Safety and immunogenicity of multiple and higher doses of an inactivated influenza A/H5N1 vaccine.

BACKGROUND: H5N1 avian influenza represents an episodic zoonotic disease with the potential to cause a pandemic, and antiviral resistance is of considerable concern. We sought to generate high-titer H5N1 antibodies in healthy volunteers for the purpose of developing hyperimmune intravenous immunoglobulin. METHODS: We conducted a dose-escalating, unblinded clinical trial involving 75 subjects aged 18-59 years. Three cohorts of twenty-five subjects were enrolled sequentially and received 90, 120, or 180 microg of H5N1 A/Vietnam/1203/04 vaccine in 4 doses administered approximately 28 days apart. RESULTS: No statistically significant dose-related increases in the geometric mean titers (GMTs) of serum hemagglutination inhibition antibody were observed when the 90-microg, 120-microg, and 180-microg cohorts were compared. When the cohorts were analyzed together to determine the effect of additional vaccinations, the GMTs of hemagglutination inhibition antibody after the first, second, third, and fourth vaccinations were 1:15.7, 1:22.2, 1:36.0, and 1:32.0, respectively (first vaccination vs. baseline, P<.001; second vs. first vaccination, P=.02; and third vs. second vaccination, P<.001). The microneutralization GMTs after the first, second, third, and fourth vaccinations were 1:17.5, 1:33.1, 1:55.7, and 1:68.4, respectively (P<.001 for all comparisons). CONCLUSION: The results of our study suggest that a third and fourth dose of the H5N1 A/Vietnam/1203/04 vaccine may result in higher hemagglutination inhibition and microneutralization GMTs, compared with the GMTs resulting from fewer doses. There was no benefit to increasing the dose of the vaccine. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT00383071.