The results are from the largest bird flu vaccine study to date, of 451 healthy adults ages 18 to 64. The study was done last year at three sites – the University of Rochester, the University of Maryland, and the University of California at Los Angeles. John Treanor, M.D., professor of medicine and director of Rochester's Vaccine and Treatment Evaluation Unit, was the overall lead investigator.
Each participant received two shots in the arm one month apart. In participants who received the biggest dose of vaccine, two shots of 90 micrograms each, 54 percent had levels of antibodies considered protective against the virus. The percentage of people who were protected decreased as the size of the dose got smaller: 43 percent of people who received two 45-microgram shots, 22 percent of people who received two 15-microgram shots, and 9 percent of people who received two 7.5-microgram shots. Most patients regarded their side effects as mild; the most common side effect was a sore arm, with people who received the largest doses complaining of a sore arm most frequently.
The dose that was most effective, two shots of 90 micrograms each, is several times larger than the conventional flu shot given each year. Depending on the number of strains targeted, a typical flu shot might include 15 to 45 micrograms (15 micrograms for each strain targeted). In addition, since the world is "immunologically naïve" to bird flu –hardly anyone has been exposed to the virus – it's thought that people should receive not just one but two shots, just as infants do when they are vaccinated against "regular" flu for the first time.
The dose most effective in the NEJM study would be difficult to produce, using conventional manufacturing methods, for a significant portion of the world's population. So researchers are turning their attention to ways to stretch the vaccine.
In one approach taking place at Rochester and several other sites, 1,200 people are taking part in a study of the vaccine together with an adjuvant, a substance designed to enhance the response of the immune system. The vaccine will be given with alum, a vaccine additive that has been used in commercial vaccines for decades to make them more effective, in two studies involving 600 participants each. If alum is effective, researchers ultimately would be able to reduce the amount of vaccine given to each person, thus making the vaccine available to more people.
The studies are sponsored by the National Institute of Allergy and Infectious Disease, the Federal agency leading the effort to create a vaccine against bird flu. NIAID is currently testing the vaccine in people 65 and older and in young children. It's also sponsoring studies looking at ways to speed the vaccine manufacturing process, and at new ways to deliver the vaccine, as officials work to head off a potential pandemic of bird flu. The disease has claimed the lives of more than half the people it has infected.
"These findings represent an important step forward in the nation's efforts to prepare for the possible emergence of a human pandemic of H5N1 avian influenza," noted NIAID Director Anthony S. Fauci, M.D. "We are working hard to address the many challenges that remain with regard to the development of an H5N1 vaccine."
In some ways the high doses necessary to create an immune response are not surprising. In a previous study of an experimental bird flu vaccine led by Treanor, conducted in 1998 when bird flu was killing chickens at an alarming rate in Hong Kong, two shots of 90 micrograms each were needed to produce protective levels of antibodies in 56 percent of participants.
"For whatever reason, the H5N1 strain of avian flu just does not stimulate the immune system as much as the regular flu does," Treanor said.
Currently Treanor's Rochester team is involved in five studies to learn more about bird flu and test a vaccine against it:
- Rochester is one of four sites of a study of 240 people testing the vaccine in people age 65 and older. Sixty-seven people in Rochester are taking part.
- About 104 people in Rochester who took part in the study reported in NEJM are taking part in an ongoing study; they received a third dose of the vaccine in the fall.
- About 40 people from the 1998 study are taking part in another study of a "booster shot." They received a third shot of the vaccine in November 2005, so scientists can measure how well a booster shot delivered years later affects a patient's immunity against the virus.
- Rochester is one of four sites of a study of 600 people testing alum as part of the vaccine in people ages 18 to 49. Approximately 150 people in the Rochester area will take part.
- Rochester is one of six sites of a study of 600 people testing alum as part of the vaccine in people age 65 and older. Approximately 100 people in the Rochester area will take part.
The studies are funded by NIAID and are being done largely through its VTEU network, which supports the government in its efforts to respond to infectious threats and protect the health of the nation's citizens. More people in Rochester have been immunized against bird flu than in perhaps any other community in the world, thanks to the University's role testing vaccines. During the last eight years, more than 450 people have taken part in studies of bird flu vaccines through the University's VTEU.
Journal
New England Journal of Medicine