Basic Principles

Active immunization typically involves administration of a primary series comprising one or more doses of vaccine to “prime” the immune system and generate effector proteins (antibodies) as well as clones of memory cells (lymphocytes and plasma cells) that are the basis for immunologic memory and “recall.” Typically, “booster” doses of vaccine are administered periodically to enhance the level of specific antibody and memory. On subsequent exposure to the specific pathogen, memory cells can be recruited to quickly generate specific antibodies and effector cells such as cytotoxic T lymphocytes (CTLs) to neutralize the pathogen before it causes disease. Some vaccines are capable of inducing sterile immunity, in which case infection and replication of the pathogen are completely blocked, whereas many vaccines induce clinical protection without completely blocking infection or replication of the organism, although the latter is typically at a much reduced level.

Types of Vaccines

Vaccines currently licensed for use in horses in North America include traditional inactivated vaccines (bacterins, toxoids, and inactivated viral vaccines) and inactivated subunit vaccines containing bacterial cell wall components or toxoid for intramuscular (IM) administration; modified live viral and bacterial spore vaccines for parenteral administration; modified live viral and bacterial vaccines for intranasal administration; and recombinant vectored vaccines and deoxyribonucleic acid (DNA) vaccines for parenteral administration.

Dead Vaccines

Inactivated Pathogen Vaccines.

Inactivated pathogen vaccines are the most common form of equine vaccine in current use and comprise microorganisms that have been treated with heat or chemicals to inactivate them while preserving their immunogenicity (Table 70-1). Phenol, formaldehyde, and β-propiolactone are among the inactivating agents used most frequently in the preparation of inactivated bacterial and viral vaccines.¹ Inactivated vaccines are inherently biologically safe because they have, in theory, no residual virulence and have a high stability in storage. They are typically suitable and safe for use in pregnant mares, debilitated or immunocompromised animals, geriatric horses, and colostrum-deprived foals. However, such vaccines typically require multiple doses and regular boosters, and efficacy frequently depends on use of potent adjuvants and high antigenic mass. Compared with vaccines of other types, disadvantages often associated with inactivated vaccines include slow onset of immunity, increased risk of local and allergic complications (high antigenic mass and inclusion of adjuvants are two factors that increase the likelihood of reactions), need for multiple doses in the primary series, need for parenteral (typically IM) administration, need for regular boosters at frequent intervals to maintain reasonable immunity, and shorter duration of immunity than achieved with modified live vaccines. Further, because inactivated vaccines are known to be weak inducers of cell-mediated immunity, they are not very efficient in eliminating virus-infected cells.²

Table 70-1 Types of Equine Vaccines Commercially Available

Protein or Subunit Vaccines.

Extracted and purified proteins naturally produced by pathogens can be used to formulate inactivated vaccines. Such vaccines can be developed only if the immunogens responsible for inducing the protective immune response are known. These vaccines often need high antigenic mass and strong adjuvants to stimulate the immune system. The major advantage of subunit vaccines is their inherent biologic safety because there is no risk of residual virulence. These vaccines have been associated with fewer injection site reactions than vaccines containing whole bacterial products. The best known examples of equine subunit vaccines are vaccines against tetanus containing tetanus toxoid and vaccines against strangles based on the M protein of Streptococcus equi subsp. equi (SeM).

Recombinant DNA technology permits synthesis of specific antigens that are important for immunity to pathogens. Such subunit immunogens can be produced only if the genetic sequence encoding for expression of the specific protective protein antigens, as well as the immunogenic characteristics of these proteins, are known. Recombinant subunit equine herpesvirus type (EHV) 1 and equine influenza vaccines have been produced experimentally but, as yet, have shown poor protection, probably because of the poor immunogenicity of the recombinant proteins.^3,4

Adjuvants

Mechanisms of Action

The mechanisms of action of most adjuvants remain poorly understood because immunization often activates a complex cascade of responses, and the primary effect of the adjuvant is difficult to discern clearly. In general, adjuvants appear to exert their effect by enhancing antigen presentation, improving antigen stability, or acting as immunomodulators.^21,22 A single adjuvant may have more than one mechanism of action. Adjuvants that influence antigen presentation can affect this complex process by improving antigen uptake by antigen-presenting cells (APCs), the cells that process antigens and present epitopes to T cells in association with major histocompatibility complex (MHC) molecules. Some adjuvants appear to trap the antigen at the injection site and provide a continuing supply to local APCs, whereas others may work by saturating Kupffer cells in the liver and subsequently may increase the amount of antigen reaching the APCs. Most adjuvants can effectively stimulate T-helper (Th) cells and humoral immunity (Table 70-2). Some, such as liposomes, also appear to deliver antigens to pathways that lead to the presentation of MHC class I molecules and the induction of a CTL response. Immunomodulation is another mechanism of action of adjuvants and is achieved by altering the cytokine network. Adjuvants can influence the type of immunity by enhancing some cytokines and reducing the concentration of others, which may shift the immune response toward a T-helper cell type 1 (Th1, cell-mediated) or T-helper cell type 2 (Th2, humoral) response. By shifting the balance of cytokines, adjuvants such as saponins may stimulate cell-mediated immunity to an antigen that would normally induce only antibodies.

Table 70-2 Adjuvants Used in Veterinary Medicine with Induced Immune Responses

One particular type of adjuvant deserving special mention is the mucosal adjuvant. Mucosal immunity has a critical role in resistance to a wide variety of pathogens, such as equine influenza and Streptococcus equi subsp. equi. Generating mucosal immunoglobulin A (IgA) responses with killed vaccines is challenging, and the only effective mucosal adjuvants defined to date are the bacterial exotoxins of enteric bacterial pathogens, such as cholera toxin or the labile toxin of Escherichia coli.

Licensing and Safety of Vaccines

The USDA Animal and Plant Health Inspection Service (APHIS) is the federal agency charged with licensing and overseeing the production and use of veterinary vaccines and other biologic products marketed in the United States. The Canadian Department of Agriculture has similar authority in Canada. These agencies license the facilities in which vaccines are produced and regularly inspect them to ensure that facilities and production methods meet established standards. All vaccines are checked for potency, stability, and safety before licensing and at regular intervals thereafter. Safety is established by testing for sterility, toxicity, freedom from extraneous organisms and other material (i.e., purity), and confirmation of the identity of the antigens or organism(s) included in the vaccine. Both “in-house” and field safety studies involving several hundred animals (typically >500 in the case of horses) are also completed before final licensing to confirm that the risk of inducing local or systemic adverse reactions is at an acceptably low level.

The starting point in potency tests is to determine the immunogenicity of a vaccine or the minimum dose of antigen that induces a defined immune response, either determined serologically or in challenge studies. Because organisms included in live attenuated or vectored vaccines inevitably die over time, a substantial excess of the organism above the minimum immunizing dose is included in the marketed product to ensure that at least this minimal amount of antigen is present in the vaccine up to the expiration date, assuming appropriate storage and handling of the product. Potency of each batch (serial) of vaccine is therefore tested before and after accelerated aging. Similarly, excess antigen is also in inactivated vaccines, even though they are considerably more stable than live vaccines. Vaccines must not be used after the stated expiration date, even though most will retain potency beyond that date if stored properly. Because live vectored vaccines are governed by the same regulations as MLVs, they typically contain substantially higher amounts of the live vector than the minimum dose needed to immunize horses. This not only adds to the expense of vaccine production, but also may be responsible for some to the systemic reactions observed occasionally in horses after administration of recently released serials of the canarypox-vectored WNV vaccine that presumably contain higher titers of the vector as a result of minimal “die-off” after release. These systemic adverse effects may include fever, lethargy, inappetence, tachycardia, abdominal discomfort, hyperemic mucous membranes, and mildly delayed capillary refill time.

The USDA has traditionally placed more emphasis on documentation of the purity, stability, and safety of veterinary vaccines than on their efficacy.^24,25 Consequently, vaccines for use in horses are typically safe when stored, handled, and administered according to label directions. Many vaccines, however, particularly those directed at pathogens of the respiratory and gastrointestinal tracts, have been found to be of questionable efficacy in the field. Furthermore, published data documenting the efficacy of equine vaccines in well-controlled blinded challenge or field studies have been sparse until recently. For those vaccines for which challenge data were available, duration of immunity (DOI) was rarely established because challenge was typically performed a few weeks after completion of the primary series, when immunity would be expected to be maximal. Without data to define DOI, label directions for revaccination were often arbitrary or ambiguous. Similarly, efficacy studies were not typically performed on foals; therefore the potential inhibitory effects of maternally derived antibodies and the age at which to commence primary immunization were typically not established. Fortunately, “the bar has been raised” considerably during recent years, to the extent that solid challenge data, including information on DOI, are available for virtually all new equine vaccines granted full licenses during the last decade. It is hoped that this type of information will be generated in the future for vaccines that were first licensed many years ago.

In addition to full licenses, USDA has the prerogative to grant conditional licenses to vaccines or antibody products that have met requirements for purity, safety, and stability but have not had efficacy documented in either experimental challenge or field studies. Other criteria used in the granting of a conditional license include a determination that the disease is an imminent and significant threat, that currently available measures for prevention and treatment are inadequate, and that the vaccine or plasma product has a reasonable expectation of efficacy. For vaccines, this expectation of efficacy is typically based on documentation of a detectable serologic response in vaccinated animals and a reasonable likelihood that this serologic response will be protective. Conditional licenses are issued for a limited period and are renewable while the manufacturer works toward documentation of efficacy to support granting of a full license. Each respective state department of agriculture decides whether to allow marketing of a particular conditionally licensed product in that state. The benefit of the conditional licensing procedure was clearly evident when Fort Dodge Animal Health (Fort Dodge, Iowa) was granted a conditional license to market an inactivated WNV vaccine (West Nile-Innovator) in 2001, before the disease had spread beyond eastern and southern states. Widespread use of this vaccine undoubtedly saved the lives of thousands of horses during the interval leading up to granting of a full license supported by challenge data in early 2003. In contrast, inactivated rotavirus and equine protozoal myeloencephalitis (EPM) vaccines have been marketed under conditional licenses for many years without apparent progress in documenting efficacy to support granting of a full license.

Although uncommon, the possibility always exists for adverse reactions (including anaphylaxis) associated with administration of a vaccine; therefore, vaccines should be administered by, or under the direct supervision of, a veterinarian. Adverse reactions should be reported to the vaccine’s manufacturer and to the USDA (1-800-752-6255) or the USP Veterinary Practitioners Reporting Program (Forms may be obtained or reports submitted by calling USP at 1-800-487-7776). Anaphylaxis constitutes a life-threatening emergency requiring prompt treatment with epinephrine, 5 mL of a 1:10,000 dilution intravenously (IV) or, in less acute situations, 1 to 2 mL of a 1:1000 dilution intramuscularly (IM) or subcutaneously (SC). Local irritant tissue reactions occur more frequently, particularly when polyvalent combination vaccines are used. These reactions are usually self-limiting, but resolution can be promoted by parenteral or oral administration of nonsteroidal antiinflammatory drugs (NSAIDs), topical application of warm compresses or the cutaneously absorbed NSAID, diclofenac (Surpass, Idexx Pharmaceuticals, Greensboro, North Carolina), and gentle exercise. Significant reactions in the neck muscles may make the horse reluctant to lower or raise its head; therefore, feed and water buckets should be positioned accordingly. The incidence of local reactions can be reduced by administration of the vaccine deep in the semimembranosus and semitendinosus muscles of the hindleg rather than in the neck, and by allowing the horse to exercise after vaccination. In addition, horses that repeatedly react to polyvalent vaccines may benefit from administration of an NSAID before administration of the vaccine, administration of the individual antigenic components separately in different sites, or use of a different brand of vaccine containing a different adjuvant or administered by a different route, such as intranasal rather than intramuscular.

If unacceptable reactions occur repeatedly, the need for continued annual or more frequent revaccination against individual antigens should be carefully reevaluated, taking into account risk of disease, balanced against the risk of an adverse reaction. Many of the horses that experience adverse reactions have received many doses of many vaccine antigens, repeated over many years. In these horses the vaccination protocol should be “pared down” so that only the most essential antigens are administered and the maximum possible interval between boosters is employed. For diseases such as rabies and tetanus for which resistance can reasonably be correlated with circulating antibody titer, one possible approach to define the maximum or optimal interval between booster doses would be to measure the antibody titer to define the need for revaccination. Unfortunately, this approach is currently limited by a paucity of laboratories that offer this type of testing on a routine basis, inexpensively, and with a short turnaround time. The introduction in recent years of commercially available enzyme-linked immunosorbent assay (ELISA) testing for antibodies to the SeM protein (Equine Biodiagnostics-Idexx, Lexington, Kentucky) and neutralizing antibody testing for WNV (Cornell University, Ithaca, New York, and EDART Laboratory, University of Florida, Gainesville, Fla) has made it possible to refine vaccination protocols for these diseases in horses that experience adverse reactions to vaccination. In addition, testing for antibodies to other pathogens may be available through state diagnostic laboratories.

Use of Exogenous Antibodies

Passive immunization through administration of exogenous plasma or serum products from immune donors is commonly practiced as a means of providing temporary protection from infection during a defined period of risk. Plasma and serum products from hyperimmunized donors are also used as an adjunct to the treatment of specific disease conditions such as tetanus, botulism, WNV infection, endotoxemia, neonatal septicemia, and hypoalbuminemia secondary to other diseases (see appropriate chapters covering these diseases for further information). The degree and duration of protection depend on the amount of total and specific immunoglobulin administered, but the rapid decay of exogenous antibodies inevitably provides only temporary protection.

By far the major indication for passive immunization through the use of plasma products is the treatment of partial or complete failure of passive transfer (FPT) of maternal antibodies in neonatal foals. Although the definitions of “complete” and “partial” FPT remain the subject of debate, most veterinarians agree that a plasma transfusion using 1 to 2 liters (20-40 mL/kg) of high–immunoglobulin G (IgG) plasma is indicated for foals with postnursing total serum IgG concentrations of less than 400 mg/dL. Some veterinarians also recommend transfusing foals with serum IgG concentrations between 400 and 800 mg/dL, particularly if other risk factors or signs suggestive of sepsis are present. All plasma products that make specific label claims must be licensed by the USDA to ensure purity, potency, sterility, stability, safety, and efficacy in treating the label indication. The sole indication for products marketed as immunoglobulin supplements is the treatment of FPT. USDA licensing requires documentation that at the recommended dose, these products increase the total IgG concentration by 400 mg/dL. USDA-licensed plasma products for intravenous (IV) administration and containing at least 2500 mg/dL of IgG include Polymune-Plus (Plasvacc USA, Templeton, California), HiGamm Equi (Lake Immunogenics, Ontario, New York), and High-Glo (Mg Biologics, Ames, Iowa). These products should be used to treat foals with complete FPT. Licensed products containing at least 1750 mg/dL of IgG (Foalimmune, Lake Immunogenics) and at least 1500 mg/dL of IgG (Polymune, Plasvacc USA) are also available and may be indicated for treating foals with partial FPT. In addition, a serum-derived concentrated IgG product containing at least 30 g of IgG per 250-mL bottle (I.V. Seramune Equine IgG, Sera, Shawnee Mission, Kansas) is available for IV administration. The same company markets a similar serum product containing at least 30 g of IgG per 300-mL bottle (Oral Seramune Equine IgG) for oral administration (20-40 mL/kg) to foals less than 24 hours of age to prevent FPT.

Several USDA-licensed tetanus antitoxin products have been available in North America for many years as adjuncts to the prevention of tetanus (see later section on tetanus) In recent years, two plasma products (Polymune R and Polymune REA, Plasvacc USA) have been granted full USDA licenses for prevention of Rhodococcus equi pneumonia. A third product (Rhodococcus equi Antibody, Lake Immunogenics) has been granted a conditional license pending acceptance by USDA of results of a published study documenting a high level of efficacy in preventing R. equi pneumonia on farms where the disease is endemic. Efficacy of these products is optimized if one dose is administered during the first week of life and a second dose is administered 3 to 6 weeks later.²⁷ Other USDA-licensed plasma products include Polymune-J (Plasvacc USA) harvested from donors immunized against the J5 core antigen of E. coli. This product has documented efficacy as an adjunct to treatment of horses with endotoxemia and colitis and is also indicated for the treatment of foals with gram-negative sepsis.²⁸ Polymune-B (Plasvacc USA) is a Clostridium botulinum type B antitoxin licensed by the USDA for prophylactic administration to horses experiencing likely exposure to C. botulinum type B toxin or spores. This product has also been used in treatment protocols to neutralize type B toxin in foals with shaker foal syndrome and horses of all ages suspected of experiencing exposure. This univalent type B antitoxin will not neutralize other toxin types. One conditionally licensed plasma product, Streptococcus equi Antibody, Equine Origin (Mg Biologics), is marketed for use in horses that are clinically ill from infection with S. equi subsp. equi and claims to reduce duration of signs, severity of disease, and mortality. Another potential indication would be prevention of disease in horses exposed to S. equi subsp. equi, although published data regarding efficacy of this product are not available at this time. Similarly, one conditionally licensed plasma product, West Nile Virus Antibody, Equine Origin (Lake Immunogenics), is currently marketed as an aid in the treatment and control of WNV infection. Efficacy is supported by data showing reduction in the level of viremia experienced by hamsters challenged either 1 day before or 1 day after administration of plasma. Evidence of efficacy of this product, and two similar products manufactured by Plasvacc USA and Mg Biologics, in horses has not yet been documented in either experimental or field studies.

Manufacturers of plasma products often infer efficacy for prevention or treatment of specific diseases by stating that the donors were hyperimmunized against specific infectious agents. This practice, although commonplace, does not indicate that efficacy in preventing or treating the specific disease has been proved in controlled studies; therefore, practitioners should view these implied efficacy claims with caution.

Passive Transfer of Maternal Immunity

Passive transfer of maternal antibodies from the mare to the foal through colostrum constitutes by far the most important form of passive immunization in horses. The epitheliochorial placentation present in the mare prevents transfer of maternal immunoglobulins to the fetus during gestation, rendering the foal essentially agammaglobulinemic at birth. Therefore, protection of the foal against specific infectious diseases that it is likely to encounter during the first few months of life, as its own immune system matures, relies heavily on postnatal absorption of specific antibodies and perhaps other factors that the dam has concentrated in colostrum during late gestation. The duration of protection afforded by maternally derived antibodies (MDAs) depends on many factors, the most important of which are the characteristics of the specific infectious agent, the challenge dose, and the magnitude of the postnursing titer of specific antibody. The latter is influenced by the dam’s history of disease exposure and vaccination, age, parity, normalcy of gestation, and prepartum leakage of colostrum (i.e., factors that influence concentration of specific antibody in colostrum). Above all, interval between foaling and nursing, the volume of colostrum ingested, and ingestion of macromolecules other than colostrum before ingesting colostrum play major roles in determining passive transfer of specific MDAs. Although several immunoglobulin isotypes are present in colostrum, the subisotypes of IgG are absorbed into the systemic circulation of the foal in much higher concentration than either IgM or IgA.²⁹ Specific IgA, however, is secreted continuously in milk and may provide passive protection against pathogens such as S. equi and enteric organisms by helping coat the pharyngeal and intestinal mucosa, thereby neutralizing pathogens.^29,30 When foals ingest adequate amounts of high-quality colostrum during the first 12 to 24 hours after birth, titers of specific antibody in the serum of the foal are typically very similar to the serum titer in the dam at the time of foaling. Whereas the rate of decay of specific subisotypes of IgG varies to some extent, the overall half-life of decline of maternal IgG antibodies is typically between 25 and 40 days.^31–37 Thus the magnitude of the postnursing antibody titer and the sensitivity of the assay used to detect passively transferred antibodies will determine persistence of these antibodies at measurable levels in the serum of foals. Use of ELISA and other sensitive assays has made it possible to detect persistence of MDAs at detectable levels for 6 months or longer in some cases.^32,37

Whereas passively acquired MDAs are important for protecting the foal against infection with many pathogens, they play a particularly critical role in prevention of infection with enteric pathogens such as rotavirus, E. coli, and other Enterobacteriaceae to which neonates are particularly susceptible. Passive transfer of immunity to these and other agents (e.g., botulism) that affect foals can be enhanced by stimulating either a primary or an anamnestic response in the mare during late gestation. This is typically an important focus of immunization programs for mares and can be accomplished through planned exposure, if the infectious agent does not pose a threat to the mare, as is the case with rotavirus, or more appropriately through administration of booster doses of vaccines to mares, 30 to 60 days before foaling. Maintaining consistent vaccination protocols for mares will maximize the likelihood that a uniformly high level of colostral antibody transfer and passive protection will be achieved within the foal crop. Whereas intranasally administered vaccines may afford good protection to the mare, they are typically less effective than parenterally administered inactivated vaccines in stimulating high levels of circulating IgG, the isotype that is passively transferred to the foal in highest concentration. Parenteral vaccines are therefore preferred over intranasal vaccines for vaccination of mares during late gestation.

It is widely assumed that pregnant mares are fully capable of mounting appropriate cellular and humoral immune responses to vaccines; however, this issue has received little research attention. Whereas mares that have been primed before breeding appear to mount appropriate anamnestic responses to vaccines administered during late gestation, it appears that the humoral response to primary vaccination with at least the inactivated WNV vaccine is downregulated during gestation. In one study, more than 75% of naive mares, vaccinated for the first time against WNV while pregnant, failed to mount a detectable serologic response to two doses of an inactivated WNV vaccine administered 4 weeks apart.³⁸ Consequently, their foals failed to acquire any WNV antibodies through colostrum and were rendered potentially susceptible to infection. At this time it is not known whether this apparent pregnancy-associated suppression of serologic responses to primary immunization applies to vaccines other than the inactivated WNV vaccine. Nevertheless, it is wise to complete primary immunization before breeding and administer booster doses of selected antigens late in gestation rather than attempting to complete the primary series during gestation, regardless of the vaccine. The common practice of administering booster doses of multiple antigens to mares during late gestation raises the possibility that “competition” between multiple antigens will compromise the response to some or all of them and increase the risk of an adverse local or systemic reaction. Although these issues have not been addressed in controlled research studies, it is nevertheless good practice to administer no more than four antigens at one time and to allow an interval of 3 to 4 weeks between administration of vaccines containing additional antigens.

Tetanus

All horses are at risk for developing tetanus, an often-fatal disease caused by a potent neurotoxin elaborated by the anaerobic, spore-forming bacterium Clostridium tetani. These organisms are present in the intestinal tract and feces of horses, other animals, and humans and are ubiquitous in soil. Tetanus is expensive to treat and has a high mortality rate; therefore all horses should be actively immunized using tetanus toxoid as part of the core vaccination program. Active immunization reduces the need to administer tetanus antitoxin, the use of which is associated with risk of inducing potentially fatal serum hepatitis. Protection against tetanus appears to be mediated by circulating antibodies, and these antibodies are transferred efficiently through colostrum. The many available vaccines are typically formalin-inactivated, adjuvanted toxoids that are inexpensive and safe and that induce an excellent serologic response and solid, long-lasting immunity. Manufacturers recommend administration of a primary series of two doses of toxoid at 3- to 6-week intervals, followed by annual boosters. Titers of specific antibody increase within 14 days after administration of the second dose in the primary series and, in adult horses, persist at detectable levels for 12 months or longer, depending on the adjuvant system used in the vaccine.^50,51

No published challenge studies are available to document the speed of onset or duration of protection induced by tetanus toxoid preparations currently licensed in North America; conclusions regarding their efficacy are therefore based on the serologic response obtained in laboratory animals. However, a challenge study conducted in Europe more than 40 years ago found that horses were resistant to challenge 8 days after receiving a single injection of tetanus toxoid, before antibody could be detected in their serum.⁵² A second study demonstrated that a series of three doses of tetanus toxoid induced protection lasting for at least 8 years, and perhaps for life, even when antibodies could no longer be detected.⁵³ In contrast, tetanus has been documented in vaccinated horses in North America,⁵⁴ although survival was strongly associated with previous vaccination. Thus it would not be prudent to recommend extension of the annual interval for revaccination with tetanus toxoid, pending publication of data documenting duration of immunity. Vaccinated horses that sustain a wound or have surgery more than 6 months after receiving their previous tetanus booster should be revaccinated with tetanus toxoid.

The annual booster for pregnant mares should be administered 4 to 8 weeks before foaling to protect the mare if she sustains foaling-induced trauma and to enhance concentrations of specific immunoglobulins in colostrum. Colostrum-derived antibodies significantly interfere with the immune response of foals vaccinated with tetanus toxoid until they are about 6 months of age.^37,51 If a foal received appropriate transfer of colostral antibodies from a vaccinated mare, that foal should receive its primary series of three doses of tetanus toxoid beginning at age 6 months or older. Foals born to nonvaccinated mares should receive this initial three-dose series starting at 1 to 4 months of age. The three-dose primary series is recommended for foals because a high proportion of foals fail to seroconvert in response to two doses of tetanus toxoid, regardless of whether maternal antibodies are detectable at administration of the first dose.^37,51 Optimally, the third dose in the primary series should be administered 2 to 3 months after the second dose.

Tetanus antitoxin is produced by hyperimmunization of donor horses with tetanus toxoid. Administration of one vial of antitoxin (1500 IU) to nonvaccinated horses induces immediate passive protection that lasts no longer than 3 weeks.⁵¹ More prolonged protection may be accomplished with higher doses. In addition to the use of high doses of tetanus antitoxin to treat tetanus, indications frequently cited include administration to newborn foals born to nonvaccinated mares and to nonvaccinated horses that sustain an injury. In these cases the concurrent administration of tetanus antitoxin and tetanus toxoid at different sites using separate syringes has been advocated, followed by administration of additional doses of toxoid at 4- to 6-week intervals to complete the primary series.⁵⁵ Because a small but significant number of horses experience serum sickness and fatal hepatic failure (serum hepatitis) several weeks after receiving tetanus antitoxin,^56,57 a preferred approach to the nonvaccinated horse that sustains a puncture or deep laceration is to thoroughly clean and debride the wound, initiate active immunization by administering tetanus toxoid, and institute a course of antimicrobial treatment with penicillin or an alternate antimicrobial that is active against C. tetani.

Equine Encephalomyelitis (Sleeping Sickness)

The encephalomyelitis viruses (EEE, WEE, VEE) are transmitted by mosquitoes, and infrequently by other bloodsucking insects, to horses from wild birds or rodents, which serve as natural reservoirs for these viruses. Risk of exposure and geographic distribution of the encephalomyelitis viruses vary by season and from year to year with changes in distribution of insect vectors and wildlife reservoirs. The distribution of EEE has historically been restricted to the eastern, southeastern, and some southern states, whereas outbreaks of WEE have been recorded in the western and midwestern states, with sporadic cases in the Northeast and Southeast United States. Because EEE or WEE (or both) is endemic in most areas of North America, vaccination against these diseases should be part of the core vaccination program for all horses. Venezuelan equine encephalomyelitis occurs in South and Central America but has not been diagnosed in the United States or Mexico for many years; therefore, routine vaccination of horses in these regions against VEE is not recommended at this time, unless transportation to endemic areas is planned.

Although correlates for protection against EEE, WEE, and VEE are not well established, circulating antibodies are assumed to be important because infection is acquired by vascular injection (mosquito bites), and current inactivated vaccines are protective.^58,59 However, despite that virtually every manufacturer of equine vaccines in North America produces one or more equine encephalomyelitis vaccines, no randomized, double-blind challenge trials using these vaccines have been published. Available vaccines are inactivated, adjuvanted, bivalent whole-virus products containing EEE and WEE (Encevac with Havlogen, Intervet; Encephaloid Innovator, Fort Dodge; Cephalovac EW, Boehringer Ingelheim) or trivalent products that also contain VEE (Cephalovac VEW, Boehringer Ingelheim). Veterinarians and horse owners often use combination products containing other antigens, such as tetanus, influenza, WNV, or equine herpesviruses for primary or booster immunization of horses against encephalomyelitis viruses.

Primary immunization of nonvaccinated adult horses is accomplished by administration of two doses of inactivated vaccine 3 to 6 weeks apart. In areas where EEE is not a threat and mosquito vectors are active for less than 6 months of the year, annual revaccination in the spring, before the peak insect vector season, is recommended. In areas such as the Gulf States where EEE is endemic and mosquitoes are active virtually year-round, most veterinarians prefer to revaccinate horses semiannually to ensure more uniform protection throughout the year. Inactivated encephalomyelitis vaccines are considered to be safe for use in pregnant mares; therefore, booster vaccination 4 to 8 weeks before foaling is routinely recommended to enhance colostral concentrations of specific immunoglobulins. Neutralizing antibodies to WEE and EEE are transferred passively to foals through colostrum and decline with an estimated half-life of 33 and 20 days, respectively. Maternally derived antibodies (MDAs) appear to confer protection and are detectable in the serum of many foals from vaccinated mares for at least 3 months and up to 7 months, depending on the postnursing titer.^31,36,60,61

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