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Fusing genes for better vaccines
By Bijal P. Trivedi

Researchers at East Carolina University, in Greenville, North Carolina and Emory University, in Atlanta, have found a novel way to improve the DNA flu vaccine that will help the immune system make better antibodies in less time. The initial studies were done in mice, but the researchers believe that the approach may also work well in humans and could offer a technique for improving all vaccines.

A. The flu vaccine is a mixture of hemagglutinin (HA) proteins, which have been purified from flu viruses.

B. A DNA vaccine containing the viral gene for the HA protein.

The current flu vaccines given in the clinic are protein vaccines. They contain a mixture of three versions of the hemagglutinin (HA) protein purified directly from what the scientists believe will be the three dominant flu viruses of that year. But these protein vaccines are expensive to produce and difficult to store, which is why scientists are shifting their attention to DNA vaccines.

The DNA vaccine is simply a piece of DNA containing the viral gene for the HA protein, which covers the surface of the virus. The difference between DNA and protein vaccines is that rather than having a company make and purify HA, the cells use the HA gene to make the protein inside the body. The major advantage of DNA vaccines is that they are inexpensive and can be manufactured quickly. This is particularly important as the influenza viruses mutate rapidly requiring new vaccines to be produced every year.

Studies in mice have shown that the major drawback of DNA vaccines is the slow immune response. It takes eight to twelve weeks after immunization with a DNA vaccine to produce the maximum load of antibodies, (the proteins that snag the infecting viruses and tag them for destruction). In contrast, a protein flu vaccine triggers the immune system to produce antibodies in just three to four weeks.

When HA appears in the body, a protein called C3d binds to it, thus labeling it as a foreign invader. At this point the immune response kicks in and B-cells begin making antibodies against the viral protein. Instead of waiting for the immune system to provide C3d, Ted Ross, of East Carolina University, decided to incorporate the protein into the vaccine.

C. The new DNA vaccine produced by Ross and colleagues, which contains the viral HA gene fused to three copies of the C3d gene. The researchers believe C3d is required to speed up antibody production.

Ross and his colleagues hastened antibody production by placing three copies of the gene for C3d next to the gene for HA. When the cells read the DNA they produce a protein that is a fusion of HA and C3d. "This way we've already told the body to treat the vaccine as an invader, so it can go straight to the business of making antibodies," says Ross.

In the body, C3d stimulates the entire immune system. When C3d is tied to the vaccine, it seems to specifically stimulate B-cells that produce antibodies against HA. The C3d-HA fusion vaccine speeds up antibody production significantly; it can produce a maximum level of antibodies in six to eight weeks.

When Ross and his colleagues tested the fusion vaccine in mice and then exposed the mice to the virus 14 weeks later, the mice that received the highest doses of the vaccine didn't appear to get any infection at all. "When mice get the flu they quit eating, just like people, and often suffer some weight loss. But these mice kept on eating and didn't lose weight, they didn't feel sick at all, it's like they never saw the virus," says Ross.

Ross' team also found that the fusion vaccine was particularly effective in tiny doses; C3d-HA could trigger the same number of antibodies as ten times the amount of the HA vaccine. "Smaller doses are cheaper, and this is tremendously important when you are talking about developing countries where a family's medical budget is no more than a three or four dollars a year," says Ross.

Ross is currently investigating whether the C3d gene will increase antibody production when fused to different genes in other DNA vaccines. Whether this technique will work in humans remains to be seen. Ross estimates that clinical trials of any sort would be at least several years in the future.

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Ross, T.M. et al. C3d enhancement of antibodies to hemagglutinin accelerates protection against influenza virus challenge. Nat Immun 1, 127-131 (August 2000).

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