- WASHINGTON -- In an isolation
ward of a Baltimore hospital, up to 30 volunteers will participate in a
bold experiment: A vaccine made with a live version of the most notorious
bird flu will be sprayed into their noses.
- First, scientists are dripping that vaccine into the
tiny nostrils of mice. It doesn't appear harmful -- researchers have weakened
and genetically altered the virus so that no one should get sick or spread
germs -- and it protects the animals enough to try in people.
- This is essentially FluMist for bird flu, and the hope
is that, in the event of a flu pandemic, immunizing people through their
noses could provide faster, more effective protection than the troublesome
shots -- made with a killed virus -- the nation now is struggling to produce.
- And if it works, this new vaccine frontier may not just
protect against the bird flu strain, called H5N1, considered today's top
health threat. It offers the potential for rapid, off-the-shelf protection
against whatever novel variation of the constantly evolving influenza virus
shows up next -- through a library of live-virus nasal sprays that the
National Institutes of Health plans to freeze.
- "It's high-risk, high-reward" research, said
Dr. Brian Murphy, who heads the NIH laboratory where Dr. Kanta Subbarao
is brewing the nasal sprays -- including one for a different bird-flu strain
that appeared safe during the first crucial human testing last summer.
- "It might fail, but if it's successful, it might
prevent hundreds of thousands of cases" of the next killer flu, Murphy
- FluMist is the nation's nasal-spray vaccine that prevents
regular winter flu. Developed largely through Murphy's lab, it's the only
flu vaccine made with live but weakened influenza viruses.
- The new project, a collaboration with FluMist manufacturer
MedImmune Inc., piggybacks cutting-edge genetics technology onto that vaccine
to create a line of FluMist-like sprays against different bird flus.
- "That is a great, great idea," said Dr. John
Treanor of the University of Rochester, among the flu specialists closely
watching the project.
- Regular winter flu shots are made with killed influenza
viruses, and the government is stockpiling experimental bird-flu vaccine
made the same way. But those bird-flu shots don't work as well as hoped.
They require an incredibly high dose, delivered in two separate injections,
to spark a protective immune response in people.
- "In theory, a live-virus vaccine might actually
work better. We don't know that because we've never tried one before,"
- Influenza is like a magician, constantly changing its
clothes to avoid detection, thus making it difficult to develop effective
- Studding the virus' surface are two proteins called hemagglutinin
-- the H in H5N1 -- and neuraminidase, the "N". They act as a
wardrobe: There are 16 known hemagglutinin versions, and nine neuraminidases.
- They're also what triggers the immune system to mount
an attack, particularly hemagglutinin, the protein the body aims for when
it makes flu-fighting antibodies.
- When people catch the flu, they usually get H1 or H3
flu strains, which their bodies can recognize because variations have circulated
among humans for decades.
- Occasionally, genetically unique strains emerge. Until
1997, H5 strains had never been seen outside of birds. The virus essentially
put on a coat that human immune systems didn't recognize. The result: Since
2003, a particularly strong H5N1 strain has infected more than 130 people
in Asia, killing at least 70.
- H9 and H7 strains also recently have jumped from birds
to people, although so far they haven't been nearly as dangerous.
- Researchers hope to create at least one live-virus nasal
spray for each "H" subtype, a project costing about $16 million
of the NIH's annual $67 million budget for flu vaccine research.
- "The hemagglutinin is the major protective antigen,
so that is what we're focusing on," explained Subbarao, a molecular
geneticist who heads the project.
- First on her list are the riskiest known bird flus: H5N1,
with human tests planned for April. H9N2, which recently underwent the
first round of human testing in an isolation ward at Johns Hopkins Bayview
Medical Center. Then an H7 strain, followed by an H6 strain believed to
share genes with the H5N1.
- "By no means are we confident we're picking the
right strain" to make first, because flu mutates so easily, Subbarao
- She chooses vaccine strains from those that U.S. scientists
who are monitoring influenza in Asia cull from ducks, chickens and geese,
and ship home for research.
- Subbarao must customize those strains for safe vaccination:
First, using a new technique called reverse genetics, she selects genes
for bird-flu H and N antigens and removes genetic segments that make them
dangerous. Then she adds the remaining gene segments to the regular weakened
- Stocks of the custom virus are grown in fertilized chicken
eggs. Each is then carefully cracked by hand to drain out virus-loaded
liquid that in turn is purified and put into a nasal spray.
- In a high-security section of the lab, Subbarao dons
a biohazard suit and exposes vaccinated mice to various bird flu strains.
- Then it's time for human testing -- in a hospital isolation
ward just in case the weakened virus could infect someone.
- It shouldn't, because "those problems don't exist
in FluMist," said Murphy, citing studies of regular FluMist in day-care
centers where youngsters routinely pass viruses back and forth.
- Some studies have found that people can shed virus shortly
after receiving regular FluMist. But, "to spread infection, you'd
need much more (virus) than replicates in the nose," he said.
- Hopkins researchers gave the first of Subbarao's vaccine
candidates -- the H9N2 spray -- to 30 volunteers last summer. To be sure
they couldn't spread the virus by coughing or sneezing, the volunteers
underwent daily tests of their noses and throats.
- The vaccine appeared safe. Scientists now are analyzing
whether it also spurred production of flu-fighting antibodies, a sign that
people would be protected if they encountered the H9N2 strain. Subbarao
expects results by February.
- In April, pending final Food and Drug Administration
permission, Subbarao will put an H5N1 spray to a similar test.
- Here's the catch: Each flu strain has subtypes. An Indonesian
version of H5N1, for example, was recently discovered that differs from
a Vietnamese strain on which Subbarao's nasal spray -- and the government's
stockpiled shots -- are based. She's now testing whether her vaccine protects
mice against that new Indonesian strain.
- If a novel flu strain begins spreading among people,
how will Subbarao tell if her stored nasal vaccines are a good match to
- NIH also will store blood samples from the people who
test those sprays. Say a new H9 strain sparks an outbreak. That virus will
be tested against those blood samples, and NIH could predict within a day
which spray candidates work. If one does, the government could order doses
manufactured from that frozen stock; if none do, scientists would have
to try to brew a new vaccine.
- How quickly doses could be manufactured is a different
issue. All influenza vaccines, shots or spray, currently are brewed in
chicken eggs, a time-consuming process that other research is seeking to
- "These are research projects," Murphy stresses
-- the nasal-spray concept could fail.
- But he's optimistic. Live-virus vaccines, he maintains,
are better immune stimulators.
- Copyright 2005 Newsday Inc.
- Patricia A. Doyle, DVM, PhD- Bus Admin, Tropical Agricultural
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