[NVIC] Testing Bird Flu Nasal Spray Vaccine

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BL Fisher Note:

Live virus vaccine has the ability to infect the recipient or a close

contact with vaccine strain virus. This is true for live virus polio vaccine

and live virus chicken pox vaccine. Pre-licensure studies of live virus

nasal flu vaccine (FluMist) demonstrated some recently vaccinated

individuals shed the virus. There is no guarantee the experimental vaccine

strain bir flu virus will not recombine with another human virus and cause

an even more virulent flu virus. There is significant risk associated with

testing a live bird flu virus vaccine squirted up the nose in humans unless

those human subjects are going to be quarantined for a period of time to

make sure they are not shedding the virus. Infected chickens may not be the

only way to start a bird flu pandemic.

www.jsonline.com/alive/well/jan06/383240.asp

jsonline.com

Spray vaccine aimed directly at bird flu

By LAURAN NEERGAARD

Associated Press

Last Updated: Jan. 8, 2006

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.

Prevention

Photo/AP

New approach to Bird Flu vaccine

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 no one should get sick or spread germs - and it

protects 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 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 , who heads the NIH

laboratory where Kanta Subbarao is brewing the nasal sprays.

FluMist is a nasal-spray vaccine that prevents regular winter flu.

Developed largely through '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 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.

Influenza constantly mutates, making it difficult to develop effective

vaccines.

Studding the virus' surface are two proteins called hemagglutinin - the H in

H5N1 - and neuraminidase, the " N. " 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 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, " said 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 s Hopkins Bayview Medical Center. Then

an H7 strain, followed by an H6 strain believed to share genes with the

H5N1.

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 FluMist virus.

Stocks of the custom virus are grown in fertilized chicken eggs. Each is

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 ,

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 the 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.

If a novel flu strain begins spreading among people, how will Subbarao tell

if her stored nasal vaccines are a good match to fight it?

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, are brewed in chicken eggs, a time-consuming

process that other research is seeking to improve.

" These are research projects, " stresses - the nasal-spray concept

could fail.

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