Focus on the Flu : Prevention and Vaccine, Part 2

by National Institute of Health

(Page 4 of 15)

In Search of the Flu's Magic Bullet

If we ever hope to find a less fickle flu vaccine, maybe we need to pick a different target.

Andrew Pekosz, Ph.D., assistant professor in the Washington University School of Medicine, St. Louis, MO, and David Milich, Ph.D., an immunologist with the Vaccine Research Institute, San Diego, CA, are setting out to do just that. Drs. Pekosz and Milich are trying to determine if the influenza A virus M2 protein would make a much better target for a flu vaccine than the currently targeted HA and NA surface proteins.

The reason to consider the switch is that HA and NA proteins are always changing (see antigenic shift and antigenic drift). To keep up, we need to be vaccinated against new strains every year.

But the M2 protein in human flu strains remains the same from year to year, and from strain to strain. One vaccine could be all we'd need to remain protected against the variety of human flu viruses. Already, Dr. Pekosz has demonstrated that M2 antibodies can protect mice from a lethal influenza A virus.

One potential drawback to using the M2 protein is far fewer copies of the protein are present on the outer coat of the influenza A virus when compared with the HA and NA proteins, so a vaccine created from a normal flu strain would generate too few M 2 specific-antibodies. But Dr. Milich has a way of getting around this. He has developed a "bulked-up" M2 vaccine-called the M2 protein core-that contains 240 copies of the M2 protein, thus making it capable of stimulating the production of many more antibodies.

The researchers are now studying how well the M2 protein core works, not just against human flu strains, but against bird and pig flu strains as well. (The M2 protein in bird and flu strains is slightly different from that in human strains.) Dr. Milich's lab is preparing M2 protein cores containing human, bird, and pig influenza A strains and studying the immune responses in mice. Dr. Pekosz's lab is testing cross-reactivity between the different species and strains. To do this, they are immunizing mice, and later other animals, with M2 vaccines against human and bird flu strains and then studying their immune responses against both.

If the studies are successful, the M2 protein could prove itself an excellent target for flu protection. But because antibodies against the HA and M2 proteins protect in different ways, Dr. Pekosz wonders if a vaccine against both proteins might be better still, offering two different but complementary levels of protection.

One Shot Fits All?

Rolling up your sleeve for a yearly flu jab could become a thing of the past if researchers can develop a long-lasting and broadly protective vaccine.

Flu vaccines act by giving the immune system a preview of certain proteins found on the coat of the flu virus. However, like a fashion diva, influenza virus changes its coat every season. The changes make each year's version of the flu unrecognizable to the immune system, and so immunity to the flu must be reestablished with a new shot every fall. Scientists are searching for less variable flu parts with the goal of using such elements to develop longer lasting vaccines.

One such stable element is a coat protein called M2. At the Wistar Institute in Philadelphia, NIAID grantee Walter Gerhard, M.D., is using mice to test candidate vaccines containing many bioengineered versions of M2. The mice are inoculated through the nose, mimicking the way flu enters the body. Scientists then can compare the vaccine-created immune response with the response that occurs following natural infection. Generally, the immune system reacts more strongly to natural infections than to vaccines. So the scientists were surprised when the opposite occurred in the vaccinated mice.

Dr. Gerhard is examining how long the immunity provided by these vaccines lasts and whether the virus can find a way of evading these vaccines by developing mutations in their M2 proteins.

Gary Van Nest, Ph.D., a researcher at the biotechnology company Dynavax, is looking inside the flu virus to find a relatively stable component for use in a new kind of vaccine. The vaccine candidate combines an internal flu protein that is less likely to be altered through mutation, NP, with a bioengineered molecule called an immunostimulatory DNA sequence, or ISS.

Dr. Van Nest is testing the NP-ISS vaccine in mice that either have or have not previously been infected with influenza virus. He will examine whether the combination vaccine stimulates certain immune system cells that can fend off different influenza A strains.

Moreover, some of the immune cells stimulated by the vaccine will become "memory" cells that may be able to remember flu virus from year to year. Memory cells against an antigen that is less likely to change through mutation, such as NP, may provide broader protection against the flu than memory cells against an antigen that undergoes numerous changes, such as HA. If the vaccine technique succeeds in mice and non-human primate studies, Dr. Van Nest's research plan includes quickly moving the candidate vaccine into human testing.

About the Author

NIH is the nation's medical research agency - making important medical discoveries that improve health and save lives. The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting medical research.