OPTIONS VI: Vaccine Adjuvant May Work in Bird Flu Pandemic

TORONTO, June 20 - An investigational oil-and-water adjuvant for flu vaccines -- tested in conjunction with a vaccine against avian flu -- is safe, a researcher said here.

Tested in more than 5,000 volunteers, the adjuvant (dubbed AS) had significantly higher rates of local and general adverse events than a placebo, but most of them were mild, Ripley Ballou, M.D., of GlaxoSmithKline Biologicals in Belgium told attendees at the Options for the Control of Influenza meeting.

Rates of withdrawal in the adjuvant arm of the randomized phase III safety trial were only 0.5% higher than in the placebo arm, he said, mainly because of pain at the injection site that dissuaded participants from returning for a second dose.

The issue of adjuvant safety has arisen because most of the candidate vaccines against the H5N1 strain of avian flu require very large doses of antigen to create an immune reaction.

Use of an adjuvant could make a scarce vaccine go further among the population-provided it was safe.

A standard adjuvant, aluminum potassium sulfate or alum, is known to be safe, but does not strongly enhance the immunogenicity of the vaccines, so the researcher turned to an older idea - oil and water emulsions.

Dr. Ballou and colleagues randomized 5,071 volunteers (on a two-to-one basis) to get one dose of the seasonal Fluarix vaccine without adjuvant or two 15-microgram doses of an experimental H5N1 vaccine, together with the adjuvant.

Earlier studies had already shown that even 3.5 micrograms of the vaccine, combined with adjuvant, led to a high antibody response, Dr. Ballou said.

The researchers found that common reactions to all vaccines were significantly higher in the H5N1 group than in the controls - redness: 38.2% versus 27.8%, swelling: 33.1% versus 17.5%, and induration: 34.4% versus 19.1%. The incidence of ecchymosis was 9.6% versus 5.8%.

The most common general adverse effects, as solicited by the researchers, were also higher in the H5N1 group - fatigue: 51.9% versus 30.8%, myalgia: 50.0% versus 24.6%, and headache: 46.9% versus 31.2%.

The withdrawal rate in the control group was 2.52% and 3.55% in the H5N1 group. Three withdrawals in the H5N1 groups were related to a serious adverse event (and none in the control group) but the events were not considered to be related to the study medication.

Oil and water emulsions date back to the 1950s, according to vaccine researcher John Treanor, M.D., of the University of Rochester Medical Center in Rochester, N.Y.

They fell out of favor because of some serious side effects, including the development of sterile abscesses at the injection site and the suspicion - later disproved - that they caused plasmacytomas, Dr. Treanor said.

The current generation of emulsions, on the other hand, appears not to have such serious adverse effects, he said, and may prove valuable, especially in the event of a flu pandemic.

"I think it's quite definitive that oil and water emulsions are very, very effective in enhancing the antibody response to neo-antigens like a flu vaccine," he said.

But researchers and clinicians still have to "think hard about what constitutes an acceptable safety profile" for such adjuvants.

The increase in the withdrawal rate for the Glaxo adjuvant "sounds acceptable" in a trial of 5,000 people, "but if you vaccinated a million people, that would be 5,000 people who wouldn't come back for the second dose," Dr. Treanor said.

On the other hand, in a pandemic, people might be more willing to accept a painful second injection, he added.