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PUBLISHED, Trivalent influenza virus A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong vaccine preparations were used in a randomized, controlled, dose-ranging phase I study. The vaccines were prepared from highly purified hemagglutinin and neuraminidase from influenza viruses propagated in embryonated chicken eggs and inactivated with formaldehyde. We assigned 100 participants to six vaccine groups, as follows. Three intranasally vaccinated groups received 7.5-?g doses of hemagglutinin from each virus strain with either 3, 10, or 30 ?g of heat-labile Escherichia coli enterotoxin (LTK63) and 990 ?g of a supramolecular biovector; one intranasally vaccinated group was given 7.5-?g doses of hemagglutinin with 30 ?g of LTK63 without the biovector; and another intranasally vaccinated group received saline solution as a placebo. The final group received an intramuscular vaccine containing 15 ?g hemagglutinin from each strain with MF59 adjuvant. The immunogenicity of two intranasal doses, delivered by syringe as drops into both nostrils with an interval of 1 week between, was compared with that of two inoculations by intramuscular delivery 3 weeks apart. The intramuscular and intranasal vaccine formulations were both immunogenic but stimulated different limbs of the immune system. The largest increase in circulating antibodies occurred in response to intramuscular vaccination; the largest mucosal immunoglobulin A (IgA) response occurred in response to mucosal vaccination. Current licensing criteria for influenza vaccines in the European Union (EU) were satisfied by serum hemagglutination inhibition responses to A/Panama and B/Guandong hemagglutinins given with MF59 adjuvant by injection and to B/Guandong hemagglutinin given intranasally with the highest dose of LTK63 and the biovector. Geometric mean serum antibody titers by hemagglutination inhibition and microneutralization were significantly higher for each virus strain at 3 and 6 weeks in recipients of the intramuscular vaccine than in recipients of the intranasal vaccine. The immunogenicity of the intranasally delivered experimental vaccine varied by influenza virus strain. Mucosal IgA responses to A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong were highest in participants given 30 ?g LTK63 with the biovector, occurring in 7/15 (47%; P = 0.0103), 8/15 (53%; P = 0.0362), and 14/15 (93%; P = 0.0033) participants, respectively, compared to the placebo group. The addition of the biovector to the vaccine given with 30 ?g LTK63 enhanced mucosal IgA responses to A/Duck/Singapore (H5N3) (P = 0.0491) and B/Guandong (P = 0.0028) but not to A/Panama (H3N2). All vaccines were well tolerated., This study was supported by European Union (EU) grant QLRT-1999-00070