Ernst Peterhans

The first records of smallpox and rabies date back thousands of years and foot-and-mouth disease in cattle was described in the 16^th century. These diseases stood out by their distinct signs, dramatic way of transmission from rabid dogs to humans, and sudden appearance in cattle herds. By contrast, infectious diseases that show variable signs and affect few individuals were identified only much later. Bovine viral diarrhea (BVD), endemic in cattle worldwide, was first described in 1946, together with the eponymous RNA virus as its cause. There is general agreement that BVD was not newly emerging at that time, but its history remains unknown. A search for associations between the nucleotide sequences of over 7,000 BVD viral strains obtained during a national campaign to eradicate BVD and features common to the hosts of these strains enabled us to trace back in time the presence of BVD in the Swiss cattle population. We found that animals of the two major traditional cattle breeds, Fleckvieh and Swiss Brown, were infected with strains of only four different subgenotypes of BVDV-1. The history of these cattle breeds and the events that determined the current distribution of the two populations are well documented. Specifically, Fleckvieh originates from the Bernese and Swiss Brown from the central Alps. The spread to their current geographic distribution was determined by historic events during a major expansion of the Swiss Confederation during the 15^th and 16^th centuries. The association of the two cattle populations with different BVD viral subgenotypes may have been preserved by a lack of cattle imports, trade barriers within the country, and unique virus-host interactions. The congruent traces of history in the distribution of the two cattle breeds and distinct viral subgenotypes suggests that BVD may have been endemic in Switzerland for at least 600 years.

Bovine viral diarrhea virus (BVDV) is endemic worldwide. Together with classical swine fever and border disease viruses, it belongs to the genus Pestivirus of the family Flaviviridae. Most infections with BVDV take a transient, acute, course. Only rarely BVDV persists in its hosts. Due to the early time point of infection in utero, persistently infected (PI) animals are immunotolerant to the infecting non-cytopathic BVDV. In such animals the virus may mutate to a cytopathic biotype, causing lethal mucosal disease. In BVD-endemic regions, approximately 1% of the animals are PI. Removal of all PI animals leads to extinction of BVD. This approach to BVD eradication has been vindicated in Scandinavia. Following the same principles, regional and country-wide eradication programs are run in different parts of the world. These programs differ in the way PI animals are detected and in the role of vaccines. The Scandinavian two-step method of detecting PI animals is based on (i) the high level of seroprevalence in herds where PI animals are present and (ii) on testing all animals for virus in such herds. However, the high average herd seroprevalence in Switzerland made it impossible to define a reasonable threshold for virus testing. Therefore, all animals were directly tested for virus in the year 2008 and all newborn calves until the end of 2012, when the PI prevalence had dropped to 0.02%. Vaccination remains prohibited. Since 2013, surveillance for BVD is accomplished by serology. As a unique consequence of eradication, over 7500 viral strains are available to us for genetic studies.

Pestiviruses cause economically important diseases among domestic ruminants and pigs, but they may also infect a wide spectrum of wild species of even-toed ungulates (Artiodactyla). Bovine viral diarrhea virus (BVDV) and Border disease virus of sheep infect their hosts either transiently or persistently. Cellular and humoral immunotolerance to the infecting strain is a unique feature of persistent infection (PI) by ruminant pestiviruses. Persistence, caused by transplacental infection early in fetal development, depends on virally encoded interferon antagonists that inactivate the host’s innate immune response to the virus without globally interfering with its function against other viruses. At epidemiological equilibrium, approximately 1–2% of animals are PI. Successful BVDV control programs show that removal of PI animals results in viral extinction in the host population. The nucleotide sequences of ruminant pestiviruses change little during persistent infection. Nevertheless, they display large heterogeneity, pointing to a long history of virus-host coevolution in which avirulent strains are more successful.

Detection of antibodies against Bovine viral diarrhea virus (BVDV) in serum and milk by enzyme-linked immunosorbent assay (ELISA) is a crucial part of all ongoing national schemes to eradicate this important cattle pathogen. Serum and milk are regarded as equally suited for antibody measurement. However, when retesting a seropositive cow 1 day after calving, the serum was negative in 6 out of 9 different ELISAs. To further investigate this diagnostic gap around parturition, pre- and postcalving serum and milk samples of 5 cows were analyzed by BVDV antibody ELISA and serum neutralization test (SNT). By ELISA, 3 out of the 5 animals showed a diagnostic gap in the serum for up to 12 days around calving but all animals remained positive in SNT. In milk, the ELISA was strongly positive after birth but antibody levels decreased considerably within the next few days. Because of the immunoglobulin G (IgG)1-specific transport of serum antibodies into the mammary gland for colostrum production, the IgG subclass specificity of the total and the BVDV-specific antibodies were determined. Although all 5 animals showed a clear decrease in the total and BVDV-specific IgG1 antibody levels at parturition, the precalving IgG1-to-IgG2 ratios of the BVDV-specific antibodies were considerably lower in animals that showed the diagnostic gap. Results showed that BVDV seropositive cows may become “false” negative in several ELISAs in the periparturient period and suggest that the occurrence of this diagnostic gap is influenced by the BVDV-specific IgG subclass response of the individual animal.