Vaccines, both in human and animal medicine, have come under attack recently with critics blaming adverse reactions and long-term health disorders on their wide-spread and frequent use. However, most immunologists agree that the risks of disease far outweigh the risks associated with the process of vaccinating. Unfortunately, to those humans and pets who comprise the minority high-risk group for vaccine reactions, the advantages offered by vaccines are understandably overshadowed by fears of debilitating or even fatal adverse reactions.

The following article provides a brief overview of the canine immune system and the benefits which canine vaccines provide. Additionally, the controversy of vaccination is examined in relation to underlying health disorders or situations that may increase potential risk to adverse reactions.

The Canine Immune System
Bacteria, viruses, fungi, foreign proteins, cancer are all organisms or conditions which constantly pose a threat to the canine body. Like all species of organisms, the canine body is equipped with an elaborate system of defense, known as the immune system, designed to protect it from these infectious enemies.

There are two major components to immunity. The first component called recognition" occurs when a foreign agent invades the body for the first time. The immune system recognizes the agent as foreign and within a short time, a series of reactions begin which eventually destroy the invader. Because it takes time for the immune system to launch its defense, first-time invaders usually will produce symptoms of illness, and severity will depend on the extent of exposure and invasiveness of the enemy agent. However, once the first-time invaders are destroyed, if that particular enemy agent attempts to invade at a later time, the immune response will occur much more rapidly and the body will experience few or no symptoms before the agent is destroyed.

The second component of the immune system is called "discrimination". The immune system must be able to differentiate the normal tissues and fluids that make up the canine body from the invading agent. To facilitate this, the cells of the dog's own body have a unique set of molecules on their surface which allows the dog's immune system to recognize them as its own cells. However, the molecules on the surface of an invading agent, called antigens, will be different and will, therefore, allow the immune system to recognize the agent as foreign and initiate a defense.

Therefore, for normal immune system function, both of these components, recognition and discrimination, are vital for the survival of the dog.

How the Immune System Works
When a foreign agent gains access to the body of the dog, the intrusion is detected through the body's security network called the lymphoid system. Lymph nodes are strategically located to guard portal entries into the body. An enemy invader will eventually reach the circulation and be filtered out through the lymph nodes or the spleen. In the lymph nodes, white blood cells called macrophages, surround and degrade the foreign agent and eventually expose antigens. The immune system then responds to the antigens in two ways. B lymphocytes, cells originating in the bone marrow, have proteins on their surface which will bind to the antigens. Binding, in turn, activates the B lymphocyte to mature into a plasma cell that multiplies and then is released into the blood circulation. Once circulating through the body, the plasma cells synthesize and secrete specific antibodies that target and destroy all invaders displaying that particular antigen. Once the infectious material is destroyed, the mature B lymphocyte, or plasma cell, remains in circulation as a "memory cell". If the body becomes invaded again by the same foreign agent, the memory cell produces antibodies to the antigen so rapidly that the infectious agent does not have an opportunity to multiply and produce symptoms of infection in the dog.

In addition to the B lymphocyte, the immune system is composed of another cell type which can recognize and bind to antigens. However, these cells do not secrete antibodies. Instead, T lymphocytes that mature through the thymus gland, have proteins on their surfaces called T cell receptors which may bind to the antigen. Additionally, these immune cells release certain biological factors that attract macrophages to the area of infection. There are three types of T cells involved in immunity: the cytotoxic or killer T cells bind to and destroy other cells which display antigens on their surface; the helper T cells which assist B cells to stimulate the growth and secretion of antibodies; and suppressor T cells which reduce B cell activity and thereby play a role in reducing the possibility of an autoimmune response.

Vaccines: Preparing the Immune System In Advance For Invasion The Theory Behind Vaccination
Canine infectious diseases are caused by organisms which gain access to the body, multiply, and in the process of their life cycles cause severe and in some cases irreparable damage to the cells which make up organs and tissues of the body. Even in animals with normal immune function, invasion and damage can proceed at a rate faster than the immune system's ability to destroy the invader. In cases where organ function is severely compromised, the dog may succumb to the disease before the immune system can eradicate the infection, or in cases where the infection is eliminated, death or debilitation may still occur as a result of irreparable cellular damage.

Based on the knowledge that the immune system responds much more rapidly if it encounters an invading organism that it has already battled and defeated, the theory that introducing just enough antigen into the body to illicit an immune response without causing disease would protect the body from contracting the disease at a later time gave rise to the procedure of vaccinating. Therefore, "vaccination," also known as "active immunization" refers to the procedure whereby administration of an antigen results in protective immunity to the disease associated with that antigen.

Types of Vaccines
Killed vaccines. Killed vaccines are composed of "inactivated" microorganisms which cause a particular infectious disease. Because these microorganisms are dead they are unable to replicate once introduced into the dog's body and therefore are incapable of producing disease. However, their presence will induce an immune response. Therefore, in terms of some adverse reactions, killed vaccines are considered to pose fewer risks. In terms of protective immunity, however, killed vaccines produce weak immune responses and provide a shorter duration of protective immunity. In many cases, killed vaccines must be administered in large or frequent antigenic doses to induce a sufficient immune response to yield protection in the event of disease exposure.

Modified live vaccines. Modified live vaccines are composed of "attenuated" microorganisms; that is, these microorganisms associated with a particular disease are altered so that they do not cause infection in most dogs, but they are still capable of replicating and inducing a protective immune response. Because these microorganisms are still capable of replicating and spreading throughout the body like an infectious agent, they elicit a stronger protective immunity of longer duration. As such, however, a higher frequency of adverse reactions is associated with use of modified live vaccines (discussed below) and therefore, not all dogs are good candidates for immunization with modified live vaccines.

Subunit vaccines. Subunit vaccines are composed not of the whole microorganism but only a component of the microorganism which will produce an immune response. Therefore, subunit vaccines are similar to killed vaccines in that they are not infectious and therefore, also present a low risk for adverse reactions. However, as with killed vaccines, subunit vaccines cannot replicate and, therefore, do not provide strong protective immunity for long periods of time. Because of these factors as well as the higher cost for production, subunit vaccines are used less frequently than modified live and killed vaccines.

The Vaccine Controversy: To Vaccinate or Not to Vaccinate Even vaccines that have been proven to be safe and effective in a majority of individuals may cause adverse reactions when administered to certain individuals. In most instances and from a historical perspective, however, when one examines the correlation between introduction of a particular vaccine and decline in incidence of the respective disease subsequent to initiation of inoculation, the benefits of immunization for preservation and protection of health are clearly evident. For example, in 1990 the number of laboratory confirmed cases of dogs infected with rabies were approximately 150 for the year. Prior to local government enforced vaccination of dogs against rabies, the reported confirmed cases of this disease were approximately 7000 cases/year. Since, on the average, modern-day canine vaccines pose only a 1:60,000 risk that an individual dog will develop an adverse reaction, the benefits of administering the rabies vaccine for protection against disease far outweigh the risks of occurrence of adverse reactions. However, some early modified live rabies vaccines posed a high risk for bringing about active disease in both the immunized host and other non-immune individuals exposed to virus shed by the vaccinated animal because the injected microorganisms reverted back to an infectious state. Under these circumstances, the risks associated with vaccinating for rabies were unacceptable. Therefore, whenever deciding whether or not to immunize it is important to take all of the following factors into consideration: the risk of infection, the consequences of the disease, the availability of a safe and effective vaccine, and the duration for which the vaccine will provide protective immunity.

Risks and Consequences of Canine Infectious Diseases (Reprinted from R. Foster and M.R. Smith, The Doctors Foster & Smith Catalog)
 

Canine distemper is a widespread, often fatal viral disease in which the early symptoms are similar to those of an upper respiratory infection in man. Fever, cough and nasal discharge occur regularly. If left untreated, signs of neural involvement may appear, including localized muscle twitching (chorea) and convulsions. Distemper is often resistant to treatment, but can be prevented through vaccination.

Canine adenovirus type-1 and type-2 cause infectious hepatitis and respiratory infection, respectively. Hepatitis caused by adenovirus type-1 may cause severe kidney damage or death. Common signs of this disease include listlessness, fever, loss of appetite, vomiting, excessive thirst, and discharges from the eyes and nose. Adenovirus type-2 is an important factor in kennel cough.

Canine bordetella may contribute to kennel cough. This bacterial infection can occur alone or in combination with distemper, adenovirus type-2 infection, parainfluenza, and other respiratory changes.

Canine leptospirosis is a bacterial infection which may lead to permanent kidney damage. The disease is easily spread to other pets and to humans. Depression, fever, and loss of appetite appear suddenly, and jaundice, vomiting, dehydration, excessive thirst, and excessive urination may indicate liver and kidney damage.

Canine parainfluenza is another cause of kennel cough. Although parainfluenza is often a mild respiratory infection in otherwise healthy dogs, it can be severe in puppies or debilitated dogs.

Canine parvovirus is a disease of widespread distribution which may cause severe dehydrating diarrhea in dogs of varying ages. Parvovirus infection is especially dangerous for puppies and very old dogs. In some instances, this disease leads to secondary heart disorders.

Canine coronavirus infection is highly contagious intestinal disease causing vomiting and diarrhea in dogs of all ages. Especially in young puppies, dehydration from coronavirus infection can be life-threatening.

Lyme disease, a bacterial disease caused by Borrelia Burgdorferi, may be spread by insects such as flies, fleas and ticks. Arthritic-like symptoms may occur.

Rabies, a disease which has reached epidemic proportions throughout the United States, is almost always fatal. Rabies virus attacks the brain and central nervous system, and is transmitted to humans chiefly through the bite of an infected animal.

Kennel Cough - There is no vaccine for complete protection against infectious canine cough. Thirteen different viruses and bacteria are implicated as its cause. Currently vaccines are available for 3 of the 13 known components of the disease complex. These three include Parainfluenza, Adenovirus Type 2, and Bordetella. By vaccinating for these 3 diseases, 90% of the cases of kennel cough can be eliminated. Canine cough is usually a mild, self-limiting disease, but it can develop into a severe bronchopneumonia, especially in younger dogs. The most common sign of this disease is a harsh unproductive cough that leads to gagging or even vomiting.

Hazards Associated With Vaccines
In addition to the antigen, vaccine suspensions also contain other ingredients which may include other antigens, protein from tissue culture or egg yolk, preservatives like antibiotics, and carrier proteins such as aluminum for enhanced immunogenicity. Therefore, adverse reactions may result as a response to the antigen or to anyone of these additional components. Over the years, improvements in techniques for antigen development and better purification procedures for the production of vaccines has resulted in fewer hazards associated with immunization. However, adverse reactions may still occur in certain individuals. The following are some potential hazards associated with vaccination.

Immunosuppression
Canine vaccines immunizing against several infectious diseases are routinely manufactured as pre-mixed for administration as all-in-one-vaccines; that is, one inoculant contains many different antigens that are administered as a single "shot". Such vaccines are termed polyvalent vaccines as opposed to monovalent vaccines, which would contain only antigen directed at immunizing against a single infectious agent.

Concerns have often arisen regarding the widespread use of polyvalent vaccines because they are believed to cause a significant decrease in immune function known as immunosuppression. Immunosuppression may result when the amount of antigen introduced into the dog exceeds the ability of the immune system to respond. Such a condition is termed antigen-overload. Immunosuppression may also occur as a result of one antigen component of the vaccine preventing the immune system from responding to another antigen component of the polyvalent vaccine. This latter form of immunosuppression is termed vaccine interference.

Clinical studies exploring different polyvalent vaccines have demonstrated a significant degree of immunosuppression associated with inoculation with polyvalent vaccines; however, duration of immunosuppression was only 7-10 days. Therefore, from a clinical standpoint, such a brief period of immunosuppression in an otherwise healthy dog is not considered cause for concern. However, if a nutritional deficiency or hereditary immune disorder already compromises a dog's immune system, the added immunsuppression may result in clinical illness if the dog is exposed to an infectious disease within the 7-10 day margin. Alternatively, if the dog has already been exposed to an infectious disease and is in the process of defending against a mild infection which is asymptomatic, the increase in immunosuppression caused by administration of the polyvalent vaccine may also result in clinical illness. In the latter situation, clinical symptoms of infection will present within 24-48 hours following vaccination. In these situations, it is common for many dog owners to blame the vaccine for causing the disease, when in actuality, the vaccine only made the underlying condition apparent. In light of this, in dogs suspected of harboring mild infections or who may be immunosuppressed due to other factors (immune disorders, seasonal allergies, certain medications), vaccination with polyvalent vaccines should be postponed until the underlying condition has resolved, or if risk for contracting infectious disease is high, use of monovalent vaccines or killed vaccines might be an alternative option.

Immune Complex Disease
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, inducesIL-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.

Vaccines in the Pregnant Bitch
Use of both modified-live vaccines and killed vaccines are contraindicated for immunization of pregnant bitches unless the vaccine has been specifically approved for this purpose or risk of contracting an infectious disease exceeds potential risks of vaccinating to the dam and litter. Problems associated with vaccination during pregnancy include fetal resorptions, spontaneous abortions, and birth defects. Advanced proper planning prior to the bitch's breeding cycle, which would include updating necessary inoculations, should exclude the necessity to vaccinate during pregnancy. Routine annual booster administration does not justify risks and should be postponed until the litter is whelped and the puppies are weaned (see Annual Boosters: How necessary are they? below).

When Vaccines Fail: Factors which may interfere with effective immunization Use, storage and administration
Many times, failure of a vaccine to protect against a particular disease is blamed on the quality of the vaccine. However, vaccine ineffectiveness is most often a result in failure, whether knowingly or unknowingly, to follow the manufacture's recommendation for schedule, storage and administration. Some common factors influencing vaccine effectiveness include the following: Since the incubation period of most infectious diseases is of shorter duration than the amount of time required for a vaccine to produce a sufficient antibody level required for protective immunity, vaccinating a dog shortly before, during or after it is exposed to an infectious disease will not protect the dog from contracting the disease. This is particularly critical during primary active immunization during which a dog is inoculated against a disease for the first time. In contrast, booster vaccines usually provide a rapid immune response and increase in protective antibodies.

Vaccines that are stored improperly or exposed to environmental extremes are at increased risk for inefficacy. Once lyophilized components of the vaccine are mixed with the accompanying vaccine diluent, the inoculant should be administered promptly and not stored for any length of time in the reconstituted form. Though many vaccines are distributed as two vials, a lyophilized component and a diluent component, which must be mixed together prior to injection, it is important to note that different vaccine brands or types should not be mixed together or administered with the same needle or syringe used to administer another vaccine. Doing so may cause an interaction of the vaccine components, which may inactivate particular antigens and prohibit proper immune response. Additionally, although killed vaccines are also susceptible to improper handling, careful handling of modified-live vaccines is critical because vaccine efficacy is dependent upon the ability of the modified viruses to replicate. Conditions that inactivate the viruses will lead to vaccine failure.

Another important factor influencing vaccine efficacy, and also safety in this case, is adhering to the route of administration recommended by the manufacturer. Today, most modified-live vaccines are approved for subcutaneous (beneath the skin) injection, however, to be effective, some vaccines still require special routes of administration. This is true of some modified-live rabies vaccines. Because the modified rabies viruses of some vaccines require nerve-tissue to replicate, these vaccines will only produce enough antigens sufficient to induce an immune response if injected into muscle (intramuscular administration). In some cases, killed vaccines also require a special route of administration. Vaccines such as those for protection against kennel cough stimulate local mucosal immunity against the disease in the respiratory tract and require intranasal administration. Furthermore, administration of some killed vaccines by a route other than directed may lead to severe systemic reactions since many of these vaccines contain adjuvant, or helper, components such as aluminum hydroxide which enhance the immune response to the killed antigen. Subcutaneous injections of such vaccines can lead to localized tissue damage or to severe systemic allergic reactions.

Maternal Antibodies
Occassionally, despite being immunized, a puppy between the ages of 4 months and 1 year will contract one of the diseases for which it has been previously vaccinated. Usually, the vaccine will be blamed, however, in such a case the cause for vaccine inefficacy usually lies elsewhere.

One of the most critical aspects of immunity, but perhaps the most often responsible for vaccine failure, is passive immunity acquired by a puppy when it ingests colostrum in the dam's milk during the first few days following birth. Colostrum, which is rich in maternal antibodies, is essential for protection against infection and survival of the puppies during the first several weeks following birth when their own immune systems are not yet developed. However, in addition to protecting the puppy from infection, maternal antibodies also have the ability to interfere with active immunization by binding to and neutralizing antigen components in vaccines before the puppy's immune system can launch its own response. Since the passive immunity acquired from maternal antibodies is not permanent and diminishes over time, eventually, passive immunity will diminish and because of maternal antibody interference, weak, if any, active immunity will have developed to protect the puppy from subsequent infections. For this reason, multiple vaccine schedules have been designed to increase active immunity in the face of diminishing maternal antibody concentrations with, ideally, the last booster vaccine administered after total depletion of maternal antibody to ensure complete active immunization.

In light of this, an increased risk for vaccine failure may occur for schedules which prematurely discontinue the booster administration. Because many factors such as level of maternal immunity, amount of colostrum produced, antibody content of the colostrum, or amount of colostrum ingested and absorbed can greatly influence levels and persistence of maternal antibody in any one individual puppy, optimum time for booster vaccines will vary from individual to individual. Because it is neither cost- nor time- effective to determine serum maternal antibody levels for each puppy, booster vaccine schedules are generalized with timing of booster administration intended to ensure protective immunization in animals demonstrating either early or late maternal antibody depletion. However, it was discovered that of the puppies vaccinated using the initial schedules which required a final vaccine administration at 16 weeks of age, more than 20% were still found to have circulating maternal antibodies as late as 18 weeks that could potentially interfere with complete protection. Therefore, a new schedule was suggested recommending that a final booster be administered between 20 and 22 weeks of age to decrease risks associated with incomplete immunization.

In further support of extended puppy booster schedules are the conclusions of a recent clinical study examining the efficacy of various brands of vaccines for promoting active immunization and disease protection in puppies. It was found that some brands of vaccines are less efficient than others at inducing protective immunity when administered to puppies between 9 to 16 weeks of age. Because ability for the vaccine to promote protective immunity increased as a factor of puppy age, vaccines that produced lower immune responses are probably more susceptible to maternal antibody interference.

Occassionally, outbreaks of canine parvo virus cause severe disease in litters between 6 and 14 weeks of age. Puppies within this age period are particularly vulnerable to contracting disease because during this time, levels of maternal antibodies may still be high enough to prevent active immunization but too low to fight off the infection. Therefore, most puppy vaccine schedules recommend administration of booster vaccines at 2-3 weeks intervals.

Medications and Vaccines
Skin ailments associated with food or seasonal allergens are a common problem in canine medicine. Such allergies are widely treated with glucocorticosteroids, such as prednisone (or prednisolone), that inhibit the immune response and decrease inflammation and symptoms of itchy skin. Because such drugs are classified as immunosuppressive agents, administration of vaccines while a dog is receiving glucocorticosteroid treatment should be considered carefully. Though clinical research has found no evidence to suggest that use of glucocorticosteroids prevents effective immunization (since dogs vaccinated while receiving drug treatment were protected against infectious disease when later challenged), adverse vaccine reactions related to immunosuppression (as previously discussed) could present potential complications. To reduce possible adverse reactions of immunosuppression that may be associated with glucocorticosteroid treatment, dogs with seasonal allergies should be vaccinated during the symptom-free time of year when they are off medication. However, for some underlying health disorders, discontinuing glucocorticosteroid treatment during immunization may be dangerous. For example, in the case of dogs with adrenal insufficiency (discussed above), glucocorticosteroid dosage should be continued and may even need to be increased during the time of vaccination to prevent adrenal insufficiency crisis. Therefore, the decision to temporarily reduce or discontinue glucocorticosteroid treatment should be carefully assessed based on the underlying condition of each dog.

Annual Boosters: How Necessary Are They?
Another topic of controversy surrounding vaccination is the procedure of annual immunization. Although many veterinary clinics still recommend annual re-boostering to protect against disease, some others are now employing a three-year re-booster schedule (see Colorado State University's Veterinary School Vaccine Protocol) . This new schedule is based on the premise that active immunization to viral antigens may persist for years or perhaps even throughout the life of the dog and, therefore, provide long-lasting protection without the need for revaccination. However, it should be noted that many factors, some of which are discussed above, such as timing of primary immunization in regard to maternal antibody levels, efficacy of a particular vaccine to induce an immune response, use of killed versus modified-live vaccine and use of polyvalent versus monovalent vaccines, as well as immune-response of the individual dog at the time of inoculation may influence outcome effecting long-term protective immunity. Therefore, some dogs, particularly young adults who may not have developed complete immunity during their primary immunizations as puppies, may not be adequately protected against infectious disease if not administered an annual booster as an adult. To reduce this risk, three-year booster schedules should be employed only after a dog receives an annual booster as an adult dog, approximately one year following its primary immunization series as a puppy.

Special Added Note on Bacterin-Based Vaccines
Though the general consensus among specialists in the field is that yearly vaccination against viral infections associated with canine distemper virus, canine parvovirus and canine adenovirus are generally unnecessary since active immunity induced by these vaccines provide at least several years of protection, this consensus, however, does not apply and should not be generalized to bacterin vaccines, which immunize against diseases associated with bacterial organisms. In fact, clinical evidence suggests that bacterin-derived vaccines including those which protect against Bordetella bronchiseptica (kennel cough), Leptospira (Leptospirosis), and Borrelia burgdoferi (Lyme disease) probably don't even provide protective immunity for 12 months suggesting that more frequent vaccination for these diseases are required. It is perhaps the common use of combination (all-in-one) vaccines containing bacterins, which immunize against bacterial infections such as Leptospirosis and/or kennel cough in addition to common viral infections, that gave rise to the practice of frequent vaccine administration. Indeed the incorrect generalization of long-term immunity, associated with vaccination against viral immunogens, to bacterin-based vaccines may lead to a decrease in annual vaccination for bacterial-based diseases and subsequently give rise to a resurgence of outbreaks of bacterial disease in the coming years. In light of this, annual re-boostering against bacterial diseases should continue despite discontinuation of yearly vaccination against viral diseases. For more information on bacterin vaccines, please refer to the following articles:
Canine Leptospirosis: Current Issues on Infection and Vaccination
Countdown to Lyme Season: What Every Dog Owner Should Know About Lyme Disease (updated and revised for 2000)
 

Homeopathic Alternatives to Vaccines: Are Nosodes an Effective Substitute for Vaccines? Homeopathic (isopathic) approaches to immunization have been utilized throughout the centuries and are currently advocated by some modern-day homeopathic practitioners and even some veterinarians in dogs who are considered to be at high-risk for adverse reactions to vaccines. However, a distinction must be made between those practitioners who advocate homeopathic alternatives to vaccination in dogs who are at high-risk of reaction and those practitioners who profess that all dogs should use homeopathic alternatives in lieu of vaccines: The first recognizes the importance of vaccines for maintaining the health of our general dog population while seeking potential alternatives for those in the population who are not candidates for vaccination; the second is simply promoting negligence.

"Homeopathic vaccines" called nosodes are prepared using high, serially agitated dilutions of infectious agents (i.e. infectious body fluids, vomitus, feces, or other tissue) which are administered to the animal orally for the purpose of protecting against later infection with the respective pathogen. Though some pet owners report efficacy of nosodes for protecting against infectious disease in their dogs, controlled clinical studies exploring the ability of nosodes to protect animals who are directly challenged with infectious disease indicate that nosodes are not effective for this purpose. In a clinical study by Larson and colleagues, nosodes administered to dogs completely failed to protect against death due to parvovirus when these dogs were administered nosodes of parvovirus-infected tissue over a period of time and then subsequently challenged with the pathogen. In another controlled clinical study by W.B. Jonas comparing efficacy of vaccination to nosode protection against infectious disease, though it was found that nosodes did increase the survival time following challenge with infectious disease, efficacy of protection was only 22% for nosodes compared to 100% protection with vaccination; that is, about 4 out of every 5 animals administered nosodes died from the infectious disease when challenged. This 22% efficacy is, in fact, the highest reported efficacy for nosode protection in any controlled clinical study to date.

In light of the data showing inefficacy of nosodes for protecting against infectious disease, why are some practitioners still promoting nosode use? Proponents of nosode-use such as Jean Dodds, DVM and others in the field do not promote the use of nosodes in lieu of vaccination of dogs in general; they promote the use of vaccine alternatives like nosodes in dogs that have a suspected predisposition (certain bloodlines with genetic risk) or underlying health conditions (as those discussed above) that put these particular dogs at higher risk for developing adverse reactions to vaccines. As will be discussed in the next section, although nosodes do not provide the assurance of protection that vaccines do, nosodes may provide some benefits over not vaccinating these dogs at all. The wide-spread notion, however, of totally replacing vaccination with the homeopathic alternative of nosodes is purported rather by some in the field of alternative medicine who continually use the reports of Dr. Dodds and others out of the context in which they were initially written.

Are nosodes a viable alternative for protection against infectious disease in dogs that cannot be vaccinated due to health complications? Vaccination remains the single most effective method for protecting against infectious disease in healthy animals. In those dogs with higher risk for developing vaccine-associated complications, alternatives such as nosodes will not provide effective protection against infectious disease if the dog is exposed to a moderate- or high-dose of infectious pathogen sufficient enough to bring about active disease or in cases of infectious disease outbreak. If one considers low-dose exposure to a pathogen, however, it is conceivable that nosodes could possibly provide some protection in regard to reducing severity of the disease. Ironically, however, this nosode protection would only be most effective in the presence of a widely vaccinated population.

The current wide-spread use of vaccination in the dog population creates a condition known as "herd-immunity". Herd-immunity occurs when vaccination of large numbers of individuals within a population decreases the occurrence of infectious disease within a population and thus actually protects those few in the population that may not be vaccinated from being exposed to and acquiring infectious disease. Though many vaccines do not prevent a carrier state (that is, a vaccinated dog that may be exposed to an infectious pathogen will be protected from disease but may still shed the pathogen in the environment), vaccination typically reduces the amount of pathogen and the duration of time that the pathogen is shed into the environment and thus decreases likelihood of exposure to and contamination of other dogs. Therefore, herd immunity alone does not assure freedom of risk from disease. In light of the Jonas' finding that nosode treatment did provide some protection, albeit minimal, to treated animals as evidenced by longer survival times prior to succumbing to infection, administration of nosodes to dogs with high-risk for vaccine reactions may provide some marginal benefit in reducing risk of infectious disease but only in a population protected by herd-immunity and only if these nosode-protected dogs were to receive very low exposure to a pathogen. More controlled, clinical studies, and not anecdotal reports, in this area are clearly needed, however, before one can make any assumptions on the reliability of nosodes to effectively protect against low-grade infections. As more dog owners, however, turn to using nosodes in lieu of vaccinations based upon the unsubstantiated claims that vaccines are dangerous to all dogs in general, herd-immunity will decline and with it any hopes of using nosodes as a vaccine-alternative in dogs that are verifiably at higher-risk for vaccine side-effects.

Finally, in absence of controlled clinical studies to evaluate nosode protection in the face of low-grade infection and the improbability of assuring that an individual dog is only exposed to low levels of a particular pathogen, to date the safest alternative for reducing risk of secondary vaccine side-effects while also providing effective protection is the use of alternate types of vaccines (i.e. killed-vaccines, sub-unit vaccines or mono-valent vaccines) rather than multivalent vaccines in dogs with an underlying health condition, as those discussed above, or with a suspected predisposition to vaccine side-effects. For example, recent clinical studies have demonstrated that using vaccines with a lower valency (i.e. monovalent, tri-valent) significantly reduces adverse side-effects that frequently occur with multivalent vaccines while still providing effective protection against infectious disease.

For a list of URLs providing more information on vaccines and the canine immune system visit the "Vaccination Issues" page of the Canine Epilepsy Resources Homepage.

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