Although vaccines are designed to be immunogens and must have potency, safety, and efficacy before licensing, no vaccine is completely free of adverse reactions or totally effective. While pre-marketing safety trials by manufacturers help ensure that vaccine-associated adverse events (VAAEs) occur infrequently, their potential has generated public and professional concern regarding overvaccination of humans and animals.

A published retrospective cohort study of over 1.25 million dogs vaccinated at 360 veterinary hospitals permitted accurate estimation of the incidence rate of practitioner-diagnosed acute VAAEs occurring within 3 d of vaccine administration. Specific clinical signs and treatments were reviewed in a random sample of 400 affected dogs. The association between potential risk factors and a VAAE was estimated by use of multivariate logistic regression.

There were 4,678 adverse events (38.2/10,000 dogs vaccinated) associated with administration of 3,439,576 doses of vaccine to 1,226,159 dogs. The VAAE rate decreased significantly as body weight increased. Risk was 27-38% greater for neutered versus sexually intact dogs and 35-64% greater for dogs approximately 1-3 yr old versus 2-9 mo old. The risk of a VAAE significantly increased as the number of vaccine doses administered per office visit increased; each additional vaccine significantly increased risk of an adverse event by 27% in dogs = or < 10 kg (22 lb) and 12% in dogs > 10 kg.

The risk of a VAAE in this study population was inversely related to a dog's weight. This weight -response relationship had been suggested previously in a study where toy breed dogs had significantly more suspected vaccine reactions than other dogs. [Vaccines, in contrast to nearly all veterinary pharmaceuticals, are prescribed on a 1-dose-fits-all basis, rather than by body weight.] A genetic predisposition to VAAEs has been documented for some dog breeds, and the relatively low VAAE rate observed in mixed-breed dogs suggests that laboratory safety trials using mixed breeds may underestimate the VAAE rates that would occur in purebreds. This is important because purebred dogs comprise at least two thirds of the US dog population. Further, the risk of allergic reaction has been reported to increase after the 3rd or 4th vaccination.

In the present study, VAAE risk increased for dogs up to 2 yr of age and then declined thereafter. The decline after 2 yr of age may have been attributable to allergen desensitization, initiation of an alternative vaccination protocol in predisposed dogs, or owner refusal to revaccinate dogs that previously had a VAAE. Neutering appeared to increase the risk of a VAAE more than sex. Females are believed to mount stronger immune responses after vaccination or infection than males because of a dimorphic enhancing effect of estrogens and a protective effect of androgens.

Research is still required to characterize the primary allergenic components of different licensed veterinary vaccines, and it remains to be determined whether vaccine allergenicity and volume can be reduced while immunologic protection is maintained, particularly for smaller dogs.

Premarketing safety studies, when fiscally or logistically limited in size, will remain limited in power to detect rare adverse events that may be more common among animals with particular risk factors.

Conclusions and Clinical Relevance—Young adult small-breed neutered dogs that received multiple vaccines per office visit were at greatest risk of a VAAE within 72 hr after vaccination. These factors should be considered in risk assessment and risk communication with clients regarding vaccination.