May 28, 2003 PHILADELPHIA - Globally, the influenza virus, or flu, is thought to cause between three and five million cases of severe illness and between 250,000 and 500,000 deaths annually, according to the World Health Organization. New strains of the virus emerge each year, so that the U.S. Centers for Disease Control and other public health services must produce and distribute a new vaccine against the new flu strains each year. And each year, people seeking to avoid a flu infection must arrange to receive a flu shot - rarely a pleasant experience - from their doctor or other health-care provider. Also, the effectiveness of the vaccine is known to decline in the elderly, a population for whom flu infections can be particularly dangerous.
A new prototype vaccine developed by researchers at The Wistar Institute, however, might be able to protect recipients not only against this year's strains of the virus, but also against those yet to come, possibly eliminating the need for an annual shot. In fact, because the vaccine would be administered as a nasal spray, it could eliminate the need for a shot of any kind. A report on the new findings appears in the June 2 issue of the journal Vaccine.
"Current vaccines are quite effective, but they are based on regions of the virus that mutate rapidly, so health officials are constantly faced with the problem of updating the vaccines," says Walter Gerhard, M.D., senior author on the Vaccine report and a professor in the immunology program at The Wistar Institute. "A vaccine directed against a more stable region of the virus would offer important public-health advantages, and this is what we are hoping to be able to develop."
Current flu vaccines trigger an immune response to a pair of prominent viral-coat proteins that mutate constantly, which is the reason last year's flu vaccine is ineffective against this year's flu strains. The experimental vaccine contains an engineered peptide that mimics a third, smaller viral-coat protein called M2 that remains largely constant from year to year.
Mice vaccinated with the vaccine generated a strong antibody response against M2. In fact, the mice generated a more powerful antibody response to the vaccine than to infections by the flu virus itself, according to Gerhard.
"We saw a significant antibody response to our peptide vaccine," he says. "Actually, the response was much stronger than what we saw in mice recovering from infections, which was surprising. This may be meaningful in terms of the potential effectiveness of the vaccine as we go forward."
The experimental vaccine was administered twice intranasally to mice. After vaccination, a steep rise in M2-specific antibodies was seen in blood samples from the mice, and the mice exhibited significant resistance to viral replication in the respiratory tract.
Ongoing experiments in the Gerhard laboratory are exploring the questions of how and why the new flu vaccine is able to produce a stronger antibody response than infections, which are generally considered the best way to generate resistance to any pathogen.
Also, Gerhard is looking into whether the M2 element of the virus might begin to mutate in the presence of the anti-M2 antibodies generated by the new vaccine. His concern is that the observed viral stability in the M2 region of the flu virus may simply be a reflection of the fact that the immune system does not mount a vigorous response to it, so that evolutionary pressure on that region of the virus is not great.
"Among human influenza virus strains, there is little variation in the M2 region," Gerhard says. "That could be due to the fact that humans do not generate a significant antibody response to it, so that the virus does not need to change to escape those antibodies."
Wistar associate professor Laszlo Otvos, Jr., Ph.D., collaborated on the study. Krystyna Mozdzanowska was the lead author. The remaining coauthors, all Wistar-based, are JingQi Feng, Mark Eid, Goran Kragol, and Mare Cudic.
Support for the research was provided by the National Institutes of Health.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center - one of only eight focused on basic research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.
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