Considerations for Use of Vaccines in Broodmares

The primary goals of vaccination programs for broodmares are (1) prevention of diseases that pose a risk to the mare or her fetus, and (2) maximizing the level of colostral antibodies that will be passively absorbed by the neonatal foal after nursing, thus providing it with protection against diseases that pose a risk during the first few months of life. Additional considerations in selecting vaccines for use in pregnant mares include (3) safety to the mare and fetus, (4) the potential for interference between multiple vaccines administered simultaneously, and (5) the influence of pregnancy on vaccine responses.

Vaccination of Foals and Influence of Maternal Antibodies on Vaccine Responses

Maternally derived antibodies (MDAs) and perhaps other immune effectors (e.g., lymphocytes) that are concentrated in colostrum and are passively transferred to the foal play a crucial role in defense against pathogens encountered during the first few months of life while endogenous immune function continues to mature. Passive transfer of MDAs should therefore be exploited in immunization programs for foals by consistently administering booster doses of selected vaccines to mares 4 to 8 weeks before foaling and by ensuring that foals ingest adequate amounts of high-quality colostrum within 24 hours of birth. Besides passively protecting the foal, MDAs may also exert a profound inhibitory effect on the active immune response of the foal to antigens, including those contained in vaccines. This phenomenon is known as maternal antibody interference.

Several studies reported during the 1990s brought this issue into focus by demonstrating that foals younger than 6 months of age consistently failed to mount serologic responses to inactivated influenza vaccines.^12–18 Of potentially greater concern was the finding that a high proportion of foals vaccinated under the cover of MDAs not only failed to seroconvert in response to the recommended primary series of two or three doses of influenza vaccine, but many also failed to respond to multiple additional doses administered during the next year, suggesting induction of a potentially detrimental immunotolerance-like phenomenon.^15,16,19 Our studies confirmed an apparent lack of response of foals to multiple doses of inactivated influenza vaccines when the hemagglutination inhibition (HI) test was used to detect serologic responses, but responses were detected when the same samples were assayed using sensitive isotype-specific enzyme-linked immunosorbent assay (ELISA). Rather than representing true tolerance, it appears MDAs may cause misdirection of the immune response away from the more important virus neutralizing IgGa and IgGb subisotypes in favor of the less effective IgG(T) sub-isotype of IgG.¹² Subsequent studies in which titers of total rather than antigen-specific IgG subisotypes were determined documented that the age-related increase in concentrations of IgGb lagged significantly behind increases in concentrations of other isotypes and remained below adult levels beyond 6 months of age.²⁰

Maternal antibody interference has now been documented to be a significant issue for many other antigens, including tetanus, EEE, WEE, EHV types 1 and 4, contained in vaccines administered to foals.^12,21–25 Even low levels of antibody below those detectable by many routine serologic tests and below those thought to be protective can completely block the serologic response to some vaccines, resulting in a potentially prolonged period of susceptibility before the foal is capable of responding appropriately to vaccines.²⁴ These findings also indicate that it is not typically feasible to serologically test samples from foals to predict whether they will respond to particular vaccines. We now recommend that primary immunization with most vaccines containing inactivated antigens should be delayed until foals are 6 months of age or older, and with the exception of rabies vaccine, three doses of vaccine should be included in the primary series rather the two doses routinely recommended by vaccine manufacturers. Typically, the third dose stimulates a serologic response of greater magnitude and durability than two doses and may also contribute to a higher “set-point” for the response to subsequent booster doses.^12,24,26,27 In contrast to the results cited, maternal antibodies do not appear to exert a marked inhibitory effect on the immune response of foals to the inactivated, live recombinant, live chimera, or DNA West Nile virus vaccines, thereby permitting antibody-positive foals as young as 3 months of age to be immunized successfully.^26,28,29 Similarly, the canarypox-vectored recombinant influenza vaccine has been shown to efficiently prime foals in the presence of MDA.³⁰

Study results should be interpreted with caution because only humoral responses are typically assessed in MDA interference studies, and infectious challenge is not performed to confirm that lack of serologic response equates to lack of protection. Lack of a serologic response may correlate well with lack of protection for some diseases and some vaccines, whereas for others this may not be the case. In contrast, the presence of a serologic response may not correlate well with protection, as is frequently the case for respiratory tract pathogens. Because many commercially available vaccines are inactivated, adjuvanted, and administered by IM injection, they have limited potential to stimulate cellular and mucosal responses, so serologic responses induced by these vaccines likely correlate well with their potential to induce protection. In turn, MDA interference with serologic responses to inactivated vaccines likely equates to failure to induce protection. In contrast, failure to detect a serologic response to a modified live, vectored, DNA, or mucosally administered vaccine may not equate to lack of protection, because vaccines of these types induce a broader array of systemic and local responses that may not be affected by MDAs.

If MDA interference were not an issue, the approach to vaccination of foals would be greatly simplified because primary vaccination against all of the important diseases could be completed before MDAs had declined to non-protective levels. In effect, the “window of susceptibility” would be eliminated. In reality, an attainable goal is to maximize the beneficial effects of MDAs while minimizing their negative impact on primary immunization. To best meet this goal it is necessary to decide which one (or both) of the following is the primary focus: (1) to protect the foal and weanling against specific high-risk infectious diseases that affect this age group and have the potential to cause significant disease, either directly or by predisposing to other secondary infections, or (2) to initiate primary immunization to protect against disease later in life.

Assessing risk takes into account both the likelihood the foal will become infected and the risk of serious sequelae or death if the horse does become infected and develop disease. If the disease affects the foal early in life, such as is the case with rotavirus (RV) infection, there is usually insufficient time to induce a protective immune response by actively immunizing the foal. Under these circumstances, the approach should be to maximize the degree of protection passively transferred from the dam via colostrum. Other diseases like rabies can affect horses of all ages, but the risk of acquiring infection is generally low.

Diseases of Moderate to High Risk to Young Foals but Low Risk to Adults

Diseases of moderate to high risk to young foals but low risk to adults include RV infection (on certain breeding farms in certain years) and, in geographic areas such as Kentucky and some other Eastern states, type B botulism. For these diseases, the following approach is appropriate:

Though uncommon, the possibility always exists for adverse reactions (including anaphylaxis) associated with vaccine administration, so vaccines should be administered by or under the direct supervision of a veterinarian. Adverse reactions should be reported to the vaccine’s manufacturer and the U.S. Department of Agriculture (USDA) (1-800-752-6255) or the U.S. Pharmacopeia (USP) Veterinary Practitioners Reporting Program (forms may be obtained or reports submitted by calling the USP at 1-800-487-7776). Anaphylaxis constitutes a life-threatening emergency requiring prompt treatment with epinephrine (0.01 to 0.02 mg/kg; equivalent to 5 to 10 mL of a 1 : 1000 dilution IM for a 450-kg horse). Repeated doses of epinephrine can be administered at 15-minute intervals if necessary. It has recently been shown that horses vaccinated with viral vaccines can develop IgE responses to non-target antigens, including bovine serum albumin (BSA), suggesting that subsequent administration of another viral vaccine containing the same component could elicit an adverse response, including anaphylaxis.³¹

Local irritant tissue reactions occur more frequently, particularly when polyvalent combination vaccines and injectable strangles vaccines are used. These reactions usually are self-limiting, but resolution can be promoted by parenteral or oral (PO) administration of nonsteroidal antiinflammatory drugs (NSAIDs), topical application of warm compresses or the cutaneously absorbed NSAID diclofenac (Surpass [IDEXX Pharmaceuticals, Greensboro, N.C.]), and gentle exercise. Significant reactions in the neck muscles may make the horse reluctant to lower or raise its head; feed and water buckets should be positioned accordingly. Occurrence of externally visible local reactions can be reduced by administration of the vaccine deep in the semimembranosus and semitendinosus muscles of the hind-leg rather than in the neck, and by allowing the horse to exercise after vaccination. Horses that repeatedly react to polyvalent vaccines may benefit from NSAID administration before vaccination, administration of the individual antigenic components separately in different sites, use of a different brand of vaccine, use of a vaccine that can be administered by a route other than IM, or use of a vaccine that contains a different adjuvant or no adjuvant at all.

Some horses develop transient self-limiting systemic signs that may include fever, anorexia, lethargy, colic, diarrhea, tachycardia, and congested mucous membranes after IM administration of vaccines. Systemic signs are perhaps more common with certain vaccines but can be associated with any vaccine.^32,33 In addition, inactivated Immune Stimulating Complex (ISCOM) and live recombinant vectored tetanus and influenza combination vaccines have been shown to elicit a prominent acute phase inflammatory response of several days’ duration in vaccinated horses.³⁴ A similar response likely occurs with other vaccines. It is therefore inadvisable to give horses any injectable vaccine within 2 weeks before a show, performance event, sale, or prolonged transportation. It may also be beneficial to minimize environmental dust when vaccinating horses known to have allergic airway disease or hypersensitivity.³²

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 horses that experience adverse reactions have received many doses of many vaccine antigens, repeated over many years. In this situation, the vaccination protocol should be “pared down” so only the most essential antigens are administered and the maximum possible interval between boosters is employed. For diseases like 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. Unfortunately, this approach is currently limited by the paucity of laboratories that offer this type of testing on a routine basis, inexpensively, and with a short turnaround time. Introduction of commercially available ELISA testing for antibodies to the SeM protein of Streptococcus equi subsp. equi (Equine Biodiagnostics-IDEXX, Lexington, Ky.) and neutralizing antibody testing for WNV virus (Cornell University, Colorado State University, the University of Florida, and the USDA Animal and Plant Health Inspection Service [APHIS] National Veterinary Services Laboratory) in recent years has made it possible to refine vaccination protocols for these diseases in horses that experience adverse reactions to vaccination. Testing for rabies antibodies is available through Kansas State University, and testing for antibodies to other pathogens may be available through state diagnostic laboratories.

Equine Encephalomyelitis (Sleeping Sickness)

The equine encephalomyelitis viruses (EEE, WEE, and VEE) belong to the Alphavirus genus of the family Togaviridae. They are transmitted by mosquitoes (and infrequently by other bloodsucking insects) to horses from wild birds or rodents that 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, with recent northward encroachment. WEE has caused minimal disease in horses in North America during the past 3 decades, but the virus continues to be detected in mosquitoes and birds throughout the western states. In the past, outbreaks of WEE have been recorded in the western and midwestern states, with sporadic cases in the northeastern and southeastern United States. Because EEE, WEE, or both are endemic in most areas of North America, vaccination against these diseases should be part of the core vaccination program for all horses. VEE is a reportable foreign animal disease. Epidemics of VEE occur when the virus undergoes genetic change and develops greater virulence for avian and mammalian hosts. These viral variants are able to multiply to high levels in the horse, and then the horse becomes a reservoir for infection in these outbreaks. VEE occurs in South and Central America but has not been diagnosed in the United States or Mexico for many years; routine vaccination of horses in these regions against VEE is not recommended at this time unless transportation to endemic areas is planned.

Available vaccines are formalin inactivated, adjuvanted, bivalent or trivalent, whole-virus products containing EEE, WEE, and VEE, typically in combination products containing other antigens such as tetanus, influenza, WNV, or EHV. 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 appear to have good efficacy.^44,45 A study evaluating the serologic response of horses to commercial encephalomyelitis-tetanus combination vaccines showed that the EEE neutralizing antibody responses to Encevac T (Merck Animal Health, Carbopol adjuvant) and Equiloid Innovator (Zoetis, squaline and surfactant adjuvant) were of greater magnitude and persistence than responses to Cephalovac EWT (Boehringer Ingelheim, saponin adjuvant).⁸ However, no comparative randomized challenge studies have been performed using these vaccines to document whether differences in serologic responses equate to differences in efficacy. Early testing of bivalent (EEE/WEE) vaccines was performed by intracranial challenge with either EEE or WEE; the formalin inactivated preparations demonstrated 100% protection.

Primary immunization of unvaccinated adult horses is accomplished by administering 2 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 like the Gulf States where EEE is endemic and mosquitoes are active virtually year-round, many veterinarians prefer to revaccinate horses semiannually to ensure more uniform protection throughout the year. Inactivated encephalomyelitis vaccines are considered safe for use during pregnancy, so booster vaccination of pregnant mares 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. 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 post-nursing titer.^23,46–48

Several studies have shown that MDAs exert a profound inhibitory effect on the ability of foals to mount serologic responses to inactivated bivalent WEE/EEE vaccines, which likely accounts for some of the reported cases of vaccine failure and resultant clinical EEE in vaccinated horses, particularly those younger than 2 years of age.^{19,23,24,46,47} Studies have shown that 3-month-old foals born to immune mares consistently failed to mount a serologic response to 2 doses of inactivated bivalent WEE/EEE vaccine, and the majority had not responded even after administration of a third dose.^24,26 Whereas many 6-month-old foals failed to seroconvert after administration of 2 doses of vaccine, most responded following administration of a third dose.²⁴ Based on these data, inclusion of a third dose in the primary series, 2 to 5 months after administration of the second dose, is strongly recommended for primary immunization of foals and yearlings.

WEE has a lower mortality rate than EEE, and prevalence of WEE in many western states is sufficiently low that the risk of foals acquiring infection during their first year of life is also low. Therefore, primary vaccination of foals of vaccinated mares in areas where mosquitoes die off in the winter and the risk of infection is low is best completed when foals are 5 to 6 months of age or older in order to minimize the potential for MDA interference. Because foals born in the late spring and summer months are still less than 6 months of age by the time the mosquito season comes to an end in many regions, primary vaccination of these foals can be delayed until the spring of the yearling year. In contrast, EEE is a highly fatal disease that poses a significant risk to foals during their first year of life, particularly in the Gulf States where competent vectors are present year-round.^19,47,49 Most veterinarians in these regions recommend commencing primary vaccination of foals at 3 to 4 months of age using a 3-dose primary series, followed by a fourth dose before the onset of the next mosquito season and semiannual boosters thereafter to maximize the chances of overcoming the inhibitory effects of MDAs and inducing protection.⁴⁷