(2002; 166 pages)
Regulatory aspects of nucleic acid vaccines
Dr Johannes Löwer, Germany
DNA vaccines are considered to be gene transfer products. Gene transfer medicinal products usually consist of genetically modified autologous, allogeneic or xenogeneic cells, or products targeted at genetically modifying human somatic cells, and which are used for the treatment, diagnosis or prevention of disease in humans or animals.
DNA vaccines are more similar to attenuated vaccines than to simple antigens. The antigens encoded by the DNA are expressed inside the body and this is advantageous to the mounting of an appropriate immune response. With DNA vaccines, the antigenicity of expressed viral antigens is similar to that observed during natural infection, and it is possible to express multiple combined antigens in the sense that several antigen genes can be combined on the same piece of DNA.
Possible applications of DNA vaccines include products to deal with viral, bacterial and parasitic diseases. Naked DNA alone is not very effective, but DNA immunization followed by boosting is better. DNA vaccines provide several benefits but they also may have disadvantages, e.g. the synthesis of antigen is considered to be relatively easy,and transport and storage simple; there is no risk of infection but there is a risk of inducing tolerance; they induce cellular and humoral immune responses but there is a risk of inducing autoimmune disease.
One difficulty in the preclinical studies was the move from laboratory rodents to human beings. DNA vaccination worked very well in mice but in humans a large amount of DNA is needed to obtain a reasonavble response. As DNA alone is not so effective in humans, it can be combined with an immunostimulating agent such as a cytokine, or with a vector carrying the gene for such a cytokine. A number of clinical trials are currently under way to study the immune response to various infective agents, e.g., the malaria parasite and influenza virus.
The special safety considerations associated with DNA vaccines which need to be addressed include the possible induction of tumours or tolerance and adverse reactions and immunopathology due to the coadministration of cytokine and/or immuno-stimulatory genes. Other concerns include the appearance of systemic lupus erythematosus due to the rise in anti-DNA antibodies, and possible adverse reactions due to the biological activity of the expressed antigen itself.
Tumour induction might result from chromosomal integration. Integration could occur in various tissues and vary with formulation, sequence, route of administration, type of tissue, and quality of the DNA. The question is what tests are needed to look for chromosome integration and what might be the regulatory requirement?
The European regulations and guidelines in “Notes for Guidance on the Quality, Pre-clinical and Clinical Aspects of Gene Transfer Medicinal Products” provide useful information. There are provisions on quality and safety evaluations, toxicity studies, and biological monitoring.
Scientific advice on gene transfer medicinal products is sought according to the EMEA centralized evaluation procedures. Expert authorities and central ethics committees in various member states are being consulted. Furthermore, regulations related to the initiation of clinical gene therapy/DNA vaccine trials in Europe will be implemented in 2003.