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VB-GL-3.23: Licensing veterinary nucleic acid vaccines

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1. Introduction

The purpose of this document is to inform veterinary biologics (VB) researchers, manufacturers and Canadian importers of the requirements for veterinary nucleic acid vaccines. The Canadian Centre for Veterinary Biologics (CCVB) of the Canadian Food Inspection Agency (CFIA) is responsible for regulating the manufacturing, testing, importation and use of VB in Canada, including veterinary nucleic acid vaccines.

The primary requirements for licensing nucleic acid vaccines are similar to any other veterinary vaccines in that they both require the fulfilment of 4 criteria - purity, potency, safety and efficacy. Nucleic acid vaccines, like other biotechnology derived vaccines, will be evaluated on a case-by-case basis.

1.1 Legal authority

Health of Animals Act

Health of Animals Regulations, Part XI

2. Master seeds

The master seeds used for the preparation of VB 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 should 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 is required. The biological characteristics of the master seed should 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 genetically and phenotypically stable beyond the number of passages used for vaccine production.

3. 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 very 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 (for example, 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 and efficacy of the vaccine.

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 should submit efficacy trial protocols for review to the CCVB prior to initiating efficacy studies to generate data for licensure.

4. Safety

Similar to other biotechnology-derived vaccines, a broader definition of safety that includes specific examination of animal, human, and environmental safety is the standard requirement for the evaluation of nucleic acid vaccines. Target animal safety is evaluated in both laboratory and field safety studies. Consideration of non-target animal safety may be required depending on the intended use, target species, and environment. 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 CCVB assess the risk for each of these considerations in the proper context and formulate test requirements for nucleic acid vaccines.

5. 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, is performed using qualitative and quantitative methods. The CFIA has started using 'scenario tree analysis' to predict the likelihood of various outcomes and their respective impacts in the development of licensing decisions.

6. Environmental assessment

The environmental assessment (EA) contains information on the molecular and biological characteristics of the biotechnology-derived organism, target animal and non-target animal safety, human safety, environmental considerations and risk mitigation measures. The manufacturer must submit all relevant data to aid the CCVB reviewer in preparing the EA. The CCVB reviewer will also independently research any potential safety issues, and may consult other federal and provincial government departments with expertise in areas of concern. For instance, potential human health and safety risks may be assessed in collaboration with Health Canada and the Public Health Agency of Canada. An EA must be completed before the CCVB will authorize the release of a novel organism into the Canadian environment.

The scheduling of the Health of Animals Act and Health of Animals Regulations under Schedule 4 of the Canadian Environmental Protection Act, 1999 (CEPA 1999) exempts new biotechnology-derived VB regulated by the CCVB from additional notification and assessment under the CEPA 1999. This scheduling is recognition that the EA authorities within the Health of Animals Act and Health of Animals Regulations provide an adequate level of regulatory control. Consequently, the CCVB is fully responsible for the environmental, human health and animal health assessment of a novel VB product.

After the CCVB has completed the draft EA for a biotechnology-derived VB, the manufacturer is provided a copy of the document and given the opportunity to identify any confidential business information. A publicly available bilingual version of the EA, which omits this confidential business information, is subsequently posted on the CFIA website, where it is accessible to the general public.

7. Additional information

Contact the CCVB if you have additional questions or need clarification on regulations and requirements for veterinary nucleic acid vaccines.

Guidelines and forms are available on the CCVB website.

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