Veterinary Biologics Guideline 3.23E
Guidelines for Licensing Veterinary Nucleic Acid Vaccines

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A. Introduction

The primary requirements for licensing nucleic acid vaccines are similar to any other veterinary vaccines in that they both require the fulfilment of four criteria - purity, potency, safety and efficacy. Nucleic acid vaccines, like other biotechnology derived vaccines, will be evaluated on a case-by-case basis. Evaluation of vaccine master seeds is an essential first step for fulfilling these requirements.

B. Master Seeds

The master seeds used for the preparation of veterinary biologics must be demonstrated to be pure, safe and immunogenic. For nucleic acid vaccines, master seeds can be defined as a clone of cells produced from a single prokaryotic cell containing the desired plasmid construct. The manufacturers are required to provide information on the sources and identity, methods of propagation, and molecular and biological characteristics of the master seed. The identity of the master seed can be determined by microbiological, biochemical and immunological methods. The molecular information required may include sequence information on the inserted genes and flanking regions, and restriction maps of regulatory elements including genetic markers. Information on the plasmid copy number per bacterial cell may also be required. The biological characteristics of the master seed may include information on growth characteristics, environmental distribution, genetic stability, phenotypic stability and data on animal pathogenicity. All master seeds must be shown to be free from extraneous agents and be stable beyond the number of passages used for vaccine production.

C. Purity, Potency And Efficacy

In the purity assessment of nucleic acid vaccines, both biochemical and microbiological purity should be considered. The final purified plasmid product may contain low levels of microbial by products such as protein, chromosomal DNA and endotoxin; and residual material from processing and purification steps. While it is desirable to reduce such contaminants as much as practically possible, the level of biochemical purity for the vaccine is likely to be determined by safety considerations related to the species and the intended use of the product. Microbiological purity is determined by tests for contaminating bacteria and fungi in the finished product.

Both in vivo (measurement of immunological responses or protection following animal inoculation) and in vitro methods (e.g. detection of the expressed gene product following transfection of mammalian cells) can contribute for potency evaluation of nucleic acid vaccines. The potency test should correlate to the immunogenicity/efficacy of the vaccine.

In common with other veterinary vaccines, a vaccination-challenge study conducted in target animals is the standard requirement for nucleic acid vaccine efficacy assessment. Efficacy studies measure the specific protective capacity of the vaccine when used in the final formulation. Label recommendations for use of the product are based on the results of the efficacy study. Manufacturers are encouraged to submit efficacy trial protocols to the Canadian Food Inspection Agency (CFIA) prior to initiating efficacy studies to generate data for licensure.

D. Safety

Similar to other biotechnology-derived vaccines, a broader definition of safety that includes specific examination of animal, human, and environmental safety will be the standard requirement for the evaluation of nucleic acid vaccines. Target animal safety is evaluated in both laboratory and field safety studies. Local and systemic reactions in animals to vaccination are monitored using predetermined criteria during the conduct of these studies.

For nucleic acid vaccines, integration of injected plasmids into host genome, germline transmission and adverse immunological sequelae such as autoimmunity and immune-tolerance have been suggested as potential safety considerations. It is important that the Canadian Food Inspection Agency assess the risk for each of these considerations in the proper context and formulate test requirements for nucleic acid vaccines.

E. Risk Analysis

The licensing decisions for nucleic acid vaccines, as for other biotechnology derived vaccines, will be based on risk analysis. The essential components of risk analysis are risk assessment, risk management and risk communication. Risk assessment, which is the process of identifying a hazard and characterizing or estimating the risk presented by that hazard, has been traditionally performed using qualitative methods. More recently, quantitative risk assessment has become available and CFIA has started using 'scenario tree analysis' to predict the likelihood of various outcomes and their respective impacts in the development of licensing decisions.

F. Environmental Assessment

In accordance with Canadian legislation, all nucleic acid vaccines like other veterinary biologics licensed in Canada are required to undergo an Environmental Assessment prior to licensing. The Environmental Assessment includes a detailed characterization of the molecular and biological characteristics of the plasmid; documentation of animal, human and environmental safety considerations; qualitative and quantitative risk assessments; risk management options including risk mitigation recommendations and monitoring strategies for the field use of product. The Environmental Assessment document is distributed to stakeholders for comment during the development, and made available to the public when finalized.

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