PMID: 

J Vet Med Sci. 1994 Oct ;56(5):961-4. PMID: 7865600

Abstract Title: 

Comparative analysis of the 5' non-coding region of pestivirus RNA detected from live virus vaccines.

Abstract: 

Comparative analysis of nucleotide sequences in the 5' non-coding region (NCR) of pestivirus RNA detected from live porcine and human virus vaccines indicated that the contaminants are of bovine viral diarrhea virus (BVDV), and that there are at least three genotypes, which are distinct from hog cholera virus, among the BVDV strains. Most of the nucleotide changes in variable regions of the 5' NCR were covariant, with complementary substitutions at other positions for secondary structures. The proposed secondary structure in the 5' NCR was similar to the prokaryotic rho independent terminator. Short open reading frames in the 5' NCR were well conserved among pestiviruses.

read more

PMID: 

Vaccine. 1995 Jan ;13(1):100-3. PMID: 7762264

Abstract Title: 

Adventitious pestivirus RNA in live virus vaccines against bovine and swine diseases.

Abstract: 

Live virus vaccines against bovine and porcine diseases were examined for the presence of adventitious pestivirus RNA or pestiviruses by reverse transcription-polymerase chain reaction (PCR). Pestivirus RNA was detected in the live virus vaccines against Akabane disease, Ibaraki disease, infectious bovine rhinotracheitis, porcine parvovirus infection, transmissible gastroenteritis and Japanese encephalitis. Pestivirus RNA or pestivirus in the fetal bovine serum used to grow the host cells used to prepare the bovine and swine viral vaccines is a likely source of the contamination. Nucleotide sequence analysis of the PCR products suggests that modified live virus vaccines being used for immunization of cattle against bovine viral diarrhoea was not responsible for the contamination of the vaccines examined.

read more

PMID: 

Microbiol Immunol. 1995 ;39(12):979-85. PMID: 8789057

Abstract Title: 

Demonstration and genotyping of pestivirus RNA from mammalian cell lines.

Abstract: 

We examined 20 cell lines of various animal origins for the presence of pestivirus contamination by the reverse transcription-polymerase chain reaction (RT-PCR), and found 15 (75%) cell lines were positive. The RT-PCR products of the 5' untranslated region (UTR) of pestivirus genome were sequenced and subjected to genotyping. Stem-loop structures at three variable regions in the 5' UTR render genotyping of the contaminated pestiviruses. Bovine cell lines tested were all contaminated with genotypes I, II, or III of bovine diarrhea virus (BVDV). Cell lines of canine, feline, and primate origin were contaminated with genotype II of BVDV. Cell line Ch1Es of caprine origin was contaminated with border disease virus (BDV).

read more

PMID: 

Vet Ital. 2004 Jan-Mar;40(1):7-21. PMID: 20437384

Abstract Title: 

Genotypes of Pestivirus RNA detected in anti-influenza virus vaccines for human use.

Abstract: 

Nine polyvalent human influenza virus vaccines were tested by reverse transcriptase-polymerase chain reaction (RT-PCR) for the presence of pestivirus RNA. Samples were selected from manufacturers in Europe and the USA. Three samples of the nine vaccines tested (33.3%) gave positive results for pestivirus RNA. The 5'-untranslated genomic region sequence of the contaminant pestivirus RNA was analysed based on primary nucleotide sequence homology and on secondary sequence structures characteristic to genotypes. Two sequences belonged to Pestivirus type-1 (bovine viral diarrhoea virus [BVDV]) species, genotypes BVDV-1b and BVDV-1e. These findings confirm previous reports, suggesting an improvement in preventive measures against contamination of biological products for human use.

read more

PMID: 

Mol Cell Probes. 2008 Jun ;22(3):212-4. Epub 2008 Feb 16. PMID: 18395415

Abstract Title: 

Simple procedures to obtain exogenous internal controls for use in RT-PCR detection of bovine pestiviruses.

Abstract: 

Pestiviruses are ubiquitous pathogens of cattle and frequent adventitious viruses in biologicals. Furthermore, it has been suggested that these agents might be related to infantile gastroenteritis and microencephaly. Since the virus is highly prevalent in fetal bovine serum, the risk of contamination is high in most laboratories. Thus, the implementation of detection methods in all laboratories is of worth. Despite continuous surveillance, these agents have been detected in cell lines, fetal bovine serum, live and inactivated animal and human vaccines and interferon for human use. In this report, DNA and RNA internal controls (ICs) which can be implemented in laboratories with minimal equipment are described. The developed standards can be added before RNA purification, allowing to monitor all steps of the protocol (viral RNA extraction, reverse transcription and cDNA amplification). It is shown that inhibitory effects that could lead to decreased sensitivity can be minimized by controlling the amount of mimic molecules added to the samples. A method to avoid the problem of DNA traces present in in vitro transcribed RNA preparations is provided.

read more

PMID: 

Biologicals. 2000 Mar ;28(1):41-6. PMID: 10799055

Abstract Title: 

Evaluation of vaccines, interferons and cell substrates for pestivirus contamination.

Abstract: 

Pestiviruses are potential contaminants of biological products produced in bovine or porcine cells or manufactured via processes using animal-derived raw materials such as bovine serum. In order to investigate possible contamination of products including those manufactured and/or licensed in the US, 38 lots of viral vaccines and five lots of interferon alpha (IFNalpha) were tested by reverse transcriptase polymerase chain reaction (RT-PCR) for the presence of bovine viral diarrhoea virus (BVDV). All vaccines and interferons were negative for contaminating BVDV RNA when tested by RT-PCR, with the exception of an experimental live viral vaccine that had been produced in BVDV contaminated rabbit kidney cells. Cell lines commonly used to produce biological products and vaccines were experimentally infected with the NADL strain of BVDV to determine if they were permissive for virus replication. MRC-5 and WI-38 cells were not infected. In contrast, Vero, CHO and CEF cells showed evidence of pestivirus infection. Taken together these data suggested that currently licensed viral vaccines were unlikely to be contaminated with pestiviruses. However, cell banks derived from non-human primate, hamster or rabbit kidney cell lines, or cultures of primary chick embryo fibroblasts, may be infected with BVDV if exposed to pestivirus contaminated raw materials during manufacture.

read more

PMID: 

Biologicals. 2010 May ;38(3):332-4. Epub 2010 Apr 24. PMID: 20456974

Abstract Title: 

Human and animal vaccine contaminations.

Abstract: 

Vaccination is one of the most important public health accomplishments. However, since vaccine preparation involves the use of materials of biological origin, vaccines are subject to contamination by micro-organisms. In fact, vaccine contamination has occurred; a historical example of vaccine contamination, for example, can be found in the early days of development of the smallpox vaccine. The introduction of new techniques of vaccine virus production on cell cultures has lead to safer vaccines, but has not completely removed the risk of virus contamination. There are several examples of vaccine contamination, for example, contamination of human vaccines against poliomyelitis by SV40 virus from the use of monkey primary renal cells. Several veterinary vaccines have been contaminated by pestiviruses from foetal calf serum. These incidents have lead industry to change certain practices and regulatory authorities to develop more stringent and detailed requirements. But the increasing number of target species for vaccines, the diversity of the origin of biological materials and the extremely high number of known and unknown viruses and their constant evolution represent a challenge to vaccine producers and regulatory authorities.

read more

PMID: 

N Engl J Med. 2011 Jun 2 ;364(22):2101-10. PMID: 21631322

Abstract Title: 

Early-childhood membranous nephropathy due to cationic bovine serum albumin.

Abstract: 

BACKGROUND: The M-type phospholipase A(2) receptor (PLA(2)R) was recently identified as a candidate antigen in 70% of cases of idiopathic membranous nephropathy, a common form of the nephrotic syndrome. The nature of antigens involved in other idiopathic and secondary membranous nephropathies remains unclear.METHODS: We searched for antibodies against bovine serum albumin and circulating bovine serum albumin by means of enzyme-linked immunosorbent assay and Western blotting in serum specimens obtained from 50 patients with membranous nephropathy and 172 controls. The properties of immunopurified circulating bovine serum albumin obtained from serum specimens were analyzed with the use of two-dimensional sodium dodecyl sulfate-polyacrylamide-gel electrophoresis. We detected bovine serum albumin in glomerular deposits and analyzed the reactivity of eluted IgG.RESULTS: Eleven patients, including four children, had high levels of circulating anti-bovine serum albumin antibodies, of both the IgG1 and IgG4 subclasses. These patients also had elevated levels of circulating bovine serum albumin, without an increase in circulating immune complex levels. Bovine serum albumin immunopurified from the serum specimens of these four children migrated in the basic range of pH, whereas the bovine serum albumin from adult patients migrated in neutral regions as native bovine serum albumin. Bovine serum albumin was detected in subepithelial immune deposits only in the children with both high levels of cationic circulating bovine serum albumin and bovine serum albumin-specific antibodies, and it colocalized with IgG in the absence of PLA(2)R. IgG eluted from such deposits was specific for bovine serum albumin.CONCLUSIONS: Some patients with childhood membranous nephropathy have both circulating cationic bovine serum albumin and anti-bovine serum albumin antibodies. Bovine serum albumin is present in immune deposits, suggesting that cationic bovine serum albumin is pathogenic through binding to the anionic glomerular capillary wall and in situ formation of immune complexes, as shown in experimental models.

read more

PMID: 

Vaccine. 2016 12 12 ;34(51):6617-6625. Epub 2016 Jun 15. PMID: 27317264

Abstract Title: 

Adventitious agents and live viral vectored vaccines: Considerations for archiving samples of biological materials for retrospective analysis.

Abstract: 

Vaccines are one of the most effective public health medicinal products with an excellent safety record. As vaccines are produced using biological materials, there is a need to safeguard against potential contamination with adventitious agents. Adventitious agents could be inadvertently introduced into a vaccine through starting materials used for production. Therefore, extensive testing has been recommended at specific stages of vaccine manufacture to demonstrate the absence of adventitious agents. Additionally, the incorporation of viral clearance steps in the manufacturing process can aid in reducing the risk of adventitious agent contamination. However, for live viral vaccines, aside from possible purification of the virus or vector, extensive adventitious agent clearance may not be feasible. In the event that an adventitious agent is detected in a vaccine, it is important to determine its origin, evaluate its potential for human infection and pathology, and discern which batches of vaccine may have been affected in order to take risk mitigation action. To achieve this, it is necessary to have archived samples of the vaccine and ancillary components, ideally from developmental through to current batches, as well as samples of the biological materials used in the manufacture of the vaccine, since these are the most likely sources of an adventitious agent. The need for formal guidance on such vaccine sample archiving has been recognized but not fulfilled. We summarize in this paper several prior major cases of vaccine contamination with adventitious agents and provide points for consideration on sample archiving of live recombinant viral vector vaccines for use in humans.

read more

PMID: 

Vaccine. 2017 03 13 ;35(11):1494-1500. Epub 2017 Feb 16. PMID: 28216185

Abstract Title: 

Sensitization to bovine serum albumin as a possible cause of allergic reactions to vaccines.

Abstract: 

BACKGROUND: Immediate type hypersensitivity to vaccines containing bovine/porcine excipients, such as the measles, mumps and rubella (MMR) vaccine is probably due to sensitization to bovine/porcine gelatin. Most patients with such reactions in Sri Lanka have cow's milk (CM) or beef allergy.OBJECTIVES: We investigated whether those who had beef and CM allergy had a higher incidence of hypersensitivity reactions to vaccines and the possible trigger of such reactions.MATERIAL AND METHODS: Twenty patients with immediate type hypersensitivity reactions to vaccines containing bovine/porcine excipients, controls with allergy to beef/pork (n=11) or CM (n=11), and 8 non atopic controls were recruited. Total serum IgE, specific IgE to beef, CM, casein, beta lactoglobulin, gelatin and bovine serum albumin (BSA) by Phadia ImmunoCap and IgE to porcine gelatin by Western blot were evaluated.RESULTS: 11/20, 5/20, 2/20, 2/20, 1/20 and 1/20 patients reported allergic reactions to measles containing, JE, rabies primary chick embryo, pentavalent, diphtheria and tetanus, and adult diphtheria and tetanus vaccines, respectively. Only one patient with allergy to vaccines had gelatin specific IgE, whereas IgE to BSA was seen in 73.3%, 90%, 66.6% and 0 of vaccine, beef or CM allergic and non-atopic controls, respectively. The mean IgE to BSA was higher in patients with allergy to vaccines, although not significant. Specific IgE to BSA was present in 54.7% of children with allergy to CM, of whom 11.8% had high levels (>17.5kUA/L). In contrast, 66.6% of these children did not have specific IgE toβ-lactoglobulin, which is one of the major components of whey protein.CONCLUSION AND CLINICAL RELEVANCE: Gelatin does not appear to play a major role in Sri Lankan children with allergy to vaccines. In contrast, due to the higher levels of BSA specific IgE, sensitization to BSA is possibly playing a role.

read more