Application of Risk Assessments in the Design of the Overall Viral Control Strategy Used during the Manufacture and Testing of Live Virus Vaccines.

CONFERENCE PROCEEDING Proceedings of the PDA/FDA Adventitious Viruses in Biologics: Detection and Mitigation Strategies Workshop in Bethesda, MD, USA; December 1-3, 2010 Guest Editors: Arifa Khan (Bethesda, MD), Patricia Hughes (Bethesda, MD) and Michael Wiebe (San Francisco, CA) It is important to include a risk assessment process in the overall viral control strategy used during the manufacture and testing of live virus vaccines. Because the product is itself a virus, traditional viral clearance steps are generally not included in the manufacturing process, and there is normally no inactivation step in the manufacturing process either. The risk assessment is therefore necessary to identify potential sources for entry of adventitious agents into the vaccine, and to develop a strategy to minimize or eliminate the sources through which adventitious agents can enter the vaccine. The risk assessment can also be used to tailor the biosafety testing that is performed on raw materials, vaccine seeds, vaccine bulk materials, and final product. Biosafety testing is normally designed to ensure the detection of both known and unknown adventitious agents, but the results of the risk assessment can be used to put in place a biosafety testing strategy designed to maximize the detection of an adventitious agent that is potentially likely to be present in the vaccine. The risk assessment therefore enables the development of a comprehensive viral control strategy and provides a higher level of assurance that the vaccine will be free from contamination by adventitious agents.

Evaluation of attenuation, immunogenicity and efficacy of a bovine parainfluenza virus type 3 (PIV-3) vaccine and a recombinant chimeric bovine/human PIV-3 vaccine vector in rhesus monkeys.

Restricted replication in the respiratory tract of rhesus monkeys is an intrinsic property of bovine parainfluenza virus type 3 (bPIV-3) strains. This host range phenotype of bPIV-3 has been utilized as a marker to evaluate the attenuation of bPIV-3 vaccines for human use. Two safety, immunogenicity and efficacy studies in primates evaluated and compared three human parainfluenza virus type 3 (hPIV-3) vaccine candidates: biologically derived bPIV-3, a plasmid-derived bPIV-3 (r-bPIV-3) and a chimeric bovine/human PIV-3 (b/hPIV-3). These studies also examined the feasibility of substituting Vero cells, cultured in the presence or absence of foetal bovine serum, for foetal rhesus lung-2 (FRhL-2) cells as the tissue culture substrate for the production of bPIV-3 vaccine. The results demonstrated that (i) Vero cell-produced bPIV-3 was as attenuated, immunogenic and efficacious as bPIV-3 vaccine grown in FRhL-2 cells, (ii) plasmid-derived bPIV-3 was as attenuated, immunogenic and efficacious as the biologically derived bPIV-3 and (iii) the b/hPIV-3 chimera displayed an intermediate attenuation phenotype and protected animals completely from hPIV-3 challenge. These results support the use of bPIV-3 vaccines propagated in Vero cells in human clinical trials and the use of b/hPIV-3 as a virus vaccine vector to express foreign viral antigens.