Amid bird flu vaccine debate, scientists aren't sure of protective dose
Last Updated: Monday, May 14, 2007 | 10:46 AM ET
The Canadian Press
Concerns about the developing world's access to affordable pandemic vaccines took centre stage Monday at the World Health Organization's annual general meeting, the World Health Assembly.
But as global health leaders struggle to ensure pandemic vaccines won't just be a tool for wealthy countries, influenza scientists admit they face an enormous conundrum, one that could stand in the way of efforts to transform vaccines for the few into vaccines for the many.
Simply put, scientists can't be certain how much vaccine is needed to protect people against novel influenza viruses such as H5N1 avian flu, because they don't know what the immune system of a person protected against a new flu strain would look like.
Sure, they can observe whether immunization with H5N1 vaccine produces certain antibodies and to what levels the antibodies rise, but they have no way of gauging how much protection those antibodies will provide if the person is exposed to the virus.
"We can't get the answer to that until the pandemic comes. There's just no way," admits Dr. Robert Webster, the renown flu researcher from St. Jude Children's Hospital in Memphis, Tenn.
The uncertainty about what protection against H5N1 actually looks like is bedevilling ongoing debates over whether people should be pre-vaccinated against the virus or whether a program of ultra-low or single dose vaccines could be safely used to stretch limited supplies and protect millions more people.
"There are two very bad scenarios. And it's not that anybody's wrong or right, it's just that the science isn't there," explains Dr. Jesse Goodman, director of the branch of the U.S. Food and Drug administration that assesses and licenses vaccines.
"So one bad scenario is that if you could have used less (vaccine per person) and you didn't have enough doses and you didn't use less. Less people are protected. But an equally bad scenario is you cut a dose to a certain thing and it doesn't protect anyone."
"The truth is probably somewhere in between. And the science … to get there is not going to be trivial."
Protective signs
Scientists don't know which immune system markers found in the blood are signs that a person has been effectively protected against infection with H5N1.
Scientists think they know what levels of which antibodies translate into protection when people are vaccinated against human flu viruses — H3N2 and H1N1. It's thought that certain levels of antibodies which block the hemagglutinin protein on the exterior of flu viruses are critical to protection against those strains.
The measurements used by industry and government regulatory agencies were devised years back based on what are called challenge studies, where people were vaccinated and researchers then deliberately tried to infect them with flu viruses. The researchers then charted the antibody responses triggered by exposure to the viruses.
But it's neither ethical nor safe to deliberately infect people with H5N1 avian flu, which has killed roughly 60 per cent of those known to have become infected with it. So scientists are using the tests and scales worked out for H3N2 and H1N1 vaccines when trying to assess whether H5N1 vaccine will be effective and at what doses.
Regulatory agencies like the FDA are using this best-guess assumption and have told vaccine manufacturers that this is the bar H5N1 vaccines will have to hurdle in order to gain approval.
But each flu subtype has its own characteristics and quirks, the tests aren't standardized, and are based on results from red blood cells drawn from chicken and horses.
H5N1 viruses are considered poorly immunogenic, meaning they don't trigger the strong immune reaction needed to guard against infection.
Lasting defence?
But Webster and vaccine expert Dr. John Treanor at the University of Rochester, N.Y., have conducted studies that provide tantalizing clues that H5N1 vaccines may be more protective than they are given credit for with current measurement techniques.
Treanor's research was on 37 people who had been vaccinated with an H5N1 vaccine in 1998 and who were willing to get a booster shot against the virus. The booster shot generated a stronger antibody response in volunteers who had been previously immunized.
That suggests the immune system still harboured defences against the virus, defences not registered by the standard tests.
Webster and a team from St. Jude's also found ferrets previously vaccinated against H5N3 survived better when given what should be a lethal dose of H5N1 although animals' antibody levels did not seem high enough to be protective.
"We can have protection in the animal models with no hemagglutinin antibody at all," says Webster. "So maybe it's the test that's wrong."
