Bovine respiratory syncytial virus ISCOMs—protection in the presence of maternal antibodies
Introduction
Bovine respiratory syncytial virus (BRSV), a Pneumovirus in the Paramyxoviridae family, is a common agent of respiratory disease in cattle [1] and an important threat to animal welfare. Animal losses, treatment costs and decreased production cause economic losses to the industry and there is a great need for effective prophylactic measures directed against infections [2], [3], [4]. BRSV commonly infects young individuals and disease occurs even in the presence of maternal antibodies [5]. Bearing in mind that the seroprevalence to BRSV is high in most countries [4], [6], ideally vaccines should be effective at an early age and be able to overcome the immunosuppressive effects of maternal antibodies.
Both live and inactivated BRSV vaccines are available on the European and North American market and both are associated with different advantages and disadvantages. Whereas parenterally administered live vaccines are immunogenic [7], [8], vaccination in the presence of a natural infection may result in enhanced disease [9] and humoral immune responses are suppressed by maternal antibody [7]. Moreover, there is a risk for contamination of live vaccines with pathogens, such as bovine viral diarrhea virus (BVDV) [10], [11]. Inactivated vaccines on the other hand, have in a few cases been reported to cause exacerbated disease upon a subsequent BRSV infection [12], [13], [14] and have repeatedly provided unsatisfactory protection against clinical disease in calves with maternal antibodies [13], [15], [16]. Nevertheless, one inactivated vaccine based on glutaraldehyde-fixed bovine nasal cells persistently infected with BRSV and with Quillaja saponin as adjuvant has been reported to reduce clinical disease in the field [17]. Furthermore, this vaccine significantly reduced virus shedding following experimental BRSV challenge, even in calves with high levels of maternal antibodies at the time of vaccination [10], [18].
Because of the difficulties in experimentally reproducing respiratory disease in calves with passively derived antibodies [19], [20], BRSV vaccines are commonly evaluated in seronegative calves [8], [21], [22], [23], [24], [25], [26], [27]. Recently, however, the bovine RSV infection model has been improved. The use of low passage isolates, grown in lung cells from the host species and administered into calves by aerosol, has made it possible to induce severe signs of respiratory disease with low doses of virus even in seropositive calves [28]. Hence, we now have the possibility to evaluate protection induced by BRSV vaccines against severe disease in conventionally reared calves. Since BRSV infections in cattle closely resemble human RSV (HRSV) infections in man, results achieved in experiments on calves with maternal antibodies will also provide information about vaccination strategies against HRSV in children.
In search of a new BRSV vaccine candidate, the bovine model was used to evaluate the efficacy of BRSV immunostimulating complexes (ISCOMs) in calves with maternal antibodies. BRSV envelope proteins were incorporated into spherical particles with inbuilt adjuvant, ISCOMs, and administered to calves subcutaneously. In addition to unimmunized controls, a group of calves immunized with a commercial inactivated vaccine (CV) against BRSV was included in the experiment. In this paper, we show that ISCOMs, in contrast to the CV, provided protection against clinical disease in calves and also significantly reduced virus shedding following BRSV challenge.
Section snippets
Cells
Foetal bovine turbinate (FBT, National Veterinary Institute, Sweden) cells and Foetal Bovine Lung (FBL, Danish Veterinary Laboratory, Denmark) cells at low passages were grown in full Dulbecco's modified Eagle medium (F-DMEM, National Veterinary Institute, Sweden), supplemented with 10 ml 2 mM glutamine, 100 mg kanamycin, and 20 ml gamma-irradiated foetal bovine serum (GibcoBRL, Life Technologies AB, Sweden) per litre (F-DMEM+).
Virus for ISCOMs
A BRSV isolate (Weybridge Hud 5), provided by Dr. M. Merza (Svanova
Clinical signs
No adverse clinical reactions were observed after first or second immunization. Following BRSV challenge, moderate (clinical score ≥4 on 3 days or more) to severe (clinical score ≥10 on 1 day or more) respiratory disease was recorded in all four unvaccinated controls from day 5 (for mean clinical scores, see Fig. 1). Two calves in this group (nos. 20 and 27) that showed pronounced abdominal breathing were, for humane reasons, euthanized on day 6. BRSV infections of these calves were confirmed
Discussion
Since first described by Morein et al. [42], a multitude of studies on ISCOMs have highlighted their ability to induce strong and durable immune responses to a variety of pathogens [43], [44]. ISCOMs incorporating BRSV have elicited neutralizing responses in guinea pig, equivalent to those of a live vaccine [45]. In view of the fact that BRSV disease often occurs in young animals [5] and that immunization is likely to be carried out in herds where the virus is circulating [9], the present
Acknowledgements
This work was funded by the European Union ‘Neovac’ Consortium, The Swedish farmers foundation (grant 343/02) and the National Veterinary Institute, Sweden (grant 60223). We wish to thank Mrs. M. Hjort, Mr. I. Larsen, and Mrs. S. Wyld for performing ELISA assays and Mr. B. Norén with staff for rearing and maintenance of experimental animals. Dr. K. Tjornehoj and Dr. U. Power are thanked for generous advices and ideas regarding the experimental BRSV challenge, Dr. P. Öhagen for help with
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