Parainfluenza Type 3 Virus Vaccines

John A. Ellis

Parainfluenza virus type 3 (PI-3V) is a ubiquitous paramyxovirus in cattle populations worldwide.¹ In uncomplicated experimental PI-3V infections, clinical signs of coughing, tachypnea, and fever have been observed from 4 to 12 days after infection.¹ Although the virus was originally detected in calves with respiratory disease (often in the absence of other agents), it has been used to experimentally reproduce respiratory disease, and exposure to the virus has been detected by seroconversion in animals with BRD complex, its importance as a pathogen has been somewhat controversial.^1, Generally PI-3V has been 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 infecting both respiratory epithelia and alveolar macrophages.¹ Although, as originally described,¹ the PI-3V quasispecies exists as one serotype, recently three serologically distinct genotypes of the virus have been molecularly defined.^2-4 This has raised unresolved questions about differences in virulence among PI-3V isolates, as well as possible genotype-specific variation in vaccine efficacy.^2-4

Five types of PI-3V vaccines are currently available commer­cially: (1) Mlv IM vaccines, (2) MLV temperature-sensitive IM vaccines, (3) MLV IN vaccines, (4) MLV temperature-sensitive IN vaccines, and (5) inactivated virus vaccines.

Opinions have been 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 IN and IM vaccines.¹ Some comparative studies reported that IN vaccination resulted in better protection against experimental challenge; others were unable to demonstrate any advantage to the use of one vaccine or route of administration over the other.¹ A notable exception, however, was young calves with maternal antibodies, in which IN 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.¹ Consequently, calves vaccinated parenterally before 6 months of age should be revaccinated after reaching 8 or 9 months of age.¹

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 MLV vaccines, as is the case with BRSV¹

There is debate about the overall utility and economic benefit of using PI-3V (and BRSV) vaccines in the field.^1,6 Much of the uncertainty is undoubtedly related to the difficulties involved in determining the relative importance of a particular agent in a multifactorial disease process such as BRD complex.⁸ Few studies¹ address the economic impact of subclinical paramyxo­virus infections in cattle.

Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Bibersteinia trehalosi

Jared D. Taylor

Mannheimia haemolytica Vaccines

M. haemolytica, serotype 1 (formerly Pasteurella haemolytica A1) is the main bacteria responsible for the clinical signs and lesions of severe bovine fibrinous pleuropneumonia (shipping fever).^1,2 The bacterium is a gram-negative commensal of the bovine upper respiratory tract (URT), whose presence in the naso­pharynx is not predictive of impending disease.^3,4 Historically, it has been hypothesized that immunosuppression resulting from stress or viral infections permits the bacterium to prolifer­ate initially in the URT, evade clearance by normal protective mechanisms, and subsequently establish infection within the lungs. It is now recognized that the lower respiratory tract (LRT) is not sterile, and M. haemolytica and other pathogenic bacteria can be present in the lung in the absence of disease.’⁹⁹’ Processes and factors that allow the organisms to proliferate and progress to induction of disease are not fully understood.

Immunity to Mannheimia haemolytica

Twelve serotypes of M. haemolytica occur (A1, A2, A5, A6, A7, A8, A9, A12, A13, A14, A16, and A17), and only partial cross-serotypic protection is seen following vaccination.⁶ Serotypes A1, A2, and A6 are the most prevalent.^7-9 Because M. haemolytica is strictly an extracellular organism, humoral immunity is far more important to controlling infection than is cell-mediated immunity. Indeed, there is substantial evidence that cattle entering a feedlot with preexisting serum antibody titers to M. haemolytica have less respiratory disease and fewer deaths than do those without serum antibodies.^10,11 Maternal antibodies to M. haemolytica and P multocida can be found in both dairy and beef cattle but decline to undetectable levels between 30 and 90 days of age.¹² Most calves subsequently and spontaneously develop antibodies to these bacteria due to natural exposure to the nasal flora.¹² Unfortunately, this antibody response is typically short lived, and calves seem to become more susceptible to disease following their decline. Antibody responses following natural exposure target numer­ous cellular components and secreted products. Those with the most potential for stimulating immunity include capsular polysaccharide, lipopolysaccharide (LPS), outer membrane proteins (OMPs), iron-regulated OMPs, a secreted leukotoxin (LKT), a serotype-specific antigen, and several other secreted enzymes including neuraminidase, a sialoglycoprotease, and bovine immunoglobulin-specific proteases.^13,14 The central dogma of M.

Use of Mannheimia haemolytica Vaccines in Beef Calves

Several studies have examined how rapidly various commercial M. haemolytica vaccines induce antibody response and how long after vaccination antibodies remain detectable. Antibody responses reach their maximum quickly (typically within 14 days after vaccination) and abruptly wane (significantly lower by day 28, and sometimes returning to baseline by day 42).^26-28 Revaccination an extended period after the initial vaccination (140 days in one case) may stimulate rapid anamnestic responses.²⁷ However, it is unclear if this suggests efficacy in protecting against disease.

When designing a vaccination program for prevention of bovine respiratory disease, four questions should be addressed: (1) Should calves be vaccinated for M.

1. Should an M. haemolytica vaccine be used?

This may be the most difficult question for the practitioner to answer. Vaccine efficacy has been demonstrated primarily with experimental models of pneumonia using one of several challenge methods including direct M. haemolytica challenge via intratracheal, intrabronchial, or transthoracic routes or using a combination viral (usually BHV-1) and M. haemolytica challenge.¹³ The majority of published reports examining vaccination efficacy through experimental challenge have used experimental vaccines and not commercial ones. There are few published reports of efficacy of individual commercial vaccines against experimental M. haemolytica challenge. Nonetheless, the studies published have, in general, sup­ported efficacy of commercial vaccines, although not in all cases.^29-31 Of course, one must consider the potential of bias favoring publication of positive results accounting for some or all of this difference (either because of simple publication or due to influence of pharmaceutical companies over dissemination of information related to their product).

Clinical studies examining field efficacy of vaccines are abundant and frustratingly inconsistent. Numerous studies have found a protective factor from vaccinating.^32-36 Similar numbers of studies found vaccination to be ineffective or inconclusive.^37-39 Perino and Hunsaker⁴⁰ reviewed 10 published studies of several commercial live and subunit M. haemolytica vaccines with respect to their efficacies in field studies of feedlot cattle. Their report concluded that commercial M. haemolytica vaccines available at the time did not consistently reduce morbidity or mortality or increase weight gains. Of those studies, five showed positive outcomes based on reduced morbidity, mortality, or increased weight gain, whereas five studies demonstrated no positive outcome. Three of those studies demonstrating positive outcomes involved the same M. haemolytica bacterin-toxoid given at arrival in the feedlot; however, two clinical trials with the same vaccine showed no significant differences when given at arrival and/or 3 weeks before shipment. A more recent, rigorous review of M. haemolytica vaccines trials using feedlot cattle found that conclusions remain conflicting at times. However, their meta-analysis determined vaccination against M. haemolytica offers a modest reduction in morbidity but not mortality.⁴¹ An observational trial also found vaccination at the ranch of origin to be associated with decreased morbidity.⁹⁶ It is important to note that the study was performed in Australia, and the vaccine examined is only available in that country.

When examining efficacy of vaccines in field trials, it is relevant to note that diagnosis and treatment in such studies is based on undifferentiated BRD (rather than disease solely attributable to M. haemolytica). Although M. haemolytica is the predominant bacterial isolate associated with BRD, it is not the sole pathogen. In order to conclude that an M. haemolytica vaccine is efficacious in reducing BRD, a study would need to have a high power (large number of cattle enrolled), a relatively high incidence of BRD, and a large proportion of that disease attributable to M. haemolytica. This may play a role in the lack of definitive evidence of vaccine efficacy. Given these considerations, if a clinician chooses to recommend vaccination, questions 2 to 4 from earlier need addressed.

2. What type of M. haemolytica vaccine should be used?

Numerous commercially available bovine biologicals contain M. haemolytica antigens.⁴² M. haemolytica vaccines are often in combination with viral vaccines, H. somni or P. multocida bacterins, and occasionally Clostridium spp. biologicals. Despite the various licensed M. haemolytica biologicals available, formulations of M. haemolytica vaccines fall into one of nine 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 (leukotoxin toxoid), (5) toxoid-cell-associated antigen, (6) adjuvanted toxoid (culture supernatant), (7) recombinant leukotoxin-extracted OMP vaccine, (8) autog­enous (herd-specific) bacterins produced from isolates submitted by practicing veterinarians, and (9) live streptomycin-dependent mutant. The latter vaccine is the only currently licensed live M. haemolytica biological. 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. Studies have occasionally compared commercially available vaccine products under field conditions.^43,44 Unfortunately, they often are supported by industry funding (creating a potential conflict of interest) and typically do not include a negative control group. Thus, the significance and validity of the findings from these studies are unclear.

Most studies comparing commercial vaccines have relied on antibody titers (typically to LKT and/or whole bacterial cell preparations) as outcome of interest. Although antibodies appear important to protection, it is unclear what antigens are most important, what titer is sufficient for protection, or if a higher titer is always better. Therefore conclusions from those studies are difficult to interpret. Direct com­parisons of two or more commercial M. haemolytica vaccines against experimental or natural challenge have rarely been published. In one such comparison between a commercial M. haemolytica bacterin-toxoid and the live streptomycin­dependent mutant vaccines, the bacterin-toxoid elicited the greatest serologic responses and significantly reduced lung lesions after experimental challenge.³¹ Calves receiving the live mutant vaccine had lesions that were not significantly lower than for control cattle. Demonstration of protection against experimental challenge, however, may not necessarily indicate that the vaccine will be efficacious against natural disease under field conditions.

3. How many doses of M. haemolytica vaccine should be given? Although many of the currently available M. haemolytica biologicals are licensed for only one injection, manufacturers recommend a booster if possible. Of course, administration of two doses of a M. haemolytica vaccine is not practical for most cow-calf operations. Shewen⁴⁵ demonstrated that one of the reasons one dose of M. haemolytica vaccine often stimulates adequate antibody response is because most cattle carry M. haemolytica in their nasopharynx and have a primed immune system that can produce a rapid anamnestic response to vaccination. However, as mentioned earlier, it is unclear if this suggests continued efficacy in protecting against disease.

4. When should an M. haemolytica vaccine be given? Given the short persistence of elevated titers following vaccination, administering a M. haemolytica vaccine at the appropriate time becomes critical.^46-48 Manufacturers of M. haemolytica biologicals usually recommend vaccination between 15 and 21 days before “weaning, shipping or exposure.”⁴² If vac­cination was more than 2 to 3 weeks before time of greatest risk, a booster should be given before shipment. This protocol is incompatible with routine management of most cow-calf operations, making it difficult to recommend vaccination as a standard practice in this segment of the industry. Further adding to the challenge of identifying an optimal time for vaccination is the possibility that concurrent administration of MLV vaccines may interfere with response to M. haemolytica vaccination. Cortese and colleagues²⁸ examined serologic response to vaccination with four com­mercially available M. haemolytica vaccines in calves naive to bovine herpesvirus 1 (BHV-1) and M. haemolytica. When the vaccines were given concurrent with an MLV product, the antibody response against LKT was consistently lower than when the M. haemolytica product was administered alone. It is unclear whether this would impact the efficacy of the vaccines in reducing disease, although previous work with an experimental vaccine suggests it could.⁴⁹ Work examining different products found no evidence of BHV-1 interference with response to a bacterin product,¹⁰⁰ but this study examined response to P. multocida vaccination, not M. haemolytica. Moreover, assessments were directed at CMI response to vaccination, not antibody titers.

A negative effect of BHV-1 vaccination on anti-LKT titers was not seen with IN administration of an MLV vaccine, although only one product was examined in this study.⁵⁰ Concurrent vaccination with IN MLV and M. haemolytica vaccines resulted in an initial anti-LKT titer equivalent to that produced by the M. haemolytica vaccine alone. Moreover, a robust anamnestic response occurred when a booster of the M. haemolytica vaccine was given 90 days later, in conjunction with a parenteral MLV. Similarly, no negative effect on response to P multocida vaccine was observed to result from concurrent IN BHV-1¹⁰⁰ (although, as mentioned earlier, there was also no negative effect from parenteral administration of BHV-1, either). Thus, it appears that some of the negative effect of concurrent MLV vaccination may exist. This effect may be muted if calves are not naive for BHV-1 and/or other viral agents or if an IN route is used.

Vaccination of cattle against pneumonic mannheimiosis on arrival at the feedlot is somewhat controversial, for numerous reasons. Most importantly, it may not allow enough time for development of adequate protection before the period of highest morbidity.⁵¹ Secondly, if cattle have been vaccinated 2 to 3 weeks before shipment and had an appropriate immunologic response, antibody titers may be adequate, making revaccination not cost effective. Finally, vaccination with an MLV vaccine at arrival is nearly universal, which may interfere with response to the M. haemolytica vaccine, if the calves have not previously been vaccinated or exposed to respiratory viruses.²⁸ Since the vaccination history is rarely known for cattle entering a feedlot, it may be impossible to make an informed decision regarding these considerations. Nonetheless, vaccination with a M. haemolytica product on feedlot entry is often practiced.^46-48 Results in several field trials indicate that this practice can potentially afford some protection against shipping fever during the first 14 days in the feedlot.⁴⁶ Selective use of M. haemolytica vaccines has also been advocated. Some feedlots designate cattle as high risk and low risk for respiratory disease. Managers may be more willing to vaccinate low-risk cattle because high-risk cattle are either sick on arrival or can break with disease soon after entry into the feedlot.⁴⁷ Therefore high-risk cattle would not have time to mount an immune response to vaccination before disease. However, low-risk cattle are less likely to break with disease soon after entry into the feedlot, and when they are vaccinated there is often adequate time for immunity to develop before a respiratory outbreak occurs.⁴⁷ While this is arguably rational, research to support or refute its effectiveness is lacking. As stated earlier, a meta-analysis of vaccination for M. haemolytica in feedlot cattle found a modest reduction in morbidity (relative risk 0.93, 95% confidence interval of 0.89 to 0.98), but no significant reduction in mortality (RR 0.75, 95% CI 0.56 to 1.04).

In summary, there is some evidence that use of M. haemolytica vaccination can be beneficial. However, M. haemolytica vaccina­tion is not warranted or appropriate in all situations. It would likely provide the most benefit when employed by cow-calf producers, but doing so correctly would require administration at an appropriate time (2 to 3 weeks before shipping). It would also be preferable to not perform MLV vaccination concurrently (unless an IN product is used or the MLV is a booster of previous administration). It would be questionable whether the additional cost and effort are justified, as weaning for at least 40 days seems more important in reducing disease than is vaccination.⁵² For stocker/backgrounder and feedlot opera­tions, use of M. haemolytica may offer less benefit. Usage is particularly questionable in lightweight, high-risk calves. These calves are likely to develop disease before vaccination could produce an immune response, and the resulting inflammatory response to endotoxin and other innate immune stimulators may have negative effects, including decreased feed intake. Usage may be justified in backgrounded or yearling cattle that are more likely to respond to vaccination before the period of greatest risk for disease.

Use of M. haemolytica Vaccination in Dairy and Veal Calves

Management differences between dairy and beef calves could be expected to impact disease incidence and severity, as well as immune status in these two classes of cattle. In addition, evidence suggests that purebred Holstein calves may not respond immunologically as well as beef or Holstein crossbred cattle.⁵³ Thus, it would seem prudent to consider this population separately. Unfortunately, studies of M. haemolytica vaccination in dairy and veal calves have been published less frequently than those in beef calves. In general, vaccination of young dairy calves has failed to produce significant antibody responses.^54,55 This is probably due to interference by colostral antibodies. As passive immunity wanes, calves develop anti-M. haemolytica antibodies as a result of natural exposure.⁵⁵ In terms of protection against natural disease, vaccinated calves had similar incidences of respiratory disease as did unvaccinated controls.^56,57 In another study, a M. haemolytica bacterin-toxoid was found to be less effective than a commercial streptomycin­dependent mutant M. haemolytica and P multocida vaccine in reducing respiratory disease in veal calves.⁵⁸ Failure of M. haemolytica vaccines to provide protection in dairy and veal calves could be because P. multocida is usually the most common isolate from dairy calf pneumonia.

Vaccination for Pasteurella multocida

P multocida, particularly serogroup A, serotype 3 isolates, is the second most common bacteria associated with pneumonia in beef cattle and the most common isolated from pneumonia in dairy calves.² Although M. haemolytica has traditionally been the major pathogenic bacterium associated with shipping fever, some studies have suggested that the incidence of P multocida in BRD has increased in beef cattle.^1,48,99

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.⁴² A commercial live streptomycin-dependent mutant P multocida and M. haemolytica vaccine is available. One study that examined this product found no difference in immune response compared with nonvaccinated controls.¹⁰⁰ However, only CMI responses were assessed rather than antibody levels.

The immune mechanisms involved in resistance to P. multocida lung infections in cattle are poorly understood. Antibodies are presumed to be important in protecting against disease, and serum antibody levels have been correlated with severity of lesions following challenge,^59,60 as well as decreased risk of natural disease.¹⁰ However, there are few peer-reviewed studies examining efficacy of vaccination in field conditions, and those that have been published suffer from severe shortcom­ings (typically sponsored by a manufacturer and often lacking a nonvaccinated control group). A meta-analysis⁴¹ reported three trials of vaccination of feedlot cattle with products containing P. multocida along with M. haemolytica. The results of these trials were not examined separately but instead were combined with results of studies examining only M. haemolytica. Nonetheless, the reported results are not compelling (one reduced BRD, one increased BRD, and one trial showed no effect). Little work has been done regarding commercial P. multocida vaccines in dairy calves, despite the prevalence of P. multocida in respiratory disease in that population. In the one trial identified, a combined M. haemolytica-P. multocida vaccine was no better than control.⁵⁶ There is more published work related to vaccines against P multocida serogroups B and E, which cause hemorrhagic septicemia in cattle and water buffalo,⁶¹ but those have limited or no relevance to BRD.

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.^13,62,63 Work on specific OMPs and cell surface antigens continues, but results have not been incor­porated into commercial vaccines as of yet. 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 cattle vaccine.¹³

In summary, significantly less is known about the immu­nogenicity and vaccinology of P multocida than for M. haemo- lytica. Products currently available are generally unrefined and have limited evidence of efficacy. As such, it is difficult to make recommendations regarding their usage. It seems reasonable to presume that these products will work no better than M. haemolytica vaccines and suffer from many of the same chal­lenges. Thus, their usefulness (if any) is likely restricted to vaccination at least several weeks before maximum risk. Vaccination of lightweight, high-risk calves is probably of limited benefit and should be avoided due to the potential negative impact of innate immune system stimulators (such as endotoxin) contained within vaccine preparations. Inadequate information exists to comment on potential usefulness of P. multocida vaccination in dairy and veal calves.

Vaccination for Histophilus somni (Haemophilus somnus)

Histophilus somni (formerly Haemophilus somnus) 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.^1,2 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),⁶⁴ several OMPs including immunoglobulin-binding proteins that bind the Fc receptor of bovine immunoglobulin and are associ­ated with serum resistance of pathogenic strains,^65,66 and iron-regulated OMPs.⁶⁷ As in most gram-negative bacteria, H. somni LOS is a dominant antigen that stimulates an antibody response to the polysaccharide moiety following natural or experimental exposure. Interestingly, H. somni LOS has been demonstrated to exhibit phase variation in its epitopes (i.e., antigenic drift), thus allowing the bacterium to escape the immune response.⁶⁴ Currently, there is no evidence that those anti-LOS antibodies are protective.⁶⁸ Likewise, several OMPs and iron-regulated OMPs have been shown to be immunogenic in cattle. The major H. somni outer membrane protein (MOMP) is weakly immunogenic and shows strain antigenic variability.⁶⁹ Given the weak immunologic reactivity and its antigenic variability, MOMP is likely of limited utility in diagnostics or subunit vaccine development. Immunoglobulin-binding protein A (IbpA) not only binds immunoglobulins but is cytotoxic for bovine alveolar type II epithelium.⁷⁰ In addition, vaccination of calves with recombinant subunits of IbpA enhanced resistance against experimental intrabronchial H. somni challenge.⁷¹ Unfortunately, sera from calves that received a commercially available vaccine showed no antibody reactivity to IbpA, sug­gesting a bacterin vaccine does not stimulate a response to

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this important virulence factor.⁹'

Several approved H. somni biologicals are available, often in combination with respiratory viruses or other bacterial pathogens (Clostridial spp.). Currently licensed H. somni bio- logicals are formalin-killed bacterins with aluminum hydroxide as 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. Overall, vaccine-induced immunity has been best against experimental and natural TME.^41,51,72,73 Using an experimental challenge model of H. somni-induced pneumonia, significant protection was afforded calves vaccinated twice with an H. somni bacterin.⁷⁴ 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.⁷⁵ Therefore the potential would appear to exist for stimulating resistance to H. somni-associated pneumonia. Unfortunately, commercial H. somni vaccines can stimulate IgE antibodies and thus potentially increase the risk for type I hypersensitivity.⁷⁶ Administration of a commercial H. somni vaccine concurrent with a formalin inactivated bovine respiratory syncytial virus (BRSV) vaccine resulted in increased morbidity and pathology following co-infection, compared with vaccination with experimental subunit vaccines.⁹⁴ The authors attributed this negative outcome to IgE response to both agents. The negative outcomes were despite a strong IgGl and IgG2 response in calves receiving the commercial H. somni vaccine. However, the co-vaccination/co-infection nature of the study precludes conclusions about effects of the H. somni vaccine alone.

Under field conditions, commercial H. somni bacterins have had limited success in inducing a protective immune response against respiratory disease.⁴⁰ In the three trials reviewed by Perino and Hunsaker, H. somni vaccination resulted in reduced treatment rate, an increased rate of cattle being treated for respiratory disease, and no significant difference from nonvac­cinated controls. In a more 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. Ribble and col­leagues demonstrated reduced steer mortality following H. somni vaccination but not heifer mortality. A meta-analysis demonstrated no benefit associated with H. somni vaccines in beef cattle,⁴¹ but the authors acknowledged that the few published trials offered little power to find a benefit, if it existed.

Vaccination for Bibersteinia trehalosi

B. trehalosi strains are hemolytic and produce leukotoxin that is antigenically related to M. haemolytica leukotoxin and can be neutralized by anti-M. haemolytica leukotoxin antibodies.⁴⁵ This suggests that vaccination of cattle with a M. haemolytica vaccine that stimulates antileukotoxin antibodies may provide some level of immunity against leukotoxin-positive B. trehalosi strains. Indeed, one study found that a commercially available M. haemolytica toxoid reduced clinical signs, mortality, and lung lesions to intratracheal challenge with B. trehalosi isolate with leukotoxin genes. The authors of this study referred to unpublished findings of leukotoxin genes being present in up to 45% of B. trehalosi isolates. However, an earlier publication found only approximately 15% of the bovine isolates produce leukotoxin. Other potential antigens, such as outer membrane proteins, appear to be substantially different from those of M. haemolytica Thus, while there is some evidence for use of commercial M. haemolytica vaccine for protection from B. trehalosi, the resulting immunity may well be inadequate for complete protection.