Biological Product Safety: Development Of Sensitive Assays for Detection of Latent Viruses in Vaccine Cell Substrates and Risk Assessment of Human Infection with Agents of Potential Concern in Biologics

Principal Investigator: Arifa S. Khan, PhD
Office / Division / Lab: OVRR / DVP / LR

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Overview

Public Health Issue: Biological products for human use must be demonstrated to be free of infectious virus. Retroviruses and some DNA viruses are a major safety concern since they can persist in host cell DNA in a latent state and thereby escape detection by standard assays used for evaluating the safety of cell substrates used in product manufacture. Activation of latent virus in the cell substrate may occur during preparation of the vaccine virus seed or during vaccine manufacture, thereby contaminating the final product. Additional sources of potential virus contamination of biological products may be the donor species, the passage history of the cell substrate or the biological raw materials used in manufacture, e.g. animal or human serum and animal trypsin. Therefore, to assure product safety, it is critical to demonstrate the absence of viruses by extensive testing at various stages of production, especially the starting cell substrate. The risk of contaminating viruses in biologics is a special safety concern in the case of live viral vaccines, gene therapy vectors and transfused whole blood, where there are no virus inactivation or removal steps that can eliminate known or unknown infectious agents.

Regulatory Contribution: Development of new products have necessitated the use of novel cell substrates and vectors. Development and standardization of sensitive assays for detection of known and novel viruses will help demonstrate the safety of novel cell substrates and facilitate safe product use. Determining the risk of human infection with viruses of concern in biological products will enhance public confidence in product safety.

Research Approach: This research program develops sensitive assays for detection of exogenously acquired and latent viruses in vaccine cell substrates including assay standardization and establishment of relevant controls for virus activation/induction studies. Additionally, the program investigates the risk of human infection with retroviruses that are a potential safety concern in biological products including vaccines, therapeutics and blood.

Mission Relevance & Outcomes: The use of sensitive assays for demonstrating absence of adventitious viruses in biologics enhances confidence in product safety, which is a major goal of CBER/FDA. Investigation and evaluation of the risk of human infection by viruses of potential concern in biological products provides a scientific basis for formulating testing recommendations and development of regulatory policy.

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Publications

Transfusion 2006 Aug;46(8):1352-9
Simian foamy virus infection by whole-blood transfer in rhesus macaques: potential for transfusion transmission in humans.
Khan AS, Kumar D