Vaccination consists of stimulating the immune system with an infectious agent, or components of an infectious agent, modified in such a manner that no harm or disease is caused, but ensuring that when the host is confronted with that infectious agent, the immune system can adequately neutralize it before it causes any ill effect. For over a hundred years vaccination has been effected by one of two approaches: either introducing specific antigens against which the immune system reacts directly; or introducing live attenuated infectious agents that replicate within the host without causing disease synthesize the antigens that subsequently prime the immune system.
Recently, a radically new approach to vaccination has been developed. It involves the direct introduction into appropriate tissues of a plasmid containing the DNA sequence encoding the antigen(s) against which an immune response is sought, and relies on the in situ production of the target antigen. This approach offers a number of potential advantages over traditional approaches, including the stimulation of both B- and T-cell responses, improved vaccine stability, the absence of any infectious agent and the relative ease of large-scale manufacture. As proof of the principle of DNA vaccination, immune responses in animals have been obtained using genes from a variety of infectious agents, including influenza virus, hepatitis B virus, human immunodeficiency virus, rabies virus, lymphocytic chorio-meningitis virus, malarial parasites and mycoplasmas. In some cases, protection from disease in animals has also been obtained. However, the value and advantages of DNA vaccines must be assessed on a case-by-case basis and their applicability will depend on the nature of the agent being immunized against, the nature of the antigen and the type of immune response required for protection.
The field of DNA vaccination is developing rapidly. Vaccines currently being developed use not only DNA, but also include adjuncts that assist DNA to enter cells, target it towards specific cells, or that may act as adjuvants in stimulating or directing the immune response. Ultimately, the distinction between a sophisticated DNA vaccine and a simple viral vector may not be clear. Many aspects of the immune response generated by DNA vaccines are not understood. However, this has not impeded significant progress towards the use of this type of vaccine in humans, and clinical trials have begun.
The first such vaccines licensed for marketing are likely to use plasmid DNA derived from bacterial cells. In future, others may use RNA or may use complexes of nucleic acid molecules and other entities. These guidelines address the production and control of vaccines based on plasmid DNA intended for use in humans. The purpose of these guidelines is to indicate:
- appropriate methods for the production and control of plasmid DNA vaccines; and
- specific information that should be included in submissions by manufacturers to national control authorities in support of applications for the authorization of clinical trials and marketing.
It is recognized that the development and application of nucleic acid vaccines are evolving rapidly. Thus, their control should be approached in a flexible manner so that it can be modified as experience is gained in production and use. The intention of these guidelines is to provide a scientifically sound basis for the production and control of DNA vaccines intended for use in humans, and to assure their consistent ssafety and efficacy. Individual countries may wish to use these guidelines to develop their own national guidelines for DNA vaccines.