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By Sean Henahan, Access Excellence

LONDON- An experimental DNA plasmid vaccine appears to overcome some of the limitations of current vaccines by offering protection against a wide variety of strains, report researchers.

The influenza virus provides a moving target to current vaccine products, as it constantly changes and evolves to avoid the human antibody and cell-based defensive systems. Since current killed-virus vaccines are typically made from the three most common strains of flu from the previous year's victims, public health authorities are always playing a game of catch-up.

In a series of animal experiments, immunization with a DNA vaccine designed to induce antibodies against influenza antigens provided both homologous and cross-strain protection against various strains of human influenza, reported Dr. Margaret A. Liu, Departments of Virus and Cell Biology, Merck Research Laboratories, West Point, Pennsylvania.

DNA-based vaccines incorporate DNA coding for virus proteins, in a plasmid (small autonomous DNA sequences that are easily manipulated in the laboratory). The plasmid vaccine is introduced into the host where it produces the viral proteins (in the absence of intact virus) to which the host immune system raises an antibody and cell-based defense, thus priming the host for a subsequent attack. The experimental DNA influenza virus vaccine is based on sequences that do not readily mutate each season.

The researchers used the ferret influenza challenge model, since the antibody responses of ferrets to influenza infection parallel those of humans in their ability to distinguish between antigenic variants, noted Dr. Liu.

The DNA vaccine provided significantly better protection against several strains of influenza compared with current killed-virus vaccines. As expected, immunization with hemaglutination DNA alone was most effective when the immunogen exactly matched the challenge strain. A combination of HA DNA and internal protein DNA from various flu strains provided significant cross protection.

DNA vaccines offer a number of potential advantages over immunization with vaccines made from whole inactivated virus, subunit vaccines, or recombinant products. For example, the DNA vaccines have the potential to protect against different antigenic variants. Also, since DNA vaccines are derived directly from human specimens, problems with divergent mutants can be minimized. The DNA vaccines should also be easier to manufacture.

Another potential advantage of the DNA vaccine is that it may induce presentation of epitopes that more closely resemble those found in native flu virus compared with viral proteins produces in E.Coli, yeast or insect cells. DNA vaccines also do not require the use of formalin (used to inactivate whole virus) which may help preserve amino acid side chains in key epitopes.

"Thus far, DNA vaccines have induced robust primary and secondary immune responses in a variety of animal systems. The experience with live DNA virus vaccines including small pox, adenovirus and varicella, points towards the anticipated safety of DNA vaccines," noted Dr. Liu.

Researchers have yet ot prove the safety and efficacy of DNA vaccines in humans. Several issues remain to be addressed. These include: concerns over the potential for induction of tolerance; and clinically significant immune responses against the injected DNA. Another concern is that the injected DNA may randomly integrate into the genome.

"The efficacy of DNA immunization has also been demonstrated for a variety of viral, bacterial, parasitic and cancer models. These studies together indicate the potential of this technology for the development of both animal and human vaccines. DNA immunization holds substantial promise as an outstanding contribution of biotechnology to modern medicine," noted Pierre Meulien, Department of Research, Pasteur-Merieux, France.

For more information on DNA flu vaccines see: Nature Medicine, 6/96, v.1, no.6, Liu et al and comments by Meulein et al.

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