Helen Branswell — Making enough vaccine to protect large numbers of people if the H5N1 avian flu strain sparks a pandemic will be more complex that previously thought, a new study reveals.

The scientific paper shows that even at extraordinarily high doses - 12 times the antigen needed to protect against seasonal flu strains - nearly half of vaccinated healthy adults did not generate the level of antibodies thought to be necessary to defend against the troublesome strain.

Testing showed only 54 to 58 per cent of people who received two doses of 90 micrograms (mcg) apiece produced the level of antibodies believed to be needed to protect against infection, the researchers reported in this week's New England Journal of Medicine.

"These are lower response rates than what one might have expected for regular flu shots in healthy people," said lead author Dr. John Treanor, director of the vaccine treatment and evaluation unit at the University of Rochester, N.Y.

"We certainly had hoped it would be better."

Typically somewhere between 75 and 90 per cent of healthy adults who get a flu shot for seasonal flu would be expected to develop protective levels of antibodies to the strains contained in the vaccine, with some variability depending on the flu strain and the recipient's age and health.

Treanor said there would be logistical difficulties in trying to produce and administer higher doses of an H5N1 vaccine. And given that this dose is already far too high to be practical during a pandemic, it seems unlikely anyone would consider that option.

With current worldwide flu vaccine production capacity, a dosing regime of two shots of 90 mcg apiece would mean approximately 75 million people around the world - or just over one per cent of the global population - could be vaccinated in the first year of a pandemic.

Dr. Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases, said it had been hoped this vaccine would protect about 75 per cent of study participants. And he admitted the dosing requirements were "sobering news."

"Having a vaccine that would require 90 micrograms times two (doses) in and of itself would not and cannot be the answer to where we want to be," Fauci, whose institute funded this research, said in a teleconference for journalists.

"It's a step towards that but it is a small step."

A vaccine expert who wrote an editorial on the issue for the journal put it in even balder terms.

"The headline here is: Back to the drawing board," said Dr. Gregory Poland, of the vaccine research group at the Mayo Clinic College of Medicine in Rochester, Minn. Poland was not involved in this clinical trial.

"If we had a pandemic this week, this month or this fall, we're not ready in terms of vaccine. This vaccine is not the answer."

Other studies are now underway or will soon begin looking for ways to lower dosages by adding boosting chemicals called adjuvants to the vaccine or by injecting the vaccine into the skin, as opposed to muscle.

Both techniques have been shown to generate good protection at lower doses, in testing done with other flu strains.

But all research to date suggests the H5 flu viruses are not very immunogenic, meaning it is unusually difficult to trigger the immune system to recognize and mount a robust response.

Initial results from a study done by vaccine giant Sanofi Pasteur suggested adding an adjuvant called alum to an H5N1 vaccine could lower dosage requirements to two shots of 30 mcgs - still far higher than public health officials would like.

Given the data generated so far and the limits on the global capacity to produce flu vaccine, authorities should be considering lowering the bar in terms of the level of protection they are aiming for, another vaccine expert said.

"If a certain dosage protects 90 per cent of people and half that dosage protects 70 per cent, you should use the lower dosage because you can vaccinate twice as many people and protect more people in the population," Dr. David Fedson, a retired vaccine industry executive, said from his home in France.

"This is a judgment call. And people are going to be very uncomfortable making it. And they will lose sleep. But it is unavoidable."

Fauci said using an H5N1 vaccine at lower than protective doses could be dangerous. "I would really be reluctant to go that route," he said.

But Treanor suggested people who developed lower than optimum levels of antibodies might actually be protected by the vaccine, saying the threshold for success that the study designers set might be "very conservative."

"I think we've very safe in making the assumption that induction of antibody against H5 viruses would provide protection against at least severe disease," he said in an interview.

"We do not know the optimal method for measuring antibody to H5 viruses and we do not know what level of antibody must be achieved in serum (blood) to provide protection. . . .

"Since we don't know either of those things, it's quite conceivable the vaccine would be much more efficacious than the data . . . would suggest."

In the study, 451 healthy adults aged 18 to 64 received two doses of either 90, 45, 15 or 7.5 mcg of vaccine or a placebo. The two shots were given 28 days apart.

All tolerated the vaccine well, though people who got the highest doses complained more about side-effects like sore arms.

One man died, but an autopsy determined his death was due to chronic alcoholism.