Dr. Ryo Harasawa
Faculty of Medicine
University of Tokyo
Bunkyo-ku, Tokyo 113, Japan

Bovine viral diarrhea virus (BVDV) is one of the RNA viruses, which causes a severe disease in cattle. Since BVDV is able to cross the bovine placenta easily, the fetal bovine tissues and serums also become infected with the virus. The rate of contamination in commercial products of fetal bovine serum are reportedly from 10% to 75%. Therefore, it is quite possible for an adventitious BVDV to be present in live virus prepared in cell cultures supplemented with fetal bovine serums. Detection of BVDV contamination in virus vaccines has been hampered because most of the BVDV strains are noncytopathic in cell cultures. BVDV RNA was demonstrated in human live virus vaccines produced in Japan, Italy and Switzerland. BVDV in fetal bovine serum that is used to grow the substrate cells used for the preparation of the virus vaccines is a likely source of the contamination. The present data so not necessarily indicate that the virus vaccines examined were contaminated with infectious BVDV, but any adventitious viral agents in a vaccine is undesirable. Although it has not been established that BVDV infections cause specific symptoms in humans, infantile gatroenteritis associated with excretion of BVDV antigens and microcephaly in infants who were born to mothers seropositive for BVDV have been reported. Serum antibodies against BVDV have been detected in approximately 30% of human population who had no contact with potentially infected animals. Since noncytopathic strains of BVDV are capable of incorporating the host cellular RNA into their genomes, BVDV contamination would raise another issue with regard to the safety of virus vaccines produced in continuous cell lines which are potentially oncogenic. Use of continuous cell lines as cell substrates for the production of human biologicals has been approved by the WHO Study Group. It is important to avoid the risk of contamination of virus vaccines for human use. In conclusion, the fetal bovine serums should be standardized for the production of vaccines, and be examined for the presence of noncytopathic strains of BVDV.

Dr. Ryo Harasawa of the University of Tokyo (Japan), Dr. Massimo Giangaspero of the University of Milan (Italy), and their colleagues in Germany, Belgium and Italy examined for the presence of BVDV in virus vaccines produced in Europe, US, and Japan, by using reverse transcription-PCR. They found six (50%) out of 12 samples were positive for BVDV RNA. Four vaccines (measles, rubella and two influenza) were from Europe and two (mumps and rubella) from Japan. It indicated that the contamination of human biopharmaceutic products with BVDV may occur throughout the world. There is no evidence presented to substantiate contamination of human virus vaccines with infectious BVDV, but they urge people to beware of the risk of infection because iatrogenic infections have been reported for veterinary virus vaccines contaminated with infectious BVDV. They also recommend that the virus vaccines be screened for the presence of adventitious BVDV by sensitive PCR in advance and ‘PCR-positive vaccines’ be further examined for the presence of infectious BVDV by culture methods.