printable versionBird flu or not, developing vaccines is critical to preventing pandemics
BY MITZI BAKER
Concerns about bird flu have led health workers in Asia, including this one in Shanghai, to gather fowl that spread the virus.
In the examination rooms of the General Clinical Research Center in Stanford Hospital, the dark specter of avian flu pervades. Not literally—there are currently no reported cases in either birds or people in Palo Alto, or for that matter the rest of the United States. But the concern over the spread of the virus in birds overseas has given Stanford studies of flu vaccine a heightened importance.
And even if an avian flu pandemic never materializes, we have plenty to worry about with other strains of influenza. Every year, a seasonal epidemic of the flu kills roughly 36,000 people in the United States, according to the Centers for Disease Control and Prevention. If a new strain circulates against which people have no prior immunity—such as the current avian flu strain—a pandemic could occur, killing a much larger number.
An influenza pandemic, if not inevitable, is nonetheless a very real threat as they have occurred several times each century. "In the event of an avian influenza pandemic, almost the entire human population is at risk," said professor of pediatrics David Lewis, MD, who is beginning a study of avian flu vaccine. "The clock is ticking in that even if the current avian influenza strain doesn't cause a human pandemic, we know it's only a question of time before we will face a pandemic from a new flu strain."
An ounce of prevention almost always being worth a pound of cure, the response to the avian flu threat has focused on how best to vaccinate people to make them less likely to become infected. At Stanford, researchers are looking at ways of stretching existing vaccine supplies and ways to make current vaccines more effective. Two of these studies are not addressing avian flu, but hope to shed light on flu vaccines in general.
One of the studies that has just wrapped up at the GCRC is seeing whether the dosages of currently available flu vaccine could be reduced while still providing adequate immunity. Last year, two articles appeared in the New England Journal of Medicine looking at the benefits of delivering a flu vaccination under the skin (intradermally) compared with the traditional shot in the arm (intramuscularly). They found that one-fifth the dose of standard flu vaccine given under the skin could give the same or a better immune response as the standard shot in the upper-arm muscle.
But a large-scale, controlled trial is necessary to confirm that lesser intradermal doses could be as effective as the standard delivery. With funding from the federal National Institutes of Health, Cornelia Dekker, MD, is leading a clinical trial at Stanford using intradermal delivery of flu vaccine.
Dekker's group at Stanford collaborated with nine other universities to give a total of 1,500 adults different doses of last year's formulation of Fluzone, an approved injectable flu vaccine, either under the skin or into the muscle. Dekker, who directs the Stanford/Lucile Packard Children's Hospital Vaccine Program, said that if they find that the doses could be stretched out, there would potentially be more vaccine to go around and it could get to people more quickly. She will likely announce her findings early next year.
Dekker is involved in another study currently under way in the GCRC, taking a detailed look at the immune response produced by the two types of approved flu vaccine, the standard Fluzone and the nasal spray FluMist. Rather than a killed vaccine, FluMist is a live, attenuated flu vaccine—created from live virus that has been weakened so that it no longer causes disease. The study is supported by a grant led by Ann Arvin, MD, the Lucile Salter Packard Professor of Pediatrics and professor of microbiology and immunology, and Harry Greenberg, MD, the Joseph D. Grant Professor of Medicine and professor of microbiology and immunology.
Given the worldwide frenzy of vaccine development currently under way, the Stanford study findings will be of particular interest. "While the studies focus on seasonal influenza vaccines, the results may be applicable for avian flu vaccine development," said Dekker, who is also on the National Vaccine Advisory Committee.
Some potential advantages of live, attenuated influenza vaccine include its ease of administration, that it's painless and that it might cause a more effective immune response because it is more accurately simulating how the flu virus infects a person.
Still, there are also advantages to the injectable killed-virus vaccine. This type of vaccine is easier to administer, particularly in less-developed countries, as it does not require freezing. It is also cheaper as well as safer to give to people who are immunocompromised. But the trade off, he said, has been that the immune response, particularly in the respiratory tract, may not be as good as using an attenuated live virus, especially in young children. Arvin and Greenberg's study may be able to answer some of the questions about the differences between the two routes of administration.
Arvin, who is also chief of infectious diseases at Packard Hospital, said that while they already know that the two available vaccines work, they don't know how they work. "The more we understand the way in which the vaccines protect the respiratory tract, the better we can understand how to create the most effective vaccine," she said.
Both Arvin and Greenberg are paid consultants on the scientific advisory board of MedImmune, the maker of FluMist. They are providing guidance in a joint effort between the company and the National Institutes of Health to develop a library of vaccines, based on the FluMist concept, for use against different types of potential pandemic flu strains, including one based on the avian flu H5N1. Greenberg said they help plan the company's studies, though they are not directly involved with MedImmune's current avian flu experiments.
Lewis is using the traditional dead vaccine to tackle new pandemics of human flu and avian flu head on. He is working with local biotechnology company Juvaris BioTherapeutics and with the Centers for Disease Control and Prevention in Atlanta to improve upon both human and avian flu vaccines. The main bird-flu vaccine against H5N1 influenza currently available is produced by Sanofi-Pasteur. It is likely to be effective, but only in doses six times the concentration of the conventional flu vaccine, and will need to be given twice over four weeks. That is not an ideal regimen for addressing what could potentially be a rapidly spreading flu outbreak.
Lewis and a colleague at Juvaris are working on optimizing an additive, known as an adjuvant, which can make vaccines vastly more effective. The hope is that the right adjuvant can not only permit much less of the vaccine to deliver effective immunity, but also can potentially trigger a more complete immune response than the vaccine without the adjuvant.
Adjuvant strategies are very promising, said Dekker, noting that last month, Chiron Corp. announced results of their vaccine against a different bird-flu virus, H9N2, with an adjuvant that has been used with the flu vaccine licensed in Europe to boost the immune response to seasonal flu strains. They found that by adding the adjuvant, they could achieve equivalent antibody levels in people using one-quarter the usual dose of vaccine required.
Lewis is starting his studies in mice. If the results are promising, a major hurdle will be to get regulatory agency approval for initial safety studies in people. Aware of the ticking clock, Lewis can just hope that the burst of research sparked by avian flu leads to some answers before they are desperately needed. Every week and month without an outbreak, he added, means more ammunition with which to potentially thwart avian flu's effects.
Meanwhile, until an avian flu vaccine is available for routine use, preventing and controlling potential avian influenza outbreaks among humans will rely on antiviral medications, such as Tamiflu, said Paul Eckburg, MD, a clinical instructor in the division of infectious diseases and geographic medicine. Eckburg is the lead author of a review of avian influenza in humans in this month's issue of the journal Infections in Medicine.
In addition, the annual human flu vaccines may play a role in decreasing the possibility of an avian flu pandemic. Currently, the avian flu virus is inefficient at spreading between people; the majority of infected people have caught it from an ill chicken. But simultaneous infection with both avian and human influenza viruses could in theory result in a hybrid virus that could spread efficiently between humans.
"Current influenza vaccines provide no protection against avian influenza," Eckburg writes in the review. "But vaccination of at-risk persons may help decrease the likelihood of genetic recombination that could lead to efficiently transmitted strains."