Jane E. Sykes

Introduction

Immunization refers to artificial induction of immunity or protection from infectious disease and may be active or passive. Active immunization involves administration of vaccines that stimulate cell-mediated or humoral immunity, or both, to a specific pathogen. Passive immunization refers to the administration of antibodies in order to provide temporary protection from disease and can occur through acquisition of maternally derived antibody (MDA) transplacentally, in colostrum, or milk; or treatment with preparations that contain specific or nonspecific immunoglobulins (see Immunomodulators, Chapter 7, and post-exposure prophylaxis for rabies, Chapter 13). Readers are referred to advanced immunology texts for detailed descriptions of the physiology of active and passive immunity.¹

The goal of immunization is to generate a protective immune response of prolonged duration against a specific infectious disease, with minimal adverse effects. Because of the potential for adverse effects, vaccination should be performed only if there is a risk for significant morbidity or mortality from an infectious disease. Since the 1950s, a huge number of vaccines for dogs and cats have been developed and marketed worldwide, and more are in development. Nevertheless, it is estimated that even in developed countries such as the United States, only 30% to 50% of dogs are properly immunized, and possibly an even smaller proportion of cats.2,3 Appropriate vaccination of a larger proportion of the pet population may assist in reduction of the prevalence of infectious diseases through the induction of herd immunity.

With the appearance of injection-site sarcomas in cats, increased emphasis has been placed on vaccine safety, and a change from annual to 3-yearly immunization protocols for some vaccines has been recommended, with administration of other vaccines based on exposure risk. Vaccines have had a profound influence in the control of infectious disease, and for many vaccines the benefits of vaccination outweigh the risks.

Vaccine Composition and Types of Vaccines

A vaccine is a suspension of attenuated live or inactivated microorganisms, or parts thereof, that is administered to induce immunity. In addition to protective antigens, vaccines may contain preservatives and stabilizers as well as specific antibiotics to preserve the antigen and inhibit bacterial and fungal growth within the vaccine. Some vaccines also contain an adjuvant to enhance the immune response to the antigen. Although the mechanisms are not completely clear, adjuvants can delay the release of antigen from the site of injection and induce the secretion of chemokines by leukocytes.⁴ The most widely used adjuvants are particulate adjuvants, such as those that contain aluminum salt precipitates such as aluminum hydroxide.⁵ Other particulate adjuvants include immunostimulators such as saponin, which is present in a canine Leishmania vaccine.

Attenuated live vaccines (or modified live vaccines) contain microorganisms that are artificially manipulated so as to negate or greatly reduce their virulence, or are field strains of low virulence. Repeated passage through cell culture is the most common means of attenuation. Because they replicate in the host, organisms in attenuated live vaccines usually stimulate an immune response that most closely mimics the protection that results from natural infection. Vaccination with attenuated live canine parvovirus (CPV) and canine distemper virus (CDV) vaccines in the absence of MDA can result in protective immune responses within 3 days of a single injection, which may be followed by immunity that lasts many years, if not for life.6–8 Partial immunity after vaccination with attenuated live CDV and feline panleukopenia virus (FPV) vaccines can occur within hours.^3,9,10 In addition, vaccine organisms that are shed can serve to immunize other animals in a population. However, the potential for reversion to virulence or vaccine-induced disease exists. Vaccine-induced disease is most likely to occur in highly immunosuppressed animals. Attenuated live vaccines also have the potential to cause some immunosuppression in their own right,11,12 or they may shift the balance from Th1 to Th2 immune responses.¹³ Rarely, this can lead to clinical disease. For example, an outbreak of salmonellosis was reported in cats after use of a high-titered attenuated live FPV vaccine.¹⁴ Very rarely, contamination of attenuated live vaccines has occurred with other pathogenic microorganisms present within cell cultures used to propagate the vaccine.

Generally speaking, inactivated vaccines are less effective than attenuated vaccines, because replication in the host does not occur. They produce weaker immune responses of shorter duration, and more frequent booster immunizations may be required. Two initial doses of vaccine 3 to 4 weeks apart are essential to produce an effective immune response, and if more than 6 weeks elapses between these doses, it has been recommended that the series should be repeated.¹⁵ Beyond the initial vaccination series, it is not clear whether lapsed annual boosters require the series to be restarted. This is not considered necessary for human immunization¹⁶ but has been suggested for dogs when more than 2 or 3 years elapses between boosters.¹⁵ Inactivated vaccines usually contain adjuvant as well as a large infectious dose to improve immunogenicity. They are safer than live attenuated vaccines for use during pregnancy and in very young or debilitated animals. Although bacterins have traditionally been associated with a greater likelihood of allergic reactions than live attenuated vaccines, newer inactivated vaccines are safer and have reaction rates that more closely approach those of live attenuated vaccines. The maximum duration of immunity that is induced by commercially available bacterins for dogs and cats remains largely unknown, partly because challenge studies that evaluate long-term duration of immunity are prohibitively expensive. However, some inactivated viral vaccines have been shown to have durations of immunity in excess of 7 years in cats.¹⁷ Caution is required when extrapolation is made from the duration of immunity for one product to that for a similar product from a different manufacturer, because it may not be equivalent. Although bacterins usually do not protect all animals from infection, they may prevent clinical illness. In some cases, natural infection of vaccinated animals serves to further boost the immune response, and this can influence duration of immunity in the field. The advantages and disadvantages of attenuated live and inactivated vaccines are shown in Table 12-1.

Subunit vaccines contain specific structural components of a microbe that stimulate a protective immune response, together with adjuvant. They contain reduced amounts of foreign protein, which minimizes the potential for hypersensitivity reactions.

Recombinant DNA vaccines are created through manipulation of the DNA of a pathogen in the laboratory, with the negation of pathogen virulence. Sometimes this also can allow diagnostic tests to differentiate naturally infected from vaccinated animals (DIVA), because of differences in the antibody response evoked by the vaccine. There are several different types of recombinant DNA vaccines:

Vaccine Storage, Handling, and Administration

Vaccines should be stored and administered according to label recommendations. Inactivation of vaccines can occur if they are inadvertently frozen or heated to excessive temperatures, exposed to excessive amounts of light, or used beyond their expiration date. Hands should be washed before preparation and administration of the vaccine. Lyophilized products should be reconstituted with the proper diluent, and different vaccines should not be mixed in the same syringe or vial. Reconstituted products should be used immediately. It has been recommended that attenuated live vaccines be discarded if more than 1 hour has lapsed since reconstitution,¹⁵ although no published reports exist of the viability of vaccine organisms over time after reconstitution or of the ability of stored, reconstituted vaccine to elicit an immune response. Vaccines should only be used in the animal species for which they are labeled, or serious adverse effects or failure of immunization can occur.

If vaccines for multiple different pathogens are to be administered simultaneously, they should be injected at distant sites or, if possible, a combination vaccine should be used. Simultaneous vaccination for more than one pathogen does not appear to interfere with immune responses to each component of the vaccine,18–20 and vaccine manufacturers must demonstrate that the protection that occurs for a specific pathogen after vaccination with a combination product equals the protection that occurs when a vaccine for only that pathogen is given. In contrast, successive parenteral administration of different attenuated live vaccines at 3 to 14 day intervals has the potential to interfere with immune responses. An interval of 4 weeks is preferred for human patients.^16,21 Inactivated vaccines do not produce interference in this way.¹⁶ If possible, administration of vaccines to animals that are under anesthesia should be avoided because adverse reactions may be difficult or impossible to recognize in this situation. It is not necessary to re-administer an intranasal vaccine if the animal coughs or sneezes after administration.

The site and route of administration, product, serial number, expiry date, and individual who administered the vaccine should be recorded for each vaccine administered.² Vaccine vials often possess adhesive labels that can be easily removed and applied to a paper medical record.

Components of the Immune Response

The immune response is divided into innate and adaptive immune responses. The innate immune response is nonspecific and acts as an immediate line of defense against an infection. Components of the innate immune response consist of natural killer cells, which recognize host cells that are infected by viruses; complement, which is activated by bacterial cell wall components; and phagocytes, such as macrophages and dendritic cells. The adaptive immune response develops over several days and involves presentation of antigen by dendritic cells in association with the major histocompatibility complex and stimulation of B and T cell responses, together with the formation of memory B cells. The nature of the innate response influences the subsequent adaptive response. Cells of the innate immune system possess pattern recognition receptors that can recognize patterns that are characteristic for various pathogens (pathogen-associated molecular patterns, or PAMPs), including Toll-like receptors and NOD-like receptors. PAMPs are under investigation for use as adjuvants in human and animal vaccines in order to create improved T cell immune responses.4,22

Determinants of Immunogenicity

All vaccines that are available for dogs and cats induce cell-mediated immunity (CMI) with induction of immunologic memory and a booster effect on repeat administration. Although the presence of antibody correlates with protection for some pathogens, such as CDV and CPV, a lack of antibody does not infer a lack of protection, because of the presence of CMI, which is more difficult to measure.

Vaccines rarely protect all vaccinated individuals from infection and disease. In particular, vaccines for canine and feline respiratory pathogens do not prevent disease but can reduce the prevalence and severity of disease as well as reduce the number of organisms shed. Limited immunity following vaccination is especially likely for infections for which immunity after natural infection is partial or short-lived.

The ability of a vaccine to induce an immune response depends not only on the target pathogen, vaccine composition, and route of administration, but also on host factors such as age, nutrition, pregnancy status, stress, concurrent infections, and immune status, including the presence or absence of passively acquired antibody (Box 12-1). Some of these factors may also influence vaccine safety. Some animals, particularly dogs of the Rottweiler breed, may have an impaired ability to respond to vaccination. These dogs have been termed nonresponders.^2,23 This situation is probably rare if efficacious vaccines are used and booster vaccines are administered. Young dogs, less than 1 year of age, have a significantly reduced response to vaccination with rabies virus vaccines when compared with adult dogs.²⁴ Small-breed dogs have a greater serologic response to rabies vaccines than large-breed dogs.²⁵ Administration of vaccines to febrile animals or animals with moderate to severe illness should be avoided if possible until recovery has occurred, because the immune response to the vaccine may be suboptimal.

Failure of immunization can result from an inadequate dose of antigen. Thus, division of a single vaccine dose for administration to a larger number of dogs and cats, or small-breed dogs as opposed to large-breed dogs, may lead to failure of immunization. Veterinarians should not split vaccine doses because this shifts the liability from the vaccine manufacturer to the veterinarian if vaccine failure occurs. Immunization can also fail in the face of an overwhelming challenge dose.

The route of administration can influence the type of immune response generated. Subcutaneous administration is associated primarily with an IgG response, and rarely induces high levels of secretory IgA antibodies. In contrast, intranasal administration results in an IgA and, to a lesser extent, an IgG response. Immunogenicity and safety may be compromised when a vaccine is administered using the incorrect route.

In young animals, MDA can neutralize vaccine antigens and interfere with effective immunization. This is one of the most common reasons for vaccine failure in dogs and cats. Any MDA titer against CPV has the potential to interfere with immunization. The amount of MDA in a puppy or kitten at any one point in time cannot be predicted because it varies depending on the titer of the dam and the amount of colostrum ingested after birth. As a result, a series of vaccinations are administered in order to increase the chance that successful immunization will occur soon after the decline of MDA titers to sufficiently low concentrations (Figure 12-2). Nevertheless, a window always exists when MDA concentrations are high enough to interfere with immunization, but not sufficient to prevent natural infection. This window is known as the window of susceptibility or the window of vulnerability. The use of recombinant vectored vaccines can overcome the interference by MDA, although the extent to which this applies in animals that have passive immunity to the vector virus (i.e., immunity transferred from a dam that was immunized with a recombinant vector vaccine) requires clarification. Because replication of the vector is aborted, the immune response to the vector itself may be reduced. As a result, passive transfer of neutralizing antibody titers to the vector may not occur. Mucosal vaccines can also provide greater protection in the face of MDA; the mucosal immune system matures shortly after birth.^26,27

Whenever possible, animals should be isolated until sufficient time has elapsed for proper immunization. For most parenteral and mucosal vaccines, this is 1 week (and at the absolute minimum, 3 days) after inoculation. Vaccine failure can also occur in animals that are incubating the disease for which vaccination is performed at the time of vaccination.

Measurement of the Immune Response

For some vaccines, such as rabies, CDV, CPV, and FPV, the presence of circulating antibodies correlates with protection (Table 12-2). Thus, serologic assays have been used in dogs and cats to decide whether vaccination is necessary or likely to be effective. These serologic assays have also been used to clear pets for travel.