Our results confirm and extend previous observations [7
] related to the use of AlOH to improve the immunogenicity of H5N1 vaccines. The frequency of injection site tenderness was increased in groups receiving vaccine with AlOH. Dose-related increases in injection site tenderness also were noted. The addition of AlOH did not clinically improve antibody responses for the antigen doses tested. Our observations are also in agreement with those of Treanor, et al. [10
] who studied this same nonadjuvanted vaccine among healthy elderly adults but also included a 90 μg dose group.
Previous studies [2
] have also detected HAI, and more often Neut, antibodies to H5N1 virus prior to vaccination. The concern is whether these results represent true antibody to H5 or antibody to a cross-reacting epitope from H1, H2, or H3 viruses. Throsby, et al. [11
] recently described a panel of monoclonal antibodies recovered from combinatorial display libraries that were constructed from human IgM+
memory B cells of recent seasonal influenza vaccinees. These monoclonal antibodies have broad heterosubtypic neutralizing activity against antigenically diverse H1, H2, H5, and H9 influenza subtypes. Neutralizing antibody also may be due to N1 specific antibody, as H1N1 viruses have circulated and been part of seasonal influenza vaccines. Subjects were not questioned regarding their past contacts with poultry or aquatic fowl. Subjects with preexisting antibody responded better to the first vaccination than subjects without preexisting antibody, an observation also made by Bernstein, et al. [9
]. This improved response may be more suggestive of a booster response. This interesting observation deserves additional study.
One strategy to improve the immunogenicity of this H5N1 vaccine could be a prime-boost regimen whereby the H5N1 vaccine is included in annual vaccinations to prime the population and then a booster dose provided at the start of a pandemic. Recent reports by Zangwill, et al. [12
] and Goji, et al. [13
] suggest that the prime-boost strategy may be feasible. In the study by Zangwill and colleagues [12
], healthy subjects 18-64 years of age who had previously received two doses (7.5-, 15-, 45-, or 90-μg each) of a nonadjuvanted subvirion inactivated H5N1 influenza vaccine received a third vaccination six months later of the same dose. The third dose of vaccine stimulated a Neut antibody response that was of greater magnitude than that seen 28 days after the second vaccination [2
]. Available elderly subjects in our study who received two doses of H5N1 vaccine are currently being enrolled in a clinical trial that will evaluate their immune responses to a third dose of H5N1 vaccine from a different clade administered more than two years after initial receipt of an H5N1 vaccine.
A second strategy could be the use of other adjuvants to improve immunogenicity. MF59 is an oil-in-water emulsion adjuvant that has been demonstrated to increase antibody titers to avian influenza H9N2 [14
] and H5N1 [9
] vaccines in healthy adults. These trials did not include adults ≥ 65 years of age. MF59 has been approved for use in seasonal influenza vaccines for the elderly in several countries in Europe [15
]. Thus, this strategy also deserves additional study.
Improving the immunogenicity of influenza vaccines will only partially meet the challenge of preparing an aging population for future epidemics and pandemics. By 2020, individuals ≥ 65 years of age will comprise about 16% of the projected population of the United States [16
]. The impact of pandemic influenza on this population group may depend on their past exposures to similar influenza viruses, either by natural infection or vaccination. The promotion of seasonal influenza vaccination among the elderly is an important first step toward pandemic preparedness.