Postvaccinal adverse events (Proceedings)

Since the original companion animal vaccines were developed and licensed more than 50 years ago, there has been a continuing effort to make vaccines safer and more efficacious. Today, it is generally agreed that the vaccines licensed for dogs and cats have not only saved millions of lives but also have an excellent safety record. Despite widespread use of vaccines today, documentation of post-vaccinal adverse reactions ('events') in veterinary medicine is limited.

In veterinary medicine, post-vaccinal adverse event reporting is "passive"…which means that data collection is limited to those reports voluntarily submitted by veterinarians to the manufacturer and/or the USDA. For a variety of reasons, there is currently no national database of veterinary vaccine adverse events accessible to the profession. In large, awareness of vaccine reactions is limited to personal experience, anecdotal reports, and a few published studies.

This presentation is intended to characterize various types of vaccine adverse events in companion animals, provide information on how to report known/suspected adverse events, and offer suggestions for mitigating the risk of vaccination in patients with a prior vaccine adverse event history.

Defining an adverse event

According to the USDA, a vaccine adverse event can be defined as any undesirable side effect or unintended effect (including lack of desired result) associated with the administration of a licensed biological product (vaccine). Adverse events include any reaction that could compromise the health of the dog or cat, including the apparent failure to immunize. NOTE: An adverse event includes any injury, toxicity, or sensitivity reaction associated with the use of a vaccine, whether or not the event can be directly attributed to the vaccine. In other words, it is appropriate to report any known or suspected negative event associated with vaccination.

HOWEVER……vaccines are biological products and, as such, can be expected to provoke minor reactions lasting from a few hours to as long as a few days. Rarely do these self-limiting side effects escalate into serious adverse events. For this reason, veterinarians are encouraged to inform clientele that their pet, regardless of breed/size, may manifest transient side effects for up to 2, and possibly 3, days following administration of any vaccine or any combination of vaccines. Side-effects commonly observed include: reduced appetite, loss of appetite (lasting for 1 or 2 feedings), pain at the injection side, lethargy (lack of activity), reluctance to walk/run (discomfort?), and mild fever. Treatment is not generally necessary; however, some veterinarians do report administering short-term treatment (e.g., a non-steroidal anti-inflammatory drug) given either before or at the time of vaccination to mitigate expected minor reactions. It is recommended that clientele be advised to contact the practice in the event any physical/behavioral manifestations progressively worsen or continue beyond 2 to 3 days. Clientele should be advised to contact the practice at any time if signs of systemic illness, such as vomiting, diarrhea, seizures, collapse, facial swelling, or difficulty breathing, develop.

Types of vaccine adverse events

The actual prevalence of vaccine adverse events in veterinary medicine is unknown. The list that follows is not considered to be comprehensive but does represent a summary of known and suspected event categories.

      - Injection-site reactions: (minor) lumps caused by abscess, granuloma, or seroma, pain, swelling, (potentially severe) hair loss associated with ischemic vasculitis.

      - Transient post-vaccinal non-specific illness: lethargy, anorexia, fever, regional lymphadenomegaly, soreness, abortion, encephalitis, polyneuritis, arthritis, seizures, behavioral changes, hair loss or color change at the injection site, respiratory disease.

      - Allergic (hypersensitivity) and immune-mediated reactions:

          • Type 1 (acute anaphylaxis): angioedema (especially the head), anaphylaxis (shock), and death.

          • Type 2 (cytotoxic): immune-mediated hemolytic anemia; immune-mediated thrombocytopenia (suspected only; causality has not been confirmed)

          • Type 3 (immune-complex): cutaneous ischemic vasculopathy associated with rabies vaccine that can occur at the injection-site or a distant location (eg, ear tips); undefined immune-mediated diseases.

      - Failure to immunize: maternal antibody interference with vaccination is considered the most common cause; administration of vaccine at a volume/dose less than that prescribed by the manufacturer; "non-responder" (genetic predisposition?); inactivation of vaccine antigen (eg, allowing reconstituted CDV vaccine to stand at room temperature for more than 2 hours), mixing of incompatible vaccines in the same syringe.

      - Tumorigenesis: vaccine-associated sarcoma (especially in cats) or other tumors.

      - Multi-systemic infectious/inflammatory disorder of young Weimaraner dogs: may be linked to a poorly characterized immune deficiency in the breed.

      - Vaccine-induced immune suppression: associated with attenuated (MLV) vaccine. Rarely may lead to development of severe disease associated with opportunistic infection.

      - Immunosuppression: When combination vaccines containing MLV CDV and CAV-1 or CAV-2, along with other vaccines, are first administered to puppies, immune-suppression occurs beginning 3 days after vaccination, and can persist for 7 or more days.

      - Reactions caused by the incorrect or inappropriate administration of vaccine: fatalities have been reported following subcutaneous administration of an avirulent-live Bordetella bronchiseptica bacterin (intended for intranasal administration); inadvertent or intentional administration of vaccine by the intravenous route.

      - Reactions associated with residual virulence attenuated vaccine: post-vaccinal sneezing associated with intranasal administration of attenuated vaccine (eg, B. bronchiseptica + parainfluenza virus)

      - Vaccine-induced interference with diagnostic tests: false-positive PCR test results for parvovirus antigen in feces in dogs recently receiving a MLV parvovirus vaccine.

      - Reversion of vaccine virus to a virulent pathogen: generally considered rare to non-existent among currently licensed canine vaccines when vaccines are used in the species for which they were licensed. This can become a significant problem when vaccine licensed for use in dogs/cats is used in wild and/or exotic animals.

Reporting an adverse event

Vaccine manufacture

Companies that manufacture vaccines maintain a technical services section that will accept and address adverse event reports from veterinarians who use their product(s). Veterinarians are encouraged to report adverse events to the manufacturer(s) prior to contacting the appropriate regulatory agency. Manufacturers are required to maintain files of any reported vaccine adverse event.

NOTE: manufacturers are under no obligation to compensate the owner or the veterinarian for diagnostic or treatment services related to a known or suspected adverse event.

USDA's center for veterinary biologics (CVB)

Subsequent to reporting a known or suspected vaccine adverse event to the manufacturer, veterinarians practicing within the United States may contact the USDA, APHIS CVB in one of the following ways:

Once an adverse event has been reported to the manufacturer, The CVB may be contacted:

     • On-line: Adverse Event Electronic Report Form.

     • By fax or mail: Download the pdf form (17kb) and FAX to (515) 337-6120 or by mail to the CVB.

     • By telephone: Adverse events may also be reported by calling the CVB at (800) 752-6255.

Management of patients at risk of an adverse event

Specific recommendations for mitigating the risk of a vaccine adverse event in dogs have not been validated. Efforts to manage risk are highly varied and largely unsubstantiated. It is not possible to completely avoid risk of a vaccine adverse event in any patient. Vaccine risk management should focus on dogs having a known or suspected history of a vaccine reaction and on small breeds. Recommendations are outlined below.

Patients with a known or suspected vaccine adverse event history

Acute hypersensitivity (non-systemic) and injection-site reactions are among the most common vaccine adverse events reported because they occur within hours or a few days after vaccination. The decision to administer vaccine to any patient with a history of having experienced an acute-onset (minutes to 1-2 days post-vaccination) reaction is left to the discretion of the veterinarian. Prior history of an acute-onset adverse event is not predictive of future risk.

Administration of an antihistamine or non-steroidal anti-inflammatory drug (NSAID) prior to vaccination to prevent transient post-vaccinal non-specific illness has not been studied adequately in dogs to make specific recommendations on their use or benefit. However, it is common practice to administer an antihistamine (diphenhydramine, 2-4 mg/kg, orally or 1 mg/kg parenterally) to patients having a history of a prior acute adverse reaction. A single dose is generally administered 15 to 30 minutes prior to administering vaccine. In such cases, it is recommended that the patient remain at the practice and be monitored for at least 30 minutes post-vaccination.

In an attempt to mitigate the risk associated with administering vaccine to any patient with acute-onset vaccine adverse event, veterinarians may also elect to administer the same vaccine type but one produced by a different manufacturer. It should be noted, however, that the same allergenic proteins found in one manufacturer's vaccine can be found in any other vaccine. Changing vaccine products is not a guarantee that the risk of an adverse event will be avoided.

It is reasonable to avoid administration of any vaccine to patients having a history of systemic disease suspected to be associated with prior vaccination (e.g., immune-hemolytic anemia, immune-mediated thrombocytopenia) or known to be caused by vaccine (vaccination-site cutaneous ischemic vasculitis following administration of rabies vaccine). In lieu of annual or triennial re-vaccination, assessment of antibody titers can be determined (CDV and CPV or FPV).

The decision not to administer Rabies vaccine for health reasons is problematic in locations that require rabies vaccinations yet do not grant rabies exemption authority to veterinarians. Some States do grant rabies vaccination exemption authority to veterinarians who have examined a patient and determined, for health reasons, vaccine should not be administered. Such waivers generally remain in effect until the patient is deemed sufficiently healthy to receive the vaccine. Veterinarians are urged to contact State and/or local authorities regarding rabies vaccination exemption authority and to determine whether or not such authority exists.

Small breed dogs

One study (over 1 million dogs/3.8 million doses of vaccine) has addressed vaccine adverse event occurrence within 3 days. This study provided important insight on risk associated with administration of multiple vaccine doses to small breed dogs at the same appointment. Prior history of a vaccine adverse event in a small breed dog is not predictive of future risk. Any dog, regardless of size, breed, gender, or age, can experience a vaccine adverse event.

Mitigating risk in small dogs (puppies and small breeds) by reducing the volume of vaccine is not recommended. Doing so may result in a sub-optimal response to the vaccine and may not eliminate risk associated with hypersensitivity to one or more vaccine constituents. As with all dogs, small breed dogs should be assessed for risk of exposure to infectious pathogens and only those vaccines considered essential should be administered. Furthermore, prioritizing administration of CORE vaccines (CDV, CPV-2, CAV-2, and rabies) to all dogs at the appropriate age is recommended.

Therefore, when administering vaccines to small breed dogs, veterinarians should consider delaying administration of NON-core vaccines (especially killed viral and bacterial vaccines) to small breed dogs until after completion of the initial CORE vaccine series.

Selected reading

Sykes JE, Hartmann K, Lunn KF, et al. 2010 ACVIM Small Animal Consensus Statement of Leptospirosis: Diagnosis, Epidemiology, Treatment, and Prevention. J Vet Intern Med 25:1-13, 2011.

Moore GE, Frana TS, Guptill LF, et al, 2005. Postmarketing surveillance for dog and cat vaccines: new resources in changing times. J Am Vet Med Assoc. 227:1066–1069.

Moore GE, Guptill LF, Ward MP, et al, 2005. Adverse events diagnosed within three days of vaccine administration in dogs. J Am Vet Med Assoc. 227:1102–1108.

Martinod, S, 1997. Adverse Effects of Vaccination in Veterinary Vaccinology. P.P. Pastoret et al (ed). Elsevier, Amsterdam, pp 574-580.

Meyer, EK, 2001. Vaccine-associated adverse events. Vet Clin N Am:Small Anim Prac. 31:493-514.

Day MJ et al. A kinetic study of histopathological changes in the subcutis of cats injected with non-adjuvanted and adjuvanted multi-component vaccines. Vaccine. 2007

Shaw SC, Kent MS, Gordon IK, Collins CJ, Greasby TA, Beckett LA, Hammond GM, Skorupski KA. Temporal changes in characteristics of injection-site sarcomas in cats: 392 cases (1990-2006). J Am Vet Med Assoc. 2009 Feb 1;234(3):376-80.