Thursday, May 6, 2010

Epizootic hemorrhagic disease virus: a future troublemaker?

Epizootic hemorrhagic disease virus (EHDV) is a double-stranded RNA virus of family Reoviridae, genus Orbivirus. This is a non-enveloped virus of approximately 60-80 nm size. This arbovirus is transmitted by a biting midge of genus Culicoides, and is closely related to another Orbivirus, the bluetongue virus. Two serotypes are endemic to cattle in North America (EHDV-1 and EHDV-2); the infections caused tend to be subclinical (asymptomatic) and therefore may go undetected.

Infections in cattle are more prevalent in areas of widespread infection within the local deer population. As shown in the figure below, the geographic distribution of infection of deer populations with EHDV and bluetongue virus includes areas within the high plains and mountain states in which bovine serum production is high (Utah, Kansas, etc.).

From Daniel Mead, Risk of Introduction of New Vector-borne Zoonoses

There have been recent outbreaks of epizootic hemorrhagic disease in cattle in Indiana (2006) as well as other states; in Israel (2006); and in Turkey (2007).

Basis of Concern: EHDV has been isolated previously from a biologics manufacturing process employing a Chinese hamster ovary (CHO) cell substrate (Rabenau et al. Contamination of genetically engineered CHO-cells by epizootic haemorrhagic disease virus (EHDV). Biologicals 21, 207-214, 1993). The infection was presumed, but not proven, to originate from use of a contaminated bovine serum in the manufacturing process.

Regulatory Expectations. EHDV is not mentioned specifically in 9CFR 113.47 (Detection of extraneous viruses by the fluorescent antibody technique as a virus of concern for raw materials of bovine origin), although this regulation requires testing for the closely related bluetongue virus. EHDV would be expected to cause cytopathic effects in Vero cells, one of the detector cells used in the 9CFR 113.47 assay, therefore this assay should detect the virus in grossly contaminated bovine sera.

Mitigating Risk. Elimination of animal-derived materials (esp. bovine sera) from the manufacturing process should reduce the risk of experiencing this virus. If this is not possible, treatment of the sera should be considered. Gamma-irradiation of the frozen serum at the dosages normally used should be effective, judging from results obtained with REO virus, another member of the family Reoviridae (Gauvin, 2009).

Conclusions. EHDV has been found previously to contaminate a biologics manufacturing process employing a CHO-cell substrate. It is therefore a virus of concern for the biopharmaceutical industry. Risk of infection of biological products with EHDV through use of bovine-derived materials such as bovine sera may increase in the event of future outbreaks of this disease in cattle from serum-producing regions of North America or Australia. Risk may be mitigated through implementation of gamma-irradiation of bovine sera and of viral purification processes capable of removing and inactivating non-enveloped viruses such as MMV and REO.

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