I. IMMUNOLOGY

The body has several mechanisms in place to protect it from invaders such as microorganisms. Mechanical protection includes the skin; the flushing action of urine or milk washing ascending invaders back out of the body; and the mucociliary apparatus of the sinuses, nasal passages, and lungs, which captures invaders in mucus and expels them by upward and outward motion of tiny hairs on the surfaces of cells and by eliciting the cough response. Chemical protection includes lysozyme, an enzyme in tears, saliva, milk, and other body fluids; low pH, as in the stomach; and the presence of chemicals that interfere with the growth of microorganisms. Finally, many areas of the body contain a normal complement of bacteria, such as the oral cavity, vagina, and large intestine. In these areas, several species of bacteria live in balance; invaders are unable to colonize because of lack of nutrients or production of chemicals by the normal flora, which discourage growth of other organisms.

The specific immune response is the body’s attempt to eradicate invaders, such as bacteria, viruses, fungi, and other proteins. These foreign substances may be inhaled, ingested, or introduced by a stab wound or bite; any way an invader can enter the body, it will be recognized by the animal’s immune system. The specific object on an invader to which the immune system responds is called an antigen. Most antigens are proteins. Antigen is defined as any material or chemical substance that can elicit a specific immune response.

Most antigens come from outside the body. Some tissues in the body are “immunologically privileged,” meaning they are surrounded by a tight capsule and are never exposed to the animal’s immune system. If that tight capsule is broken, this tissue will be recognized as foreign and will be attacked by the immune system. Immunologically privileged tissues in the body include the lens of the eye, the fatty tissue surrounding the neurologic tissue in the spine and brain, and the testes.

Occasionally the immune system will destroy normal tissue, presumably because it has lost the ability to recognize that tissue as “self.” Diseases attributable to this process are called autoimmune diseases. Examples include rheumatoid arthritis and systemic lupus erythematosus.

The body responds to the presence of an antigen in several ways (Figure 5-1). As an antigen enters the body, it is picked up by an immune cell called a macrophage. The macrophage binds to the antigen and presents it to another immune cell, a lymphocyte. There are two populations of lymphocytes and two types of response to the presence of the antigen, called the cell-mediated response and the humoral response.

Figure 5-1 Immune response.

Cell-mediated immunity is due to activation of T lymphocytes. Many different types of T lymphocytes are activated by the presence of the antigen, including T cytotoxic cells, T killer cells, natural killer (NK) cells, T helper cells, and T memory cells. Most of these cell types act by destroying the macrophage and attached antigen or destroying infected cells of the body that contain the antigen. T memory cells recognize the antigen and then go into “reserve,” remaining latent in the body until that animal is exposed to that same antigen another time.

Humoral immunity is due to activation of B lymphocytes. When B lymphocytes are activated by the presence of the antigen, they differentiate either into plasma cells or into B memory cells. B memory cells act like T memory cells, remaining inactive until the animal is exposed to that antigen another time and then differentiating into plasma cells. Plasma cells produce antibodies, also called immunoglobulins. These proteins bind specifically to a given antigen and promote its destruction by phagocytic cells in the body. Phagocytic cells are capable of engulfing and destroying foreign proteins, “eating” them. The two main phagocytic cell types in dogs are macrophages and polymorphonuclear cells (PMNs). PMNs are very active in the presence of inflammation but live only a short time in tissue. Macrophages do not migrate as quickly through the body but live a long time.

In dogs, four types of antibodies are produced. All antibodies are large, Y-shaped proteins (Figure 5-2). Immunoglobulin M (IgM) is produced first. It is a very large protein, which increases the speed with which it is recognized by phagocytic cells. Concentrations of IgM against a specific antigen fall fairly quickly. IgG is produced next. Concentrations of IgG get very high and remain high a long time after exposure of the animal to the antigen. IgE is the smallest of the antibody molecules and does not achieve high concentrations in the body. IgA is produced on surfaces that are exposed to the antigen directly, such as the mucous membranes of the respiratory tract, mouth, and urogenital tract. Concentrations of IgA are very high in secretions from these surfaces.

Figure 5-2 Antibody (immunoglobulin) molecule.

Antibodies bound to antigen also activate a series of proteins called complement. Complement releases chemicals that attract phagocytic cells and causes agglutination, or bunching, of antibodies bound to antigen to increase efficiency of the phagocytic cells once they reach the site of infection.

What has been described thus far is termed active immunity. The animal’s body responds to the invader. Puppies do not have the capacity to respond well to invaders. Puppies younger than 4 weeks do not have functioning T-cell systems. Most bitches have a large number of antibodies circulating in their bloodstream, but few of these large proteins cross the placenta. Therefore, newborn pups cannot respond well to infection because they do not have circulating antibodies and cannot generate their own antibodies or activate T cells to destroy invading microorganisms directly. Colostrum, the first milk generated by the bitch postpartum, contains many antibodies. The intestinal tract of newborn pups is capable of directly absorbing these very large proteins for only about the first 24 hours of life; after that time, there is a change in the intestinal lining preventing absorption of large molecules and the antibody proteins are broken down and digested.

Passive immunity is the introduction of antibodies from another source, with the classic example being the newborn pups just described, that develop antibody circulating in their bloodstream after ingesting colostrum and absorbing antibody proteins through the intestinal wall. Antibodies also can be administered by drawing blood from a well-vaccinated adult animal and centrifuging the sample. The fluid that separates from the red blood cells, the serum, contains antibodies that animal has produced. This serum can be given to puppies by mouth for the first day of life and can be given under the skin (subcutaneously) to provide protection against disease until the puppy becomes capable of creating its own antibodies.

II. VACCINATION

Vaccination, or immunization, is purposeful, controlled introduction of an organism into an animal’s body to generate an immune response. The idea is that generation of T memory cells and B memory cells allows the animal to respond quickly to any subsequent exposure to that organism.

The type of organism and amount of organism to which the animal is exposed alter the immune response and generation of adequate protection against subsequent exposure. If the “dose” of organism to which the animal is exposed is too small, there will be only a short-lived immune response and no memory cells will be formed. If the “dose” is too high, the immune system may be overwhelmed and the animal may become ill, still without generating an adequate response. Some organisms do not elicit a strong immune response; for example, bitches infected with canine herpesvirus do not have high concentrations of antibodies against herpesvirus for very long after exposure because the virus is not a very strong or reactive antigen.

Vaccine manufacturers strive to produce vaccines that stimulate an immune response adequate to handle a subsequent challenge but that do not cause disease in the animal. Adjuvants are compounds added to vaccines that stimulate the immune response and may allow lower doses of antigen to be used. There are three types of vaccines produced: killed, modified live, and recombinant. Killed vaccines contain a variety of the organism that is incapable of causing disease and that cannot reproduce. These vaccines generally do not produce a strong or long-lived immune response, and so immunization with these vaccines must be repeated fairly frequently. Modified live vaccines contain a variety of the organism that is capable of reproducing in the animal but that does not cause disease. These types of vaccine elicit a much stronger and longer-lived immune response than do killed vaccines, and revaccination can be performed less frequently. Recombinant vaccines contain only some of the antigenic portions of the organisms and cannot cause disease; response to recombinant vaccines varies by organism.

A final type of immunization involves vaccinating not for the organism that causes the disease but for one that is so similar that antibodies will be produced that will react with the organism of interest. For example, dogs cannot become ill from measles. However, if a dog is vaccinated with measles, it produces antibodies that bind to the virus that causes canine distemper. In some situations, it is more beneficial to vaccinate animals with the similar organism to keep them from getting infected while allowing them to mount an effective immune response.

The frequency with which animals need to be vaccinated to allow them to maintain a protective concentration of antibodies in serum varies with age of the animal, the type of vaccine used, and the animal’s responsiveness to the vaccine. At birth, puppies have few circulating antibodies in their bloodstream. Only about 3% of the antibodies they need to protect them from disease cross the placenta and are present at the moment of birth. Antibodies ingested passively in colostrum protect puppies until they can generate their own immune response at about 4 weeks of age. Puppies usually are immunized several times, with a 2- to 4-week interval, to ensure a good immune response. The factors that can prevent a good response are (1) our inability to recognize exactly at what time the animal becomes capable of responding to an antigen introduced by vaccination and (2) the presence of antibody from the dam, which will neutralize antigens introduced with the vaccine. Immunization of puppies is therefore a balancing act in which we try to promote the pup’s own immune response without allowing the concentration of antibody derived from the dam to fall so low as to risk the pup being exposed to disease without adequate protection. Because there is no good way to know whether or not a pup has responded to vaccination or whether it still has protection against disease from its dam, it is not recommended to expose pups to strange people or dogs much before vaccination at about 8 weeks of age. For most vaccines, it is recommended that pups be immunized at 8, 12, and 16 weeks of age. Some people prefer to begin vaccinating their pups at 6 weeks of age; the manufacturer’s recommendation always should be followed. The occasional puppy does not respond to vaccination; measurement of antibody concentration in serum 2 weeks after the final vaccination in the series may allow a veterinarian to determine whether the puppy is adequately protected or should receive another vaccination before the annual booster as an adult.

Puppies are capable of generating an immune response to more than one organism at a time. Some people worry about vaccinating pups too frequently and “overwhelming” their system. Anecdotal reports cite instances of autoimmune disease from too frequent vaccination; one lecturer stated that 1 of every 2500 dogs develops autoimmune destruction of red blood cells (autoimmune hemolytic anemia) after vaccination. There is no scientific documentation of this phenomenon. Vaccination failure may occur. This is defined as failure of the animal to generate a protective immune response after immunization (Table 5-1). It is thought that some animals may have a genetic predisposition to vaccination failure; no genetic test for such is available at this time.

Table 5-1 Types of Vaccine Failure

It is understood that if enough animals are vaccinated, the overall incidence of disease will decline and animal health will improve (“herd health”). However, some animals respond poorly to vaccination and owners question whether it is necessary to regularly vaccinate their individual animal to help maintain health of the dog “herd” in their area.

At present, there is controversy in the veterinary community regarding the frequency with which dogs should be vaccinated. Studies evaluating immunity in dogs suffer from lack of knowledge about what is a protective concentration of antibodies in the bloodstream. Studies have declared animals as having adequate antibody concentrations for up to 4 to 7 years after vaccination as adults. However, every study varies in its definition of “adequate,” and few studies test their definition by exposing the animals to disease and seeing what number get sick. That makes it impossible to draw blood from an individual animal, measure the concentration of antibodies present, and definitively state that the animal is safe from exposure to disease, with the exception of animals that are tested and determined to have no significant antibodies. Such animals are termed nonresponders and definitely should be vaccinated again.

Too frequent vaccination has been hypothesized to cause an actual decrease in the ability of the body to respond to immunization; high concentrations of antibody in an adult animal may neutralize vaccine just like passive antibodies do in puppies. Dogs may be allergic to adjuvants or preservatives in vaccines, some to a life-threatening extent. Occasionally the dog acquires the illness from the vaccine; it is reported that 1 in 10,000 to 50,000 dogs (depending on the type of organism used in the vaccine) develops disease from canine distemper vaccine (see Table 5-1). Formation of a mass or localized hair loss may occur at the site of vaccination. Some authors contend that too frequent administration of vaccinations may induce autoimmune disease in dogs, in which the immune system destroys normal body cells, such as red blood cells. In cats, tumor formation at the site of some vaccinations is a well-documented phenomenon. For these reasons, several alternatives to annual vaccination have been proposed.

The American Animal Hospital Association (AAHA) has suggested that vaccination every 3 years is probably adequate for most adult pet dogs. Dogs that have greater exposure to disease should be vaccinated more frequently. The AAHA breaks down vaccines into two classifications: core and noncore (Table 5-2). Core vaccines are those that should be given regularly to all dogs. Noncore vaccines are those that need not be given to all dogs but may be necessary in an individual dog or kennel, depending on likelihood of exposure. In 2004 the Food and Drug Administration approved the first 3-year core vaccine, Duramune Adult, from Fort Dodge Animal Health, which is intended for vaccination of adult dogs against canine distemper, parvovirus, and adenovirus.

Table 5-2 Core and Noncore Vaccines for Dogs

* Incubation time is the time from animal exposure to signs of disease.

Rabies is a core vaccine that is required by law. The frequency with which it must be administered varies by municipality. Rabies vaccination must be administered by a veterinarian or by a veterinarian’s agent under supervision.

Several tools have been described that can assist veterinarians and owners in deciding the frequency of immunization for their dogs. Issues to consider include the health and lifestyle of the animal, the probability of exposure, the susceptibility to disease if the animal is exposed, the severity of the disease in question, the safety and effectiveness of the vaccine, and public health concerns (can this disease be spread from animals to people?).

The Vaccinometer was developed by Dr. Larry Glickman of Purdue University (Table 5-3). It is intended for use by veterinarians to help them determine necessity of vaccination in a given situation. The company Merial has developed a tool that uses lifestyle considerations to determine which vaccines should be given (Table 5-4). Breeders and pet owners are strongly encouraged to discuss vaccination frequency with their veterinarian.

Table 5-3 Vaccinometer for Determining Vaccine Necessity