~~~ What the Heck is a DNA Vaccine? ~~~

DNA vaccines are made of a modified form of an infectious organism's DNA. This material, when injected into a person - usually into muscle cells of the person - leads to the expression of the genes within this modified, foreign DNA. This gene expression ultimately leads to synthesis of infectious organism proteins inside the injected cells. As a result, the person's immune system responds in a protective manner almost the same way as would occur if the person were actually infected by the true organism, itself.

What is a vaccine?
Vaccines are preparations of material such as viruses or bacteria that are injected into a person to help prevent harm from infectious diseases or products of harmful, infectious organisms. A vaccine is used to specifically stimulate a person's immune system to respond against the material. By stimulation of an immune response against non-harmful components of a harmful infectious organism, if the harmful organism or product is later encountered, the body will respond very quickly and will generate protective cells and substances, and the disease caused by this organism or product will be prevented. The material may be made of either (1) dead, whole organisms, (2) weakened, non-harmful, live organisms, or (3) inactive specific parts of or products of, an organism. Examples of each type are as follows:

(1) Dead, whole organisms: Influenza virus vaccine. This vaccine usually consists of three different strains of Influenza virus that have been "killed" -i.e., rendered completely inactive. Another example is the currently recommended polio vaccine for use in the United States. This vaccine consists of the completely inactivated forms of the three known strains of Poliomyelitis virus that infect humans.

(2) Live but severely weakened (attenuated) organisms: Measles, mumps and rubella virus vaccine (MMR). This vaccine is made from live but attenuated forms of Measles virus (Rubeola), mumps virus (Rubulavirus) and German measles virus (Rubella). The attenuated forms of the viruses are designed not to cause disease, but to infect cells and to thereby generate a potent immune response against these viruses.

(3) Inactive specific parts or products of infectious organisms: Tetanus vaccine is the best example of this kind of vaccine. In this case, the very potent and harmful bacterial protein toxin, tetanus toxin, is treated in such a way as to render it harmless - but - still able to stimulate an immune response against it's molecular shape. The presence of protective antibodies in our system against this toxin prevents harm from the real toxin if we happen to be infected with the bacterium that produces this toxin.

How are vaccines provided to us?
Usually, we receive an injection of material underneath our skin (MMR) or into our muscle tissue (influenza vaccine) and tetanus vaccine. New vaccines are being designed that allow a spray of the infectious but weakened organism (virus) onto the surface of our mucosa tissue inside the nose. To my knowledge, however, such sprays have not yet been approved by the FDA for human use.

What is a DNA Vaccine?
The DNA is isolated from an infectious organism such as a virus or bacterium. This DNA, in highly purified form, is altered by special techniques to provide what are known as eukaryotic promoters in front of the gene or genes on this DNA. The promoter region is located at the beginning of a gene. A promoter is a special DNA nucleotide sequence that forms a recognition site for the enzyme required for gene expression - the synthesis of messenger RNA using the DNA sequence of the gene as a template (you may wish to read What the Heck is a Gene?). This recognition site allows the enzyme to associate with the DNA and to be oriented properly along the DNA to synthesize messenger RNA.

This messenger RNA (mRNA) will ultimately be interpreted by protein-synthesizing machinery inside the cell known as the ribosome. This interpretation of the message, i.e., the interpretation of the nucleotide sequence of mRNA, will lead to the synthesis of a protein (amino acids covalently connected one after the other to form a long amino acid polymer) by the ribosome.

Since each species of all organisms have their own kinds of promoter sequences, the recognition sites for genes, i.e., th promoters, for each species of organism are different. Therefore, bacterial gene promoters are not recognized by the mRNA-synthesizing enzyme in human cells. Consequently, if bacterial DNA were to be injected into one of our cells, no gene expression from the injected DNA would occur. Therefore, it is necessary to provide a eukaryotic promoter at the beginning of this bacterial gene - of a kind that human genes have - in order for mRNA to be synthesized.

This altered infectious organism DNA that contains a eukaryotic promoter is then integrated into what is known as a plasmid vector. A plasmid is made of double-stranded DNA and is usually in a closed circle. Quite amazingly, if such plasmid DNA is injected inside a human cell, the injected DNA's genes will be expressed inside that cell. Presently, the muscle cell is the most common target for injection. This expression of mRNA ultimately leads to the synthesis of infectious organism proteins inside the injected human cell. The presence of such proteins inside the cell allows the body's immune system to readily recognize that something is amiss, and a powerful protective immune response will be generated against the expressed infectious organism proteins. This immune response development activates and maintains a protective response against the true, live, organism - almost as if the cell had been infected with the dangerous, live organism, itself.

Why make a DNA vaccine when we already have vaccines that work?
Present vaccines have certain drawbacks. It is very clear that survival of an actual infection is the very best way to develop a life-long immune protection from subsequent exposure to the same infectious organism. If a dead organism or product is used as a vaccine to stimulate our protective immune response, the degree and longevity of the protective response can not only vary among individuals, but may not lead to life-long protection. Too, if a live, attenuated form of virus, for example is used to prepare a vaccine, the virus itself may revert to the wild-type - strong form - of the virus and cause disease. Also, for certain individuals who have a weakened immune system, even injection with an attenuated form of virus that is safe for the majority of individuals, can cause disease and even, death.

So, there is still a lot to learn about how to prepare a vaccine that itself is not potentially harmful, can generate life-long or at least very, very long immune protection responses, and that can lead to complete immune protection from both antibodies and cells (you may wish to read What the Heck is an Antibody?).

Since a DNA vaccine leads to synthesis of foreign proteins (from a virus or bacterium) inside the muscle (usually) cell, the immune system recognizes this event much more correctly. Here is why. A small percentage of every one of the protein molecules produced for every one of the proteins synthesized within a cell are destined to be chewed into small fragments (peptides). These protein fragments ultimately appear on the surface of the cell in association with special proteins known as MHC Class I proteins (major histocompatibility protein class I). You may wish to read, What the Heck is an MHC Molecule?.

Our immune system's cells constantly survey the surface of our cells for the presence of foreign protein fragments. Therefore, if a foreign protein is synthesized within one or more of our cells - such as from a virus that has invaded the cell and is making new virus particles - special cells of the immune system known as cytotoxic (killer) T-cells molecularly recognize these foreign shapes and respond to them by killing them. The immune system cannot tell nor does it particularly care if the foreign protein fragments came from a DNA vaccine instead of a true infection of the cell. Other kinds of T cells are also activated that lead to the activation of antibody-producing cells known as B cells. Thus, an infection or a DNA vaccine, lead to a very similar complete activation of the immune system - the generation of killer T cells as well as the generation of soluble, circulating antibodies that react with the foreign material. Therefore, if we are actually infected by a live organisms at a later time, our immune system responds quickly and well - having been previously primed to respond, because of a previous infection or the DNA vaccine.

What might be some potential problems with a DNA vaccine?
Probably th issue of most concern to investigators is the possibility that the injected DNA will actually become a part of (will be integrated) into one of the human chromosomes inside the cell. The effect of such integration of DNA into a chromosome could range from no effect whatsoever or could potentially lead to cancer through alteration of normal DNA. Therefore, many, many efforts are made to examine DNA vaccines for any evidence - even slight - of integration of the injected DNA into the chromosomes of the injected cell.

Do such DNA vaccines presently exist?
Yes - there are such vaccines and some of them are in human clinical trials to be tested for efficacy. Most of DNA vaccines are still at the early investigative stages and have not yet reached the level of knowledge about them to be used in a human clinical trial. If you use a search engine on the internet and use the key words DNA vaccine, or dna vaccine, or dna vaccine clinical trials, etc., you can find up-to-date articles that specifically discuss such vaccines.

Book: Don't Touch That Doorknob!

Copyright John C. Brown, February, 2002

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