WASHINGTON - The World Health Organization has called an unprecedented summit meeting next week of flu vaccine makers and nations to expand plans for dealing with the growing threat of a flu pandemic.

Sixteen vaccine companies and health officials from the United States and other large countries already have agreed to attend the summit in Geneva, Switzerland, on Nov. 11, said Klaus Stohr, influenza chief of the United Nations?health agency.

With increasing signs that bird flu is becoming established in Asia and several worrisome human cases that can磘 be linked directly to exposure to infected poultry, it´s only a matter of time until such a virus adapts itself to spread more easily from person to person and cause a severe worldwide outbreak, he said.

"We believe that we are closer to the next pandemic than we ever were," Stohr said Sunday in an interview before a speech at an American Society for Microbiology meeting in Washington, D.C.

Stohr said several European countries had been invited to the meeting, but he declined to name them. Vaccine makers in Russia and Japan were also invited.

The world´s total capacity for flu vaccine now is only 300 million doses, and it would take at least six months to develop a new vaccine to fight a pandemic. The WHO wants to get "all issues on the table," monetary and scientific, that prevent getting more vaccine more quickly, he said.

"If we continue as we are now, there will be no vaccine available, let alone antivirals, when the next pandemic starts," Stohr said. "We have a window of opportunity now to prepare ourselves."

Flu kills about 36,000 people in the United States and a million worldwide each year by conservative estimates, Stohr said. But tens of millions die in a pandemic, which occurs every 20 to 30 years, when a flu strain changes so dramatically that people have little immunity from previous flu bouts.

There were three pandemics in the 20th century; all spread worldwide within a year of being detected.

The worst was the Spanish flu in 1918-19, when as many as 50 million people worldwide were thought to have died, nearly half of them young, healthy adults. More than 500,000 died in the United States.

The 1957-58 Asian flu caused about 70,000 deaths in the United States, followed by the 1968-69 Hong Kong flu, which caused about 34,000 U.S. deaths.

The current vaccine shortage in the United States, caused by loss of one of the country´s two major flu shot suppliers, reveals how vulnerable the world is and serves as a "dress rehearsal" for the kind of rationing and emergency measures that would be needed in a pandemic, said Dr. Wendy Keitel of Baylor College of Medicine in Houston.

"The ability to respond with the production of billions of doses of vaccine is quite limited," Keitel said. "We need to think through these problems now. Ninety percent of vaccines are produced in 10 countries that have 10 percent of the world´s population."

The United States is the only nation that has commissioned work on potential pandemic bird flu vaccines, Stohr noted. The National Institutes of Health has given Aventis Pasteur and Chiron Corp. contracts to produce prototype bird flu vaccines that are expected to be ready for human tests late this year. Aventis already has made 8,000 doses at its plant in Swiftwater, Pa.; Chiron is making its doses at a factory in Europe, not the one in Britain that regulators shut down last month, causing the U.S. vaccine shortage.

If a pandemic occurred and a vaccine wasn磘 ready, antiviral drugs could play a key role in slowing its spread, said Dr. Frederick Hayden, a University of Virginia virus expert who has researched and consulted on many flu vaccines and drugs including oseltamivir, or Tamiflu, which showed some activity against bird flu in lab experiments.

It, too, is in short supply.

"It´s hard to get explicit numbers but the production capacity worldwide is very limited," making it difficult to develop an international stockpile that could be used in a pandemic, Hayden said.

The WHO has 120,000 packages of the drug, Stohr said, and the United States is stockpiling several million doses.

"That will not go very far" he said, but if targeted to a region where a pandemic was breaking out, "we might be able to buy time" and limit its spread while a vaccine was being readied, he said.

Bird flu actually describes three deadly strains of avian influenza, which have wiped out millions of chickens in Asia. So far they have not spread easily from person to person but have been very deadly to those who have become infected. They磖e named and numbered for the two "H" and "N" proteins on the surface of the virus.

The first strain, H5N1, appeared in Hong Kong in 1997, causing 18 human infections and six deaths. It reappeared last year and so far this year has caused 44 human cases and 32 deaths throughout Asia, according to Stohr.

A second strain, H9N2, appeared in 1999 in Hong Kong and China, and caused two human cases in Hong Kong last year. A third strain, H7N7 appeared in 2003 in the Netherlands.

When public health officials and vaccine manufacturers convene in Geneva Thursday, they´ll keep an eye on the past as they try to anticipate the future.

Their goal: To plan for the eventuality of a worldwide flu pandemic - a global outbreak on the scale of the deadly Spanish flu of 1918. It is an issue considered urgent because of the persistent presence of bird influenza in Asia.To date, 44 cases of bird flu and 32 deaths have occurred in humans there, including a case in which a killer flu virus may have been transmitted from a nursing mother to her infant daughter. Scientists remain flummoxed about the ability of such strains, now under study, to efficiently jump the species barrier. But they say that if it turns out humans can effectively transmit the infection to each other, the stage is set for a rapid spread.

The World Health Organization scheduled the Geneva meeting, saying there is more evidence now than in the recent past that a global flu pandemic can develop.

Pandemic is a term referring to widespread infections occurring throughout the world. An epidemic, by contrast, refers to a widespread outbreak but without the global impact.

Experts at the summit are expected to confront a chilling fact: No one has yet developed a vaccine against the type of flu viruses capable of causing a pandemic.

Representatives will attend from 16 vaccine manufacturers and public health agencies from the United States, Europe, Japan, Russia, Australia and other industrialized nations.

Pandemics have circled the globe in 1968, 1957 and, in the most devastating of all, 1918, when the Spanish flu killed millions around the world. It led to the deaths of nearly 600,000 people in the United States during the 1918-19 season, said Dr. Ben Schwartz, senior science adviser for the National Vaccine Program Office at the Centers for Disease Control and Prevention. An estimated 40 million people died worldwide.

"People talk about the magnitude and potential of pandemic influenza. But the one thing I do point out is that the 1918 flu was the single most fatal event in all of U.S. history," he said.

"The impact of a pandemic can be catastrophic but at the same time, not inevitably so," Schwartz said. Indeed, there were far fewer deaths in the global flu pandemics of 1957, with 70,000 deaths, and 1968, when 34,000 people died.

Pandemics, like flu transmission in ordinary seasons, depend on a host of variables - including the virulence of the particular pathogen.

"So the magnitude of the next one cannot be predicted with any degree of certainty," Schwartz said.

Experts are poised not to take any chances.

A WHO spokeswoman in Washington said the summit is driven by the presence of a flu strain in Southeast Asia, dubbed H5N1, "which is creating more opportunity for new strains to emerge. That´s one of the drivers for having the discussion now." Flu viruses get their designations, H and N, from the two proteins on their surfaces, which determine their degree of virulence.

The H stands for the protein hemagglutinin and the N stands for the protein neuraminidase. The numbers refer to any one of the 15 viral subtypes that have been identified to date. Virtually all forms of pathogenic flu originated in migrating birds, particularly wild ducks. Viral strains with H and N designations are collectively known as "A" strains of flu. Vaccines routinely include protection against H1 and H3 strains.

An H5N1 is a type of strain to which humans have no immunity, just as they had no immunity to the strain in 1918, H1N1.

Schwartz added that the H1N1 strains that have swept around the globe since 1918 are no longer linked to pandemics because people have developed enough immunity to fight them - even without vaccination.

Reporting on U.S. pandemic flu preparations last month, Schwartz said preparations against an H5N1 include increasing the nation´s cache of antiviral drugs in the National Strategic Stockpile. Millions of doses, federal health officials say, are being added.

Antivirals, such as oseltamivir (Tamiflu) or amantadine (Symmetrel), zero in on surface proteins of flu viruses and block their ability to replicate. The drugs can be used to shorten the course of the flu or prevent it altogether. Four such medications have been approved by the Food and Drug Administration since 1976.

Pandemic flu preparedness is not a new concept in the United States. The first such plans were drawn up in 1978 after the expected 1976 swine flu outbreak fizzled.



Lack of global effort

Dr. George Curlin, deputy director of microbiology and infectious diseases at the National Institutes of Health, said a key drawback today is the lack of a coordinated global effort to develop suitable vaccines. Manufacturers would have to respond with the ability to produce billions of doses rapidly, once a circulating pandemic strain is identified.

As a result, the United States is investing $50 million to study new production techniques that avoid cumbersome and lengthy manufacturing of vaccines in fertilized chicken eggs. Such old production methods date back a half century, Curlin said. Newer ones are needed to accommodate surge capacity, when billions of doses would be required. Currently, vaccine makers produce 300 million doses of flu vaccine worldwide for an ordinary flu season.

Curlin added that using cells as the production medium instead of eggs would be key, shortening manufacturing time and producing more vaccines. A major study by the University of Rochester is examining how effectively flu vaccines can be manufactured in silk worm cells.

"WHO has taken the global lead for pandemic preparedness," Schwartz said. "In 1999, it issued guidelines for global preparedness at its 56th World Assembly. In 2003, WHO called on all nations to develop pandemic plans. One of the critical global issues is that vaccine manufacturers are located in only a few industrialized countries."

The public health infrastructure of underdeveloped nations is so poor, he said, that industrialized nations would have to assume the job of producing all vaccines.

Chiron Corp., the company that this year lost half of the U.S. flu vaccine supply to contaminated doses, has been awarded a contract by the National Institutes of Health to produce a vaccine against bird flu. Aventis Pasteur, MedImmune and ID Biomedical in Vancouver, Canada, also have been awarded contracts to produce vaccines against potential pandemic strains.

A window of opportunity exists to conduct the research, Curlin said, because there is not an overwhelming amount of evidence that dangerous strains are spreading among people. "Right now, the H5N1 is mostly in aquatic birds," he said.



Evidence of a jump

When viruses jump from one species to another - from birds to humans, for example - scientists become more concerned. Flu viruses change in the second species, becoming more virulent and more easily transmissible. There is mounting evidence that the jump has occurred.

Bird flu refers to several distinct viral infections that have been circulating throughout Asia. The first, H5N1, was identified in Hong Kong in 1997. Eighteen people caught the strain and six died. It cropped up again last year, scientists say, and by this year was responsible for 44 human cases and 32 deaths.

Dr. Richard Webby, a virologist and flu expert at St. Jude Children´s Research Center in Memphis, Tenn., said there is more than one type of dangerous virus that can lead to a flu pandemic.



H type strains dangerous

"There are at least 15 types of avian flu viruses out there, and they all circulate in wild aquatic birds. So the potential is there for any of these types to jump over and infect humans," he said. "We don´t know if all of them can, or if some can."

Webby said it´s important to prevent two specific strains of the virus, H5 and H7, from making the leap into the human population. "These two H types have the ability to transform into a very virulent virus," he said. "We only partially know how they do this."

Schwartz said a major part of U.S. pandemic planning centers on who should be vaccinated first. Plans so far call for vaccinating health care workers in the first wave of shots to provide a corps of people capable of taking care of everyone else.