Bovine respiratory disease complex

Bovine respiratory diseases (BRD) and undifferentiated fevers are estimated to cost the North American cattle industry up to US$1 billion each year. From 2011 to 2015, BRD in preweaned calves cost the US cow-calf industry about US$165 million annually. It is equally significant in other cattle-producing countries. BRD has a complex etiology and its occurrence depends upon age, weight, origins (ranch or sales barn), genetics, environmental problems, and stresses such as transportation, weaning, and overcrowding in addition to exposure to potential pathogens. In general, stress causes immunosuppression that permits viral infection that is followed by secondary bacterial invasion of the respiratory tract. The common viruses involved in BRD include bovine herpesvirus 1 (BHV-1), parainfluenza 3 (PI3), bovine respiratory syncytial virus (BRSV), and bovine virus diarrhea virus (BVDV). Other viruses that may be involved include bovine coronavirus, enteroviruses, and reoviruses. Bacterial pathogens may include Mannheimia haemolytica, Pasteurella multocida, Mycoplasma bovis, and Histophilus somni. Because of the complex pathogenesis of BRD, combined vaccines containing multiple antigens are usually used to control these pathogens. Combination vaccines may contain antigens against the five major respiratory viruses: BVD types 1 and 2, BRSV, BHV-1, and PI3. Mannheimia, Pasteurella, Histophilus, Campylobacter, and Leptospirosis antigens may also be added to these vaccine mixtures.

When calves arrive at a feedlot, the initial processing usually includes vaccination for the common bacterial and viral organisms associated with shipping fever. However, pneumonia often develops within two weeks after arrival before these vaccines have had sufficient time to confer immunity. Ideally these vaccines should be given at least two to three weeks before shipping to the feedlot. They can then be boosted on arrival.

Mannheimia haemolytica

M. haemolytica is the predominant bacterium found in bovine pneumonic lesions. This is commonly M. haemolytica serotype 1, but there are at least 12 other bacterial serotypes based on their capsular antigen structure. Protective immunity to M. haemolytica requires the development of neutralizing antibodies against its leukotoxin and its outer membrane proteins. Most M. haemolytica vaccines are therefore of the bacterin-toxoid type. These vaccines are also effective against the related respiratory pathogen Bibersteinia trehalosi.

Pasteurella multocida

Histophilus somni

Leptospirosis

This disease is caused by multiple Leptospira serovars and spreads through a herd via animal contact and contaminated water. The most important of these serovars are Leptospira borgpetersenii serovar, Hardjo-bovis, and Leptospira interrogans serovars, Hardjo and Pomona. The acute disease causes agalactia, icterus, and hemoglobinuria. The chronic disease results in abortions, stillbirths, and weak calves.

Multivalent killed adjuvanted Leptospira bacterins are available. Of the 55 licensed Leptospira combination vaccines currently available in the United States, all contain Pomona, 36 contain Hardjo, and 23 contain Hardjo-bovis. These provide immunity against disease caused by most serovars with the possible exception of serovar Hardjo. However, as with all Leptospira bacterins, the immune response is directed against the bacterial lipopolysaccharide. As a result, immunity is strain-specific and is not long lasting. Even under the best of conditions these do not provide protection for much longer than six months. Other serovars occasionally implicated in cattle include Grippotyphosa, Bratislava, and Icterohaemorrhagiae.

Clostridial vaccines.

Brucellosis

Brucella abortus causes abortions, reduced milk yield, and infertility. It has been controlled in North America and Europe by a vaccination, test, and slaughter program. Brucellae are facultative intracellular bacteria and as a result they cannot be effectively controlled by antibodies alone. Antibodies may influence the initial phase of infection, but once the organisms enter cells, they can only be controlled by T cell-mediated macrophage activation. Cell-mediated immune responses are therefore essential and this means that only live organisms can serve as effective vaccines. Unfortunately, none of these live vaccines are entirely satisfactory.

Campylobacteriosis

A formalin-killed, oil-adjuvanted bacterin is available against C. fetus. It provokes an antibody response in the serum, uterus, and vagina. This vaccine should be given at weaning, when cows are palpated, and then revaccinated annually. Breeding bulls must also be vaccinated eight and four weeks before the breeding season and annually thereafter.

Salmonellosis

Bovine salmonellosis is a matter of public health concern and also an economically important infection. Although it may affect cattle of all ages, it is of greatest significance in calves under 10 weeks of age. The most common serotypes are Typhimurium and Dublin. They are responsible for acute diarrhea in calves and multisystemic illness in adult cattle in addition to invasive septicemia. Even when not clinically apparent, Salmonellae may be carried by healthy cattle and transmitted to humans through meat or milk products. It is important therefore to control Salmonella-mediated disease in addition to the carriage and shedding of these organisms. Killed bacterins and modified live vaccines have both been employed. As expected, the live vaccines usually give better protection than the killed ones. A rough mutant of serotype Dublin (EnterVene-d, Boehringer Ingelheim) is the most widely employed live vaccine. An SRP vaccine using siderophore receptor and porin proteins is also available. It reduces the shedding of serotype Newport in dairy cattle.

Colibacillosis

Enteric colibacillosis caused by enteropathogenic Escherichia coli in neonatal calves is a significant disease and a major cause of economic loss. It commonly occurs in calves 2 to 10 days after birth but may begin as early as 12 hours. In addition to hygiene, good nutrition, and stress issues, its occurrence is linked to insufficient colostrum intake. Because of its very early onset it must be largely controlled by vaccination of pregnant cows and the induction of colostral antibodies. Available bacterins contain enterotoxic E. coli possibly supplemented by the addition of F5 (K99) adherence pili. These are usually administered to pregnant cows in two doses three to four weeks before calving. Revaccination is recommended at each subsequent pregnancy. A polyclonal equine anti F5 serum is available for the oral treatment of neonatal calves. Note that vaccination is only one part of a comprehensive management strategy to control calf scours.

A vaccine against E. coli O157 is also available for use in cattle. Its function is to reduce the carriage rate of this significant human pathogen. It is administered to cattle over five months of age. Given the importance of cattle in the transmission of this organism, the vaccine, if used, is likely to cause a significant drop in the prevalence of this infection.

Anaplasmosis

Footrot

Infectious bovine keratoconjunctivitis (pinkeye)

Pinkeye is a severe conjunctivitis caused by the bacteria Moraxella bovis, Moraxella bovoculi, and Moraxella ovis. It is not uncommon to find other bacteria in eye lesions as well. These organisms attach to the cornea through their pili and trigger severe inflammation, resulting in corneal edema, ulceration, and partial or total blindness. Consequently, there is a drop in feed intake, body condition, and milk yield. The initial attachment of M. bovis to corneal cells is mediated through the Q pilus, but persistent attachment is caused by the bacterial I pilus. Thus bacterins should contain both pilus antigens. An effective bacterin is available against M. bovis and there is a multivalent bacterin available against M. bovoculi as well. They may be combined with clostridial vaccines.

In the United States, a Moraxella vaccine is also available for implantation in pellet form. Two pellets are inoculated at one time under the skin at the base of the ear or in the neck. One pellet is designed for immediate antigen release to promote rapid protection. It rehydrates rapidly and begins antigen release at once. The other pellet rehydrates slowly and releases Moraxella antigens over a two to three week period. It is thus designed for prolonged antigen release, effective boosting, and longer-term immunity. Because of the diversity of bacterial strains involved, autogenous vaccines are often used for this disease.

Mycobacterium avium, subspecies paratuberculosis

Mycobacterium avium, subspecies paratuberculosis (MAP) is the cause of Johne’s disease, a chronic enteritis that results in a drop in milk yield, significant weight loss, and decrease in body condition. In the United States, MAP-positive herds lose almost US$100/cow and production losses may reach US$200 to US$250 million. Many vaccines have been developed in different countries for this disease. These included heat-killed bacterins, live attenuated vaccines incorporated with oil and pumice powder, and lyophilized live attenuated vaccines combined with oil adjuvants.

A single paratuberculosis vaccine (MAP strain 18) is available in the United States (Mycopar, Boehringer Ingelheim). Interestingly the organism in this vaccine is not a MAP but Mycobacterium avium serovar 2. It is a whole cell bacterin suspended in oil and it is injected into the dewlap. The withdrawal time for this product is 60 days.

MAP vaccine may only be administered by a veterinarian who has been approved by state health officials. The herd owner and the veterinarian must enter an agreement with the state veterinarian regarding its use. Three conditions must be met before this can be done. First, it must be confirmed that the premises are actually infected with MAP either by isolating the organism or detecting it by polymerase chain reaction (PCR). Second, all the animals in the herd must have a negative tuberculin test and replacement stock must also be tuberculosis free. Third, the owner and the state animal health authorities must sign an agreement regarding its use.

Only replacement heifers and bull calves between 1 and 35 days of age may be vaccinated. Vaccinated calves must have external identification and a tattoo indicating that they have been vaccinated against Johne’s disease.

Vaccinated cattle develop a delayed hypersensitivity that may result in a false positive caudal fold skin test for tuberculosis. In such cases confirmatory comparative cervical tests must be performed, using bovine and avian tuberculin. The M. avium response should be much greater than the response to M. bovis. In a large herd the cost of this can be significant and the herd must be quarantined until its true TB status is clarified. As a result, many states do not permit MAP vaccination.

Although this vaccine may not prevent new infections, much depends on the age of the cattle, the level of mycobacterial contamination, and herd management standards. It generally reduces clinical disease, fecal shedding, and MAP burden. These factors, plus an increase in herd immunity, should reduce herd transmission.

In countries such as Australia, ovine Johne’s disease is a significant problem, and there is widespread use of a heat killed, mineral oil adjuvanted MAP vaccine (MAP strain F316, Gudair, Zoetis). It appears to be very effective in sheep and goats. A similar vaccine (Silirum Zoetis), is used in young farmed deer in New Zealand.

Bacille Calmette-Guerin (BCG) vaccine, an attenuated strain of Mycobacterium bovis, is of limited effectiveness in protecting humans against tuberculosis, but can protect cattle against M. bovis with 55% to 86% efficacy. Its developers, Calmette and Guerin demonstrated this in 1911. Low dose BCG (3 × 10⁵ organisms) has been used successfully to control tuberculosis in free-ranging cattle in New Zealand. Unfortunately, the conventional dose of BCG (10⁸–10¹⁰ organisms) sensitizes cattle resulting in positive tuberculin skin tests and cannot therefore be used routinely.

Infectious bovine rhinotracheitis

Bovine herpesvirus 1 (BHV-1), a member of the genus Varicellovirus, subfamily Alphaherpesvirinae, causes reproductive, respiratory, enteric, and neurologic disease in cattle. The infection is characterized by upper respiratory tract disease with a purulent nasal discharge, hyperemia of the muzzle and conjunctivitis. Systemic disease causes abortions in nonimmune pregnant cows and may result in a loss of up to 60% of fetuses. The virus can also invade the genital tract to cause pustular vulvovaginitis. BHV-1 plays a significant role in the bovine respiratory disease complex.

Inactivated vaccines contain virus or purified viral glycoproteins and are adjuvanted. They are given subcutaneously or intramuscularly. Although inactivated vaccines do not induce a long-lasting response and vaccinated animals are slow to develop immunity, they can be given safely to pregnant cows. BHV-1 glycoprotein E or -D-deleted attenuated mutants are available and can be used as components in a DIVA strategy.

A temperature sensitive (ts), cold-adapted strain of BHV-1 is also available to be administered intranasally. This vaccine induces a rapid protective response, within 24–48 hours of administration. However, it may also induce mild respiratory disease and a drop in milk production.

An attenuated BHV-1 field strain passaged in tissue culture has generated small plaque variants. These variants proved to have lost the genes for gE and US9. These are the basis of current DIVA vaccines. A thymidine kinase deleted (TK^–) BHV-1 vaccine has also been developed. It appears to be very safe but, like other herpesvirus vaccines, is unable to prevent latent infections.

Bovine virus diarrhea

Bovine virus diarrhea viruses (BVDVs) are Pestiviruses in the family Flaviviridae. This genus contains four important livestock pathogens: BVDV1, BVDV2, classical swine fever, and border disease virus. A new species called “HoBi-like” or BVDV3 has been identified in South America and Asia. The two BVD viruses have multiple subgenotypes (15 in BVDV1 and 2 in BVDV2). They induce enteric, respiratory, and reproductive diseases in cattle. BVDV includes two distinct biotypes: cytopathic (cp) and noncytopathic (ncp). (The name describes their behavior in cell culture, not their pathogenicity in animals.) Ncp strains suppress type I interferon (IFN) production but permit type III (IFN-λ) production by dendritic cells. The type III interferon suppresses some T cell subsets and enables the virus to cause persistent infections. Cp strains, in contrast, induce type I IFN production and do not cause persistent infections. Ncp BVD infections occurring in pregnant cows between 50 and 120 days postconception, before the fetus develops immune competence, result in asymptomatic persistent infection (PI) because the fetal calves develop tolerance to the virus. Once born, these PI calves remain viremic, yet because of their tolerance they do not make antibodies or T cells against BVDV. Some of these calves may show minor neurologic problems and failure to thrive, some die suddenly, but many are clinically normal. These persistently infected calves grow slowly and often die of opportunistic infections such as pneumonia before reaching adulthood (BVDV has a tropism for T cells and is therefore immunosuppressive). Because they are tolerant to BVDV, persistently infected calves can shed large quantities of the virus in their secretions and excretions.

The cp strains, however, can cause mucosal disease (MD), a severe enteritis resulting in profuse diarrhea, dehydration, and death. Mucosal disease results from a mutation in the gene that controls the BVDV biotype while the animal fails to produce neutralizing antibodies or T cells. The cp strain can spread between tolerant animals and lead to mucosal disease outbreaks.

Recombination may occur between persistent wild-type ncp strains and vaccine cp strains and this may also cause MD. Some of the lesions in MD are attributable to the direct pathogenic effects of BVDV, but glomerulonephritis and other immune-complex–mediated lesions also develop. Because persistently infected calves can reach adulthood and breed, it is possible for BVDV to persist indefinitely within carrier animals and their calves.

Modified live vaccines (MLVs) stimulate much higher levels of antibodies than do inactivated ones, and also stimulate cell-mediated immunity. Protection may develop as soon as three to five days following vaccination with MLVs. They reduce viremia and nasal shedding in addition to preventing disease and mortality. There is little field evidence to suggest that MLV cp strains can cause mucosal disease, but a recent report described MD in cattle after vaccination with BVDV1a and -2a and the gene sequence of the isolated virus resembled the vaccine strain. At least one BVD-MLV vaccine has been shown to induce a leukopenia and suppress the lymphocyte response to mitogens as a result of a drop in T cell numbers,

Parainfluenza 3

Bovine respiratory syncytial virus

Bovine coronavirus and rotaviruses

These viruses cause diarrhea in very young calves. As a result, they are usually controlled by a single combined vaccine that is either given to neonatal calves or to pregnant cows several weeks before calving. Two live vaccines are available for the vaccination of newborn calves. One MLV vaccine can be given orally immediately after birth. Another MLV vaccine can be administered intranasally to calves at three days. The rapid onset of immunity in calves receiving the oral or intranasal live vaccines is probably due to the production of interferon. Inactivated vaccines are also available for use in pregnant cows.

Foot-and-mouth disease

Foot-and-mouth disease (FMD) is one of the most contagious of the diseases affecting cloven-hoofed animals, and the most important disease limiting the global trade in animals and animal products. Its cause is a virus of the genus Aphthovirus of the family Picornaviridae. Infected cattle and pigs develop vesicles on their feet, nose, mouth, tongue, and mammary glands. The mouth and nose vesicles rupture and result in excessive salivation and nasal discharge. The foot lesions located around the coronary band cause lameness. In adult sheep and goats the disease may be mild or subclinical, but in juvenile lambs and kids, mortality may reach 50%. Infected animals shed large amounts of virus, and because the infectious dose is low, the virus can spread very rapidly among susceptible animals.

FMD has the potential to cause great economic losses as a result of reduced weight gain, growth failure, reductions in milk production, and loss of traction potential. About half the infected animals remain persistently infected virus carriers. There are seven known serotypes of FMDV: A, O, C, SAT1, SAT2, SAT3, and Asia-1. In addition, there are more than 60 subtypes of FMDV, and there is no universal vaccine against all of these. Infection or vaccination with one serotype does not confer protection against the other serotypes.

The United States has been free of this disease since 1929. It is also absent from Canada, New Zealand, Australia, and most of Europe. Most disease-free countries have never vaccinated their livestock. They rely on surveillance, movement controls, and controls on the importation of animal products. Sporadic outbreaks in FMDV-free countries have been controlled by the prompt slaughter and destruction of infected animals and potential contacts. In recent outbreaks, the death of very large numbers of mostly uninfected animals has led to a public outcry and questions regarding the decision to implement depopulation policies. The disease is endemic in much of the rest of the world.

All currently available FMDV vaccines are inactivated. The first vaccines originally contained formaldehyde-inactivated virus obtained from tongue lesions. Subsequently it became possible to grow the virus in cultured tongue epithelium. It is now grown in large-scale suspension cultures using baby hamster kidney (BHK21) cells. Unwanted components and tissue culture residues are removed by ultrafiltration and chromatography. When the virus reaches its maximum yield, the culture is clarified by centrifugation and/or filtration. It is then inactivated with binary ethyleneimine and concentrated by ultrafiltration. These vaccines are then adjuvanted with a mineral oil emulsion or an aqueous adjuvant such as aluminum hydroxide or saponin. Pigs respond poorly to these vaccines, and double adjuvants, such as water in oil in water, are required to generate significant immunity in this species. FMDV vaccines must undergo efficacy testing in addition to the usual identity, sterility, safety, and freedom from contamination. In endemic countries, calves should be vaccinated every six months until two years of age and then annually thereafter.

FMD vaccines may be classified as “standard” or “higher potency” vaccines. Standard potency vaccines contain about three PD₅₀ (protective dose 50) whereas “higher potency” vaccines contain more than 6 PD₅₀. The latter are used to protect naïve animals in the presence of an outbreak. In countries where vaccination is practiced, vaccines are given twice a year because it is essential to maintain a high level of herd immunity. Immunity develops within seven to eight days. Because of the lack of cross-protection between serotypes and subtypes of FMDV the appropriate vaccine strain must be carefully selected if vaccination is to be effective.

Lumpy skin disease

Lumpy skin disease (LSD) is a poxvirus-mediated disease of cattle, sheep, and goats. It is characterized by fever, nodules on the skin mucosa and internal organs, emaciation, lymphadenopathy, and death. LSD is endemic in Africa, the Middle East, and also southeast Europe. Attenuated strains may be used as live vaccines. Strains of capripox virus cross-react with LSDV and have been used as vaccines but they may produce severe local reactions.

Rift valley fever

Rift Valley fever (RVF) is a disease of humans in addition to sheep, cattle, and goats, and is restricted to Africa and the Arabian Peninsula. It is caused by a mosquito-borne Phlebovirus of the Bunyaviridae family. Rift Valley fever virus causes mass abortion and high neonatal mortality when it infects pregnant animals. Both live attenuated and inactivated vaccines are available for use in regions where RVF is endemic. The mouse-adapted Smithburn strain induces strong immunity within six to seven days. It should not be used in pregnant animals in which it may cause abortion or fetal malformations. Protection lasts for several years. These MLV vaccines should not be used in nonendemic countries. A formalin-inactivated vaccine is also available for use in pregnant cattle, sheep, and goats. It requires two doses, three to six months apart and annual revaccination.

Bovine ephemeral fever

This is an important arboviral disease affecting cattle, yaks, and water buffalo in East Asia and Northern Australia where it causes serious economic losses. It is caused by an Ephemerovirus. It causes a short (three-day) fever with profound depression, stiffness, and lameness. Cattle may be unable to rise. Vaccination is widely employed and both modified live and killed vaccines are available. They should be given in two doses, two to six weeks apart, well before the start of the mosquito and sand-fly season.