Abstract
Bovine neonatal pancytopenia (BNP) was a vaccine-induced alloimmune disease observed in young calves and characterized by hemorrhages, pancytopenia, and severe destruction of the hematopoietic tissues. BNP was induced by alloreactive maternal antibodies present in the colostrum of certain cows vaccinated with a highly adjuvanted vaccine against bovine viral diarrhea. Bioprocess impurities, originating from the production cell line of the vaccine, are likely to have induced these alloreactive antibodies. One prominent alloantigen recognized by vaccine-induced alloantibodies is highly polymorphic bovine major histocompatibility complex class I antigen (bovine leukocyte antigen 1—BoLA I). Aim of this study was to define the fine specificity of BNP-associated anti-BoLA I alloantibodies. In total, eight different BoLA I alleles from the production cell line were identified. All genes were cloned and recombinantly expressed in murine cell lines. Using these cells in a flow cytometric assay, the presence of BoLA I specific alloantibodies in BNP dam sera was proven. Three BoLA I variants were identified that accounted for the majority of vaccine-induced BoLA I reactivity. By comparing the sequence of immunogenic to non-immunogenic BoLA I variants probable minimal epitopes on BoLA I were identified. In general, dams of BNP calves displayed high levels of BoLA I reactive alloantibodies, while vaccinated cows delivering healthy calves had significantly lower alloantibody titers. We identified a subgroup of vaccinated cows with healthy calves displaying very high alloantibody titers. Between these cows and BNP dams no principle difference in the BoLA I reactivity pattern was observed. However, with a limited set of dam-calf pairs it could be demonstrated that serum from these cows did not bind to BoLA I expressing leukocytes of their offspring. By contrast, when testing cells from surviving BNP calves with the corresponding dam’s serum there was significant binding. We therefore conclude that predominantly highly alloreactive cows are at risk to induce BNP and it depends on the paternally inherited BoLA I whether or not the calf develops BNP.
Highlights
Bovine neonatal pancytopenia (BNP) was a hemorrhagic disease in young cattle that emerged in most EU states in 2007 [1,2,3,4,5] and later in New Zealand [6]
A comprehensive panel of 969 serum samples that had been collected over the course of 3 years by Mark Holsteg was analyzed for alloreactive binding to the BK cell line that had been used for the production of PregSure®bovine viral diarrhea (BVD) using a previously described flow cytometric assay [13]
The induction of opsonizing alloantibodies was unique for this anti-BVDV-vaccine [1], which led to a voluntary sale stop in 2010 [17] and the withdrawal of the marketing authorization by the manufacturer
Summary
Bovine neonatal pancytopenia (BNP) was a hemorrhagic disease in young cattle that emerged in most EU states in 2007 [1,2,3,4,5] and later in New Zealand [6]. The condition was characterized by an increased susceptibility to bleeding from various body parts in young calves and a high-mortality rate. Epidemiological data and experimental studies revealed that the dams that gave birth to calves affected by BNP were immunized with PregSure®BVD, a highly adjuvanted vaccine against bovine viral diarrhea (BVD) [4, 8]. Several publications thereafter showed that bioprocess impurities in the vaccine, originating from the cell line used for viral propagation and vaccine production induced these alloreactive antibodies in the vaccinated cattle [1, 9]. BNP-associated alloantibodies target highly polymorphic major histocompatibility complex class I antigen (MHC-I) (bovine leukocyte antigen 1—BoLA I) [10, 11]
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