Making Immunity More Than Skin Deep

I write my column Making Immunity More Than Skin Deep in TCS Daily on 9 March 2005.

DNA vaccines, will they save the day?

Vaccines are one of the greatest blessings science has bestowed on humanity. It was not so long ago millions of people died in epidemics of transmittable diseases like measles, smallpox, polio and diphtheria (the risk of dying from diphtheria was previously 10% in the US and Europe). They still do in many parts of the world. Vaccines have contributed to increased life span even in less developed nations, with many splendid successes -- like the worldwide eradication of smallpox in 1980.

Despite these successes, in the face of the most serious influenza scare for over a decade, the US recently basically ran out of flu vaccine. Europe is also seeing the first signs that a similar crisis could be possible in the near future, when a scare hit about the risk of a strain of avian influenza from Asia spreading to the continent. A public debate started about rationing and stockpiling of medicines and fears deepened because a vaccine has not been developed yet against avian flu. The risks of a pandemic are most probably exaggerated, but still we should not take the problems surrounding vaccines today too lightly either. The scare about influenza vaccine shortages might even have been a lesser worry. In fact, European influenza vaccine stocks are generally better off than those for diseases like tetanus or chickenpox.

In 1970 there were 25 companies producing vaccines, today there are only five producers left: Aventis Pasteur, Chiron, Glaxo Smith Kline, Merck and Wyeth. The pharmaceutical companies have a problem today: the vaccine market has a revenue of just $6.5 billion in total, while a single drug like Lipitor (used to lower blood cholesterol) earns its producer $9 billion. The biological production process of vaccines is costly and complex compared with the production of chemical drugs. Furthermore biological production processes get tied to dedicated facilities, and the production in those facilities is seasonal.

The best thing about vaccines is that they are extremely cost efficient per life saved: for the relatively low cost of producing the vaccine a great number of lives can be saved. Producing the vaccines is not necessarily that expensive, but the testing for passing a new vaccine through the drug administration preclinical trials is very difficult and costly compared to drugs.

Worsening the problems is that vaccines are expected by politicians and the public to be cheap, even free! Since the incidence of many of the diseases that the vaccines have cured has declined they are not taken as seriously as previously, and people do not value vaccines as much anymore. Thus we see price controls enacted by the governments reducing revenues. Add to this our increasingly litigious society and a heavier body of regulation and we understand why companies are getting out of the vaccine business.

Thus the opportunity cost of developing a new vaccine vs. developing a new drug tilts heavily towards developing a new drug, even if vaccines are more efficient. This has negative effects. Research is progressing towards an HIV-vaccine, but it is simpler to develop drugs, thus we have about 15 functioning anti-retroviral drugs in use.

But the introduction of a new technology might solve these problems: vaccines based on our knowledge of how the human genome works and biotechnology.

Development of DNA vaccines started as late as in 1993, but the first drug using a DNA-modified plasmid (Swedish KabiGen's drug Genotropin) was approved for use already in 1985. DNA vaccines might provide the pharmaceutical industry with the opportunity to solve many of the problems since the industry desires:

• A breakthrough technology for many unconquered diseases that also promises ease to manufacture, safety and stability in vaccines
• A platform technology for a single vaccine to work on multiple diseases at the same time 
• Therapeutic and prophylactic uses for vaccines

All of these would be possible with DNA vaccines.

DNA vaccines are being studied for many diseases, including HIV, influenza, tuberculosis, malaria, Hepatitis C, SARS, and virus induced forms of rota cancer. DNA from an infectious organism such as a virus or bacterium is isolated, and then the specially reproduced genetic material of the organism is injected directly into the body. This genetic material, tailor made to the patient, encodes information that makes the individual's own cells produce the vaccine, thus rending her immune to the disease. If actually infected by a live organism at a later occasion, the immune system responds quickly and well, having been previously primed to respond.

In recent years research has progressed rapidly, showing impressive results in animal tests. In 1997 the US Army developed a DNA vaccine against malaria. Studies by the Merck Corporation in 1998 demonstrated that a DNA vaccine can prevent influenza in animals and in 1997 the Karolinska Institute of Stockholm developed an HIV vaccine.

The problem with these immunizations is that the effect is still, at best, very short lived and ceases after about 3-4 months. Most DNA vaccines are still at the early investigative stages and have not yet reached the level of knowledge to be used in human clinical trial.

The main difficulty of developing them is not that researchers lack the appropriate biotechnology, but that they still do not have enough knowledge about immunology in order to understand the often very complicated genetic variations between different strains of the same virus.

There is also concern of the risk that the injected DNA actually would be integrated in the human chromosomes inside the cell. The effect of such could potentially lead to cancer through the alteration of normal DNA. Thus DNA vaccines are examined for any evidence of integration of the injected DNA into the chromosomes of the injected cell.

In the end, science will probably overcome these concerns, and DNA vaccines might prove to be a solution to the present vaccine crisis. DNA vaccines are more robust; easier prepared, cheaper and do not need to be transported in a "cold chain".

Better vaccines, new applications through DNA-technology and stronger health consumer's demands -- rather than government monopsony -- are necessary to make immunity more than skin deep.