key: cord-009381-q9s38fkh
authors: Roth, James A.
title: Mechanistic Bases for Adverse Vaccine Reactions and Vaccine Failures
date: 2007-09-28
journal: Adv Vet Med
DOI: 10.1016/s0065-3519(99)80053-6
sha: 
doc_id: 9381
cord_uid: q9s38fkh

nan

Vaccines have proven to be very beneficial for controlling diseases in domestic animals. Their widespread use has dramatically reduced the incidence of severe and fatal diseases in companion animals (canine distemper, canine parvovirus, infectious canine hepatitis, and feline panleukopenia). They have also enabled the intensification of livestock production, thus enabling great increases in efficiency in animal origin food and fiber production. In addition, animal vaccines have improved human health through control of zoonotic diseases such as rabies, brucellosis, and leptospirosis. Indeed, it can be argued that animal vaccines have had a profound impact on modern society. Without effective rabies vaccines many people would not opt to keep companion animals in their homes, and without effective vaccines for controlling major diseases in food-producing animals the availability of animal proteins for human consumption would be greatly reduced. However, in spite of the success of animal vaccines, vaccines sometimes induce adverse reactions in animals and sometimes they fail to protect animals. When making decisions regarding vaccination programs for animals, veterinarians and animal owners must weigh the risks of vaccinating vs. the risks of not vaccinating. They must also use vaccines in a manner that induces optimal protection. This article provides an overview of some of the reasons why vaccines occasionally produce adverse reactions (Table I) and reasons why vaccines sometimes fail to protect animals from disease (Table II) .

To produce protective immunity, a vaccine must stimulate a reaction in the animal. There usually must be a reaction both at the site of injection and systemically in order to produce an effective immune response. This reaction involves extensive activity by antigen-presenting cells, production of a variety of cytokines, and alterations in the trafficking of lymphocytes within the body. In addition, if the vaccine contains live organisms, they probably need to replicate to induce effective immunity. Live viruses must infect and replicate within cells. These essential reactions to a vaccine may induce observable clinical signs. Hopefully, the reaction to the vaccine will be mild and either unnoticeable or acceptable to the animal owner.

To understand vaccine safety and efficacy, it is important to understand the process by which vaccines are developed and tested by vaccine producers, and licensed by the United States Department of Agriculture (USDA), Animal and Plant Health Inspection Service (APHIS), Center for Veterinary Biologics (CVB). The federal government regulations for the United States of America regarding veterinary vaccines 9 Contamination with extraneous agents 9 Failure to inactivate agent in killed vaccine 9 Residual virulence of vaccine organisms 9 Vaccination of immunosuppressed animal 9 Immune suppression induced by the vaccine 9 Excessive induction of cytokine release 9 Multiple vaccines administered concurrently 9 Hypersensitivity to vaccine antigens Type I--immediate type Type IImcytotoxic type Type IIImimmune complex type Type IVmdelayed type 9 Triggering or exacerbation of hypersensitivity to nonvaccine antigens Allergies Autoimmune disease 9 Induction of neoplastic changes 9 MLV BVD vaccine triggering mucosal disease in persistently infected cattle are found in the Virus Serum Toxin Act (VSTA) in Title 9 of the Code of Federal Regulations (9 CFR). The VSTA gives the USDA the authority to regulate veterinary vaccines in the United States. According to the 9 CFR a USDA licensed biological must be "pure, safe, potent, and efficacious, and not be worthless, contaminated, dangerous, or harmful." To understand this statement, it is important to understand what is meant by safe and efficacious. The definition found in the 9 CFR for safe or safety regarding veterinary biologics is "freedom from proper ties causing undue local or systemic reactions when used as recom-mended or suggested by the manufacturer." This definition has two important qualifiers for the term safety. It does not state that a vaccine should produce no reaction, rather it states that a vaccine should not cause "undue local or systemic reactions." This is a recognition of the fact that stimulating a potent immune response is likely to produce at least a mild local and systemic reaction in the animal. The second important point is that according to the definition the safety of the vaccine is only ensured when it is used as recommended or suggested by the manufacturer. The recommendations and suggestions can be found on the label for the vaccine. Most vaccine label statements will indicate that a particular vaccine is only for use in healthy animals of a particular species. Healthy is defined as "apparently normal in all vital functions and free of signs of disease."

The 9 CFR definition for efficacious or efficacy is "specific ability or capacity of the biological product to effect the result for which it is offered when used under the conditions recommended by the manufacturer." The label found on the vaccine will indicate the "result for which the vaccine is offered" and will also indicate the conditions under which the vaccine is recommended for use. Therefore, it is very important to read and follow label instructions in order to achieve maximum safety and efficacy from vaccine usage.

When animals develop adverse clinical signs within a few days to weeks after vaccination it is important to determine whether those clinical signs were vaccine induced or were not due to vaccination and only coincidentally occurred after the vaccine was administered. Animals commonly experience adverse clinical signs from a wide variety of causes and animals are commonly vaccinated. Therefore, it is to be expected that occasionally adverse clinical signs will occur after animals have been vaccinated for reasons unrelated to vaccine administration. There are also many reasons why vaccines may induce adverse reactions in the animal. It is important to differentiate true adverse vaccine reactions from false adverse vaccine reactions. Some of the causes of true adverse vaccine reactions are summarized in Table I and explained next.

A prominent example of this occurred when it was discovered that some lots of the live oral human poliomyelitis vaccine were contami-nated with live simian virus 40 (SV40) in the 1950s (Pennisi, 1997; Shah and Nathanson, 1976) . Millions of people were potentially exposed to live SV40 through administration of polio vaccine. To date, there is no solid epidemiologic evidence that any adverse health affects can be attributed to exposure to this agent. The SV40 virus had not yet been discovered when the human polio vaccine was produced. This raises the question of how does one test for all potential known and unknown viruses in each production lot of modified live virus vaccines. (Gard and Lycke, 1957; Nathanson and Langmuir, 1963) . This resulted in several cases of poliomyelitis in people that had received the vaccine. There have also been cases where formaldehyde failed to inactivate the foot-and-mouth disease virus (Beck and Strohmaier, 1987; King et al., 1981) and the Venezuelan equine encephalitis virus (Kinney et al., 1992) in their respective vaccines. In both of these cases the vaccine was shown to induce disease because of the lack of complete inactivation of the virus by the formaldehyde (Brown, 1993) . An example of a failure to completely inactivate a bacterial pathogen in a killed bacterin occurred when thimerosol was used to inactivate Haemophilus somnus in an H. somnus vaccine. The thimerosol failed to kill the H. somnus. Approximately half the ani- mals on one farm that were injected with vaccine shortly after its production developed thromboembolic meningoencephalitis and died.

Modified live vaccine organisms have been attenuated to have reduced virulence. The attenuation must be shown to be stable when passaged through animals; therefore, reversion to virulence is thought to be a rare event. However, the attenuated vaccine strains may be capable of producing disease in immunosuppressed animals. Induction of disease by the vaccine organism has occasionally been reported when modified live virus (MLV) vaccines have been administered to healthy animals. However, it has occurred much more frequently when MLV vaccines are administered to unhealthy animals, by a nonrecommended route of exposure, to animals younger than the intended age for use of the vaccine, or when the vaccine is used in other than the intended species. Examples of MLV vaccines occasionally causing disease in healthy animals of the recommended species without apparent predisposing causes include the induction of rabies in dogs and cats after administration of an MLV rabies vaccine (Bellinger et al., 1983; Esh et al., 1982; Erlewein, 1981; Whetstone et al., 1984; Pedersen et al., 1978) and the induction of ovarian lesions and infertility in seronegative heifers administered MLV bovine herpesvirus 1 (BHV1) vaccine during estrus Chiang et al., 1990; Miller et al., 1989; Van der Maaten et al., 1985) . Since most heifers already have antibody to BHV1 due to either vaccination or previous exposure, this is thought to be a rare occurrence.

An example of vaccine-induced disease resulting from administration of vaccine to unhealthy animals is the induction of encephalitis by MLV canine distemper virus vaccine in dogs infected with canine parvovirus (Krakowka et al., 1982) . An example of adverse vaccine reaction after exposure of an animal to an MLV vaccine by a nonrecommended route of exposure is the induction of clinical feline viral rhinotracheitis after inadvertent exposure by the intranasal route to an MLV vaccine that was intended for intramuscular administration only (Povey and Wilson, 1978) . MLV vaccines that have been shown to be safe in older animals may not be safe in neonatal animals. An MLV BHV-1 vaccine induced fatal BHV1 infection in neonatal purebred Salers calves (Bryan et al., 1994) . This may have been partially due to the breed of the animals since there are other reports that MLV BHV1 vaccines are apparently safe in neonatal calves (Schuh and Walker, 1990 ).

There have been several examples of MLV vaccines inducing lethal disease when administered to a species other than the target species. An MLV pseudorabies virus vaccine produced fatal pseudorabies in lambs (Clark et al., 1984; Van Alstine et al., 1984) . This occurred when a syringe that had been used to administer the pseudorabies vaccine to pigs was used without proper disinfection to vaccinate lambs with another vaccine 3 days later. The MLV canine distemper virus vaccine has been shown to induce canine distemper infection in gray foxes (Halbrooks et al., 1981) , kinkajous (Kazacos et al., 1981) , and lesser pandas (Bush et al., 1976 ). An MLV rabies vaccine has been shown to induce rabies in a pet skunk (Debbie, 1979 ). An MLV feline panleukopenia vaccine induced cerebellar hypoplasia when given experimentally to neonatal ferrets (Duenwald et al., 1971 ).

An MLV bovine viral diarrhea (BVD) virus vaccine has been shown to suppress neutrophil function and lymphocyte blastogenesis in cattle (Roth and Kaeberle, 1983) . This correlates with the observation that cattle tend to be somewhat more susceptible to bacterial pneumonia after administration ofMLV BVD vaccines, especially if the animals are stressed at the time of vaccination. Several commercially available canine vaccines have been shown to be capable of inducing lymphopenia and suppressing blastogenesis of peripheral blood lymphocytes (Phillips et al., 1989; Mastro et al., 1986; Kesel and Neil, 1983) . Lymphopenia and suppression of blood lymphocyte blastogenesis must be interpreted with caution, however, because it may only be an indication of changes in lymphocyte trafficking between the blood and lymphatic systems rather than an indication of depressed lymphocyte function. Vaccination with an MLV BHV1 vaccine has been shown to exacerbate the lesions of infectious bovine keratoconjunctivitis after experimental intraocular challenge with Moraxella bovis (George et al., 1988 ).

Interleukin 1 (IL-1), IL-6, and tumor necrosis factor ~ (TNF-~) are potent proinflammatory cytokines that are released by macrophages and other cells in response to infection, endotoxin and other bacterial components, and some vaccine adjuvants. These proinflammatory cytokines can induce a wide range of clinical signs. They may induce acute inflammation at the local site of production, they may induce rapid synthesis and secretion of acute phase proteins by the liver, they may act on the hypothalamus to induce fever and malaise, they may reduce rate of gain and feed efficiency, and in sufficiently high concentrations they may induce hypoglycemia, reduce cardiac output, cause hypovolemic shock, and cause disseminated intravascular coagulation. Lipopolysaccharide (or endotoxin) from gram-negative bacteria is one of the most potent inducers of the proinflammatory cytokines (Cullor, 1994; Ellis and Yong, 1997; Galanos and Freudenberg, 1993) . A number of other bacterial components, listed in Table IV , have also been shown to induce proinflammatory cytokine production (Erdos et al., 1975; Henderson and Wilson, 1995; Allison and Eugui, 1995) . These components are generally the most active if they are released from the degraded bacterial cell. Killed bacterins that contain excessive amounts of these bacterial components can induce clinical signs due to excessive induction of cytokine release. This is more likely to occur if multiple killed bacterins are administered at the same time and if these bacterins contain adjuvants that also induce cytokine release. The production of small amounts of proinflammatory cytokines is beneficial to the induction of a protective immune response. However, overproduction of the proinflammatory cytokines can have mild to very severe adverse side affects. (Bonin et al., 1973; Wilson et al., 1968; Erdos et al., 1975) . As with all of the hypersensitivity reactions, the animal will not react on first exposure to an antigen (unless it has received passive antibody responsible for the reaction). It will only react after there has been sufficient time to produce the sensitizing antibody or memory T cells.

A local type I hypersensitivity reaction may occur due to IgE induced against infectious agents by the vaccine. Immunization against bovine respiratory syncytial virus under experimental conditions was shown to induce IgE antibodies specific for BRSV which apparently contributed to the development of symptoms following aerosol challenge with BRSV (Stewart and Gershwin, 1989a,b) .

Vaccine-induced type II (cytotoxic type) hypersensitivity reactions can occur when vaccines are used that contain normal cell antigens. For example, vaccines that contain erythrocyte antigens may induce anti-erythrocyte antibodies leading to immune-mediated hemolytic anemia.

Type III (immune complex type) hypersensitivity can occur when circulating antibody specific for vaccine antigens is present at the time of vaccination. This can lead to an Arthus reaction at the site of injection due to complement fixation and neutrophil recruitment to the site. This mechanism is commonly responsible for the local inflammatory reaction at the site of injection, especially when administering booster vaccinations with killed vaccines. Sometimes, hypersensitivity can be one component of a more complex adverse vaccine reaction. Antibody induced by the vaccine may lead to immune complex type hypersensitivity reactions after the animal becomes infected when the antibody binds to replicating infectious agents. Examples include anterior uveitis and corneal edema (blue eye) after vaccination with canine adenovirus (Carmichael et al., 1975; Wright, 1976 ) and the sensitization to the effusive form of feline infectious peritonitis after vaccination with experimental killed vaccines (Pedersen and Black, 1983) .

Sometimes, hypersensitivity may be one component of a more complex adverse vaccine reaction. Bacterins for Pasteurella haemolytica which were marketed and widely sued for several years were of marginal efficacy and were even capable of increasing the severity of lesions in animals either experimentally (Wilkie et al., 1980) or naturally exposed (Bennett, 1982) to the P. haemolytica. There are at least two hypothesized mechanisms by which the immune response induced by the bacterin could potentiate pneumonia after P. haemolytica challenge. First, the high concentration of complement-fixing antibody in-duced by vaccination with a bacterin could rapidly activate complement if a large number of P. haemolytica organisms were introduced into the lung either naturally or artificially. This could cause a type III hypersensitivity response leading to acute inflammation in the lung and severe pneumonia. Second, antibody against cell surface antigens will opsonize the P. haemolytica in the lung and enhance phagocytosis by alveolar macrophages and neutrophils. Because there may be insufficient leukotoxin-neutralizing antibody or cell-mediated immunity to activate phagocytes, the bacteria present in the alveoli and ingested by phagocytes are not efficiently killed and may produce leukotoxin that could destroy the phagocytes. This destruction would cause the phagocytes to release their hydrolytic enzymes into the lung.

In the last few years concern has been expressed that vaccination may trigger or exacerbate autoimmune disease or allergies (hypersensitivities), especially in dogs and cats (see article by Dr. Jean Dodds in this volume). Vaccination has been shown to augment production of IgE antibody to pollen in inbred atopic dogs (Frick and Brooks, 1983) . Remember that animals with allergies or autoimmune diseases are not healthy animals, and that vaccines are only recommended for use in healthy animals. Dr. Harm HogenEsch addresses the topic of vaccineinduced autoimmunity in another article in this volume.

In recent years, an increased incidence of fibrosarcoma occurring at sites commonly used for vaccination in cats has been observed (Hendrick et al., 1992 (Hendrick et al., , 1994 Kass et al., 1993) . The causal relationship and mechanistic basis for vaccine-associated fibrosarcomas in cats has not been firmly established (Ellis et al., 1996) .

Shortly after MLV BVD vaccines were introduced, it was recognized that a very small percentage of cattle developed a syndrome 7-20 days after vaccination that closely resembled BVD mucosal disease (Lambert, 1973; Peter et al., 1967) . Based on the current understanding of the pathogenesis of mucosal disease (Bolin et al., 1985; Brownlie et al., 1984) this was almost certainly due to the cytopathic BVD virus in the vaccine triggering mucosal disease in calves that were immunotolerant to, and persistently infected with, a noncytopathic BVD virus. The mechanistic basis for the induction of the lesions of mucosal disease is not clearly understood. This unique syndrome is primarily due to abnormalities in the animal rather than to a defect in the vaccine.

Vaccines are tested for safety and efficacy when administered to healthy animals in the formulation in which they are packaged to be sold. Vaccines are not required to be tested for safety and efficacy when administered concurrently with other vaccines. This would not be practical since there are too many possible vaccines that may potentially be used in combination. An example of a safety problem that occurred when two different vaccines were administered concurrently involved a newly developed MLV canine coronavirus and parvovirus vaccine given at the same time as an MLV canine distemper-hepatitis virus vaccine. The evidence indicated that the other MLV components allowed the canine coronavirus in the vaccine to induce neurologic disease in some vaccinated animals (Wilson et al., 1986) .

Injection site lesions are a common occurrence and are of great concern in food-producing animals. They may lead to unacceptable blemishes in, or decreased quality of, meat intended for human consumption. There are many possible causes of injection site lesions, including organisms introduced with a contaminated needle, live contaminating organisms in the vaccine, adjuvant induced reactions, cytokine release, hypersensitivity reactions (types I, II, III, or IV), trauma, and hemorrhage (Straw et al., 1985 (Straw et al., , 1990 Droual et al., 1993; Littledike, 1993; Stokka et al., 1994; Dexter et al., 1994; Apley et al., 1994; Straw, 1986) .

Vaccines that are licensed by the USDA have been tested to determine that they are safe and effective. However, "effective" is a relative term. It does not mean that the vaccine must be able to induce complete immunity under all conditions which may be found in the field. This would not be realistic since the immune system is not capable of such potent protection under adverse conditions.

To be federally licensed, the vaccine must have been tested under controlled experimental conditions. The vaccinated group must have had significantly less disease than the nonvaccinated control group. This testing is typically done on healthy, nonstressed animals under good environmental conditions and with a controlled exposure to a single infectious agent. Vaccines may be much less effective when used in animals that are under stress, incubating other infectious diseases, or exposed to a high dose of infectious agents due to overcrowding or poor sanitation.

It is important to remember that for most diseases the relationship between the infectious agent and the host is sufficiently complicated that vaccination cannot be expected to provide complete protection. The vaccine can increase the animal's resistance to disease, but this resistance can be overwhelmed if good management practices are not followed. Some of the causes for vaccine failure are summarized in Table II and explained next.

The host requires several days after vaccination before an effective immune response will develop. If the animal encounters an infectious agent near the time of vaccination, the vaccine will not have had time to induce immunity. The animal may come down with clinical disease resulting in apparent vaccination failure. In this situation, disease symptoms will appear shortly after vaccination and may be mistakenly attributed to vaccine virus causing the disease (McKercher et al., 1968) .

Improperly handled and administered vaccines may fail to induce the expected immune response in normal, healthy animals. Modified live bacterial and viral vaccines are only effective if the agent in the vaccine is viable and able to replicate in the vaccinated animal. Observing proper storage conditions and proper methods of administration are very important for maintaining vaccine viability. Failure to store the vaccine at refrigerator temperatures, or exposure to light, may inactivate the vaccine. Even when stored under appropriate conditions, the vaccine loses viability over time. Therefore, vaccines that are past their expiration date should not be used. The use of chemical disinfectants on syringes and needles can inactivate modified live vaccines if there is any residual disinfectant.

The use of improper diluent or the mixing of vaccines in a single syringe may also inactivate modified live vaccines. Diluents for lyophilized vaccines are formulated specifically for each vaccine. A diluent that is appropriate for one vaccine may inactivate a different vaccine. Some vaccines and diluents contain preservatives that may inactivate other modified live vaccines. For these reasons, multiple vaccines should not be mixed in a single syringe unless that particular combination has been adequately tested to ensure there is no interference.

Vaccine failures may occur because a vaccinated animal is not able to respond appropriately to the vaccine. Vaccine failure in young animals may be due to the presence of maternal antibody which prevents adequate response to vaccination. It can also be due to immunosuppression from a variety of causes.

Maternal antibodies derived from colostrum are a well-known cause of vaccine failure (Greene, 1990) . These antibodies in the young animal's circulation may neutralize or remove the antigen before it can induce an immune response. Typically, virulent infectious agents are capable of breaking through maternal immunity earlier than modified live or killed vaccines. This means that even if young animals are immunized frequently, there still may be a period when they are vulnerable to infection. Vulnerability occurs between the time that young animals lose their maternal antibody and before they develop their own active immune responses. This period can be shortened by the use of less-attenuated and/or higher titered modified live vaccines or the use of killed vaccines with high antigenic mass and strong adjuvants (Smith-Carr et al., 1997; Larson and Schultz, 1996) .

A high challenge dose of infectious agents will break through maternal immunity sooner than low exposure to infectious agents. Therefore, overcrowding and poor sanitation exacerbate the problem of inducing immunity in young animals before they come down with clinical disease.

Veterinarians commonly recommend that puppies and kittens be vaccinated every 3 weeks between approximately 6 and 18 weeks of age. However, for large domestic animals, a single vaccination is commonly recommended to induce immunity during the first few weeks or months of life. There is no inherent difference between large and small domestic animals in their responses to vaccination in the face of maternal immunity. The frequent vaccinations recommended in pup-pies and kittens minimizes the period of vulnerability to infectious diseases.

Because only one vaccination is commonly recommended for large domestic animals, the timing of vaccination is important. If the vaccine is administered too soon, it may be ineffective because of the presence of maternal antibody. If the vaccine is administered after all maternal antibodies are gone from animals in the group, there may be a prolonged period of vulnerability before they develop their own immune response. The optimal age to vaccinate young animals is highly variable. It will depend on the antibody titer of the mother and the amount of colostrum ingested. It is impossible to predict an optimal age to vaccinate a young animal, unless its antibody titers are determined. Most veterinarians and producers decide that because of time and expense considerations it is impractical to vaccinate young food-producing animals frequently to minimize their period of vulnerability to infection. However, frequent vaccination may be justified in cases of unusually high disease incidence in young animals.

Immunosuppression due to a variety of factors including stress, malnutrition, concurrent infection, or immaturity or senescence of the immune system may also lead to vaccination failure. If the immunosuppression occurs at the time of vaccination, the vaccine may fail to induce an adequate immune response. If the immunosuppression occurs sometime after vaccination, then disease may occur due to reduced immunity in spite of an adequate response to the original vaccine. Therapy with immunosuppressive drugs (e.g, glucocorticoids) may also cause this to occur.

Most vaccines do not produce complete immunity to disease. They provide an increased ability to resist challenge by infectious agents. If a high-challenge dose of organisms is present due to overcrowding or poor sanitation, the immune system may be overwhelmed, resulting in clinical disease.

The peak response to a vaccine typically occurs 2-6 weeks after vaccination. The level of immunity then begins to gradually decline. A common recommendation is to revaccinate annually. However, if the animal did not have a strong initial immune response due to stress at the time of vaccination, or if it is stressed and exposed to a highchallenge dose several months after vaccination, there may not be enough residual immunity to protect the animal. This is especially true for certain killed vaccines. Under these circumstances, it may be necessary to revaccinate more frequently than once per year.

For certain types of infectious agents, particularly bacteria that are vulnerable to control by the development of antibodies against surface components and viruses which use RNA as their genetic material and consequently have high mutation rates, there are often several antigenic variants of each agent. For antibody-mediated protection to be effective, the antibodies formed must bind the important strain-specific antigens on the surface of the bacteria or virus. Cell-mediated immunity is usually not as strain specific as antibody-mediated immunity. To determine if a vaccine's failure to protect is due to antigenic differences between the vaccine and field strains it is necessary to isolate the field strain and compare it to the vaccine strain. Antigenic differences between strains leading to lack of vaccine efficacy are usually more of a problem with killed vaccines than modified live vaccines.

As mentioned earlier, vaccines are tested for safety and efficacy when administered singly to animals. However, multiple vaccines are commonly administered concurrently to animals. Very little published data are available concerning the efficacy of vaccines when used in combination. One study demonstrated that there was no detrimental effect on the antibody response to a bovine respiratory syncitial virus vaccine when administered in combination with up to 17 different immunogens (Carmel et al., 1992) . In contrast, an MLV BHV1 vaccine when administered in combination with an experimental Pasteurella haemolytica vaccine containing outer membrane proteins and genetically attenuated leukotoxin significantly reduced the antibody response to the leukotoxin and the efficacy of the P. haemolytica vaccine in preventing morbidity and mortality due to bovine respiratory disease (Harland et al., 1992) .

Mild local and systemic reactions to vaccines are to be expected as a natural consequence of vigorously stimulating the immune system. Dramatic adverse reactions to vaccines are occasionally due to mistakes during the production or handling of vaccines. More often, they are due to not following label instructions, particularly the restriction to only use vaccines in healthy animals. It is important to publish welldocumented instances of adverse vaccine reactions so that producers and users of vaccines can all learn from the experience and avoid similar problems.

Vaccine failure to protect from disease is usually due to problems with either client education or compliance with good animal management practices. It is important for clients to understand the proper timing and method of vaccine administration, what to realistically expect for vaccine efficacy, and the importance of minimizing immunosuppressive factors and exposure to high doses of infectious agents in vaccinated animals.

Veterinary vaccines have produced dramatic benefits in terms of animal health, human health, and efficiency of food production. Advances in research and the accumulating experience with vaccines are leading to safer and more effective vaccines. Proper usage of vaccines and adherence to good management practices will continue to be essential to achieve maximal vaccine safety and efficacy.

Live SV40 in human polio vaccine (Pennisi

Killed hog cholera virus in pseudorabies vaccine

Live Mycoplasma in multiple live virus veterinary vaccines

Live border disease virus in Orf vaccine

Live bovine leukemia virus in babesiosis and anaplasmosis vaccines

Live bovine viral diarrhea virus in hog cholera vaccine

Live border disease virus in pseudorabies vaccine

Live blue tongue virus in a canine vaccine

Live bovine viral diarrhea virus in bovine vaccines

Induction of cytokine formation by bacteria and their products. In 'Virulence Mechanisms of Bacterial Pathogens

Subcutaneous injection site comparison of two multiple valent clostridial bacterin/toxoids in feedlot cattle

Subtyping of European foot-and-mouth disease virus strains by nucleotide sequence determination

Rabies induced in a cat by high-egg-passage Flury strain vaccine

Efficacy ofPasteurella bacterins for yearling feedlot cattle

Severe clinical disease induced in cattle persistently infected with noncytopathic bovine viral diarrhea virus by superinfection with cytopathic bovine viral diarrhea virus

Sensitization against calf serum proteins as a possible cause of allergic reactions after vaccination

Review of accidents caused by incomplete inactivation of viruses

Experimental production of fatal mucosal disease in cattle

Fatal, generalized bovine herpesvirus type-1 infection associated with a modified-live infectious bovine rhinotracheitis parainfluenza-3 vaccine administered to neonatal calves

Vaccine-Induced canine distemper in a lesser panda

Effects of vaccination against 18 immunogens in beef replacement heifers at weaning

Viral-antibody complexes in canine adenovirus type 1 (Cav-1) ocular lesions: Leukocyte chemotaxis and enzyme release

The effect of infectious bovine rhinotracheitis vaccine on reproductive efficiency in cattle vaccinated during estrus

Pathogenicity of a modified-live pseudorabies vaccine virus in lambs

Safety and efficacy of gram-negative bacterial vaccines

Vaccine-induced rabies in a pet skunk

Incidence of Injection-site blemishes in beef top sirloin butts

Local reaction and serological responses in commercial layer chickens injected intramuscularly in the leg with oiladjuvanted Mycoplasma gallisepticum bacterin

Feline panleukopenia: Experimental cerebellar hypoplasia produced in neonatal ferrets with live virus vaccine

Systemic adverse reactions in young Simmental calves following administration of a combination vaccine

Use of immunohistochemistry and polymerase chain reaction for detection of oncornaviruses in formalin-fixed, paraffin-embedded fibrosarcomas from cats

The demonstration of the sensitizing effect of the residual animal serum content of vaccines

Post-vaccinal rabies in a cat

Vaccine-induced rabies in four cats

Canine fatalities associated with the use of a modified live vaccine administered during late stages of pregnancy

Immunoglobulin E antibodies to pollens augmented in dogs by virus vaccines

Mechanisms of Endotoxin Shock and Endotoxin hypersensitivity

Inactivation of poliovirus by formaldehyde. Analysis of inactivation curves

Enhancement of infectious bovine keratoconjunctivitis by modified-live infectious bovine rhinotracheitis virus vaccine

Infectious Diseases of the Dog and Cat

Response of gray foxes to modified live-virus canine distemper vaccines

The effect of subunit or modified live bovine herpesvirus-1 vaccines on the efficacy of a recombinant Pasteurella haemolytica vaccine for the prevention of respiratory disease in feedlot calves

Modulins: A new class of cytokine-inducing, proinflammatory bacterial virulence factor

Postvaccinal sarcomas in the cat: Epidemiology and electron probe microanalytical identification of aluminum

Comparison of fibrosarcomas that developed at vaccination sites and at nonvaccination sites in cats: 239 cases (1991-1992)

Hog cholera antibodies in pigs vaccinated with an Aujeszkyvaccine based on antigen produced in IB-RS-2 cells

Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats

Vaccinationinduced distemper in kinkajous

Combined MLV canine parvovirus vaccine: Immunosuppression with infective shedding. VM / SAC

Biochemical identification of viruses causing the 1981 outbreaks of foot-and-mouth disease virus in the U.K

Molecular evidence for the origin of the widespread Venezuelan equine encephalitis epizootic of 1969 to 1972

Canine parvovirus infection potentiates canine distemper encephalitis attributable to modified live-virus vaccine

Bovine viral diarrhea: Prophylaxis and postvaccinal reactions

High-titer canine parvovirus vaccine: Serologic response and challenge-of-immunity study

Variation of abscess formation in cattle after vaccination with a modified-live Pasteurella haemolytica vaccine

Investigation of dams and their offspring inoculated with a vaccine contaminated by bovine viral diarrhea virus. VM/ SAC

Outbreaks of border disease in goats induced by a pestivirus-contaminated orf vaccine, with virus transmission to sheep and cattle

Repeated suppression of lymphocyte blastogenesis following vaccination of CPV-immune dogs with modified-live CPV vaccines

Complications in cattle following vaccination with a combined bovine viral diarrhea-infectious bovine rhinotracheitis vaccine

Infertility in heifers inoculated with modified-live bovine herpesvirus-1 vaccinal strains against infectious bovine rhinotracheitis on postbreeding day 14

The Cutter incident. Poliomyelitis following formaldehyde-inactivated poliovirus vaccination in the United States during the spring of 1955

Which BVD vaccine should I use?

Attempted immunization of cats against feline infectious peritonitis, using avirulent live virus or sublethal amounts of virulent virus

Rabies vaccine virus infection in three dogs

Monkey virus DNA found in rare human cancers

Characteristics of a condition following vaccination with bovine virus diarrhea vaccine

Effects of vaccines on the canine immune system

A comparison of inactivated feline viral rhinotracheitis and feline caliciviral disease vaccines with live-modified viral vaccines

Bovine leucosis virus contamination of a vaccine produced in vivo against bovine babesiosis and anaplasmosis

Suppression of neutrophil and lymphocyte function induced by a vaccinal strain of bovine viral diarrhea virus with and without the concurrent administration of ACTH

Outbreaks of neonatal infectious bovine rhinotracheitis

Human exposure to SV40: Review and comment

Nicrotic oophoritis in heifers vaccinated intravenously with infectious bovine rhinotracheitis virus vaccine during estrus

Canine Parvovirus. Part I. Pathogenesis and vaccination

Role of IgE in the pathogenesis of bovine respiratory syncytial virus in sequential infections in vaccinated and nonvaccinated calves

Detection of IgE antibodies to bovine respiratory syncytial virus

Inflammatory response to clostridial vaccines in feedlot cattle

Injection reactions in swine

Comparison of tissue reactions produced by Haemophilus pleuropneumoniae vaccines made with six different adjuvants in swine

Antibody production and tissue irritation in swine vaccinated with Actinobacillus bacterins containing various adjuvants

A survey of mycoplasma detection in veterinary vaccines

Vaccineinduced pseudorabies in lambs

Ovarian lesions induced in heifers by intravenous inoculation with modified-live infectious bovinerhinotracheitis virus on the day after breeding

Contamination of a live virus vaccine against pseudorabies (Aujeszky's disease) by an ovine pestivirus pathogen for the pig

Bovine viral diarrhoea virus infections in piglets born to sows vaccinated against swine fever with contaminated vaccine

Use of monoclonal antibodies to confirm vaccine-induced rabies in ten dogs, two cats, and one fox

Abortion and death in pregnant bitches associated with a canine vaccine contaminated with bluetongue virus

Response of calves to lung challenge exposure with PasteureUa haemolytica after parenteral or pulmonary immunization

A neurologic syndrome associated with use of a canine coronavirus-parvovirus vaccine in dogs

Detection of sensitizing tissue culture components in viral vaccines

Canine adenovirus: Its role in renal and ocular disease: A review