Evaluation of an inactivated subunit H5N1 influenza virus vaccine in humans

Results from a clinical trial demonstrate that high doses of an experimental H5N1 avian influenza vaccine can induce immune responses in healthy adults.

Approximately half of those volunteers who received an initial and a booster dose of the highest dosage of the vaccine tested in the trial developed levels of infection-fighting antibodies that current tests predict would neutralize the virus. The National Institute of Allergy and Infectious Diseases (NIAID) funded the study, published in the New England Journal of Medicine. Preliminary results from this trial were first disclosed late last summer.

"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," notes NIH Director Elias A. Zerhouni, M.D.

"We are working hard to address the many challenges that remain with regard to the development of an H5N1 vaccine," adds NIAID Director Anthony S. Fauci, M.D. "For example, potentially protective immune responses were seen most frequently at the highest dose of this vaccine. We are investigating other options that may allow us to reduce the dosage--for example, adding an immune booster, or adjuvant, to the vaccine--so we can achieve a more practical immunization strategy." In addition, the U.S. Department of Health and Human Services is pursuing other approaches to an H5N1 vaccine, including vaccines made in cell cultures rather than grown in eggs.

H5N1 avian influenza viruses are of enormous concern to public health officials worldwide. The potential for a human avian flu pandemic looms large, say experts, as daily reports indicate an increasing spread of infection in bird populations in Southeast Asia, Europe, the Middle East and Africa. According to the World Health Organization, as of March 24, 2006, 186 people had been infected with avian flu viruses, and more than half of them had died.

Generally, flu viruses are easily transmitted from person to person, but so far, the H5N1 avian influenza viruses have not demonstrated this characteristic. In the worst-case scenario, if an avian flu virus became easily transmissible from person to person, it could trigger an influenza pandemic because humans have no pre-existing immunity to these viruses.

The trial, conducted between March and July 2005, was carried out at three NIAID-supported Vaccine and Treatment Evaluation Units located at the University of Rochester Medical Center in Rochester, NY; the University of Maryland School of Medicine Center for Vaccine Development in Baltimore; and the Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles, Medical Center. John Treanor, M.D., of the University of Rochester, led the group.

The study was conducted in two stages. In the first stage, the research team enrolled 118 healthy adults ages 18 to 64 years old. Each participant was assigned at random to one of five groups. Volunteers in each group received an initial dose of vaccine (7.5 micrograms [mcg], 15 mcg, 45 mcg or 90 mcg) or saline placebo into the upper arm muscle; about one month later, they received a booster shot of the same vaccine dosage or the placebo. The research team collected blood samples before each vaccination and one month after the second vaccination.

Before the study could be expanded, an independent Data and Safety Monitoring Board assessed the vaccine's safety by reviewing data collected through day 7 after the second vaccination; no safety concerns were found. The investigators then began stage two of the study, eventually enrolling an additional 333 healthy adult volunteers into the trial according to the same protocol design as in stage one.

The NEJM article describes an analysis of data on the safety and immune responses to the vaccine. In general, the higher the dosage of vaccine, the greater the antibody response produced. Of the 99 people evaluated in the 90-mcg, high-dose group, 54 percent achieved a neutralizing antibody response to the vaccine at serum dilutions of 1:40 or greater, whereas only 22 percent of the 100 people evaluated who received the 15-mcg dose developed a similar response to the vaccine.

Generally, all dosages of the vaccine appeared to be well tolerated:

• Almost all reported side effects were mild
• The second dose of vaccine did not cause more local or systemic symptoms than the first
• Systemic complaints of fever, malaise, muscle aches, headaches and nausea occurred with the same frequency in all dosage groups as in the placebo group
• Lab tests did not reveal any clinically significant abnormalities

The vaccine, made from an inactivated H5N1 virus isolated in Southeast Asia in 2004, was manufactured by sanofi pasteur, Swiftwater, PA, under contract to NIAID. Because there are no manufacturers licensed in the United States to use adjuvants in inactivated influenza vaccines, NIAID's first step was to test an H5N1 influenza vaccine made in a way that mimics the process used to make conventional flu vaccines. The clinical data collected in this study are now available to support the potential use of this vaccine should it be needed for an emerging pandemic.