MODIFIED LIVE VIRUS PARENTERAL VACCINES

The modified live virus parenteral vaccines were the initial vaccines licensed for use in cattle for protection against BHV-1.²³⁸ Vaccines are attenuated by multiple passages in cell culture and often retain their ability to replicate in a susceptible animal, possibly causing a viremia. Modified live virus parenteral vaccines are relatively inexpensive, offer a convenient route of administration, and stimulate a rapid onset of immunity (i.e., within 3 days of administration).^239-241 In general, one dose given to a susceptible animal stimulates protective immunity, which varies in duration depending on the clinical form of the disease challenge. Calves receiving a combination modified live virus vaccine with BHV-1 were protected for at least 126 days after vaccination as measured by protection against infection²⁴² The modified live virus parenteral vaccines may cross the placenta and infect the fetus, causing abortion.²⁴³ Almost all modified live virus BHV-1 parenteral vaccines are not approved for use in pregnant heifers or cows nor for nursing calves.²³⁴ Recently two companies have received label claim approval for BHV-1 and BVDV modified live virus vaccine use in pregnant cows providing they vaccinated with that line of vaccines within 12 months of being vaccinated during pregnancy and to nursing calves provided their dams were vaccinated within 12 months.²³⁴

MODIFIED LIVE VIRUS INTRANASAL VACCINES

Modified live virus intranasal vaccines generally can be divided into two types, based on the attenuation process: (1) those modified by passage in a cell culture^244,245 and (2) those modified by treatment such that they become “temperature sensitive”²⁴⁶ (i.e., they do not replicate at internal body temperature). Modified live virus intranasal vaccines stimulate protection in susceptible animals with only one dose, in contrast to the chemically altered modified live virus parenteral vaccines. The label directions for selected, but not all, modified live virus intranasal vaccines may indicate that they can be safely used in pregnant cattle.²³⁴ These vaccines induce a rapid onset of protection (within 3 days of administration), possibly through IFN in the nasal secretions.²⁴⁴ One benefit of modified live virus intranasal vaccines is that they stimulate immunity at the upper respiratory tract, the portal of entry of the virus. Another benefit is their potential to immunize calves that are already seropositive because of maternal (humoral) antibodies passively transferred through the colostrum.²⁴⁷ Animals vaccinated with modified live virus intranasal vaccines may transiently shed virus in the nasal secretions and therefore might infect susceptible contact animals.²⁴⁸

CHEMICALLY ALTERED LIVE VIRUS VACCINES

The chemically altered BHV-1 vaccine strain was modified by nitrous acid treatment, which caused changes in the viral genome that resulted in a strain that is temperature sensitive, meaning that it has limited replication at internal body temperature.²⁴⁹ Presumably, because of the limited viral replication, the vaccine requires two doses to stimulate immunity. Because it is temperature sensitive, the vaccine can be used in pregnant cattle.^234,249,250 In one study, heifers received two doses of the vaccine and were challenged with BHV-1 7 months later (at 6 months’ gestation). These heifers showed a significant reduction in the number of abortions and stillbirths compared with controls.²⁵⁰

INACTIVATED VIRAL VACCINES

Inactivated viral vaccines are prepared by growing virus in cell cultures and then inactivating them with chemicals. An adjuvant is added to the inactivated strain to help stimulate an immune response. Inactivated BHV-1 vaccines require two doses (14 to 28 days apart) when used for the initial vaccination of susceptible cattle. Historically it has been thought that inactivated vaccines against viruses did not induce as long a DOI as the modified live virus vaccines, nor did they confer protection against mucosal infections. Controlled studies should be performed to determine the DOI induced by inactivated BHV-1 vaccines and modified live virus vaccines, both for respiratory disease and for fetal infections. A disadvantage of inactivated vaccines is that the onset of protection may not be as rapid as with modified live virus parenteral or modified live virus intranasal vaccines. An advantage of the inactivated vaccines is that they can be used in pregnant cows and nursing calves.

PREGNANT ANIMALS OR ANIMALS NEARING BREEDING SEASON

The modified live virus parenteral vaccines may infect the fetus if pregnant susceptible heifers or cows are vaccinated. Abortions have been reported subsequent to vaccination with modified live virus parenteral vaccines.²⁴³ The modified live virus vaccine virus may also result in corpus luteum infection or disease.^251,252 Experimental studies have indicated a reduced conception rate in susceptible cattle that received a modified live virus parenteral vaccine 3 to 4 days before or 14 days after breeding.^251,252 It has been reported that pregnant cattle raised in contact with calves recently vaccinated with modified live virus parenteral vaccines had a greater incidence of BHV-1 abortion than those that did not have contact with vaccinates.²⁵³ Consequently, the labels of modified live virus parenteral vaccines have usually stated that the vaccine should not be used in calves nursing pregnant cows. Recent studies have shown that calves given a modified live virus parenteral vaccine did not shed virus in their nasal secretions, nor did contact animals become infected with the vaccine virus.^254-256 One company received label claim of prior vaccination for the modified live virus vaccine containing BHV-1 and BVDV for pregnant cows, provided the cows had received the same line of vaccines with the modified live virus BHV-1 and BVDV within 12 months of being vaccinated during pregnancy.²³⁴ Likewise, that vaccine could be used in nursing calves if the cows had been previously vaccinated with that line of vaccines within 12 months of prior vaccination.²³⁴ Another concern is that the modified live vaccine virus may recrudesce, with resulting shedding of virus in cattle either stressed or receiving corticosteroids.²⁵⁷ Realistically, concern about transmission of BHV-1 to animals in contact with those receiving modified live virus parenteral vaccines would be negligible if the contact animals were properly immunized and immune to BHV-1.

Until the vaccine labels on most modified live virus parenteral vaccines are changed, modified live virus intranasal vaccines or the inactivated or chemically altered live virus vaccines usually are recommended for pregnant cattle or those near breeding. The one exception is the approved vaccine cited previously. Vaccine recommendations should be weighed using the benefits of vaccination as a guide and especially with the realization that properly vaccinated cattle are better protected when exposed to either field (virulent) or vaccine strains shed by vaccinated animals.

RAPID ONSET OF IMMUNITY

Cattle that are susceptible and likely to be exposed to BHV-1 should receive either a modified live virus parenteral vaccine or a modified live virus intranasal vaccine because both types induce immunity within 3 days of the initial dose. Rapid onset of immunity is desirable in such situations as stocker calf and feedlot operations, in which calves are transported long distances to pastures or feedlots, which stresses the animals and makes them more susceptible to infection. Such calves also are exposed to infection with BHV-1 from contact cattle in the markets. The drawback to inactivated vaccines is that two doses are required to obtain good immunity.

DURATION OF IMMUNITY

Controlled studies on the DOI are limited. A degree of protection against challenge existed at 6 to 9 months after vaccination with a modified live virus intranasal vaccine or an inactivated vaccine.^258,259 A parenteral modified live virus BHV-1 vaccine provided protection up to 126 days after vaccination.²⁴² A second parental modified live virus BHV-1 vaccine provided protection against BHV-1—induced abortions for 12 months after vaccination.²³⁴ Challenge studies for licensure usually are performed on calves within days of vaccination, at the time of peak immunity. Also, the challenge may be for only one form of disease, usually the respiratory type. Such challenges may detect only protection against a severe form of the respiratory disease. BHV-1 manifests itself in other forms, such as abortions, neonatal disease, genital disease (male and female), and conjunctivitis. Yet little or no data are available regarding the efficacy of vaccines against these other forms of disease. For example, in one case the genital form of BHV-1 disease (infectious pustular vulvovaginitis) occurred in heifers that had received a modified live virus parenteral vaccine 5 months earlier.²⁶⁰ Given the lack of DOI studies for all BHV-1 vaccines individually and the cost of vaccines, breeding animals usually are vaccinated at least annually. In some feedyard situations the animals may be revaccinated during the feeding period. It is industry practice that feedlot cattle receive a monovalent BHV-1 modified live virus parenteral vaccine at reimplant time at approximately 100 days after arrival. There have been field reports of BHV-1 respiratory disease (IBR) in feedlot cattle a few months after entry or processing, at which time they received modified live virus vaccines containing BHV-1.

VACCINATION OF CALVES WITH MATERNAL ANTIBODY

The possibility exists that maternal BHV-1 antibodies acquired by the calf through ingestion and absorption of colostrum may interfere with vaccination. The level of these serum BHV-1 antibodies in the calf depend on the amount in the colostrum, the amount absorbed, and the half-life of the particular antibody; for BHV-1, it is 21.2 days.²³⁶ Some calves receive no BHV-1 antibodies through the colostrum, or they may lose them within 1 month. Some calves, however, may have serum BHV-1 antibodies for up to 6 months after birth.²⁵⁷

Vaccination recommendations for neonatal calves include use of multiple doses of a modified live virus parenteral, an inactivated, or a chemically altered live virus vaccine or administration of a modified live virus intranasal vaccine. The maternal antibodies may block the parenterally administered modified live virus or inactivated vaccine. However, the modified live virus intranasal vaccine may induce BHV-1 antibody immunity.²⁴⁷ Calves often are revaccinated at 6 to 8 months of age regardless of their prior vaccination history.

ADVANCES IN VACCINES

Molecular techniques of biotechnology have been applied to the study of vaccines and the response to vaccination (vaccinology). These advances are especially noted for herpesviruses, including BHV-1. In addition to conventional vaccines manufactured via propagation of modified live virus and inactivated BHV-1 strains, current and future technologies offer opportunities for other vaccines.^261,262 These include subunit vaccines with a portion of the virus, deletion mutants with specific viral genomic fragments deleted, live vectored strains, DNA vaccines using plasmids, and plant-based vaccines. Deletion mutant BHV-1 vaccines as marker vaccines with selected glycoprotein genes deleted along with diagnostic tests for the deleted genes permit identification of vaccinates under control programs.²⁶¹ Recently, needle-free delivery of vaccines has been developed and implemented.²⁶¹ By high pressure gas delivery, vaccines may penetrate the skin and be administered intradermally, subcutaneously, or intramuscularly.²⁶¹ Such delivery is designed to minimize damage resulting from intramuscular injections. Two studies compared needle-free intramuscular injection of multivalent modified live virus vaccine containing BHV-1 with conventional subcutaneous injection via syringe in dairy calves and feedlot cattle. In both studies, antibody titers to BHV-1 were higher at day 21 postvaccination than after conventional needle injection.^263,264

Vaccination Programs

The best possible vaccine provides protective immunity in the host against infection (viral replication) when challenged; protects the animal against all forms of disease, including multiple organ and systemic forms; and provides lifelong mucosal and systemic immunity. Ideally the vaccine recommendations would incorporate the results of field trials that are carefully designed to show the efficacy of the vaccine against a pathogen. Unfortunately little information is available, as can be seen by a review of the literature, for evaluating the field efficacy of the respiratory disease vaccines.²⁶⁵ The summary of results was mixed for BHV-1 vaccines and for other respiratory viral and bacterial vaccines.

Veterinarians therefore must make recommendations based on (1) experimental studies of vaccination followed by challenge under controlled laboratory conditions apart from the field conditions of normal cattle management and (2) clinical experience with vaccines. Data from challenge studies often are under the control of universities, the federal government, or a biologic manufacturer and may not be published. Government licensure studies require efficacy and safety evaluations, but these studies may not be available in scientific publications for review by those making recommendations. For these reasons the veterinarian may not have access to all the data needed to make a good decision on vaccines.

The veterinarian’s dilemma is confounded by other factors. First, licensure may be granted for vaccination efficacy that demonstrated protection against one form of disease, such as respiratory type. However, the virus may be just as important a pathogen of other organs, such as the developing fetus, as is the case with BHV-1. Second, information about the DOI induced by each commercially available BHV-1 viral vaccine is not available or is limited. Licensure studies may use challenge of vaccinated animals within 2 to 4 weeks of initial vaccination, yet cattle may be in feedyards (months) or breeding herds (years) after vaccination. Third, vaccines may induce a strong parenteral immunity, yet the surface mucosal defenses at the portal of entry may still be susceptible to infection even in presumably well-vaccinated animals. Thus it is entirely possible that natural infections could still occur in these vaccinated animals. Ecologically this point is reinforced, because viruses for which there are good immunization products are still circulating in cattle populations after years of vaccination.

The veterinarian therefore must weigh both the benefits provided by vaccines and their limitations. This probably is best done by focusing on the real, economic effects of certain disease manifestations, including morbidity, mortality, and treatment and prevention costs. Historically this approach has been applied to two important forms of BHV-1 disease: the respiratory form, singularly or in combination with pneumonic bacterial diseases, and the fetal disease (abortions). As a result, most vaccine regimens focus on preventing respiratory disease in both young or adult animals and on protecting the pregnant breeding herd of cows and heifers against abortions. Another fact to be considered is that many vaccines may have multiple viral or bacterial components (or both), which may require multiple doses for an immunogen mixed with one that requires only one dose.

GUIDELINES

BOVINE VIRUS DIARRHEA VIRUS VACCINES

Victor S. Cortese

Our knowledge of the different vaccines’ ability to protect against infection with BVDV is increasing rapidly. Currently, three kinds of BVDV vaccines are available: modified live virus vaccines, temperature-sensitive vaccines (available only in Europe), and inactivated virus vaccines (Table 48-12). Modified live virus BVDV vaccines have demonstrated advantages over the newer inactivated vaccines. Most of these advantages are common to all modified live virus vaccines^268,269: (1) modified live virus vaccines are less expensive; (2) postvaccination anaphylactic reactions occur less often than after administration of some inactivated vaccines; (3) immunity is achieved more rapidly after administration of a single dose (within 7 to 10 days); (4) modified live virus vaccines produce much higher levels of serum neutralizing antibodies²⁷⁰; (5) immunity lasts longer^271-273; and (6) modified live virus vaccines are effective against a broader spectrum of viral strains.²⁷⁰

Table 48-12 Currently Licensed* Vaccines for Bovine Virus Diarrhea Virus

On the other hand, modified live BVDV vaccines have certain disadvantages compared with inactivated BVDV vaccines; these disadvantages are that (1) some modified live virus vaccines can produce mild immunosuppression for brief periods after administration²⁷²; (2) some have been associated with what is usually a rather low incidence of a highly fatal disease syndrome, postvaccinal mucosal disease (MD)^273,274 (see later); and (3) until recently, modified live virus vaccines were not ordinarily recommended for routine use in pregnant cattle.

Studies have shown that the duration of cross-neutralizing antibodies stimulated by inactivated BVDV vaccines depends on the antigenic similarity between the vaccine strain and the wild type virus to which the cow is exposed.^275,276 If there are few common proteins, the ability to neutralize can be as short as 4 months; if there are many common antigenic sites, neutralization may last a year. Modified live BVDV vaccines stimulate cross-neutralizing antibodies that can still be detected 18 months after vaccination.²⁷⁰ This longer duration was further demonstrated when a modified live BVDV vaccine received a USDA label describing a 1-year duration of immunity against the birth of both type 1 and type 2 persistently infected calves.²⁷⁷

Recent studies have demonstrated the ability of both modified live^278,279 and inactivated type 1 vaccines²⁸⁰ to -provide protection against type 2 BVDV strains, although the protection afforded by the modified live virus vaccine was more complete. USDA/APHIS has established a licensing protocol for BVDV vaccines to obtain a type 2 BVDV protection claim. Most of the vaccines licensed against both BVDV type 1 and type 2 contain BVDV type 1 and type 2 isolates (see Table 48-10). The question of current vaccines’ability to cross-protect against BVDV type 1b strains has been raised,²⁸¹ and further studies are needed to determine the level of protection afforded by current vaccine strains.

VACCINATION AND MUCOSAL DISEASE

MD is seen when an animal that is persistently infected is exposed to another closely related cytopathic strain of BVDV. Also, theoretically a noncytopathic BVDV strain can mutate spontaneously into a cytopathic strain, resulting in MD without any subsequent exposure. High stress and immunodepression may be involved in this mutation.^282,283

A major concern with the modified live virus vaccines is whether they can cause MD.^275,284,285 For MD to occur, the cytopathic strain in the modified live virus vaccine must be closely related to the noncytopathic strain in the persistently infected animal. With the degree of attenuation of modified live virus vaccines today, an animal must be nutritionally deficient or severely stressed, or both, to face an increased likelihood of developing MD from the vaccine. This suggests that a specific set of circumstances is required and that MD caused by vaccination, when it occurs, is rare.

BOVINE VIRUS DIARRHEA VIRUS VACCINES AND REPRODUCTIVE CONTROL

Control of BVDV centers on prevention of persistent infection and elimination of persistently infected cattle; this means that identifying and removing persistently infected animals and continued vaccination to prevent persistent infection are necessary for effective control. Persistent infections occur through in utero infection of the fetus (up to approximately 125 days’ gestation) with a noncytopathic strain of BVDV.^270,282 The mechanism of transplacental transfer of BVDV is unknown; however, small amounts of virus in the dam’s bloodstream appear to be sufficient to produce these immunotolerant cattle. Protection of the dam may or may not correlate with protection of the fetus from subsequent persistent infection if viremia of the dam occurs. To break the vicious cycle of in utero infection and persistent infection, it is essential that vaccination provide fetal protection.

Several studies have been performed to assess the ability of vaccines to protect the fetus against either natural or artificial challenge. The results of these studies showed that most inactivated vaccines failed to provide much fetal protection,^275,286-291 except for one experimental vaccine, which is reported to give a high level of fetal protection. With the experimental vaccine, the lack of virus isolation from offspring of vaccinated animals indicated good protection.²⁹² However, the challenge of controls resulted in only approximately a 50% rate of persistent infection. Recently, the new inactivated vaccine has demonstrated a high level of fetal protection and was given the appropriate label by the USDA (see Table 48-9). Other published reports demonstrated that modified live virus BVDV vaccines were more effective at protecting the fetus^293-295 and that inclusion of a type 2 vaccine broadened the strains against which the vaccine protects.²⁹⁶ To date, vaccines licensed in the United States have not been required to provide fetal protection. However, label indications are now being granted by the USDA to vaccines that have demonstrated the ability to prevent the development of persistently infected calves. Several vaccines have achieved this label (see Table 48-9).

BOVINE RESPIRATORY SYNCYTIAL VIRUS VACCINES

John A. Ellis

BRSV is a prevalent paramyxovirus that can cause disease in cattle of all ages but that primarily affects calves in recurrent seasonal outbreaks.^306-308 Clinical disease is characterized by pyrexia, coughing, and tachypnea, which can progress rapidly to severe expiratory dyspnea.^307,309 BRSV is also considered one of the viral agents that predisposes animals to secondary bacterial infections in the bovine respiratory disease (BRD) complex; however, secondary infections often are absent in fatal BRSV-associated respiratory disease.^310,311 As well, subclinical BRSV infection or mild respiratory disease resulting from BRSV infection in dairy cattle may have a negative impact on milk production.³¹²

PARENTERAL VACCINES

Modified live virus and inactivated parenteral BRSV vaccines have been commercially available since the 1980s. Most of these vaccines are formulated in combination with other viral respiratory pathogens, including PI-3, BHV-1, and BVDV.¹⁶⁸ The efficacy of commercial modified live virus nonadjuvanted and adjuvanted combination BRSV vaccines in protecting calves from severe clinical disease subsequent to experimental infection with a virulent field isolate has been demonstrated.³¹³ Most vaccinated calves shed virus, but the peak virus titer was suppressed compared with unvaccinated controls. Viral clearance was coincident with the simultaneous appearance of mucosal antibody, cytotoxic T cells in the lungs, and anamnestic or primary serum antibody responses. In contrast, virus clearance in unvaccinated calves was coincident with the appearance of BRSV-specific cytotoxic cells before mucosal antibody was detected. Although administration of modified live virus BRSV vaccines by the intramuscular route to passively immune calves reportedly did not elicit mucosal memory IgA or serum antibody responses, or even prime for such responses,³⁰⁸ T cell responses have been demonstrated after parenteral vaccination in passively immune calves.³¹⁴ Whether these responses correlate to a protective cell-mediated memory response when maternal antibodies decline has not been determined.

More recent investigations using the same challenge model in BRSV-seronegative calves have documented a similar efficacy of at least two combination inactivated vaccines containing BRSV formulated with different adjuvants.^315,316 Clinical protection was associated with serum concentrations of BRSV-specific IgG as determined by ELISA^315,316 and in one case³¹⁵ the presence of IFN-γ—secreting BRSV-specific CD4⁺ T lymphocytes in the blood of vaccinated calves. There are conflicting data concerning the ability of commercial inactivated BRSV vaccines to override maternal antibodies and stimulate protective responses after parenteral immunization, which may be related to the vaccine formulation and adjuvant.^317,318

Most experimental studies concerning the efficacy of commercial BRSV vaccines are consistent with previous field trials, demonstrating the safety and efficacy of parenterally administered vaccines.^319,320 In addition, one study suggested the usefulness of combination vaccines in reducing the impact of subclinical BRSV infections.³¹³

Protection against BRSV infection and disease is associated, at least in part, with an IgA response^306-308; however, serum IgG acquired from either passive or active immunization can significantly reduce the severity of clinical respiratory disease that results from BRSV infection. Several studies have reported that the incidence and severity of disease in calves were inversely related to the maternal antibody titers.^308,321,322 In the case of herd immunity, passive antibodies were detectable in 50% of the calves for 3 months after birth and were present in some calves until 7 months of age.³²³ Therefore administration of BRSV vaccines to cows in late gestation to booster colostral antibody titers is a rational strategy to deal with BRSV-induced respiratory disease in young calves (1 to 3 months of age) in problem herds, without having to be concerned about the immunizing potential of particular parenteral vaccines in young seropositive calves.

INTRANASAL VACCINES

Because BRSV is an endemic infection in most cow herds, most young calves will have BRSV-specific maternal antibodies, unless there is failure of passive transfer. As well, given the endemic nature of BRSV, it is likely that many calves are exposed to BRSV early in life and will contract BRSV-associated respiratory disease if their passive protection is poor or has waned. Considering the mixed results, to date, with parenteral administration of BRSV vaccines to young seropositive calves, the availability of a safe, effective intranasal modified live virus BRSV vaccine may represent the most effective means of immunizing young calves. In fact, it was demonstrated in the late 1980s that intranasal inoculation of tissue-culture—attenuated BRSV to passively immune calves primed for mucosal memory and an anamnestic IgA response subsequent to challenge.³²⁴ More recent similar studies with culture-attenuated BRSV confirmed this phenomenon.³²⁵ In addition, two recent studies suggest that currently available parenteral combination modified live virus vaccines can be efficacious if administered intranasally.^326,327 Single intranasal administration of these vaccines to young calves primed for protective responses to subsequent experimental challenge. In one of these studies,³²⁶ results demonstrated that effective priming was achieved in BRSV-seropositive calves, confirming the previous observations with experimental single component BRSV vaccines.^322,323 Recently an intranasal BRSV vaccine was licensed in Europe and the United Kingdom.

ADVERSE REACTIONS TO BOVINE RESPIRATORY SYNCYTIAL VIRUS VACCINES

The major factor hampering the development of a vaccine for human respiratory syncytial virus (HRSV) is the dramatic HRSV vaccine failure in the 1960s, in which vaccination with a formalin-activated (FI), alum-adjuvanted HRSV predisposed children to more severe disease after subsequent HRSV infection.³²⁸ Although this same disease-enhancing phenomenon has been demonstrated in some studies of experimental FI-BRSV vaccines in cattle,^329,330 it is unlikely that modern manufacturing practices would use formalin inactivation for BRSV or other viral vaccines. Nevertheless, there are documented cases of apparent enhancement of BRSV-associated respiratory disease in cattle that received either inactivated or modified live virus vaccine in the field, indicating that some commercial vaccine formulations may stimulate potentially pathogenic immune responses in some cattle.^329,330 The immunologic mechanisms responsible for vaccine-associated disease enhancement are not completely understood. The current hypothesis is that some BRSV vaccines, notably FI-BRSV, mainly prime Th2-like responses involving eosinophil influx into the lung and production of high concentrations of BRSV-specific IgE.^329,330 Several studies have consistently documented a disparity in the type of antibody responses induced in cattle by modified live virus and inactivated BRSV vaccines.^330-335 Parenterally administered modified live virus BRSV vaccines generally stimulate moderate to high concentrations of VN antibody in the serum, whereas inactivated vaccines stimulate high concentrations of partially neutralizing or nonneutralizing antibody. The data are conflicting concerning the prophylactic or disease-enhancing properties of these different types of vaccine-induced antibody responses.^329,333 Alternatively, as was suggested in the case of disease enhancement after parenteral administration of a combination modified live virus BRSV vaccine,³³¹ the timing between vaccination and infection could be a critical factor. This may be related to the stage of the immune response—specifically, a predominance of BRSV-specific IgM at the time of infection may somehow predispose to enhanced disease.

Currently there is little information about the duration of the protective response after vaccination; however, cattle can be experimentally reinfected by 35 days after initial infection with virulent BRSV even in the presence of circulating antibody.³³¹ Nevertheless, as the epidemiology of BRSV-associated respiratory disease in the field indicates, disease caused by reinfection usually is less severe than that after the initial infection.^306-308 These observations indicate that most cattle do not develop an allergic (IgE) response to BRSV from naturally acquired infections, or to most BRSV vaccines, in the vast majority of cases.

PARAINFLUENZA TYPE 3 VIRUS VACCINES

John A. Ellis

Parainfluenza virus type 3 (PI-3V) is a ubiquitous paramyxovirus in cattle populations worldwide.^336,337 In uncomplicated experimental PI-3V infections, clinical signs of coughing, tachypnea, and fever have been observed from 4 to 12 days after infection.³³⁶ Although respiratory disease has been experimentally reproduced in calves infected with PI-3V, seroconversion has been demonstrated after outbreaks of respiratory disease,³³⁸ and PI-3V has been identified in the lesions of BRD complex at postmortem examination, the importance of this agent in the BRD complex remains controversial.³³⁶ Generally PI-3V is viewed as a potentiating agent in mixed infections, predisposing the animal to bacterial pneumonia by altering bacterial clearance in the upper and lower airways and by infecting both respiratory epithelia and alveolar macrophages.³³⁶

Currently five types of PI-3V vaccines are available commercially: (1) modified live virus intramuscular vaccines; (2) modified live virus, temperature-sensitive, intramuscular vaccines; (3) modified live virus intranasal vaccines; (4) modified live virus, temperature-sensitive, intranasal vaccines; and (5) inactivated virus vaccines. All PI-3V vaccines available in North America are combined at least with a BHV-1 vaccine. Currently, a single-antigen, modified live virus PI-3V intranasal vaccine is available in Europe. The efficacy of this formulation recently was demonstrated in a severe challenge model.³³⁹

Opinions are divided as to the relative importance of mucosal versus systemic immune responses in achieving protection from PI-3V—associated respiratory disease and, by extension, the comparative efficacy of intranasal and intramuscular vaccines. Some comparative studies^339,340 reported that intranasal vaccination resulted in better protection against experimental challenge; others³⁴¹ were unable to demonstrate any advantage to the use of one vaccine or route of administration over the other. A notable exception, however, was young calves with maternal antibodies, in which intranasal administration was thought to produce a more effective immune response. Passive antibodies may persist in calves until 8 months of age and may interfere with active immunization.³⁴² Consequently, calves vaccinated parenterally before 6 months of age should be revaccinated after reaching 8 or 9 months of age.³⁴²

Although not experimentally documented, as in the case of BRSV, it is likely that, given the similar biology of PI-3V infection, a mucosal (IgA) response is necessary to prevent PI-3V infection but that passively (maternal) or actively acquired serum IgG is likely to mediate significant sparing of clinical disease subsequent to infection. The cell-mediated (cytotoxic T cell) response in the clearance of PI-3V is a poorly documented but probably important effector mechanism stimulated by modified live virus vaccines, as is the case with BRSV.

There is debate about the overall utility and economic benefit of using PI-3V (and BRSV) vaccines in the field.^343,344 Much of the uncertainty undoubtedly is related to the difficulties involved in determining the relative importance of a particular agent in a multifactorial disease process such as BRD complex. Few studies^344,345 address the economic impact of subclinical paramyxovirus infections in cattle. No recent studies (in the last 5 years) directly address the economic impact of inclusion of PI-3V in combination vaccines. One large study³⁴⁶ conducted under commercial feedlot conditions demonstrated an economic benefit to using a four-way combination modified live virus vaccine containing PI-3V together with BHV-1, BRSV, and BVDV versus a single component BHV-1 vaccine; however, it was not possible to determine which antigen(s) were responsible for disease sparing.

MANNHEIMIA (PASTEURELLA) HAEMOLYTICA, PASTEURELLA MULTOCIDA, AND HISTOPHILUS SOMNI (HAEMOPHILUS SOMNUS)

Anthony W. Confer

MANNHEIMIA HAEMOLYTICA VACCINES

M. haemolytica serotype 1 is the main species of bacteria responsible for the clinical signs and lesions of severe bovine fibrinous pleuropneumonia (shipping fever).^347,348 The bacterium is a gram-negative commensal in the bovine nasopharynx, and after stress or viral infections the bacterium proliferates and is inhaled into the lungs where it stimulates a series of pathologic events leading to acute, severe fibrinopurulent inflammation and necrosis. The bacterium was renamed Mannheimia haemolytica because of substantial genomic differences between it and other members of the Pasteurella genus; however, it is still often referred to in commercial vaccines by its previous name, Pasteurella haemolytica.³⁴⁹ In this discussion the organism’s current and correct scientific name, M. haemolytica, will be used.

Commercial Vaccines

When a vaccination program for prevention of BRD is designed, four questions should be addressed:

Should M. haemolytica vaccine be used?

What type of M. haemolytica vaccine should be used?

How many doses of M. haemolytica vaccine should be given?

When should M. haemolytica vaccine be given?

The practicing veterinarian must answer these questions based on the cattle production situation; stocker, dairy, or feedlot management; interpretation of published literature; consultations with colleagues; and personal experience.

Numerous commercially available bovine biologics contain M. haemolytica antigens.³⁶³ M. haemolytica vaccines are often in combination with viral vaccines, H. somni or P. multocida bacterins, and occasionally Clostridium species biologics. Despite the various licensed M. haemolytica biologics available, formulations of M. haemolytica vaccines fall into one of eight categories, seven of which are nonliving vaccines. These are described by their manufacturers as follows: (1) bacterin with aluminum hydroxide adjuvant; (2) bacterin with water-in-oil adjuvant; (3) outer membrane extract; (4) bacterin-toxoid (LKT toxoid); (5) toxoid—cell-associated antigen; (6) adjuvanted toxoid (culture supernatant); (7) autogenous (herd-specific) bacterins produced from isolates submitted by practicing veterinarians; and (8) live streptomycin-dependent mutant. The last vaccine is the only currently licensed live M. haemolytica biologic. In the past, several live M. haemolytica vaccines were commercially available, and those vaccines showed potential efficacy; however, untoward side effects such as severe local and systemic reactions often occurred after vaccination.

PASTEURELLA MULTOCIDA VACCINES

P. multocida, particularly serogroup A, serotype 3 isolates, is the second most common bacterium associated with pneumonia in beef cattle and the most common isolated from pneumonia in dairy calves.³⁴⁷ Although M. haemolytica has traditionally been the major pathogenic bacterium associated with shipping fever, recent studies suggest that the incidence of P. multocida in this disease has increased in beef cattle.^348,372

The pneumonia produced by P. multocida is less acute and severe than M. haemolytica—associated pneumonia. The antigenic makeup of nonliving P. multocida vaccines presently available are proprietary and are described in the Compendium of Veterinary Products as bacterial extracts, cell-associated antigens, soluble antigens, and/or bacterins. Conventional formalin-inactivated, whole-cell, aluminum hydroxide—adsorbed bacterins have been the industry standard and are not considered highly efficacious.³⁶³ A commercial live streptomycin-dependent mutant P. multocida and M. haemolytica vaccine is available. Its efficacy is not well documented in the literature.

The immune mechanisms involved in resistance to P. multocida lung infections in cattle are poorly understood. There is more published work related to vaccines against P. multocida serogroups B and E, which cause hemorrhagic septicemia in cattle and water buffalo.³⁸⁵ Recent studies suggest that P. multocida OMPs or iron-regulated OMPs could be important immunogens for protecting cattle against pneumonia, and vaccination of calves with outer membrane preparations substantially enhanced resistance against experimental challenge.^350,386,387 Although the P. multocida toxin, which is produced primarily by serogroup D isolates, is an important virulence factor and immunogen for P. multocida in atrophic rhinitis of swine, there is no evidence that this toxin is important in pneumonia of cattle, nor would it be beneficial to include the toxin in a vaccine for cattle.³⁵⁰

HISTOPHILUS SOMNI (HAEMOPHILUS SOMNUS) VACCINES

Haemophilus somnus’ name was recently changed to H. somni, which we will use in this discussion. H. somni is the cause of thrombotic meningoencephalitis (TME), septicemia, and reproductive disorders in cattle. In addition, it is the third most common bacterial isolate from beef cattle pneumonia in most epidemiologic surveys.^347,348 Cases of H. somni—induced pneumonia are often associated with concurrent myocardial necrosis. Potential immunogens have been experimentally studied in H. somni and consist of lipooligosaccharide (LOS),³⁸⁸ several OMPs—including a surface protein that binds the Fc receptor of bovine immunoglobulin and is associated with serum resistance of pathogenic strains³⁸⁹—and iron-regulated OMPs.³⁹⁰ As with most gram-negative bacteria, H. somni LOS is a dominant antigen that stimulates an antibody response to the polysaccharide moiety after natural or experimental exposure. It is interesting to note that H. somni LOS has been demonstrated to exhibit phase variation in its epitopes (i.e., antigenic drift), thereby allowing the bacterium to escape the immune response.³⁸⁸ Currently there is no evidence that those anti-LOS antibodies are protective.³⁹¹ Likewise, several OMPs and iron-regulated OMPs have been shown to be immunogenic in cattle. The major H. somni OMP is weakly immunogenic and shows strain antigenic variability.³⁹² Their role in stimulating immunity is not known.

Several approved H. somni biologics are available, often in combination with respiratory viruses and Pasteurella species. All of the currently licensed H. somni biologics are formalin-killed bacterins with aluminum hydroxide as an adjuvant. Efficacy of H. somni bacterins has been generally favorable in stimulating protection against experimental pneumonia, against intravenous and intracisternal H. somni challenge as a model of TME, and against natural TME.³⁵⁴ Overall, vaccine-induced immunity has been best against experimental and natural TME.^364,380,393 Using an experimental challenge model of H. somni—induced pneumonia, significant protection was afforded calves vaccinated twice with an H. somni bacterin.³⁹⁴ Resistance correlated with a high serum antibody response to the bacterium. One study demonstrated a reduced risk for respiratory disease in cattle that had high antibodies titers to H. somni on arrival in a feedlot.³⁹⁵ Therefore the potential exists for stimulating resistance to H. somni—associated pneumonia. In addition, commercial H. somni vaccines can stimulate IgE antibodies and thus potentially increase the risk for type I hypersensitivity.³⁹⁶

Under field conditions, commercial H. somni bacterins have had limited success in inducing protection against respiratory disease. Published reports have shown conflicting results. Perino and Hunsaker³⁷⁸ reassessed the results of three published commercial H. somni bacterin field trials and reaffirmed that this is the case. In one trial H. somni vaccination resulted in a reduced treatment rate when vaccinations were given at arrival and 21 days later.³⁹⁷ In another study, vaccination once with a commercial bacterin was associated with significantly more animals being treated for respiratory disease compared with unvaccinated cattle or those vaccinated twice at 21 day intervals.^398,399 In another study, vaccination with a commercial H. somni bacterin on arrival at the feedlot was associated with no significant differences between the number of animals treated for respiratory disease compared with unvaccinated controls.⁴⁰⁰ In a recent study, partial reduction in feedlot respiratory disease was associated with vaccinating for H. somni, whereas a significant reduction in respiratory disease was associated with H. somni vaccine in combination with M. haemolytica or M. haemolytica vaccine alone.⁴⁰¹ Ribble and colleagues,⁴⁰² however, demonstrated reduced steer mortality after H. somni vaccination, but not heifer mortality.

BOVINE REPRODUCTIVE DISEASE VACCINES

Victor S. Cortese

Carol A. Bolin

As explained earlier, cows have a multilayered placenta, which leaves the fetus susceptible to infection. Infection of the placenta, inflammation of the ovary, death of the fetus, or disruption of the cervical plug all may cause abortion. Reproductive disease therefore is the most difficult disorder against which to achieve protection. Vaccination must minimize the amount or duration (or both) of the viremia or septicemia, or it must prevent the pathogen from moving through the cervix or crossing the placenta.

The reproductive diseases and protection against them through vaccination are areas of active research. With current research a vaccination program can be designed to aid in the control of reproductive diseases. Unfortunately, there is little or no research on the efficacy of many vaccines currently used to prevent reproductive disease. Because the causes of reproductive failure are so numerous (infectious agents account for only a small percentage), vaccination to prevent infectious reproductive losses many not appear to be effective. This often is a result of the fact that diagnostic testing has not been attempted or has not determined the cause of reproductive inefficiencies. A vaccination program may be inappropriately instituted when the cause is not infectious, or the current program may unfairly be deemed ineffective. A Neospora vaccine against Neospora-induced reproductive disease in cattle has been granted a license. Little published information is available on this product. Although safety has been shown, the efficacy is questionable.

The use of viral vaccines to help prevent reproductive diseases was discussed earlier in the chapter.

BRUCELLA ABORTUS VACCINE

Brucella vaccination has best shown the effectiveness of vaccination in controlling a reproductive disease. The successful control or even eradication of B. abortus in many areas of North America is a testament to the ability of a program involving testing, culling, and vaccination to control a reproductive disease. Vaccination with either strain 19 or strain RB51 Brucella has proved to be effective; however, many herd owners have stopped vaccinating against this disease as states have been declared Brucella free.

Abortions caused by B. abortus usually are seen after 5 months of gestation. Retained placentae and subsequent metritis usually follow. The abortion is caused by severe placentitis. Brucella infections have also been associated with a decrease in conception rates and an increase in services per conception. A higher number of dead and weak calves has also been demonstrated in infected herds. Orchitis or seminal vesiculitis or both may characterize infections in bulls.

Only heifer calves can be vaccinated for brucellosis. Both of the two licensed B. abortus vaccines are modified live bacterins, and vaccination of bulls may lead to orchitis.⁴⁰³ Legal use of the vaccines usually is confined to heifer calves 4 to 12 months of age, because vaccination of older animals with the strain 19 vaccine may lead to false-positive results on routine Brucella screening tests. Because the strain 19 vaccine may cause septicemia, clinical illness, and occasionally death,⁴⁰⁴ sick, unhealthy, or stressed cattle should not be vaccinated. The RB51 strain vaccine is an O antigen—deficient mutant of B. abortus strain 2308. The RB51 vaccine has three primary advantages:

Antibodies induced by this vaccine do not react with the serologic tests routinely done to diagnose Brucella infections.

The vaccine can be used in adult cattle at a lower dosage under special circumstances and with the permission of the USDA.

The vaccine tends to cause less postvaccination fever and stress than the traditional strain 19 vaccines.

The long-term immunity conferred by Brucella vaccination is the cell-mediated type.^405,406 Calfhood vaccination does not prevent a herd of cattle from becoming infected with B. abortus. However, it does largely prevent abortions and protects 65% to 75% of the cattle in the herd from infection while infected reactors are identified and slaughtered.⁴⁰⁷ For these reasons, in addition to vaccination, a control program should include testing and culling of all animals that test positive.

LEPTOSPIRA BACTERINS

Leptospirosis occurs worldwide and is caused by infection with the spirochete Leptospira. The pathogenic leptospires were formerly classified as members of the species L. interrogans; the genus has recently been reorganized, and pathogenic leptospires are now identified in seven species of Leptospira.⁴⁰⁸ As part of this reclassification the serovar names have remained the same, but some of the common leptospiral pathogens of cattle have different species names than before. The key changes for this discussion include the following: (1) L. interrogans serovar Grippotyphosa is now L. kirschneri serovar Grippotyphosa, and (2) the two types of serovar Hardjo have been formally split into two species; serovar Hardjo type hardjo-bovis (found in the United States and much of the world) is now L. borgpetersenii serovar Hardjo, and the less common serovar Hardjo type hardjo-prajitno (found primarily in the United Kingdom) is now L. interrogans serovar Hardjo.

Although traditionally associated with abortions, infection with various serovars of Leptospira are associated with a variety of clinical signs including severe systemic disease most often in young animals, decreased milk production, birth of weak calves, and infertility. In addition, infected cattle are known to present a risk of zoonotic transmission of the infection to humans. Many different serovars of Leptospira have been shown to cause reproductive failure and abortions in cattle. Of these serovars, Hardjo, Pomona, and Grippotyphosa^409-412 are more common, with serovars Canicola, Icterohaemorrhagiae, and Bratislava occasionally implicated. The epidemiology of infection of cattle with these serovars differs, with cattle serving as the reservoir or maintenance host for serovar Hardjo and as an incidental host for the other serovars. In general, maintenance host infections are associated with a high prevalence of infection, a poor immune response, and long-term infection and shedding, whereas incidental host infections are characterized by low overall prevalence of infection with epidemics recognized, a vigorous immune response, and short-term infection and shedding. These differences in the epidemiology of leptospirosis caused by different serovars of Leptospira require different strategies for prevention.

Leptospirosis can cause abortion storms in which a high number of cattle may abort within a short period. There may also be an increased number of stillbirths and births of premature and weak calves during these periods.⁴¹³ Although serovars Pomona and Grippotyphosa tend to cause abortions in the last trimester of pregnancy, serovar Hardjo can cause abortions at any stage of pregnancy. Abortions usually are caused by fetal infection and subsequent death of the fetus, although placentitis may also occur. Serovar Hardjo can also colonize the oviducts and uterus,^410,414,415 diminishing fertility. After an initial serovar Hardjo infection, cattle may remain infected and shed the spirochete for long periods,^416,417 whereas infection and shedding of the others serovars is relatively brief.

Current bacterins generally contain combinations of leptospiral serovars Pomona, Grippotyphosa, Canicola, Icterohaemorrhagiae, and either L. interrogans serovar Hardjo (hardjo-prajitno) or L. borgpetersenii serovar Hardjo (hardjo-bovis). At the time of this writing a monovalent L. borgpetersenii serovar Hardjo (hardjo-bovis) vaccine is also available. There has been considerable debate in recent years regarding the efficacy of leptospiral bacterins for cattle. The bacterins have label claims that indicate they are to be used as an “aid in the prevention of disease.” Therefore these bacterins should be expected to decrease the severity of clinical signs, including abortion, associated with such infection. In general, the evidence supports such claims for serovars for which cattle are an incidental host, that is, serovars Pomona, Grippotyphosa, Canicola, and Icterohaemorrhagiae. Protection mediated by these bacterins for these serovars is thought to occur because of induction of antibodies directed against the LPS on the surface of the Leptospira.⁴¹⁸ However, vaccination does not always prevent infection and leptospiruria caused by serovar Pomona.^419-421

The efficacy of bacterins for prevention of infection, leptospiruria, and clinical signs associated with serovar Hardjo infection is significantly more controversial. The evidence that the efficacy of traditional serovar Hardjo vaccines is less that optimal includes induction of a relatively poor antibody response in vaccinated animals, the common presence of Hardjo infection in herds despite routine vaccination, and experimental trials that did not demonstrate protection afforded by these traditional vaccines for prevention of infection, colonization of the renal or genital tract, or transplacental infection on challenge with Leptospira borgpetersenii serovar Hardjo (hardjo-bovis).^422-424 In these studies, cattle were not protected from infection despite the induction of antibody directed against serovar Hardjo LPS. Further investigation and evaluation of other serovar Hardjo bacterins has led to a hypothesis that CMI may play a role in protective immunity against serovar Hardjo in cattle.^425-429 Newer bacterins for serovar Hardjo have been introduced in monovalent and polyvalent formats, and there is evidence that these bacterins provide significant protection of cattle against infection, tissue colonization, shedding, and transplacental infection.^424,428-430 Other new bacterins for serovar Hardjo are also entering the marketplace, but as of this writing extensive data regarding the performance of these products are not available in the literature.

Some Leptospira bacterins are labeled as single initial dose products, but a booster dose is recommended approximately 1 month after the first dose.⁴¹⁸Leptospira bacterins must be administered by intramuscular or subcutaneous injection. Although some manufacturers specify revaccination at 12-month intervals, this DOI has been questioned, and more frequent revaccination often is needed to control Leptospira abortions.^419,420,422 One of the newer serovar Hardjo bacterins has documented a 1-year DOI for this component, but this DOI has not been documented for other Hardjo vaccines or for the other serovars, making vaccination every 6 months a reasonable recommendation in many circumstances. Nevertheless, because leptospiral abortions are uncommon during the first half of pregnancy, it may be possible to use an annual vaccination schedule (serovar Hardjo excepted) in seasonally calving herds such as beef herds. Cattle in such herds can be vaccinated when they are 2 to 4 months pregnant, usually at the time that pregnancy is diagnosed, and protected through the balance of the pregnancy with a single annual dose.⁴¹⁹

Prevention of leptospirosis caused by serovar Hardjo requires a somewhat different approach. Prebreeding vaccination of heifers that is effective in managing reproductive sequelae of other types of leptospirosis may be too late to prevent the consequences of serovar Hardjo infection. Heifers exposed very early in life may remain infected well into the time of breeding. Therefore efforts to control serovar Hardjo infection should be targeted at preventing the initial infection and is best done by vaccinating young stock well before the time when they are mixed with older animals. In addition, bulls can carry serovar Hardjo and transmit the infection quite readily during breeding.⁴³¹ Therefore bulls should be fully included in efforts to control serovar Hardjo infection by vaccination.

BOVINE GENITAL CAMPYLOBACTERIOSIS VACCINES

Originally classified as Vibrio, Campylobacter fetus subsp. veneralis causes a venereal infection of cattle. The bacteria are introduced during natural breeding by infected bulls or by artificial insemination (AI) with infected semen. Bulls usually are infected by breeding with infected cows, but contact with infected bedding may also be a cause. Older bulls (over 4 years of age) are more likely to be infected. After deposition in the vagina, the bacteria rapidly colonize the vagina and cervix, and in 25% of these cows the bacteria are found in the oviducts. The organism can persist for months after infection of these sites. It has been shown that fertility never returns to normal in some infected animals, and some animals may be permanently sterile because of the damage caused by salpingitis.

Vaccination with Campylobacter vaccines has been shown to be effective in protecting heifers even when vaginal cultures test positive for the bacteria.⁴³² It appears that the uterus is very resistant to the bacteria after vaccination. Studies have demonstrated improved breeding efficiency in vaccinated herds.⁴³² Vaccination of bulls with oil-adjuvant vaccines not only prevents infection of bulls for up to 1 year⁴³³ but also aids in prevention of mechanical transfer of organisms during natural service.⁴³⁴ Furthermore, vaccination with two doses has been shown to be effective at clearing infections from carrier bulls.^435,436

BOVINE TRICHOMONIASIS VACCINES

Bovine trichomoniasis is a venereal infection of cattle caused by the protozoal agent Tritrichomonas foetus. Early in the course of the disease, abortions with pyometra may be seen in 5% of infected cows. These abortions occur early in gestation.⁴⁴⁰ However, infertility is the most common sign, with long interservice intervals.^441,442 Early embryonic death is followed by a period of conception failure. Some natural resistance develops after infection, but carrier cows may be an important component of the epidemiology of this disease. In rare cases a cow may be left sterile after an infection because of uterine destruction.⁴⁴³

The efficacy of Tritrichomonas vaccines is questionable, ^444-446 but the vaccines do appear to reduce actual reproductive losses.⁴⁴⁷ Heifers, cows, and breeding bulls should be vaccinated twice at 2- to 4-week intervals, the second dose given 4 weeks before the beginning of the breeding season.⁴⁴⁸ Subcutaneous administration is recommended. In subsequent years a single annual booster vaccination should be given 4 weeks before the beginning of the breeding season.

In a problem herd, trichomoniasis vaccination must be coupled with other control measures, such as culturing, culling, and treatment to effectively control the disease.

NEONATAL CALF ENTERIC DISEASE VACCINES

Gerald E. Duhamel

Neonatal calf enteric diseases (NCEDs) can have a devastating impact on the profitability of beef cow-calf and dairy operations. In addition to mortality, medical, and labor costs, NCED can significantly reduce body weight of beef calves at weaning and performance of replacement dairy heifers.⁴⁴⁹

Several well-characterized infectious causes of NCED have been described.⁴⁵⁰ Some of the more common infectious agents are group A RVs, coronavirus (CV), enterotoxigenic E. coli, salmonellae, and Cryptosporidium species.^451-457 Sporadic outbreaks of necrohemorrhagic enteritis affecting 3- to 10-day-old calves have been associated with infection with C. perfringens type C.⁴⁵⁸ Other less well-characterized viruses (group B RV, calicivirus, torovirus, astrovirus), bacteria (enterotoxigenic Bacteroides fragilis, attaching-effacing enteropathogenic and enterohemorrhagic E. coli, Enterococcus durans), and protozoans (Giardia duodenalis) also have been associated with NCED.

Because of the continuous calving and constant introduction of replacement heifers on dairy farms and the continuous flow of susceptible calves on veal calf operations, infections caused by more than one agent should be suspected in these types of operations.^{451-457,459-461} In addition to different infectious agents, mixed infections with different groups and serotypes or genotypes of viruses and bacteria also can occur. As a consequence, the severity, duration, and spread of clinical disease associated with complicated infections are usually greater than with a single agent, and control may be more challenging. When scours occurs in a herd that has been vaccinated against enteric diseases, possible contributing factors should be considered, including concurrent infection with pathogens not present in the vaccine (e.g., Cryptosporidium species, salmonellae, nongroup A RVs, other pathogens) and suboptimal management, including poor control of environmental contamination. Under these conditions, strategic improvement in husbandry practices might be sufficient to reduce the infectious threshold for NCED and obtain the full benefit of pathogen-specific vaccination. In any situation, thorough laboratory diagnostic investigation is essential in order to correctly identify the primary cause of NCED and any other possible contributing factors and to serve as a basis for appropriate control strategies for the present and future calf crops.

Management practices and risk factors associated with the development of NCED are sufficiently different between dairy and beef herds that control measures can be tailored according to the type of production. For example, in dairy herds, high turnover of older cows and continuous introduction of replacement heifers pose a higher risk for introducing new strains of enteric disease pathogens in a susceptible population than in closed beef herds. Similarly, the continuous calving and the proximity of susceptible calves on dairy farms create an ideal environment for recirculation of enteric disease agents back into the adult population. This in turn may increase and broaden herd immunity such that the efficacy of a vaccine in these herds might be enhanced, partly because of the booster effect vaccine can have on preexisting immunity. Beef cattle herds, in contrast, are generally relatively closed, and a susceptible calf population is present only for a relatively short period annually during the calving season. Introduction of new pathogens or new strains of enteric disease agents, particularly during the calving season, can have a devastating effect because of the potential for exposure of a high number of susceptible animals over a relatively short period of time. Conversely, after an outbreak, herd immunity might be more stable and the occurrence of NCED might be reduced during the following calving seasons.

Under both types of production systems, vaccination for NCED is rarely successful without reasonably good management programs and sanitation aimed at providing adequate intake of protective colostrum and minimizing environmental contamination. General herd health management steps that can affect the success of a vaccination program for NCED should include a calving cow-calf care plan aimed at minimizing exposure of newborn calves to infectious agents that can overwhelm innate or passively acquired immunity. This is accomplished by eliminating all potential means of NCED transmission and by reducing the load and duration of exposure to pathogens present in the calving environment by following eight simple recommendations:

Giving calves a healthy start maximizes their genetic production potential while reducing the costs and labor associated with treatment of sick animals.

ROTAVIRUS AND CORONAVIRUS VACCINES

RVs and CVs are ubiquitous in the cattle population; most adult cattle have VN serum antibodies.^465-469 RV infections are widespread in both dairy and beef cow-calf productions, whereas infection with CV most often occurs as sporadic outbreaks of severe diarrhea in beef cow-calf herds or chronic low-grade diarrhea in dairy and veal calf operations. In addition to causing NCED, CV has been associated with winter dysentery in adult cattle⁴⁷⁰ and respiratory tract infections in calves⁴⁷¹ and as a contributing infectious cause of BRD complex in feedlot cattle.⁴⁷² Fecal shedding of RV and CV is common among adult cattle,^473-476 which provides an immediate source of virus challenge for naive newborn calves and allows persistence of these agents at the herd level.

Although only one type of CV is known to cause NCED,⁴⁷⁷ different subtypes of CVs can be identified on the basis of minor genomic and antigenic differences.^477-481 On a herd basis, however, affected calves can display a range of clinical signs from enteric only to mixed enteric and respiratory signs. A recent molecular epidemiologic investigation based on comparative analyses of the gene encoding the S glycoprotein, a major structural protein of bovine CV, revealed (1) identical CV strains in different animals from the same herd and from paired nasal and fecal samples from the same animals, suggesting herd outbreaks are associated with a single strain circulating among susceptible cattle, (2) identical CV strains in affected cattle from different herds in the same region, suggesting transmission between herds, and (3) different CV strains in cattle affected during different outbreaks occurring over several years in the same herd, suggesting herd outbreaks are associated with the introduction of new strains in a recovered herd.⁴⁸²

Currently RVs are classified into at least seven distinct groups, A through G.⁴⁸³ Although RVs that belong to groups A, B, and C have been found to naturally infect cattle,^476,483-487 group A RVs are by far the prevalent type.^485,487 Members of the group A RVs are further classified according to antigenic and genetic differences in their outer capsid proteins, G and P.^488-490 Because both of these proteins are involved in neutralization of infectivity in vitro and protection in vivo,^491-493 consideration of the G-P configuration of RVs is critical to development of an effective vaccination program for prevention of NCED.

Although a good correlation has been found between the antigenicity of the G proteins and their corresponding gene sequences, a similar relationship has not been found for the P proteins. Therefore 14 different G serotypes, which correspond to 14 G genotypes, have been identified among group A RVs, whereas 10 serotypes identified on the basis of the antigenicity of the P proteins have been assigned to 20 genotypes when compared on the basis of the nucleotide sequence of the P protein genes.⁴⁹⁰ At least eight distinct G serotypes or genotypes (G1, G2, G3, G6, G8, G10, G11, and untypeable) are known to infect cattle in the United States^494,495; G6 is the most widespread, and G8 and G10 account for lower percentages of infections.^469,495-500 Conversely, RVs with any of four P serotypes or genotypes—P6(1), P7(5), P8(11), and untypeable—are known to infect catte, with P7(5) being the prevalent type.^495,498,501

The genome of RVs is composed of 11 gene segments that can be exchanged among RV isolates when animals are infected by more than one virus type at the same time.⁴⁸⁹ Therefore mixed infections produce virus with a genetic makeup derived from either parental strain by a mechanism called gene reassortment. Because the G and P proteins independently are involved in generation of specific VN antibodies, reassortment of these genes during mixed infections can generate new progeny viruses that can evade what once was a protective immune response, thus allowing persistence of RVs in susceptible populations.⁵⁰⁰ Therefore the potential occurrence of RVs carrying any of 36 possible antigenic configurations (4 Ps × 8 Gs = 32 potential types) underscores the limitation of vaccination programs and also the importance of sound management practices designed to minimize exposure by limiting environmental contamination.

ROTAVIRUS AND CORONAVIRUS VACCINATION PRODUCTS

BACTERIAL SCOURS VACCINES

Victor S. Cortese

Charles A. Hjerpe

ENTEROTOXIGENIC ESCHERICHIA COLI (CALF SCOURS) BACTERINS

Most cases of scours caused by E. coli occur within the first 72 hours of life. More than 90% of these cases are caused by E. coli containing the K99 pilus attachment fimbriae.^552-554 These strains also may have other fimbriae types, such as F41 and F1 (type 1).^552,555 Villous attachment and colonization by strains of enterotoxigenic E. coli having multiple fimbriae types appear to be effectively prevented by vaccination with bacterins that have only a single pilus antigen in common with challenge strains.^552,555 However, disease occasionally may be caused by non-K99 E. coli.⁵⁵⁶ The attaching and effacing E. coli types, which may cause disease at 7 to 21 days of age, often do not produce K99 pilus and are not protected by current E. coli K99 bacterins.^557,558 This apparent lack of efficacy may be seen with other non-K99 E. coli; therefore typing of E. coli isolates from scours cases may be important in determining which vaccine to use.

Because E. coli scours occurs so early in life, the newborn calf does not have enough time to derive protection from vaccination. Therefore control of E. coli infection has been aimed at controlling calf exposure to the pathogens and vaccinating the cow to increase the colostral antibody levels against this pathogen (i.e., usually against the K99 pilus antigen).⁵⁵⁴ Cows are vaccinated in late gestation to ensure high concentrations of anti-K99 colostral antibodies. When colostrum from vaccinated cows is fed to newborn calves, the antibodies act in the small intestine to block the pili from binding to specific receptor sites on the brush border of small intestinal villous enterocytes.^552,559 E. coli bacteria that are prevented from attaching to the jejunal and ileal villi are carried into the large bowel by peristalsis. In this way, colonization of villi and production of enterotoxin are avoided. By the time they are 48 to 96 hours old, most calves are highly resistant to infection.^552,560 Thus feeding calves colostrum with a high concentration of antibodies against K99 antigen, even though restricted to the first day of life, often is sufficient to prevent the disease.⁵⁵⁵ Passive circulating humoral antibodies, which are absorbed into the bloodstream from the calf’s gut, are thought to play little or no role in immunity to neonatal enteric disease caused by enterotoxigenic E. coli.⁵⁵² In dairies these vaccines are only as good as the colostrum program that is in place.

Nearly all strains of enterotoxigenic E. coli that have been isolated from neonatal calves have K99 pili.⁵⁶¹ Currently there is no evidence that bacterins with multiple pilus antigen types are more effective than those with only one pilus antigen type, as long as the vaccine and the challenge strains share a common pilus antigen.⁵⁵² However, vaccines with multiple pilus antigens are more likely to have at least one of the antigens found on the virulent challenge strain of E. coli.

Escherichia coli Vaccination Programs

The general recommendations for use of E. coli bacterins are summarized in Table 48-13. E. coli bacterins are offered as single-antigen vaccines and in combination with other antigens. Oil-adjuvant E. coli bacterins are administered by intramuscular injection in a single dose 2 weeks to 6 months before calving, and administration is repeated -annually.⁵⁶¹ Non—oil-adjuvant E. coli bacterins are recommended for intramuscular or subcutaneous injection in two doses administered at a 2- to 4-week interval, with the second dose given 3 to 6 weeks before calving. In subsequent years a single booster dose should be administered 3 to 6 weeks before calving. E. coli bacterins do not protect calves that do not ingest sufficient amounts of colostrum sufficiently soon after birth. Also, because this protection is based on passive immunity, high challenge levels may overwhelm the finite amount of antibodies present.

Table 48-13 Currently Licensed^* Escherichia coli Bacterin-Toxoids, Salmonella Bacterins, and Core Endotoxoid Vaccines

SALMONELLA VACCINES

Salmonella outbreaks can be caused by myriad Salmonella serotypes and strains (see Chapter 32). These bacteria may cause diarrhea or septicemia or both. Most outbreaks in cattle have historically involved either Salmonella Dublin or Salmonella Typhimurium; therefore all but one of the commercial Salmonella vaccines contain either Salmonella Typhimurium alone or Salmonella Typhimurium and Salmonella Dublin. More recently, S. Newport and other group C Salmonella have greatly increased in importance. All currently licensed products are formalin-inactivated, whole-cell, aluminum hydroxide—absorbed bacterins, except for a modified live S. Dublin vaccine,* and the newest vaccine against bovine Salmonella, the siderophore receptor vaccine.^† The gram-negative core antigen vaccines may also provide some protection from morbidity and mortality associated with salmonellosis.

A modified live, genetically altered (via deletion) S. Dublin vaccine is marketed as Entervene-d for parenteral use in young calves. Research indicates that it is effective in calves 2 weeks of age and provides some cross-protection to challenge with virulent S. Typhimurium.^561a,561b As with many gram-negative vaccines, adverse reactions to this vaccine have been reported. Anecdotal reports of effective oral use in calves younger than 2 weeks of age indicate that this route may help avoid some adverse reactions associated with injection of an endotoxin-containing product.

Killed Salmonella bacterins can produce measurable antibody responses to bacterial proteins in calves and mature cattle. However, calves vaccinated with a killed bacterin are not able to produce anti-LPS antibodies until 12 weeks of age,⁵⁶² and optimum responsiveness does not occur until 1 year of age.⁵⁶³ Most controlled studies in which calves were vaccinated with a killed Salmonella bacterin and orally challenged reported lack of protection.^564-566 One small study that reported good protection after vaccination of 3- to 6-week-old calves with two doses of killed bacterin used intramuscular challenge.⁵⁶⁷ Another study in 6-month-old cattle found that a single intradermal dose of heat-killed Salmonella Dublin protected against intravenous challenge.⁵⁶⁸ Vaccination of cattle 3 months of age or older with two doses of killed Salmonella bacterins is likely to be useful for preventing salmonellosis. A newer Salmonella vaccine (SRP) using subunit technology has been conditionally licensed. Although little has been published on this vaccine, the clinical impression is that it has been successful in controlling disease caused by multiple different serotypes of Salmonella in some cases.

Vaccination of adult cows, with passive transfer of antibody to calves through colostrum, frequently is used in dairies to control calfhood salmonellosis. Controlled trials evaluating passive protection have produced mixed results, with some indicating lack of protection^566,569 and others demonstrating some protection in very young calves (5 days old).⁵⁷⁰ Vaccination of dry cows may be useful for helping to control salmonellosis in calves younger than 3 weeks of age but is probably minimally effective for controlling salmonellosis in calves older than 3 or 4 weeks. Anecdotal reports exist of protection against salmonellosis from vaccinating young calves several times with a gram-negative core antigen vaccine (Endovac-Bovi*). Another gram-negative core antigen vaccine, a J5 E. coli bacterin (J Vac^†, J-5^‡), reduced the mortality rate from naturally occurring salmonellosis in dairy calves vaccinated at 3 and 17 days of age.⁵⁷¹

GRAM-NEGATIVE, CORE ANTIGEN BACTERINS

All genera and species of gram-negative bacteria contain a common set of gram-negative core antigens, which are present in the deeper layers of the bacterial cell wall.⁵⁷² Endotoxin from gram-negative bacteria is thought to play an important role in the production of the clinical signs, biochemical and hematologic alterations, and pathologic lesions associated with a wide variety of bovine diseases caused by gram-negative bacteria,⁵⁷² including coliform mastitis (caused by E. coli, Klebsiella species, or Enterobacter aerogenes), Pasteurella bronchopneumonia and fibrinous pneumonia, and salmonellosis. Gram-negative core antigen vaccines are designed to reduce the severity of clinical signs associated with gram-negative sepsis and endotoxemia. They offer breadth against all gram-negative infections.

CLOSTRIDIAL VACCINES

J. Glenn Songer

Clostridia produce acute and frequently fatal disease, with pathogenesis often mediated by toxic proteins.⁵⁷⁹ Prevention is often based on immunoprophylactic amelioration of the effects of these molecules. However, the ready availability of inexpensive, efficacious bacterins, toxoids, and bacterin-toxoids has not eliminated clostridial infections. Accurate diagnosis remains an important component in management of clostridial diseases.^580,581

Immunization against clostridial diseases can be complicated by the development of “site reactions,” leading to trimming at slaughter.⁵⁸² These problems are exacerbated by the multivalent nature of many modern products and have stimulated the biologics industry to seek a new paradigm for preparation and delivery of immunoprophylactic products. Approaches have included concentration of the antigen into a smaller dose and use of alternate adjuvants; recombinant proteins, delivered by conventional means, by application of “slow-release” media, or by in vivo expression from attenuated bacterial delivery systems, will likely be a major focus of effort.

CLOSTRIDIUM CHAUVOEI (BLACKLEG) BACTERINS

Blackleg is not uncommon, in spite of the long-term availability of generally effective bacterins. Ingestion is probably the most common route of exposure in cattle, and dormant spores seeded to skeletal muscle germinate when muscle damage provides appropriate conditions. Affected animals have fever, anorexia, depression, and lameness, with extensive dry and emphysematous to edematous, hemorrhagic, and necrotic lesions. Diagnostically, it is important to distinguish between blackleg and malignant edema.

As with other histotoxic clostridial infections, vaccination against blackleg is universally advocated, especially in cattle under the age of 2 years. Dogma is that protection arises from the immune response to a heat-labile soluble antigen, but C. chauvoei produces alpha-toxin and several other toxic factors, which may be equally important targets.^583,584 Recommendations for immunization are summarized in Table 48-14.

Table 48-14 General Considerations for Use of Clostridial Seven-Way and Eight-Way Bacterin-Toxoids*

* Note that many combinations are available commercially, including some that also contain immunogens against nonclostridial diseases. Some of these combinations also include tetanus toxoid.

† No currently licensed product is produced by use of cultures of C. perfringens type B, but protection against type B infection is implied by the inclusion of toxoid prepared against type C (beta-toxin) and type D (epsilon-toxin) strains.

CLOSTRIDIUM SEPTICUM (MALIGNANT EDEMA) BACTERINS

Wound infections caused by C. septicum (malignant edema)⁵⁸⁵ usually follow direct contamination of a traumatic wound, including genital tract infections after mismanaged deliveries. Infection spreads along fascial planes, and lesions proceed from warm and pitting to crepitant and cold. Death commonly occurs in less than 24 hours. Braxy is a form of enteric infection that occurs not uncommonly in calves.⁵⁸⁶ Diagnosis is often by use of a fluorescent antibody test.⁵⁸⁷

A single immunizing dose of C. septicum bacterin yields adequate protection, but annual booster vaccination is recommended in high-risk situations⁵⁸⁸ (see Table 48-14). Vaccines elicit antibody responses to both somatic and toxin antigens, and recent findings suggest a central role for alpha-toxin.^589,590

CLOSTRIDIUM NOVYI TYPES A AND B (BIGHEAD AND INFECTIOUS NECROTIC HEPATITIS) BACTERINS

CLOSTRIDIUM BOTULINUM (BOTULISM) AND CLOSTRIDIUM TETANI (TETANUS) TOXOIDS

Botulism is caused by C. botulinum neurotoxins, which block acetylcholine release from cholinergic nerve endings.^595,596 Type C is most common in cattle in the United States. Direct contamination of feeds by the organism sometimes leads to intoxication, but it is more commonly associated with an animal carcass in the feed. Clinical signs include incoordination, flaccid paralysis, and difficulty in swallowing; respiratory paralysis eventually causes death.^597,598

Toxoids of botulinum toxins can be employed for immunoprophylaxis, but vaccination is usually practiced only in populations at immediate risk, such as beef cattle grazed on phosphorus-deficient range land.⁵⁹⁹ Feeding of poultry litter poses as similar problem, in that it may contain animal remains.

Spores of C. tetani originate in soil and are usually introduced traumatically to animal hosts, where they germinate and produce tetanus neurotoxin.⁶⁰⁰ Tetanus can develop in dairy cows as a postparturient complication and in calves after castration by the elastrator method.⁶⁰¹ Toxin moves retrograde, binding to presynaptic axonal terminals and resulting in muscular tremor and increased stimulus response; continued motor neuron hyperactivity causes sustained tetanic spasms in the innervated muscles and then permanent rigidity. Death is due to respiratory failure.

Acquired resistance to tetanus is based on circulating antitoxin, and widespread vaccination with toxoid has dramatically lessened the impact of tetanus on animal production. Neonatal passive immunity is followed by active immunization with toxoid after 2 to 3 months. Boosters are commonly recommended at 1- to 5-year intervals. Passive immunotherapy is directed toward neutralization of preformed toxin, although it is much more effective when used prophylactically than therapeutically. Universal vaccination is not usually recommended as a cost-effective means for control of tetanus.

CLOSTRIDIUM PERFRINGENS TOXOIDS

C. perfringens causes a wide variety of diseases in domestic animals, and those of greatest importance affect the gastrointestinal tract⁶⁰² (Table 48-15) (see Chapter 32). Type B infections are apparently extraordinarily rare in the United States, but it has been speculated that their pathogenesis can be explained by additive or synergistic effects of beta- and epsilon-toxins. Type C strains multiply rapidly in the gut of neonates, and in this relatively trypsin-free environment, beta-toxin produces local hemorrhage and necrosis, as well as systemic effects.⁶⁰³ Type D strains fill intestinal niches opened by sudden dietary changes, and epsilon-toxin in circulation damages the central nervous system and other systems distant from the gut.⁶⁰⁴ Type E causes hemorrhagic enteritis in calves, and its virulence is based apparently on the action of iota-toxin.⁶⁰⁵

Table 48-15 Diseases of Cattle Caused by Clostridium perfringens

The current enigma is type A infections. Although long accepted as causes of lamb enterotoxemia,⁶⁰⁶ fowl necrotic enteritis, and enteritis in dogs and horses, they are increasingly recognized as causes of enteritis in piglets and calves. Little is known about the pathogenesis of type A enteric infections, but type A strains are commonly found in cases of tympany, abomasitis, and abomasal hemorrhage and ulceration in calves.^607,608

Most agree that routine vaccination against type C enterotoxemia is required only in herds in which the disease has been documented. The usual practice is to vaccinate the dam, providing passive immunity via colostrum. Initial immunization should be followed by a booster after 3 to 4 weeks, with the second dose (and subsequent annual boosters) administered approximately 2 weeks before calving. Type D enterotoxemia occurs sufficiently infrequently in cattle that many believe vaccination to not be cost-effective. No commercial products are licensed in the United States for use against infections by strains of types A and E, and production of autogenous toxoids or bacterin-toxoids has become quite common; anecdotal evidence suggests remarkable efficacy in many cases. Similar products have been produced from strains of type E. These should be used with the awareness that, unlike beta- and epsilon-toxin concentrations in commercial products, alpha- and iota-toxin concentrations in autogenous toxoids may not be optimal.

CLOSTRIDIUM SORDELLII BACTERINS

C. sordellii is commonly found in feces of domestic animals, as well as in the soil, and is occasionally isolated from fatal myositis, liver disease, and sudden death in cattle. Edema in the subcutaneous tissues and along fascial planes of muscles and subendocardial hemorrhage are common signs. The organism produces numerous toxic or putatively toxic substances, foremost of which is a toxin that resembles toxins A and B of Clostridium difficile.⁶⁰⁹ Immunization is achieved by administration of multiway bacterin-toxoids (see Table 48-13).

MISCELLANEOUS BOVINE RICKETTSIAL, BACTERIAL, AND VIRAL DISEASE VACCINES

Derek A. Mosier

ANAPLASMOSIS

Anaplasmosis is a vector-borne or mechanically transmitted disease caused by the rickettsia Anaplasma marginale.⁶¹⁰ The disease occurs worldwide and is most prevalent in tropical and semitropical areas. Anaplasmosis is the only major tick-borne disease of cattle in North America, being enzootic in the southeastern and some midwestern and western states and sporadic in the northern states and Canada.^610-612 In enzootic areas with adequate numbers of arthropod vectors, most adult cattle become naturally immune through repeated exposure. Maternal antibodies protect calves until they also become subclinically infected and develop immunity. Disease is more severe in older cattle than in calves, and nonimmune older cattle are particularly at risk when they are moved into an endemic area.⁶¹⁰ Susceptibility to disease occurs when there is a lack of arthropod vectors to maintain natural infection and immunity or when a nonimmune adult is introduced into an enzootic area. In these situations or when vector or environmental conditions suggest an increased risk of disease, vaccination can be beneficial.

No widely marketed commercial vaccines against anaplasmosis were available as of 2006 in North America. A killed vaccine* is available in some states including Florida, Louisiana, Texas, Oklahoma, Arkansas, California, Oregon, Nevada, Tennessee, Mississippi, Indiana, Iowa, Illinois, and Kansas and in Puerto Rico. The vaccine employs the same A. marginale antigens and purification procedure that was used for the discontinued Plazvax^† vaccine. The killed vaccine is not USDA licensed, but it is USDA approved for use as an experimental vaccine. The vaccine has reportedly been used successfully in cows at all stages of pregnancy without an episode of neonatal isoerythrolysis. In endemic areas the vaccine is recommended for use just before the onset of the vector season. Vaccine-induced immunity does not generally occur until 2 weeks after administration of the second dose of an initial series or 2 weeks after a booster dose in previously immunized cattle.⁶¹² Vaccination does not prevent infection or clinical disease and does not eliminate A. marginale from a herd, but it does reduce the severity and incidence of disease.^610,611 Inactivated vaccines could be used in conjunction with oxytetracycline in the face of outbreaks to provide both temporary and more prolonged protection.⁶¹¹

A sheep-passaged, modified live vaccine^‡ has been used in California and Latin America.⁶¹³ Because this vaccine causes mild clinical disease, it has limited use for vaccination of mature susceptible cattle.^610,613 If the vaccine is administered to cattle over 2 years of age, anemia, severe clinical disease, and death may occur, especially in bulls and heavily lactating cows.⁶¹³ The vaccine is recommended for use in healthy cattle between 1 month and 2 years of age and is most commonly administered to 7- to 24-month-old cattle in herds in endemic areas. Concurrent use of certain antibiotics or other live or modified live virus vaccines is contraindicated.

A live vaccine* derived from A. marginale subsp. centrale, a less pathogenic species or subspecies of A. marginale, is used in some countries but not in North America.^614,615 This vaccine consists of standardized and frozen red blood cells from splenectomized cattle that were infected with A. marginale subsp. centrale. The vaccine is recommended for use in 4- to 9-month-old cattle; older cattle have an increased risk of severe vaccine-induced disease. The vaccine produces mild disease but protects against subsequent severe disease caused by A. marginale. Immunity is considered long term, or possibly for life if subsequent natural exposure occurs to ensure the development of durable immunity.

Immunity to A. marginale is proposed to involve humoral responses to a variety of major surface proteins and enhanced macrophage phagocytosis and killing, both mediated by IFN-γ—producing CD4⁺ T lymphocytes.^{610,612,616-618} Inadequate protection from vaccines during field use can result from antigenic variability of the organism, geographic differences in the organism that result in a lack of cross-reactivity between A. marginale strains, and weak immune responses to protective A. marginale antigens.^{610,615,617,618} Purified native, recombinant, and tick culture—derived A. marginale immunogens and DNA vaccines are being investigated for possible commercial use in the future.^{615,617,619-622}

INFECTIOUS BOVINE KERATOCONJUNCTIVITIS

The most common infectious agent associated with infectious bovine keratoconjunctivitis (IBK) is M. bovis.⁶²³ Vaccination is most effective when done before fly season in herds with a history of problems. Certain breeds, such as Herefords and Hereford crosses, are particularly susceptible and may benefit from vaccination.⁶²³ Commercial vaccines used to help prevent the disease consist of inactivated cultures of various strains of M. bovis.⁶²⁴ Some products recommend two doses given 3 weeks apart for initial vaccination, beginning as early as 3 weeks of age to no earlier than 5 months of age. Other products recommend a single dose administered 3 to 6 weeks before the predicted onset of the disease season, with annual vaccination thereafter. M. bovis bacterins are also available in combination with seven-way clostridial bacterin-toxoids.⁶²⁵ Although multivalent M. bovis bacterins can provide some protection in field use, efficacy varies depending on the M. bovis strains present in the bacterin and those responsible for disease.^623,626-630 Seven different disease-producing serogroups of M. bovis are recognized based on differences in pili, and there is variable cross-reactivity between serogroups.⁶²⁴ Furthermore, pilin gene rearrangements and pilin-type switching can allow M. bovis to switch from expression of one type of pilus antigen to another, making it difficult to predict what serogroup(s) may be necessary for protection.^624,627,631 Therefore monovalent bacterins are generally ineffective in field use, and multivalent bacterins provide neither consistent nor reliable protection.^{624,626,627,629} Vaccines must incorporate pili from all major serogroups or conserved, immunogenic portions of all serogroups to provide optimum protection.^{624,627-630,632} Experimental recombinant vaccines containing cloned pili of various serogroups have demonstrated some promise for future vaccines.^624,626,628 Another immunogen considered important for protection is M. bovis hemolysin/cytolysin.^623,624 Experimental vaccines containing hemolysin/cytolysin preparations have shown some efficacy in experimental trials.^{623,624,633,634} Other potential immunogens include iron-regulated OMPs, proteases, fibrinolysins, and phospholipases.^623,624 Vaccine-induced protection is correlated predominately with a suitable lacrimal (IgA) mucosal immune response and not with serum antibody levels to M. bovis antigens.^623,624 Therefore an antigen delivery system that enhances mucosal immunity is an important feature of an effective vaccine. The presence of other agents contributing to IBK (e.g., Moraxella [Branhamella] ovis, Mycoplasma bovoculi, or BHV-1) should also be considered when there is poor M. bovis vaccine efficacy.⁶³⁵ Autogenous M. bovis vaccines have not been consistently effective against the disease.^623,636 Use of modified live virus vaccines for IBR is contraindicated in the presence of an outbreak of IBK because it may exacerbate the IBK.⁶²³

STAPHYLOCOCCAL MASTITIS

Staphylococcus aureus is considered one of the most important causative agents of bovine mastitis.⁶³⁷ Vaccination against S. aureus may be beneficial in dairy herds that have an existing mastitis problem.^637,638 However, vaccination in well-managed dairy herds with a low level of staphylococcal mastitis may not provide much economic benefit.⁶³⁸ Staphylococcal bacterins contain antigens from multiple strains or serotypes of S. aureus.^639,640 The recommended vaccination protocol is two doses given 2 weeks apart followed by revaccination at 6-month intervals. Vaccination can start at 6 months of age, and one of the semiannual doses should be given 3 to 4 weeks before calving. Vaccination with S. aureus bacterins does not generally eliminate disease but can substantially reduce clinical mastitis and the incidence of subclinical and chronic staphylococcal infection.^638,641-644 Vaccination may be more effective in heifers because of their initial lower basal immunity compared with older cows.⁶⁴² The benefits of immunity induced early in life include the abilities to clear the organism and to resist chronic infection on initial natural exposure.⁶⁴⁵ Vaccination during the dry period may be more effective than vaccination during lactation.⁶³⁷ In some but not all studies, vaccination has reduced somatic cell counts in milk.^642,643,645 Vaccination in combination with antimicrobial therapy has been successfully used to eliminate chronic staphylococcal mastitis.⁶⁴⁶

In considering the use of staphylococcal vaccines, the prevalence of various pathogens that can cause mastitis must be considered. For mastitis caused by S. aureus, differences between the S. aureus strains in vaccines and the strains specifically responsible for the disease may diminish the efficacy of the vaccine.^637,640,644 Experimental trials suggest that more effective vaccines may be derived by stimulating immune responses to combinations of S. aureus capsular polysaccharide.⁶⁴⁷ A vaccine based on technologies used for human staphylococcal vaccines that incorporates capsular polysaccharide from the three S. aureus serotypes most commonly associated with mastitis stimulated immunologic parameters necessary for protection.⁶⁴⁸ These studies may form the basis for more effective vaccines in the future.

In herds in which other pathogens are a major cause of mastitis, S. aureus vaccines may be of minimal benefit.^638,641 Other important causes of bovine mastitis include Streptococcus species (e.g., Streptococcus uberis, Streptococcus dysgalactiae, and Streptococcus agalactiae) and coliform bacteria (e.g., E. coli).^637,649 Streptococcus agalactiae vaccines generally are not protective, but other Streptococcus species are responsive to vaccination.⁶⁴⁹ Experimental vaccines composed of bacterial proteins derived from S. uberis and S. dysgalactiae reduced somatic cell counts compared with controls after challenge.^650,651 E. coli J5 vaccines have also been used to successfully reduce the severity of mastitis (reviewed elsewhere in this section).

ANTHRAX

Anthrax is an acute, highly fatal disease caused by B. anthracis.⁶⁵² Vaccination has proven to be an effective means of controlling the disease in endemic areas and in the face of outbreaks.^653,654 Bovine anthrax vaccines are derived from the live toxigenic, nonencapsulated spore vaccine developed by Sterne and consist of spores suspended in a diluent containing saponin and glycerin.⁶⁵⁵ Annual vaccination of livestock in areas of endemic anthrax is recommended 4 weeks before outbreaks are expected. A single dose generally provides adequate immunity, but a second dose given 2 to 4 weeks after the first is often recommended.⁶⁵⁶ Cattle should not be vaccinated within 42 days of slaughter. Antibiotics should not be administered within 7 days of vaccination to avoid interference with in vivo growth of the vaccine organism. Vaccination in the face of an outbreak does not protect all cattle, but the spread of infection and the number of new cases generally declines within 10 days.^654,657 Localized subcutaneous edema commonly develops at the injection site within 24 hours; it may last for several days and is sometimes severe.⁶⁵³ Since the intentional release of B. anthracis via the mail system in 2001, there has been increased interest in technologies for the development of an efficacious, long-acting human vaccine for anthrax.^653,658-662 Although some of these technologies could hold promise to reduce some of the localized side effects of the current bovine vaccine, it is unlikely that a new bovine vaccine will match the safety and efficacy of the Sterne strain vaccine in the foreseeable future. All anthrax outbreaks should be reported to local regulatory and public health officials, and appropriate guidelines for vaccination should be followed, including quarantine and vaccination of all susceptible livestock on affected and surrounding premises.

INTERDIGITAL NECROBACILLOSIS (FOOT ROT)

Interdigital necrobacillosis (foot rot) in cattle results from interdigital infection with Fusobacterium necrophorum with lesser contributions from Prevotella (Bacterioides) melaninogenica and sometimes Dichelobacter (Bacterioides) nodosus and other bacteria.^663-665 Commercial F. necrophorum bacterins to aid in the prevention of foot rot (and hepatic necrobacillosis) are available for use in cattle. Recommendations for initial vaccination are two doses given 3 to 4 weeks apart, followed by annual revaccination. Vaccination is also recommended when endemic conditions exist or when exposure is imminent. The efficacy of F. necrophorum vaccines is not clear, but some benefit has been demonstrated in experimental studies and field trials.^666,667 Vaccination is especially recommended in herds that have a high incidence of disease.⁶⁶⁶ Protective immunity most closely correlates with the level of anti-LKT antibodies.^668,669 A leukotoxoid vaccine composed of cell-free supernatant from a high LKT—producing strain of F. necrophorum was effective in reducing experimental hepatic necrobacillosis⁶⁶⁹ and presumably would have some benefit against interdigital F. necrophorum infection. An autogenous vaccine containing D. nodosus reduced the severity of interdigital dermatitis but not of necrobacillosis.⁶⁷⁰

PAPILLOMATOUS DIGITAL DERMATITIS (FOOTWARTS)

Papillomatous digital dermatitis, or footwarts, can be a serious problem in dairy cattle.^671,672 The disease is characterized by ulcerative to proliferative digital lesions that most often occur in replacement heifers and younger cows after introduction into a milking herd.^671-673 Risk is greatest in larger dairy breeds in herds of greater than 500 head. The cause of the disease is uncertain, but Treponema species—like spirochetes and flexible, gram-negative rods (Serpens species) have been incriminated.^673-676 Commercial bacterins are available for use as preventatives and/or aids to treatment and consist of killed cultures of Serpens species or Treponema species organisms. The recommendations are for three doses administered subcutaneously at 3- to 4-week intervals, followed by revaccination every 4 to 6 months. Company field trials report reduced onset of new infections and sometimes more rapid resolution of existing infections in vaccinated cattle. Another study of clinically affected cattle in which vaccination was combined with treatment with topical lincomycin showed no significant improvement in vaccinated cows compared with unvaccinated ones.⁶⁷⁷ The high recurrence rates of natural infection suggest that immunity to the disease is short-lived or weak.⁶⁷³

RABIES

Rabies is a highly fatal, zoonotic neurologic disease caused by a rhabdovirus.⁶⁷⁸ Routine vaccination of cattle is not common in most situations. However, vaccination may be cost-effective in rural areas of Latin America, where vampire bats are important sylvatic vectors.^679,680 In endemic areas vaccination of valuable cattle or herds may be a reasonable precautionary measure.⁶⁷⁸ This is particularly true in situations in which cattle are in frequent contact with human beings, in order to reduce the anxiety of animal workers and minimize the likelihood of human exposure. Currently licensed rabies vaccines for cattle contain inactivated, cell culture—derived virus.⁶⁸¹ The recommended regimen is initial vaccination at 3 months of age followed by annual vaccination thereafter. The duration of protective neutralizing antibody levels after initial vaccination can vary.⁶⁸² Therefore some experts have suggested that a second booster dose be given either 1 month after initial vaccination or at 6 months of age.^682,683 Subsequent annual revaccination induces strong anamnestic responses that persist for 1 year or longer.^682,683 In Latin America, modified live vaccines are sometimes used.⁶⁸⁰ However, these do not stimulate the same level of immunity as do the inactivated virus vaccines. A Capripoxvirus vector expressing rabies virus glycoprotein has shown promise in providing long-term protection against rabies (and lumpy skin disease) and may be a cost-effective mechanism for rabies control in cattle in some developing countries.⁶⁸⁴

FIBROPAPILLOMAS (WARTS)

Fibropapillomas (warts) are manifested in a variety of forms and locations, each caused by a specific bovine papillomavirus (BPV).^685,686 Lesions associated with papillomaviruses can occur in the epidermis of the head, face, neck, and legs (BPV-1 and BPV-22), upper alimentary and urinary tracts (BPV-4), teats and udder (BPV-1, BPV-3, BPV-5, and BPV-6), and genital epithelium (BPV-1).^685-688 Immunity after infection or vaccination is virus type specific and is induced by viral structural proteins.^685,687-690 Therefore the efficacy of both autogenous and commercial vaccines depends on which viral antigens are incorporated into the vaccine and which virus type is responsible for the disease. Vaccines containing BPV-1 and BPV-2 are generally effective for prevention but not treatment of disease caused by the homologous virus.⁶⁸⁷ Vaccines usually are ineffective for treatment or prevention of disease caused by BPV-3 and BPV-5.⁶⁸⁷ Vaccination with recombinant capsid proteins of BPV-4 was effective in preventing papillomas after experimental challenge with BPV-4.⁶⁹¹ The interpretation of the response to vaccination against fibropapilloma can be complicated by spontaneous regression of some lesions.⁶⁸⁵ Lesions associated with BPV-1 and BPV-2 usually spontaneously regress within 1 to 12 months, whereas lesions caused by BPV-3 and BPV-5 do not normally spontaneously regress.^687,692

Commercial vaccines consist of inactivated, virus-laden tissue extracts derived from bovine papillomas.⁶⁹³ The recommended regimen is an initial dose divided and given in at least two different sites, followed by a second dose in 3 to 5 weeks. Vaccination should continue for at least 1 year after elimination of disease from the herd. Autogenous vaccines can be made by homogenization and inactivation (0.3% formalin) of excised wart tissue, followed by dilution of the homogenate in physiologic saline and filtration through gauze. Three 1- to 5-mL intradermal injections given at 1-week intervals are recommended. Vaccination is most commonly used with valuable animals destined for competitive shows or for overseas sale.⁶⁸⁷ Vaccination can also be helpful as a preventive measure in herds with a high incidence of cutaneous fibropapillomas or to reduce the risk of penile fibropapillomas in groups of young bull calves.⁶⁸⁵ Recombinant BPV proteins have shown promise in experimental studies and could form the basis for a vaccine that protects against all BPV types.^691,694 Vaccination with avian Newcastle disease virus vaccine has also enhanced clinical recovery from disease.⁶⁹⁵