This chapter discusses the present uses of and experiences with swine vaccines. Unlike in many other countries, swine vaccines in the United States can be purchased over the counter or by catalog. According to the National Animal Health Monitoring System (NAHMS), only 55% of the vaccines were provided by a veterinarian. However, 83% of herds using a herd veterinarian also used vaccines, compared to 48% of herds without a consulting veterinarian. Thus, veterinarians appear to have a great impact on the use of vaccines. The regulatory controls of biosafety and efficacy of vaccines, exercised by the U.S. Department of Agriculture (USDA), have increased significantly during the 1980s and 1990s. However, a conflict of interest seems to exist when efficacy assessments, challenge models, sample size, number of replications, trial allocations, and result analysis are largely sponsored and done by the biologics industry itself. A common critique has also been that the pharmaceutical industry generally uses experimental challenge for efficacy tests instead of natural exposure to the pathogen.
In conclusion, it is remarkable just how farsighted many of the early vaccine investigators were. Jenner was apparently very comfortable with contagion and even recognized that infectious agents could gradually change and adapt to a new species. Pasteur, long before his fowl cholera experiment, dreamed that attenuation could yield safe vaccines and it took him no time at all therefore to recognize the significance of that serendipitous experiment. The fact that two other investigators were also developing anthrax vaccines simultaneously is yet another example of how the times favor certain discoveries. Finally Ferry, while constrained by the fact that he had no idea that distemper was caused by a virus, recognized well the concept of secondary infection and rationalized, not unreasonably, that his vaccine might assist in controlling this. It is also clear that we must look skeptically at the accepted historical record. Thus, it is clear that Jenner used horse-derived material as a source of vaccine material and that vaccinia may in fact be the long-lost agent of horsepox. Certainly this would not be news to many nineteenth-century investigators and veterinarians. Individuals planning to use live vaccinia in recombinant vaccines may wish to keep this in mind. Who discovered anthrax vaccine? Burdon-Sanderson clearly recognized that he could attenuate the organism. Greenfield showed that this could protect against disease although he was far from developing an effective vaccine. Poor Henri Toussaint was probably the first to develop an effective product but did not publicize his results widely. It was left to Louis Pasteur to take the risks inherent in a high-profile public experiment and win. I believe that he richly deserves the prize. Finally, who deserves the credit for distemper vaccine? First, Carré deserves much more credit than hitherto for discovering that distemper was caused by a virus. Second, Ferry, although misled by his identification of B. bronchiseptica deserves credit for realizing that his vaccine could play a role in controlling secondary infections. The true discoverer of an effective distemper vaccine was the Italian, Puntoni, but once again the publicity went to others, Laidlaw and Dunkin. Thus a pattern emerges that prior discovery matters little in the face of aggressive publicity. If nobody knows you did the experiment you might as well have never done it in the first place. Publish or perish is by no means a new phenomenon.
Immune-induced cachetic response is an example of a biological opportunity to develop technologies that ensure improved performance in animal agriculture. We have estimated that reduced performance of immune stimulated animals, whether by exposure to conventional environments or through vaccination, results in more than U.S. $500 million in reduced productivity. Nontraditional methods to alleviate the adverse effects of the immune response provide an opportunity for those skilled in the art of vaccinology and immunology to develop new technologies and feeding practices. Too often, biologists are blinded by the limits of their disciplines and rarely venture to the fringe of their field to engage in collaborations that at first glance do not seem logical. The examples of CLA and antigastrointestinal peptides suggest that new opportunities await in ensuring that the cost of the immune response is minimized and that new approaches to animal agriculture await discovery.
This chapter discusses immunization and diagnosis in bovine reproductive tract infections. Bovine genital tract infections that result in pregnancy loss are large economic problems in the cattle industry. Such infections can occur by either a hematogenous or an ascending route. Because the diseases acquired by the former route are primarily septicemic whereas local ascending infections are primarily sexually transmitted diseases (STDs), diagnosis and control may differ between these two categories. Systemic infection with localization in the gravid uterus occurs in leptospirosis, systemic campylobacteriosis (caused by Campylobacter fetus subsp, fetus), listeriosis, brucellosis, neosporosis, and Haemophilus sommus infection. In these syndromes, systemic immunity and serologic diagnosis are often reliable. Brucellosis is a good example of hematogenous infection with localization in the gravid uterus because systemic vaccination and serologic assays for diagnosis have been practiced for decades. Haemophilus sommus infection is also presented because it is a septicemic disease causing abortion and many other sequelae, thus immunity is complex.
This chapter discusses international association of biological standardization and international harmonization. During the past several years, the regulatory authorities of the United States, Japan, and the European Union (EU) met on several occasions in an attempt to harmonize the regulations dealing with human and veterinary biologics. In veterinary biologics, the discussions were held between U.S. and EU authorities. The obstacles being so numerous, the current trend is to aim for mutual recognition rather than a change of the existing standards within a given geographic area. Even with this “smoother” approach, several years will be needed to achieve this objective. A proposed way to speed up this process is to use the tools offered by the International Association of Biological Standardization (IABS). The IABS was founded in 1955 by a group of independent experts who identified an urgent need for an improvement in the quality and comparability of data being exchanged among scientists working in research, development, production, regulation, and standardization of biological products.
This chapter describes the equine influenza surveillance program. Equine influenza is endemic in many equine populations throughout the world with the exception of Iceland and Australasia and periodically causes explosive epizootics often associated with the introduction of subclinically affected animals into areas where the indigenous equidae have little or no immunity. In recent years most epizootics have been associated with the A/equine 2 (H3N8) subtype, however serologic evidence of A/equine 1 (H7N7) infections continues to be reported. International movement of horses for competition and breeding purposes on a worldwide basis increases the likelihood of equine influenza being transmitted long distances, and control measures require a global approach. For health certification to be effective, particularly in vaccinated populations, efficient laboratory diagnostic support and epidemiology surveillance is required to alert veterinarians to the presence of influenza in their locality and the necessity to exclude subclinical infections in vaccinated horses.
The large amount of scientific progress made in the last 5 years has allowed a more rational approach to the design of nematode vaccines to develop. Successful experimental trials have been published using two different approaches, one aiming to boost acquired host immunity through vaccination with natural immunogens, the other affecting parasite viability by targeting parasite molecules crucial for nutrition or survival in the host. The individual or combined action of these two vaccination procedures will need to be evaluated with respect to their potential effects on animal health and productivity in the field. To this effect, more data are required concerning the level and duration of immunity of the vaccine-induced protection using acceptable adjuvant systems. In addition, the age at which vaccination is effective and the effect of vaccination on highly susceptible or temporarily immunosuppressed individuals will need to be considered. In the case of gastrointestinal nematodes, the level of pasture contamination with infective larvae is dependent on the worm burdens in the host animal and, in turn, affects the buildup of natural resistance in the host. An appreciation of these complex interactive factors is best achieved through computer simulation models using the powerful simulation software that has recently become available. Further animal trials will need to be performed to establish the necessary data to incorporate into the models and to adapt the model outcomes to the trial results. These epidemiologic and simulation studies should be pursued in parallel with vaccine development so that a better appreciation is gained of the requirements of a successful commercial vaccine.
This chapter discusses the evaluation of risks and benefits associated with vaccination against coronavirus infections in cats. The current status of feline infectious peritonitis (FIP) varies among types of cat populations. It is the most feared disease today in breeding catteries, but is less common and of less concern in the general pet population. There is no effective treatment for FIP, and once classical disease occurs, mortality is nearly 100%. The only available commercial vaccine is less than 100% effective. Available laboratory tests detect feline coronavirus antibodies and therefore are not specific for FIP. Till now, there was no test to detect FIP antigen, virus, or to identify virus carrier cats. The reliability of new antigen detection tests is still being evaluated. A cattery with enzootic FIP is difficult to manage. The great variability in incubation period of FIP (weeks, months, or even years) presents a serious challenge to prevention and control. The causative agent of FIP, feline infectious peritonitis virus (FIPV), is a pleomorphic, enveloped virus classified as a coronavirus.
Increased susceptibility of animals to infectious disease during the periparturient period results in suffering and economic losses. Stress appears to delay inflammation by reducing efficiency of CD62L-mediated immune surveillance by phagocytes. It is important to note that the effects of stress are not limited to alteration of leukocyte trafficking patterns since various stressors (e.g., transport, parturition, and castration) also decrease IFN-gamma secretion by lymphocytes, and may decrease antigen presentation efficiency by down-regulating class II molecule expression on antigen presenting cells, and delay or impair immune responses to vaccination. Documented immunosuppression in periparturient animals, particularly the bias toward Th2 immune responses, and also changes in general leukocyte trafficking patterns suggest that vaccination intending to elicit cell-mediated immunity may not be efficacious at this point of the production cycle. Based on findings of numerous periparturient studies on immunosuppression in cattle, waiting at least 30 days after parturition before administering routine vaccinations is recommended.
This chapter discusses the T-cell responses and the influence of dendritic cells in cattle. The major T-cell populations in cattle have been identified with monoclonal antibodies (mAbs) to differentiation antigens expressed by the cells produced and characterized in the laboratories of origin or within a series of international workshops that have been held. The nomenclature used follows the human canine distemper (CD) nomenclature where there is sufficient evidence to conclude that the homologous molecule is being identified in cattle and humans. If human CD homologs are not evident WC (workshop cluster) numbers were assigned to the mAb and molecules recognized. Thus cattle leukocytes are defined in terms of the CD or WC antigens expressed. A question, asked in relation to specific infections—that is central to vaccine design—is whether a particular T-cell population is primarily responsible for recovery from infection or immunity to reinfection. Differences among different infections would influence the appropriate strategy selected for immunization.
During the last 40 years vaccines have been developed that have greatly reduced the incidence of infectious diseases of dogs. In general, modified live products have been superior to inactivated vaccines for dogs. It can be expected that recombinant and/or DNA vaccines may dominate the market in the future. Although most vaccines on the market are safe and efficacious, there have been exceptions where disease was induced by vaccination or dogs were not protected. The failure of protection may in part be due to variations in individual vaccine batches. Only potency tests but not efficacy tests are required, which may not be sufficient. For example, a virus titer in a vaccine may be meaningless if the minimum protective dose is not known. Overattenuated virus (e.g., CDV-Ond or parvovirus in cat cells) may have a high titer in tissue culture but is not immunogenic. The question of frequency of vaccination of dogs should be addressed. Annual revaccinations for CDV, CPV, and CAV are probably not needed. However, it would be desirable to collect more data to support less frequent vaccinations. Annual immunization for bacterial diseases such as kennel cough, Lyme disease, and leptospirosis should continue. It also would be desirable to develop more oro/nasal vaccines, perhaps combined with newly developed vectors that are less likely to induce undesirable side effects that may be seen after parenteral vaccination. Finally a word of warning against homeopathic "nosodes" to replace tested canine vaccines. They will appear highly effective as long as the majority of dogs remain vaccinated. As soon as a nonvaccinated dog population is large enough to allow virulent agents to spread, disease outbreaks will occur and we will be back where we began 40 years ago.
This chapter discusses the analysis of the protective immunity induced by feline immunodeficiency virus (FIV) vaccination. Since its discovery in 1986, FIV infection has been shown to result in an immunodeficiency in cats that is similar to AIDS in human beings. The virus is now recognized as a long-established and important feline pathogen and an appropriate animal model for human immunodeficiency virus (HIV) infection, playing a key role in the development of vaccines against HIV. Furthermore, because FIV induces significant disease in cats, the development of an effective FIV vaccine is of great veterinary interest. Protection against FIV infection has been achieved by immunizing cats with a whole inactivated virus (WIV) vaccine produced from the FL4 feline lymphoblastoid cell line, which is persistently infected with the Petaluma isolate of FIV (FIV/PET). This cell line appears to be unique, because it produces large amounts of FIV/PET rich in envelope glycoprotein (Env) that is well preserved during purification.
This chapter discusses past, present, and future of bovine viral vaccines, diagnostics, and eradication. Foot-and-mouth disease (FMD) virus (FMDV) has been eradicated from the Western world. In the recent past, various European countries have become free of bovine herpesvirus 1 (BHV1), which causes infectious bovine rhinotracheitis (IBR) and pustular vulvovaginitis (IPV). Other countries have eradication schemes implemented for this virus. Recently, in the Scandinavian countries, programs have been started with the aim of eradicating bovine virus diarrhea (BVD) virus (BVDV) and in the future other European countries may follow this example. These three bovine viral diseases are used to illustrate the evolution in vaccines and diagnostics in relation to eradication. FMD is among the most contagious viral diseases of cloven-hoofed animals and is causing enormous economic losses. The virus belongs to the genus Aphtovirus of the family Picornaviridae and consists of seven serotypes, A, O, C, SAT 1, SAT 2, SAT 3, and Asia 1, that do not cross-protect.
The impact of recombinant technology in veterinary and human medicine can only be hypothesized at this time. The development of vaccines and other biological products that go beyond the abilities of conventional products demonstrates the benefits of this new technology. Raboral V-RG was developed as an alternative rabies vaccine with the novel attribute of being effective by the oral route. Within 10 years after its first application as an experimental vaccine in European, red foxes it developed into a useful tool and is being used to curtail rabies epizootics in three wildlife species in the United States. The use of this vaccine can be considered as monumental in contributing to the control of rabies in species that were at one time considered to be incapable of vaccination in large-scale campaigns.
Any analysis of spontaneous AER data must consider the many biases inherent in the observation and reporting of vaccine adverse events. The absence of a clear probability structure requires statistical procedures to be used in a spirit of exploratory description rather than definitive confirmation. The extent of such descriptions should be temperate, without the implication that they extend to parent populations. It is important to recognize the presence of overdispersion in selecting methods and constructing models. Important stochastic or systematic features of the data may always be unknown. Our attempts to delineate what constitutes an AER have not eliminated all the fuzziness in its definition. Some count every event in a report as a separate AER. Besides confusing the role of event and report, this introduces a complex correlational structure, since multiple event descriptions received in a single report can hardly be considered independent. The many events described by one reporter would then become inordinately weighted. The alternative is to record an AER once, regardless of how many event descriptions it includes. As a practical compromise, many regard the simultaneous submission of several report forms by one reporter as a single AER, and the next submission by that reporter as another AER. This method is reasonable when reporters submit AERs very infrequently. When individual reporters make frequent reports, it becomes difficult to justify the inconsistency of counting multiple events as a single AER when they are submitted together, but as separate AERs when they are reported at different times. While either choice is imperfect, the latter approach is currently used by the USDA and its licensed manufacturers in developing a mandatory postmarketing surveillance system for veterinary immunobiologicals in the United States. Under the proposed system, summaries of an estimated 10,000 AERs received annually by the manufacturers would be submitted to the USDA. In quantitative summaries, AERs received from lay consumers are usually weighted equally with those received from veterinary health professionals, although arguments have been advanced for separate classifications. The emphasis on AER rate estimation differentiates the surveillance of veterinary vaccines by the USDA CVB from the surveillance of veterinary drugs as practiced by the Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM). The FDA CVM does, in fact, perform a retrodictive causality assessment for individual AERs (Parkhie et al., 1995). This distinction reflects the differences between vaccines and drugs, as well as the difference in regulatory philosophy between the FDA and the USDA. The modified Kramer algorithm (Kramer et al., 1979) used by the FDA relies on features more appropriate to drug therapy than vaccination, such as an ongoing treatment regimen which allows evaluation of the response to dechallenge and rechallenge. In tracking AERs, the FDA has emphasized the inclusion of clinical manifestations on labels and inserts, while the USDA has been reluctant to have such information appear in product literature or to use postmarketing data for this purpose. The potential for the misuse of spontaneous AER data is great. Disinformation is likely when the nature of this type of data is misunderstood and inappropriate analytical methods blindly employed. A greater danger lies in the glib transformation of AER data into something else entirely. Since approval before publication is not required, advertisements for veterinary vaccines appear with claims such as "over 3 million doses, 99.9905% satisfaction rating," or "11,500,000 doses, 99.98% reaction free." These claims, presumably based on spontaneous AERs, are almost fraudulent in their deceptiveness. Are we to suppose that 11.5 million vaccinations were observed for reactions? In comparing the two advertisements, we find the second presumed AER rate is double the first. (ABSTRACT TRU
Several small and large viruses (e.g., adenovirus, poxvirus, and herpesviruses) have been investigated as vaccine vectors. Each viral system has its advantages and disadvantages. One major advantage for viral vector vaccines is their ability to elicit a protective cell-mediated immunity as well as a humoral response to the antigen delivered by the vector. One major problem to using recombinant viruses as vaccines is the pathogenic potential of the parent virus. Therefore, it is important that along with the optimal expression of the foreign genes and ability to provide protection, the pathogenicity of the vector virus must be reduced during genetic manipulation without affecting its multiplication. The requirements to develop a viral vector, for example, swinepox virus, are a cell culture system that will support the growth of the virus, a suitable nonessential region(s) in the virus genome for insertion of foreign DNA so that virus replication is not affected, a foreign gene(s) that encodes for an immunogenic protein of a swine pathogen, strong transcriptional regulatory elements (promoters) necessary for optimal expression of the foreign genes, a procedure for delivering the foreign gene(s) into the nonessential locus, and a convenient method of distinguishing the recombinant viruses from the parent wild-type virus. Using this methodology, recombinant swinepox virus vaccines expressing pseudorabies virus antigens have been developed and shown to provide protection against challenge. These studies and evidence of local infection of the oral tract by swinepox virus indicate its potential as a recombinant vector for providing immunity against various swine pathogens including those that infect the respiratory and gastrointestinal tracts.
This chapter presents a philosophical review of vaccination. Vaccination is the most successful medical and veterinary measure: More lives have been saved by immunization, more animal production safeguarded than through all other medical and veterinary activities combined. It has been possible to eradicate a disease worldwide (human smallpox), and attempts to reach the same goal for poliomyelitis and measles are viewed with optimism. But this optimism does not apply for diseases where the causative virus has a reservoir in the wild fauna (such as in the case of distemper and parvoviruses that occur in mustellids). Against these diseases vaccination will have to continue. Vaccines are being used long before the mechanisms of immune protection became known. Today the discipline of vaccinology has acquired proper scientific status as a interdisciplinary research area that emerged from microbiology and immunology. Because vaccines make money—for the veterinarian and as a corollary also for the pharmaceutical industry—money is being invested in vaccine research.
This chapter discusses the specific licensing considerations for modified live pseudorabies vaccines in the United States. All veterinary biologics licensed in the United States—including pseudorabies vaccines—must be in compliance with the Virus Serum Toxin Act (VSTA) of 1913 as amended by the Food Security Act of 1985. Guidelines to clarify the requirements for licensing these products are found in Veterinary Services Memorandums, Notices, and General Licensing Considerations. The Center for Veterinary Biologics-Laboratory (CVB-L) provides Supplemental Assay Methods (SAM) that are the recommended protocols for conducting some of the tests required by the regulations. The National Environmental Policy Act (NEPA) of 1969 must also be considered in the licensing of any live product, particularly products produced through biotechnology. NEPA governs the release of organisms into the environment as a result of field testing and/or licensing. The establishment where the vaccine is produced must either have an establishment license or be able to qualify for an establishment license at the time the pseudorabies product license is issued.
This chapter describes some observations on the occurrence of canine distemper (CD) on mink farms and experimental trials using mink and ferrets. Ferrets—because of their high susceptibility to canine distemper virus (CDV)—show an invariably fatal course, which makes them the most satisfactory animal for conducting many distemper experiments. Vaccination is the only suitable means for the control of mink and ferret distemper. Attenuated live CDV vaccines produce a more dependable, longer lasting immunity and have replaced inactivated vaccines for ranch-raised mink and pet ferrets. Present-day distemper vaccines for mink are inexpensive and effectively immunize susceptible mink, and they can be combined with other vaccines to protect against mink virus enteritis, botulism, and Pseudomonas infections. In the case of dogs, foxes, mink, and ferrets and perhaps all other Mustelidae, Canidae, and Procyonidae, maternal antibody is a double-edged sword protecting young animals from distemper and conversely blocking early chicken embryo propagated (CEP) vaccination.
More than 80% of the U.S. broiler industry has converted to the in ovo vaccination process for control of Marek's disease. Providing certain criteria are met, including timing and site of vaccine placement, vaccine mixing, machine sanitization, and hatchery management specifications, this has proven to be an efficacious and convenient method of vaccination. Efforts to extend the technology for other viral vaccines including Newcastle, bronchitis and bursal disease, and bacterial and parasitic vaccines are in progress. Collectively, these studies demonstrate that in ovo vaccination technology using approved vaccine is a safe, efficacious, and convenient method for vaccination of poultry.
