When a circulating antibody encounters the specific antigen it is directed against in the body, it binds to that antigen in order to destroy it. This binding creates an immune-complex. In some instances, when there is extensive formation of immune complexes, these large molecules may be deposited in certain organs of the body and result in inflammation of local tissue resulting in immune complex disease. An example of this in relation to vaccination occurred with the use of early Canine Adenovirus-1 (CAV-1) vaccine in which, shortly after being administered the vaccine, dogs developed a bluish cast to the cornea of the eyes. This abnormal condition was determined to be caused by fluid retention and inflammation of the corneal tissue resulting from the deposit of antibody-antigen complexes. Though dogs usually regained full vision, CAV-1 vaccines soon became overlooked in favor of the CAV-2 vaccines which protected against both adenovirus type-1 and type-2 but which did not cause the bluish cast. To this day, CAV-1 vaccines are still available, however, they are regarded unfavorably for widespread vaccination despite the fact that the immune-complex disease was later found to be an effect not of the CAV-1 antigen, but rather the high concentration of the carrier protein, bovine serum albumin (BSA), used in the early CAV-1 vaccines. The modern CAV-1 vaccines available today no longer cause "blue eye."

Vaccine-Induced Vasculitis (An Immune Complex Disease)
Vaccine-induced vasculitis is an adverse reaction that occurs very rarely in dogs, but it has been most often associated with administration of the rabies vaccine (although other vaccines may also be involved). This condition may present as many as 3-6 months following immunization. Additionally, there are causes other than vaccine reactions that may produce vasculitis in canines such as food allergy, drug reactions (i.e. ivermectin and itraconazole), lymphosarcoma, or unknown causes (idiopathic vasculitis). The vaccine-induced form of vasculitis, however, has a distinct, consistent histologic inflammatory (mononuclear/nonleukocytoclastic) pattern that may be helpful for differentiating this reaction from other underlying causes for vasculitis. In general, though cutaneous forms of vaccine-induced vasculitis may be identified by areas of hair loss and large red or purple spots ("purpura.") on the skin that may look like large bruises, the lesions may also appear as hives, a rash, or painful or tender lumps. In more severe cases, loss of blood flow to the skin may produce necrosis (death) of the skin, which will appear as ulcers or small black spots at the tips of the ears or toes.

Symptoms of systemic vasculitis are vague and appear similar to symptoms of many other disorders: fever, lethargy, muscle and joint pain, poor appetite, weight loss, and fatigue. More specific symptoms of vasculitis will be dependent upon the organ or organ systems involved which may include the brain and nervous system (behavioral disturbances, tremors, muscle weakness, seizures), gastrointestinal system (abdominal bloating, pain, bloody stools), the heart and lungs (difficulty breathing, coughing, exercise intolerance, heart enlargment), and the eyes (loss of vision).

In general, vasculitis associated with immunization is another form of "immune complex disease" and is believed to occur in dogs that have abnormal T-cell function. That is, T-cell unresponsiveness to circulating antigens (vaccine components) results in these antigens circulating in the blood for prolonged periods of time and thus providing time for the antigens to be deposited in tissues of the body, primarily the blood vessel walls. When this occurs, white blood cells (macrophages) will recognize the antigen as foreign and commence an attack on the vaccine component. Unfortunately, the inflammatory responses that accompany destruction of the antigen can injure the blood vessel, which will produce the condition of vasculitis. Damage to minor blood vessels may only result in mild symptoms of red patches on the skin where immune-complexes have been deposited. When larger blood vessels are involved or in cases of major systemic involvement, symptoms may be severe. Dependent upon the extent of the organ involvement and damage, many dogs will respond favorably to prompt administration of glucocorticoids (anti-inflammatory steroids). As with other immune-related hematologic disorders, however, dogs with vaccine-induced vasculitis are at high risk to developing and succumbing to the secondary complication of pulmonary emboli (when blood clots formed during vascular damage break free and are deposited in the lungs).

T-cell unresponsiveness that occurs primary to this type of adverse reaction may occur as an inherited defect, but more commonly it occurs as age-related compromise of the immune system. As dogs and humans get older, it is more common to encounter immune-system dysfunction. This presents a dilemma for veterinarians in regard to administration of vaccines because an aged immune system does not only increase risk for the older dog to contract and be more susceptible to infectious diseases, but also increases risk for adverse reactions to immunization. Therefore, not vaccinating places an older dog at considerable risk for acquiring and dying from infection, while vaccinating may cause auto-immune complications (most commonly immune-mediated hemolytic anemia) in some of these older dogs. Because, on average, risks of disease still outweigh immune reactions in older dogs and in absence of any previous indication that a dog may harbor immune dysfunction (currently there are no standard tests that could differentiate those dogs that will have an immune reaction from those who will not), veterinarians will typically recommend vaccination for older dogs. The use of antihistamines in conjunction with vaccinations, however, may be indicated to reduce some components of the inflammatory response associated with immune-complex formation for which these older dogs may be at higher risk (since histamine has been found to play a role in platelet aggregation associated with allergic vasculitis).

Reversion of Modified Vaccines to Cause Disease

The strategy employed to create modified-live vaccines is to diminish the disease-producing effects of the microorganism while retaining their ability to replicate and produce strong immunity in the immunized host. The method for attenuating an infectious virus is to grow it for long periods of time under unfavorable conditions, usually in cells from a species other than its usual host. To survive under these undesirable conditions, the virus will undergo changes which will help it adapt to the new host environment. These changes usually come about as random mutations in the genetic material of the virus. However, not all viruses will adapt through the same type or number of mutations. Prior to recombinant DNA technology which now allows for site-directed mutations, the number and types of mutations in attenuated viruses used in modified-live vaccines were unknown. As a result, some viruses used for immunization had mutations that reverted back to the disease-producing or "wild-type" form when inoculated back into the original host. In this situation, immunization was actually responsible for causing the disease which it was originally designed to protect against. This occurred with some early modified-live rabies vaccines and in human medicine, the type 1 and type 2 polio vaccines.

Nowadays, modern recombinant DNA technology provides the means for selective mutations with low-risk reversion frequency, making the reversion of modified-live vaccines to cause disease very unlikely and thus, inoculation much more safe and effective than earlier forms of these vaccines. However, because some live, attenuated viral components may be shed after immunization, it is recommended that dogs living in an environment with other dogs who are ill or immunosuppressed for reasons discussed above be administered killed vaccines and not modified-live vaccines to prevent possibility of infection in the immunocompromised dog.

Neurologic Disease (Epilepsy and Acute Disseminated Encephalomyelitis)

Recently in clinical medicine, there is the realization that some forms of epileptic seizures may manifest as a direct effect of immunologic mechanisms. In some of these cases, vaccination may trigger these mechanisms because introduction of an antigen sets off an immune assault directed on the nervous system. Though a rare condition, in canine medicine, neurologic disease has been associated with use of modified-live canine distemper antigen. As is often the case with adverse reactions using modified-live vaccines, immunosuppression may also play a role in development of neurologic reactions. Similar to the actual disease process of canine distemper, when modified-live virus is introduced into the dog, if the immune system does not respond rapidly enough then attenuated virus can cross the blood-brain barrier or enter the cerebrospinal fluid and gain access to the central nervous system. Replication of the attenuated virus in the tissues of the brain, though not pathogenic, cause an inflammatory immune response in the brain tissue resulting in tissue damage and lesions that give rise to neurologic symptoms. Such symptoms, which can present several days to weeks following the vaccination, include motor weakness, incoordination, difficulty breathing and/or epileptic seizures and may be preceded 24-48 hours by fever, depression, nausea and vomiting. Dogs demonstrating neurologic disorders following vaccination may be immunosuppressed or more predisposed to immunosuppressive effects of polyvalent vaccines and, therefore, should be considered candidates for immunization with killed vaccines or monovalent vaccines when available.

Orthopedic Disease (Vaccine-induced Hypertrophic Osteodystrophy; HOD)

The underlying pathologic changes that bring about Hypertophic Osteodystrophy (HOD; often called metaphyseal osteopathy in the research literature-- refer to "Growing Pains: Growth-Associated Bone Disorders in the Dog") are identical for both vaccine (or pathogen)-associated HOD and developmental/dietary-associated HOD. This was established by A.P. Mee and colleagues in a series of peer-reviewed publications.  In fact, Mee's group, physicians using canine models to explore cellular mechanisms responsible for Paget's disease in humans, characterized the cellular mechanisms responsible for HOD.  Mee's group provided considerable evidence that the defect in osteoclasts (increased number and size), which occur as the primary step in HOD development, occur as a result of increased levels of interleukin-6 (IL-6; a multi-functional cytokine produced by immune cells--macrophages, T-cells, B-cells--and endothelial cells).

In their reports, Mee et al. described a mechanism by which IL-6 is up-regulated as a result of production of reactive oxygen species that activate Nuclear Factor kappa-beta (NF-kb) which in turn, induces IL-6. Pathogens like bacteria and viruses, but also certain nutrient-overloads (iron-overload for instance) induce these reactive oxygen species. Therefore, exogenous factors that may activate the cellular pathway of IL-6 induction lead to osteoclast defects that are the underlying pathologic cause of HOD.

As described above under Neurologic Disease, modified-live canine distemper vaccine has been linked to Acute Disseminated Encephalomyelitis in dogs. It is conceivable that similar to inducing inflammatory responses in neurologic cells, the modified-live distemper component of multivalent vaccines may similarly induce inflammatory responses in osteoclasts. In fact, a recent study by Harrus et al. suggests that as with acute encephalomyelitis, the use of multivalent vaccines increases risk for HOD development since dogs vaccinated with only trivalent, modified-live canine distemper have a lower risk for HOD. Therefore, the CDV vaccine (when administered as a multivalent vaccine) could induce the same IL-6 pathway thus leading to HOD in the same manner as virally-induced HOD or dietary-induced HOD.

So if HOD is the same disease for pathogen-induced, vaccine-induced, or dietary induced HOD, why do dogs with dietary-induced HOD typically have a better anticipated outcome than those with vaccine-induced HOD? This probably is explained by duration of the exogenous-causative factor. Dietary agents typically have rapid pharmacokinetics (metabolic inactivation and clearance from the body). Once the dietary imbalance is corrected or the offending nutrient is discontinued, induction of IL-6 will discontinue because the nutrient will be cleared from the body and the number of reactive oxygen species will decrease. In contrast, the modified-live viruses in CDV vaccines, though non-pathogenic, have the ability to continue to reproduce themselves (to augment the immune response) and will be around until the immune system can produce sufficient antibody titer to eradicate the viral component--this might take a considerable amount of time particularly when considering that HOD presents in puppies prior to 6 months of age who have immature immune systems or in puppies that are immunocompromised for other reasons. Interestingly, if one observes age of HOD incidence one may find a correlation between loss of circulating maternal antibodies--which immediately neutralize vaccine components but gradually decrease in the puppy's circulation beginning about 6-8 weeks of age--and onset of HOD. That is, maternal antibodies may protect puppies or reduce severity of vaccine-induced HOD for the first few months, but as maternal antibody titer decreases, incidence and severity of vaccine-induced HOD will increase. This may explain the observation that symptoms of HOD are most severe between 3-6 months. Therefore, in breeds or lines predisposed to HOD, immunization with only killed-, monovalent-, or subunit vaccines is recommended.

Autoimmune Disease

Recent research exploring the cause for persistent arthritic symptoms in human patients previously diagnosed and treated for Lyme disease has linked recurrent arthritic symptoms to autoimmunity triggered by a protein carried by the Lyme disease organism, Borrelia burgdorferi. Put more simply, it has been found that some people have inherited a protein on their normal cells that is very similar to an antigen on the surface of the Lyme bacteria. When these people contract Lyme disease, their bodies launch an immune defense directed at the Lyme bacteria by targeting this particular antigen. As a result, their immune system will attack both the bacteria carrying this protein as well as their own normal cells that also carry this protein. Therefore, even after the infectious microorganisms are eradicated, symptoms of arthritis persist because the immune system continues to attack their own normal cells. This condition is known as "molecular mimicry," and these findings are of particular relevance to immunologists, especially to those who have developed vaccines against Lyme disease. Immune response derived from Lyme vaccines currently undergoing testing in clinical trials are directed at this protein antigen, therefore, it is anticipated that a small population of individuals may have a genetic predisposition for developing autoimmune symptoms after immunization with these vaccines. Interestingly, the observation that some dogs develop arthritic symptoms following vaccination with Lyme vaccine, despite the absence of clinical Lyme disease, suggests that an autoimmune reaction to the Lyme vaccine may develop in canines as well as humans. To date, however, "molecular mimicry" has not yet been demonstrated in the canine host.

Anaphylactic Reactions and Acute Adrenal Insufficiency Crisis

Allergic reactions to vaccines are extremely rare; however, they may occur as a result of hypersensitivity to antibiotics or preservatives, or to an antigenic component of the vaccine, commonly the leptospirosis bacterin (see Canine Anaphylaxis). Allergic reactions to vaccines can result in mild symptoms of localized swelling to severe physiologic symptoms leading to systemic shock and eventually death. Recent clinical findings suggest that cases of severe anaphylaxis may be a result of underlying endocrine disorders. The endocrine system is composed of glands that control the secretion of hormones involved in a number of normal bodily functions including the regulation of immune response. Certain hormones are synthesized by the endocrine glands in response to immune factors and act as a negative feedback to control and balance the immune reaction. In particular, glucocorticoids, such as cortisol, which are produced by the adrenal glands are hormones which through a number of pathways regulate and suppress the function of B cells, T cells, macrophages and other mediators of inflammation as well as controlling a number of other physiological processes including electrolyte balance. However, although uncommon, some dogs may have an underlying disorder of the adrenal glands that causes a condition referred to as hypoadrenocorticism (Addison's disease) which precludes the ability of the adrenal glands to secrete glucocorticoids in response to various stress stimuli including immunization. As a result, deficiency of glucocorticoids in response to immunization can result in symptoms of lethargy, loss of appetite, weakness, vomiting, diarrhea, seizures and in more severe cases leads to life-threatening systemic shock known as Addisonian crisis. Hypoadrenocortism is more common in females than males and usually presents in dogs between 1 and 7 years of age. Evidence suggests a genetic predisposition to the development of this disorder particularly in Standard Poodles, Labrador retrievers and Portuguese water spaniels. Although some dogs may present with symptoms indicative of disease (depression, generalized weakness, dehydration), many cases remain subclinical and are only diagnosed after hypoadrenal crisis precipitated by physical stress associated with trauma, infections, surgery, or immunization. Because symptoms of adrenal insufficiency are similar to adverse systemic reactions resulting from allergic anaphylaxis, dogs which have exhibited severe adverse reaction to immunization should be tested for this endocrine disorder. The adrenocorticotrophic hormone (ACTH) stimulation test is currently the method for clinical diagnosis.