suggested by other investigators: in a study19 in which patient body weight was not specifically evaluated, toy breeds were significantly more susceptible to AEs than were other breeds. Canine vaccines are administered on a dose per dog basis, rather than as a concentration per unit of body weight. The results of our study indicating that the risk associated with body weight (specifically, that for dogs < 4.5 kg, compared with dogs ≥ 45.5 kg) was greater than that for any other factor evaluated as a predictor for owner-reported AEs additionally support the contention that more research is needed to determine optimal vaccination strategies and vaccination safety, particularly for very small dogs.
The risk of having an owner-reported AE among young dogs (< 6 months of age) of the present study that received any vaccine was 2.3 times that of dogs in the oldest age group (≥ 7 years of age), similar to findings in the 2005 study by Moore et al.19 In the aforementioned study,19 the risk of such an AE peaked in dogs at 2 years of age and declined thereafter.
Some breeds in our study had a higher IR for owner-reported postvaccination AEs, compared with that for the overall population of study dogs. In the cohort study by Moore et al,19 breeds with the highest IRs were typically small, such as Dachshund, Pug, Boston Terrier, Miniature Pinscher, and Chihuahua, although body weight was not controlled for in the analysis. We also found some small breeds (Bichon Frise, Miniature Poodle, Miniature Pinscher, Maltese, Yorkshire Terrier, Miniature Schnauzer, Toy Poodle, Chihuahua, and Dachshund) had an apparent increase in IR for owner-reported AEs relative to that of the overall population, although most differences were not statistically significant and low weight alone was a risk factor as well. Some large-breed dogs also had a high IR of owner-reported AEs, such as German Shorthaired Pointer, Mastiff, and Pit Bull Terrier, suggesting that both body weight and genetic predisposition are among the factors that contribute to postvaccination AEs. Because of small sample size, the IR for some breeds could not be precisely estimated, and this was reflected in wide 95% CIs.
Although administration of the Leptospira vaccine in the present study was associated with an approximately 2-fold increase in the risk of postvaccination AEs as reported by owners, relative to that of the referent group of dogs that were vaccinated but not against leptospirosis, the risk was still extremely low. Moreover, when broken down by type of owner-reported AE, the IR of hypersensitivity-type AEs only increased from 6.2/10,000 dogs to 8.5/10,000 dogs with administration of Leptospira vaccine, and this difference was not significant. These data suggest that vaccination against leptospirosis should be performed for all dogs at risk of the disease except those that have had hypersensitivity reactions previously.
Strategies for prevention or management of postvaccination AEs can include pretreatment with antihistamine, monitoring dogs after vaccination, developing vaccines or vaccination schedules that allow for administering a lower antigen or adjuvant mass per visit while maintaining quadrivalent protection, or reducing frequency of vaccination for dogs that already have high antibody titers against canine distemper or canine parvovirus. The risk of illness and death from infectious disease should be considered and may outweigh the risk for postvaccination AEs in most cases.
ABBREVIATIONS
| AE | Adverse event |
| CI | Confidence interval |
| IR | Incidence rate |
VIP PetCare, Windsor, Calif.
SPSS Statistics, version 20, IBM Corp, Armonk, NY.
R, version 3.1.3, R Development Core Team, Vienna, Austria.
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