Key Point

Immune responses considered necessary for protection against influenza A (H5N1) were observed in almost half of participants who received the highest dose of an inactivated vaccine.

ROCHESTER, NY—In the largest avian influenza vaccine study to date, researchers found that an immune response considered necessary for protection against avian influenza (H5N1) infection was observed in approximately half of participants who received the highest dose of an inactivated subvirion influenza A vaccine.¹

"The seed virus for the production of the experimental H5N1 vaccine was generated from the human isolate influenza A/Vietnam/1203/2004 virus with the use of a plasmid rescue system," explained lead author John J. Treanor, MD, and his research colleagues. Gene segments encoding hemagglutinin and neuraminidase were derived from the A/Vietnam/1203/2004 virus, and all other genes were derived from a laboratory strain known as A/PR/8/34. "The hemagglutinin gene was further modified to replace the stretch of six basic amino acids at the cleavage site between hemagglutinin 1 and hemagglutinin 2," noted the investigators.

A total of 451 healthy adults ages 18 to 64 were randomly assigned to receive two intramuscular doses of H5N1 vaccine (90, 45, 15, or 7.5 mc) or placebo. Initially, 118 people were given the vaccine and observed for adverse events. Then, after safety data were reviewed, the remaining 333 subjects were included in the trial. In both stages of the study, serum samples were obtained before each vaccination and again 28 days after the second vaccination to assess antibody responses. The primary immunogenicity end point was the proportion of participants in each vaccination group in whom a neutralizing titer of 1:40 or greater was observed against the virus at day 28 after the second vaccination.

According to Dr. Treanor and colleagues, median age of the participants was 39, and 54% were female. Seventy-nine percent were white, 11% were Asian, and 8% were black. Forty-two percent had received conventional influenza vaccine in the previous year.

EFFECTIVENESS OF THE VACCINE

Dr. Treanor’s group found that the frequency of serum antibody response was highest among individuals receiving two 45- or 90-mc doses. Among those receiving two 90-mc doses, 54% achieved neutralization antibody titers of 1:40, and 58% achieved hemagglutination-inhibition titers of 1:40. Forty-three percent, 22%, and 9% of people who received two 45-, 15-, and 7.5-mc doses, respectively, achieved neutralization antibody titers of 1:40 or greater. No response was seen in those who received placebo.

"Generally, the vaccine was well tolerated at all doses, and 84% of all reported symptoms were graded as mild by the subjects," said the investigators. "There was no indication that the frequency or severity of either local or systemic symptoms was greater after the second dose than after the first dose, and there were no instances of anaphylaxis, hives, or other serious allergic reactions." Mild pain at the injection site was the most common adverse event for all doses of the H5N1 vaccine.

LIMITATIONS

"It is possible that lower titers of neutralizing antibody could be associated with protection, as has been observed in studies of conventional human influenza viruses.... [B]ut the level of antibody associated with protection in this assay has yet to be determined," noted the investigators.

"An antibody titer of 1:40 does not guarantee protection from infection. People with lower titers show protection against influenza, and people with higher titers can have symptomatic infection. Moreover, the assumption that a titer of 1:40 is seroprotective is based on circulating strains of seasonal influenza. Whether the same will prove to be true for new influenza viruses in people whose immune systems have not been primed is unknown," editorialist Gregory A. Poland, MD, wrote.² "However, even moderate levels of seroprotection could be useful for the public health by preventing or decreasing transmissibility, severe symptoms, complications, or death," he added.

FUTURE RESEARCH EFFORTS

"The need for a vaccine with a total dose of 180 mc would pose a considerable barrier to rapid production of a supply that would be adequate to meet the world’s requirements should a pandemic occur. Therefore, dose-sparing approaches should be pursued aggressively," said the investigators.

Dr. Treanor’s group is currently conducting two studies—each involving 600 participants—at the University of Rochester Medical Center, Duke University Medical Center, and several other sites—assessing the effectiveness of the vaccine with an adjuvant known as alum.

"The immediate development and testing of such antigen-sparing vaccines administered with adjuvant are imperative both to improve immunogenicity and to increase the number of doses available," Dr. Poland wrote in his accompanying editorial.

Studies evaluating the response to the vaccine in the elderly, persons with impaired immunity, and children are also under way, noted Dr. Treanor and colleagues.

—Karen L. Spittler

References
1. Treanor JJ, Campbell JD, Zangwill KM, et al. Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med. 2006;354:1343-1351.
2. Poland GA. Vaccines against avian influenza—a race against time. N Engl J Med. 2006;354:1411-1413.

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