Another vaccine story

There's a report on the wires that scientists at the Vaccine Research Center (VRC) at U.S. National Institute of Allergy and Infectious Diseases have developed a DNA vaccine that protects mice against the reconstructed 1918 virus. The paper just appeared online in the Proceedings of the National Academy of Sciences (PNAS, also known as "penis" in the trade). At this point the paper is more important for what it reveals about how the mouse immune system protects against this notorious virus than as a demonstration of a vaccine technology for use in people. That is much further down the road.

The bottom line here is that the NIH and CDC team successfully immunized mice using a DNA vaccine. The idea behind a DNA vaccine is to insert DNA coding for an immunogenic viral protein into the host's own cells, inducing it to make the protein and thus stimulate an immune response. The PNAS paper shows that the DNA vaccine technique can protect mice from the lethal effects of the 1918 flu. It is not obvious that this technique will work in people. H5N1 vaccines that seemed to work fine in mice have sometimes not been very potent producers of immunity in human trials, so this is still pretty early days.

Using the genetic sequence information for the 1918 flu virus, Dr. [Gary] Nabel and his VRC colleagues created plasmids--small strands of DNA designed to express specific characteristics--carrying genes for the virus' hemagglutinin (HA) protein, the surface protein found in all flu viruses that allows the virus to stick to a cell and cause infection. The researchers created two types of plasmids: one to reflect the HA found in the original 1918 flu virus; the other an altered HA protein designed to attenuate (weaken) the virus.

Mice were then injected with a DNA vaccine containing both types of plasmids to determine whether they would generate immune responses to the 1918 virus. The researchers found significant responses both in terms of production of T-cells, the white blood cells critical in the immune system's battle against invading viruses, as well as the production of neutralizing antibodies.

To determine the vaccine's protective effects, the CDC's Dr. Tumpey intranasally exposed a group of mice to live, reconstructed 1918 virus 14 days after they were immunized with the experimental DNA vaccine. All 10 vaccinated mice survived the challenge with the deadly virus. To explore how the vaccine protected the animals, the researchers first depleted other mice of T-cells; however, this had no effect on the immunity of the vaccinated mice to the 1918 virus. In contrast, the researchers discovered that transferring antibody-rich immunoglobulin (IgG) from immunized mice to non-immunized mice resulted in antibody levels in the animals at levels only slightly lower than those that were immunized. Further, when the animals were exposed to the reconstructed 1918 flu virus, 8 of 10 mice that received antibodies from the immunized mice survived; none of the 10 mice that received IgG from the unvaccinated control group survived. (NIAID Press Release)

The DNA vaccine affected both the mouse cell-mediated immune system (the T-cells) and the humoral immune system (antibodies). Both are important in protecting against disease, and these mice survived challenge with the virus after vaccination. To see whether it was the T-cells or the antibodies, the research team also challenged vaccinated mice whose T-cells had been depleted and found they were still protected. Thus the working hypothesis was that the protection was from the antibodies produced in reaction to the protein, not the T-cells. To test this further, they took the fraction of mouse blood that contains antibodies (the immunoglobulin G, or IgG fraction) and injected it into unvaccinated mice and showed they, too, were protected, presumably from the antibodies generated by the vaccinated mice.

Thus this vaccine protects by raising antibodies to the virus -- in mice. As the authors point out, this does not mean cell mediated responses aren't important in humans. Moreoever, this mode of vaccination seems to work better in mice than humans, so at this point this paper is more important for its investigation of how the mouse immune system works against this virus.

There is already a company in the UK, PowderMed, that has been developing the DNA vaccine technique and it has just been bought by the world's largest drug maker, Pfizer (Bloomberg). It is relatively quick to prepare large amounts of specific DNA and no eggs are needed for this. thus this is one of several new vaccine techniques being developed. The PowderMed product uses needle-free administration by shooting the DNA into cells, coated onto gold particles, with a compressed gas injector. PowderMed is now conducting clinical trials.

There is another part of the paper related to preparing "pseudotyped viruses" that are safer to handle than the real thing. A lentivirus with the influenza HA protein coat was engineered and shown to be adequate for characterizing influenza virus antibody response. This would be very useful in allowing a better way to test for vaccine efficacy in neutralization tests (seeing whether the vaccine produces antibody that actually protects against infection), without the danger and cumbersome biosafety requirements of challenge with wild type virus.

So this is more vaccine news. Too bad we didn't do this kind of work several years ago. We might be there now and breathing easier. I'm not sure "better late than never" will be good enough if we have a pandemic.

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Is there any additional risk from..."by shooting the DNA into cells" ?

Are there any DNA human vaccines currently in use?


Tom: No DNA vaccines in use I am aware of. I don't know of any risks specifically from the administration method (DNA uptake by cells occurs normally, so this isn't a problem). Try Googling PowderMed to see if anything has come up on their phase I clinical trials (for safety and efficacy).

Revere. Thanks. Wasn't there something about DNA vaccines and cancer and retroviruses inserted in the human genome?

This paper is a little weird in that the authors write: raising the question of whether it is possible to develop protective immunity to [the 1918] virus, but Kobasa et al.'s 2004 Nature paper(*) showed that there certainly was neutralizing antibody to the 1918 strain in sera from those who survived it, so I am kind-of wondering what's new here?

(*) vol 431, pp. 703-707.

By Red Crayon (not verified) on 19 Oct 2006 #permalink

Red: Disentangling the T-cell from the humoral in the mouse -- and the pseudotype construction.

Revere is this the same stuff that VICAL unveiled yesterday regarding ferrets and mice? If so again shooting DNA modified vaccine would still be years away from going into my arm wouldnt it?

If not, this too would be years away from my arm..Correct?

By M. Randolph Kruger (not verified) on 20 Oct 2006 #permalink

Randy: I have a post in gestation about the Vical announcement. It is the same principle but not the same work. The NIH work was basic science of mouse immune system. The Vical work is a Press Release for a possible upcoming product. They probably would like a suitor like Pfizer. I'll post some more details that address you timig concerns. But yes, years away or it may never get there.

Tom, there have been a number of problems in gene therapy during which the vector--for example, an adenovirus--coupled with its extra gene or two caused cancer. From my limited reading of the subject the researchers involved acknowledge it as a problem, but don't think it's an insuperable problem.

Marrissa Thank you for answering my question. The unleashing of an unregulated pharmaceutical industry with huge potential profits and potential for liability removed, has added to the opportunity for 'harm' instead of benefit...beware the snake oil salesman.