Bovine Herpesvirus-1
Vaccination

Immunity following natural infection

Duration of immunity
Types of immune responses
Vaccination during pregnancy: Why select inactivated BHV-1 vaccines

There are two ways to approach control of BHV-1 infection in cattle. The first is from the perspective of the host. Cattle have the ability to mount immune responses to BHV-1 infection. This host-mediated protection can be augmented by vaccination of the susceptible animal prior to infection. The second method is directed at controlling the virus through farm management, surveillance and eradication programs. For more information on eradication programs, please consult with the World Organization for Animal Health link that can be found on our useful links page.

The purpose of a vaccine is to selectively enhance the host immune response in such a manner as to better protect against infection. The following criteria should be considered when selecting a BHV-1 vaccination protocol:

            1) Practical criteria such as availability, cost, ease of administration and frequency of administration.

            2) Prevalence of BHV-1.

            3) Immunological properties of the vaccine, including antigenic specificity, the type of immune response that is induced and duration of immune memory. 

            4) Ability to test for vaccine efficacy.

Currently, there are 71 BHV-1 vaccines which are licensed for use in Canada. All of these vaccines are multivalent, including protection for bovine viral diarrhea (BVD) and parainfluenza-3 (PI3).  Many of the vaccines also protect for respiratory synctial virus (RSV). Only 17 of the 71 vaccines are exclusively killed or subunit vaccines; the rest are either modified live virus or a mix of modified live and killed virus. The form of the antigen delivered in the vaccine is important in determining how the immune system responds to the vaccine.  In many instances the best vaccine induces an immune response that mimicks that following natural infection. Therefore to be able to evaluate the efficacy of vaccination against BHV-1, one must understand how the virus and immune system interact with one another. It is also necessary to be able to differentiate between an immune response resulting from natural infection and one that is induced by immunization with a vaccine.


Immunity following natural infection

In the case of natural infection, BHV-1 specific adaptive immune responses are detectable starting at 7-10 days post-infection, when the virus starts to replicate and involve both humoral (antibody) and cell-mediated immunity (Babiuk et al., 1996; Engels and Ackermann, 1996). Antibodies are produced against gB, gC, gD and gE and these antibodies protect against virus attachment (neutralizing antibodies prevent infection, spread and viremia) as well as take part in antibody-mediated cell-cytotoxicity (Tikoo et al., 1995). Cell-mediated immunity is involved in recovery from infection and is characterized by the presence of macrophages, IL-2, IFNg, and CD4+ and CD8+ T cells specific for gC and gD (Hutchings et al. 1990; Tikoo et al. 1995b). Protection is enhanced when type-1 CD4+ T helper cells predominate over type-2 CD4+ T helper cells (Mena et al. 2002). While the immune system aids in the recovery from infection, it does not provide sterile immunity and recovered animals do continue to shed virus. Natural infection, does however, prevent the reoccurrence of clinical disease. Periodic screening for BHV-1-specific serum antibodies in a naturally infected animal should reveal relatively high background titers that reflect continued boosting of the immune memory via reactivation of virus or exposure to cross-reactive antigens in the environment.

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Vaccination: Duration of immunity

The immunity provided by the BHV-1 vaccines that are currently available may not be as effective as that provided by natural infection. In particular, all the BHV-1 vaccines that are commercially available require a prime-boost protocol within a 2 - 4 week period in order to achieve protection from clinical disease. Also, immunity that is induced by vaccination does not persist for the lifetime of the animal. In theory, a modified live vaccine should induce longer-lasting immunity than a killed vaccine. Killed vaccines are rapidly cleared from circulation whereas live viruses infect host cells, converting the cells to antigen factories. In a study by Hage et al. (1998), a prime-boost with a temperature sensitive modified live BHV-1 strain resulted in the gD-specific antibody titers that were detectable for up to 30 months. They hypothesized in this study that the duration of antibody responses was due to the establishment of a latent infection by the modified virus. However, protection against further virus challenge was not assessed in this study and detectable antibody titers do not necessarily confer protection against clinical disease or viral shedding. A study by Ellis et al. (2005) showed that prime-boost vaccination of calves with a modified live BHV-1 vaccine resulted in decreased clinical signs and reduced viral shedding up to 126 days post-challenge. This study by Ellis et al. supports the observation by the World Organization for Animal Health that many existing BHV-1 vaccines have not been tested to the standard of inducing protective immunity for at least 1 year.

 

Virus isolation and serological test are used to determine the efficacy of a vaccine and the immune-status of an individual animal. With respect to BHV-1, the World Organization for Animal Health requires that immune status of bovids be evaluated by serology.  Serology is the testing of serum for the presence of BHV-1-specific antibodies in individual animals. The two methods of serological testing accepted for international trade purposes are the virus neutralization assay and enzyme-linked immunosorbent assay (ELISA).  Because herpesviruses are fairly ubiquitous in the environment and have a high degree of antigenic cross-reactivity, most animals have detectable levels of non-specific/cross-reactive antibodies that will bind to BHV-1 antigens. The World Organization for Animal Health (OIE) has defined control sera for evaluating levels of BHV-1-specific serum antibody titers: strong protection, weak protection and naïve sera. These controls are available through the OIE Reference Laboratories for infectious bovine rhinotracheitis (OIE Manual of Standards for Diagnostic Tests and Vaccines). Alternately, serial serological testing can be used to determine seroconversion; a 4-fold increase in BHV-1 reactive antibody titers is considered seroconversion. The accepted serological tests for international trade purposes are shown in the table below.

Serological tests

1.

ELISA (for antibody)

·    Prescribed test for international trade

·    Easy to carry out. Different protocols available for different purposes.

·    No international standardized protocol exists and results obtained from different laboratories/experiments/protocols/kits/reagents are not comparable to one another.

·    The benefit of the ELISA is the ability to differentiate between antibody classes and antigenic-specificity.  The latter enables differentiation between antibody responses due to vaccination compared with natural infection.

2.

Virus neutralization

·    Prescribed test for international trade.

·    Looks for the presence of BHV-1 specific neutralizing antibodies in serum.

·    Standardized positive, weak positive and negative serum controls are available from OIE Reference Laboratories for IBR/IPV.

Reference: http://www.oie.int/eng/normes/mmanual/A_00056.htm
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Types of immune responses

The serological tests available in most diagnostic laboratories do not characterize the class of immune response that is induced following vaccination. In 1982, Frerichs et al. conducted a vaccine experiment on which calves were vaccinated with either commercial modified live virus vaccines or an inactivated polyvalent calf pneumonia vaccine, and then challenged with BHV-1. Both live vaccines stimulated a serum neutralizing antibody response, but calves vaccinated solely with the inactivated vaccine were clinically indistinguishable from unvaccinated control calves. As inactivated vaccines are presented to the immune system by class-2 MHC molecules, these results strongly suggested that type-2 immune responses are not protective against clinical BHV-1. In contrast, vaccines which present antigen via the intracellular class-1 MHC pathway do provide protection against clinical disease. These results are consistent with the dogma that induction of type-2 immune responses are non-protective and potentially pathogenic with respect to protecting against intracellular pathogens. CD8+ T cells (part if cell-mediated immunity) also provide longer lasting immune memory in the absence of re-exposure to specific-antigen, (Hou et al. 1994; Lau et al. 1994; Geraghty et al. 1998; Connolly et al. 2001).

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Vaccination during pregnancy: Why select inactivated BHV-1 vaccines


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Both modified live and inactivated vaccines have drawbacks such as contraindication for young or pregnant cattle, uncertain efficacy, onset if clinical disease in immunosuppressed cattle, interference with serological diagnosis, and live vaccine transmission to unvaccinated cattle (Kahrs, 2001; Lovato et al. 2003). Theoretically, inactivated and subunit vaccines have a higher safety index than modified live vaccines.

 

During pregnancy, the maternal immune system is suppressed to prevent immune rejection of fetal allogeneic antigens (derived from paternal DNA). Throughout pregnancy, early pregnancy factor is expressed and preferentially suppresses cell-mediated immune functions. The absence of early pregnancy factor expression correlates with an increased incidence of miscarriage or abortion (Shahani et al., 1994). Vaccination of pregnant dams with live virus has been proposed to stimulate cell-mediated immunity, thus increasing the risk of abortion.

 

Availability of a safe vaccine alternative is especially important in diseases such as BHV-1 and BVD, where passive immunity from maternal antibodies in colostrum is necessary to protect against neonatal infection (Mechor et al. 1987). Vaccination of pregnant cows is also necessary to prevent the risk of BHV-1 abortion storms. It should be noted that BHV-1 is not capable of crossing the epitheliochorial placental barrier (personal observation). Most producers and veterinarians vaccinate cows yearly - pre-breeding - with a multivalent (BHV-1, BVD and parainfluenza-3) modified live virus vaccine. While efficacious in preventing abortion storms, a single-pre-breeding vaccine does not maximize maternal antibody titers in colostrum. To maximize colostrum antibody titers, a BHV-1/BVD vaccine should also be administered midway through the third trimester of gestation. Studies conducted at the Vaccine and Infectious Disease Organization (Saskatoon, SK) have shown that anamnestic antibody responses specific for BHV-1 gD and gE reach peak titers approximately 1 week post-boost, and maternal antibodies have a biological half-life of 3 weeks (Mechor et al., 1987).  Since maximal absorption of maternal antibodies occurs during the first 24 hours of life, a pre-parturition vaccine administered approximately 1 to 2 weeks prior to calving should maximize passive immunity in the newborn calf. Pre-breeding vaccines should not be administered during the last week of gestation due to the rising cortisol levels associated with parturition (Kindahl et al., 2003) and the general immunosuppressive effect of rising cortisolemia (Munroe 1971; Anderson et al. 1975; Inaba et al. 1999).

Keeping in mind the risk of abortion associated with live virus vaccination, it may be preferential to administer either a killed virus or subunit vaccine to a pregnant cow – provided that she has been previously immunized with a modified live virus vaccine that preferentially induced cell-mediated immunity. Prior immunization with the intention of inducing a cell-mediated immune response is necessary to provide protection. Activation of CD8+ memory T cells during the primary immunization also has the added benefits of providing longer-lasting immunity and imprinting a type-1/CMI response on the immune system upon further exposure to antigen. Therefore, if the primary or pre-pregnancy vaccinations are administered using live virus, boosting with a killed or subunit vaccine in the mid-third trimester of gestation should boost waning immune memory, without necessarily inducing type-1/cell-mediated effector functions. An example of a potential pre-breeding-pre-calving vaccination protocol* may include pre-breeding vaccination with PyramidÒ (Fort Dodge Animal Health), which is a multivalent live vaccine administered either sub-cutaneously or intrasmuscularly that is contraindicated in pregnant cows, followed by a pre-calving vaccination with the multivalent subunit TriangleÒ vaccine (Fort Dodge Animal Health).

* Note that this suggested protocol is strictly hypothetical, has not been tested in experimental or field trials to the knowledge of the author, and is not part of the label for the named vaccines.

Although the Merck (2005) clearly advises against intramuscular administration of live BHV-1 vaccines in pregnant cows, newer versions of multivalent modified live virus vaccines are indicated for intramuscular administration in pregnant cows. One example is Pfizer’s CattleMaster® 4. There are also many websites which are proponents of intranasal vaccination of pregnant cows with live BHV-1 vaccines.  Intranasal delivery targets the vaccine to the respiratory-associated lymphoid tissues, which enhances IgA secretion and mucosal immunity, thus directing immune responses to the site of viral entry. Experiments have been conducted which show that parenteral immunization is not an effective means of stimulating mucosal immunity (Brokstad et al. 2002; Cox et al. 2004).

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