Bovine Respiratory Syncytial Virus Vaccines

John A. Ellis

Bovine respiratory syncytial virus (BRSV) is a pneumovirus in the paramyxovirus family that endemically infects cattle populations worldwide. Although the virus can cause disease in all ages of cattle, it primarily occurs in recurrent seasonal outbreaks in calves with decayed concentrations of maternal antibodies.^1-3 Resulting respiratory disease is characterized by pyrexia, coughing, and tachypnea, which can progress rapidly to severe expiratory dyspnea.^2,4 BRSV is also considered one of the viral agents that predisposes animals to secondary bacterial infections in the bovine respiratory disease complex (BRDC); however, secondary infections are often absent in fatal BRSV- associated respiratory disease.^2,5,6 Subclinical BRSV infection or mild respiratory disease due to BRSV infection in dairy cattle may have a negative impact on milk production.⁷

Parenteral Vaccines

MLV and inactivated parenteral BRSV vaccines have been commercially available since the 1980s.⁸ Most of these vaccines are formulated in combination with other viral respiratory pathogens, including PI-3, BHV-1, and BVDVs.

The efficacy of parenterally delivered MLV vaccines in calves with MDAs, the most relevant candidates for vaccination in the field, remains controversial and incompletely resolved.^8,10 In classical studies conducted in small numbers of calves in the 1980s, administration of attenuated BRSV by the IM route to passively immune calves reportedly did not elicit mucosal memory IgA or serum antibody responses or even prime for such responses.¹¹ In contrast, several studies have documented a variety of BRSV-specific T-cell responses after parenteral vaccination in passively immune calves.⁸ However, it has not been determined in a challenge experiment whether these in vitro responses are associated with a protective cell-mediated memory response once maternal antibodies have decayed. Available data from one challenge study conducted with a representative commercial combination parenteral MLV BRSV vaccine given to young BRSV-seropositive calves indicated that priming for protective immunity was blocked by MDA concentrations typical of good passive transfer.¹² Although the ability of parenteral modified live BRSV vaccines to prime for protective immunity in the context of MDAs is likely to vary with the concentration of MDA, the antigenic mass of the vaccine, and/or vaccine formulation,¹³ it is probably most prudent, in the absence of serologic data on individual calves, to assume that a biologically significant amount of inhibition of priming will occur in the face of MDA and use mucosal (IN) vaccines in young BRSV-seropositive calves.¹⁴

Disease-sparing efficacy similar to that demonstrated for parenteral MLV BRSV vaccines has also been documented in the case of some combination inactivated vaccines containing BRSV formulated with different adjuvants⁸ when tested in a disease-producing challenge model in young BRSV-seronegative calves.

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.⁸ In addition, one study suggested the usefulness of combination vaccines in reducing the impact of subclinical BRSV infections.⁷

As alluded to, protection against BRSV infection and disease is immunologically multifactorial. Certainly, IgA is part of that response,^1-3,8 but serum IgG acquired from either passive or active immunization can significantly reduce the severity of clinical respiratory disease that results from BRSV infection.⁸ Several studies have reported that the incidence and severity of disease in calves were inversely related to maternal antibody titers.^2,8 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.¹⁵ 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.

Conceptually, it was demonstrated in the late 1980s that IN inoculation of tissue culture-attenuated BRSV to passively immune calves primed the calves for immunologic memory, as evinced by anamnestic local IgA and systemic IgG responses after challenge.¹⁶ Subsequent studies with culture-attenuated BRSV, then with single-component and combination parenteral BRSV vaccines administered intranasally and, finally, with commercial IN BRSV vaccines confirmed these phenomenona. Importantly, in addition, these studies documented an association between immunologic responses and significant disease-sparing.⁸

As epidemiologic studies suggest is the case in nature,^1,2,8 iatrogenic mucosal exposure to BRSV IN vaccines is capable of “overriding” MDA, resulting in effective priming of young calves.⁸ This has been confirmed by experimental challenge studies and documenting enhanced BRSV-specific antibody responses, compared with nonintranasally vaccinated controls, following parenteral administration of commercial vaccines at approximately 2 months of age to commercially reared beef calves.⁸ However, the duration of immunity to neonatal IN vaccination is apparently short, probably less than 4 months.¹⁴ Therefore the current focus of applied research in BRSV vaccines is determining an optimal protocol for boosting of neonatally, mucosally primed immunity. One study¹⁷ suggests that parenteral inactivated BRSV vaccines, used in a “heter­ologous prime-boost” protocol¹⁸ at 2 months of age, may be superior to similar modified live vaccines, used in the same way, in conferring clinical immunity.

Adverse Reactions to Bovine Respiratory Syncytial Virus Vaccines

A major factor hampering 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- inactivated (FI), alum-adjuvanted HRSV predisposed children to more severe disease after subsequent HRSV infection.¹ Historically, deriving primarily from these observations, there has been a concern about the use of inactivated BRSV vaccines in cattle.⁸ Although this same disease-enhancing phenomenon has been demonstrated in some studies of experimental FI-BRSV vaccines in cattle,⁸ it is unlikely that modern manufacturing practices would use formalin inactivation of BRSV or other viral vaccines in cattle. Moreover, there are documented cases of apparent enhancement of BRSV-associated respiratory disease in cattle that received either inactivated or MLV vaccine in the field, indicating that some commercial vaccine formulations may stimulate potentially pathogenic immune responses in some cattle, but that it is not necessarily a strict function of inactivation per se.⁸ The immunologic mechanisms responsible for vaccine-associated disease enhancement in pneumovirus infections are not completely understood; it may have more to do with the timing between vaccination and BRSV infection than being completely a function of vaccine formulation.⁸ However, it is unlikely that the current hypothesis applied in studies of vaccine enhancement of disease in HRSV infections, namely a strict dichomotization between protective T-helper cell (Th1)-like responses versus pathogenic Th2-like responses involving IgE and/or “hypersensitivity “ reactions in response to BRSV vaccines, is particularly relevant to cattle.⁸ Neverthe­less, given the history of adverse reaction to RSV vaccines in humans and, to a lesser extent, cattle, care should be taken in making assumptions about the efficacy and safety of BRSV vaccines. Data from the laboratory and field use situations should be evaluated before using a particular BRSV vaccine to best avoid adverse reactions.