Bovine Herpesvirus Type 1: Infectious Bovine

Rhinotracheitis Virus

Bovine Herpesvirus Type 1 Vaccines viral diarrhea (BVD) viruses types 1 and 2; bovine parainfluenza type 3 (PI-3) virus, bovine respiratory syncytial virus (BRSV), Leptospira spp., Histophilus somni, M.

BHV-1 MLV parenteral vaccines induce both B-cell (humoral) and T-cell (cell-mediated) active immune responses after administration of MLV vaccine.^2,3 Calves born to dams with circulating BHV-1 antibodies may absorb the colostrally derived maternal antibodies to BHV-1 and other viruses.⁴ The mean half-life of viral antibodies to BHV-1 in calves receiving maternal immunity was 21.2 days.⁴ Potentially, calves receiving passive immunity to BHV-1 may have a reduced response to BHV-1.⁵ Calves seronegative to BHV-1 were given BHV-1 neutralizing antibody intramuscularly and subsequently given MLV BHV-1 intranasally. The passive BHV-1 immunity via BHV Ig had a reduction on the efficacy of MLV BHV-1.⁵ The passively administered BHV-1 antibodies protected against viral shedding in viral-challenged calves.⁵

Modified Live Virus Parenteral Vaccines

The MLV parenteral vaccines were the initial vaccines licensed for use in cattle for protection against BHV-1.⁶ Vaccines are attenuated by multiple passages in cell culture and often retain their ability to replicate in a susceptible animal, possibly causing viremia. MLV parenteral vaccines are relatively inexpensive, offer a convenient route of administration, and stimulate a rapid onset of immunity (i.e., within 3 to 5 days of administration).^7-12 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.^3,12 Duration of immunity studies are important to determine length of protection after initial vaccination.

Modified Live Virus Intranasal Vaccines

MLV IN vaccines generally can be divided into two types, based on the attenuation process: (1) those modified by passage in a cell culture^19,20 and (2) those modified by treatment such that they become “temperature sensitive”²¹ (i.e., they do not replicate at internal body temperature).

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 (RLB 106) that is TS, meaning that it has limited replication at internal body temperature.²⁵ Presumably, because of the limited viral replication, the vaccine requires two doses to stimulate immunity. Because it is TS, the vaccine can be used in pregnant cattle.^1,25,26 This vaccine containing the TS protected cattle against respiratory disease in challenged calves and abortions and stillbirths in challenged females.²⁶ In one study heifers received two doses of the vaccine and were challenged with BHV-1 seven months later (at 6 months' gestation). These heifers showed a significant reduc­tion in the number of abortions and stillbirths compared with controls.²⁶

Inactivated Viral Vaccines

Inactivated viral vaccines are prepared by growing virus in cell cultures and then inactivating them with chemicals.

Use of Vaccines to Prevent and

Control BHV-1 Diseases

Many vaccines are available for preventing and controlling the different forms of BHV-1 disease, and each vaccine has certain characteristics that should be considered when designing a vaccination program. Each vaccine also has both benefits and limitations. Probably more important is management of the cattle for which the vaccines are used.

Pregnant Animals or Animals Nearing Breeding Season

The MLV parenteral vaccines may infect the fetus if pregnant susceptible heifers or cows are vaccinated. Abortions have been reported subsequent to vaccination with MLV parenteral vaccines. In many cases the abortions may have occurred to the inadvertent use of the MLV vaccines in pregnant cows.^30,31 However, there has been a report of BHV-1 abortions in pregnant cows after MLV BHV-1 in late gestations in cows vaccinated according to the label (three doses including two as calves and one before breeding).³² This study indicates that some animals may not develop required immunity despite following protocol.

Until the vaccine labels on many MLV parenteral vaccines are changed, MLV IN vaccines or the inactivated or chemi­cally altered live virus vaccines are usually recommended for pregnant cattle or those near breeding. The exceptions are the approved vaccines cited.¹ Vaccine recommendations should be weighed, with 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. In a meta-analysis of publications to determine efficacy of BHV-1 vaccination to prevent abortion in pregnant cattle, both inactivated and MLV vaccines decreased abortion risk.⁴⁴ Because of the potential of some vaccinated animals to not respond to MLV vaccines used according to label and being susceptible to MLV vaccine causing abortion if given in late gestation, a recent study indicated protection if the previously MLV-vaccinated cows were given an MLV strain with the temperature-sensitive strain at late gestation.⁴⁵ A recent publication indicated that large-scale field studies demonstrated that conception was highest in animals previously vaccinated and revaccinated with inactivated vaccine compared with animals revaccinated with MLV.³⁰

Rapid Onset of Immunity

Cattle that are susceptible and likely to be exposed to BHV-1 should receive either an MLV parenteral vaccine or MLV IN 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 duration of immunity are limited, and there was variation of the duration of immunity. A degree of protection against challenge existed at 6 to 9 months after vac­cination with an MLV IN vaccine or an inactivated vaccine.^46,47 A parenteral MLV BHV-1 MLV vaccine provided protection up to 126 days after vaccination.¹³ In a subsequent study, a parenteral BHV-1 vaccine provided protection in calves after 97 days' vaccination when challenged with virulent field BHV-1 strains and the antibodies induced by the MLV vaccine neutralized the field BHV-1 strains.⁴⁸ An additional study reported that BHV-1 MLV vaccination provided a 1-year-long duration of immunity following vaccination of seronegative calves, and the challenge was by the respiratory route.⁴⁹ Challenge studies for licensure are usually 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 and often with the USDA virulent Cooper strain as challenge. Such challenges may detect only protection against a severe form of the respiratory disease. However, an MLV vaccine containing BHV-1 administered 8 or 13 months before challenge provided significant protection against fetal infection resulting from a severe challenge (intravenous challenge with the USDA Cooper strain).⁵⁰ 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 about 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 an MLV parenteral vaccine 5 months earlier.⁵¹ Given the lack of duration of immunity studies for all BHV-1 vaccines individually and the cost of vaccines, breeding animals are usually vaccinated at least annually. In selected feedyards the animals may be revaccinated during the feeding period. In these feedlot cattle processing protocols, cattle receive a monovalent BHV-1 or multivalent viral combination MLV 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 after a few months of entry/processing at which time they received MLV vaccines containing BHV-1.⁵²

Vaccination of Calves With

Maternal Antibody

Vaccination recommendations for neonatal calves include use of multiple doses of an MLV parenteral, an inactivated, or a chemically altered live TS virus vaccine or administration of an MLV IN vaccine. The maternal antibodies may block the parenterally administered MLV or inactivated vaccine. However, the MLV IN vaccine may induce BHV-1 antibody immunity.²³ Calves given a TS IN MLV vaccine and possessing maternal antibodies were able to override the maternal antibody when later challenged by the respiratory route with virulent virus. To date, there are limited if any studies on the use of parenteral MLV BHV-1 in challenge studies to determine efficacy of the parenteral MLV BHV-1 to override maternal antibody in the calves. However, in studies on calves with BVDV maternal antibodies, BVDV MLV stimulated protective immunity when the calves were later challenged with BVDV⁵³ 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 (vac- cinology). These advances are especially noted for herpesviruses, including BHV-1. In addition to conventional vaccines manu­factured via propagation of MLV and inactivated BHV-1 strains, current and future technologies offer opportunities for other vaccines.^54,55 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. DNA vaccines comprising combina­tions of plasmids encoding for genes along with immunostimula­tory CpG motifs have been evaluated for safety and efficacy in vaccinated cattle.⁵⁶ Deletion mutant BHV-1 vaccines as marker vaccines with selected glycoprotein genes deleted along with diagnostic tests for the deleted genes may permit identifica­tion of vaccinates under control programs.^57,58 Needle-free delivery of vaccines has been developed and implemented.⁵⁵ By high-pressure gas delivery, vaccines may penetrate the skin and be administered intradermally, subcutaneously, or intra- muscularly.⁵⁴ Such delivery is designed to minimize damage resulting from IM injections. Two studies compared needle-free intramuscular injection of multivalent MLV 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 59 60

conventional needle injection.,

Vaccination Programs respiratory disease, resulting in less morbidity and mortality and treatment costs, and often resulted in greater economic return to the producer.^63,64

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 is not available or limited about the duration of immunity induced by each BHV-1 viral vaccine commercially available. 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 is probably 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 and 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

CALVES. Calves may be vaccinated at branding, weaning, or 30 days before weaning. Calves vaccinated before 6 months of age should be revaccinated because the earlier vaccination may have been blocked by maternal antibodies. The MLV parenteral and IN vaccines require only one dose in susceptible calves, whereas the chemically altered live virus or inactivated vaccines require two doses. Although the labels for most MLV parenteral vaccines state that the vaccine should not be used if the calf is nursing a pregnant cow, the likelihood of infection of the pregnant cow may be minimal, especially if she is already immune. Yet as described earlier, MLV parenteral vaccines are available for use in pregnant cows and nursing calves.

BREEDING COWS AND HEIFERS. Yearling heifers (12 to 14 months of age) should be vaccinated at least 1 month before breeding. Any of the vaccines may be used, but if two doses are required, the second dose should be given at least 1 month before breeding.

Pregnant cows may be vaccinated with a vaccine that has a label description warranting such use; these include MLV IN vaccines, chemically altered live virus vaccines, inactivated vaccines, and approved MLV parenteral vaccines. Generally one dose is used, primarily because of management considerations. However, following the vaccine label for number of doses and safety for pregnant cow use is important. Administering booster doses of the BHV-1 vaccines may have two conflicting outcomes as a result of booster dose stimulation of an increase in colostral BHV-1 antibodies, which are transferred to the newborn calf in the colostrums; consequently, (1) it may be beneficial to the calf to have increased BHV-1 serum antibodies for protection against BHV-1 disease, or (2) the calf may have longer duration of BHV-1 antibodies, which may block BHV-1 immunization. There are no published multiyear duration of immunity studies in vaccinated cattle challenged with virulent BHV-1. Because of the relatively low cost of BHV-1 vaccines and the need to vaccinate against other pathogens, many breeding cows are given a BHV-1 vaccine annually.

STOCKER AND FEEDER CATTLE. Cattle to be shipped to forage pasture after weaning (wheat pasture or native grass) or to feedyards should be vaccinated 2 to 3 weeks before shipment. However, management practices and marketing may only permit vaccination at initial collection point, market site, or stocker/feedlot delivery. All the major types of BHV-1 vaccines may be used, but those that require only one dose have two advantages: rapid onset of immunity and less handling required (one dose vs. two).

Cattle presented for purchase immediately before shipment, with no known vaccination history, pose a challenge. Presumably healthy cattle may be candidates for the 1-dose MLV parenteral or MLV IN vaccines because these calves may benefit from rapid immunity. Cattle already infected with BHV-1 may not be protected by vaccination.

Cattle entering the feedyard usually receive either the MLV parenteral or MLV IN vaccine, particularly for the rapid onset of immunity.⁶⁵ Cattle are often revaccinated during the feeding period in some operations to ensure protection against BHV-1 disease later in the feedyard.⁵² Recently studies have shown that delaying MLV vaccination (BHV-1, PI3V, BVDV1, BVDV2, and BRSV) 30 days after processing in stressed auction market calves resulted in a significant decrease in the number of calves requiring additional treatment for BRD.⁶⁶

Breeding Services

Veterinarians should consult the breeding bull center for vaccination requirements for bulls, especially relating to export shipment and collection for artificial insemination (AI). MLV IN vaccines have been used in AI bulls because these vaccines are less likely to cause latent infections than MLV parenteral vaccines.^67,68 The MLV parenteral vaccines cause latent infections that may recrudesce with stress after administration of corticosteroids, which means the virus may be present in semen.^43,65

Advances in Diagnostic Medicine and Future Research

In recent years, diagnostic laboratories have moved to newer technologies including immunohistochemistry and genomic tests for infectious agents including viruses.⁶⁹ The genomic tests focus on real-time PCR (RT-PCR) and sequencing of the viral genome by whole genomic testing and/or sequencing of PCR products. Reliance on genomic testing has often replaced traditional isolation attempts in cell culture, which are more laborious and time consuming. Sequencing of the viral nucleic material permits the differentiation of field strains from vaccine strains due to the SNPs' pattern. This is important as BHV-1 strains are often isolated from cattle with prior MLV vaccination. BHV-1 parenteral MLV strains may migrate to other sites such as the respiratory tract (nasal passage and lung) with shedding and the fetus from the injection site. The MLV and field strains may initially be identified by RT-PCR; however, the primers for the PCR do not differentiate field from MLV strains. Thus, genomic sequencing is required to differentiate the strains.

Future research should include developing live virus seed stocks for BHV-1 vaccines that are nonabortifacient and do not induce latency in vaccinated animals. Possibly MLV BHV-1 latent infections may remain in the herd for some time (years perhaps) and then be shed, exposing other susceptible animals including susceptible heifers/cows resulting in BHV-1 fetal disease (abortions).