Dose ranging of adjuvant and antigen in a cell culture H5N1 influenza vaccine: Safety and immunogenicity of a phase 1/2 clinical trial

BackgroundDose-sparing strategies and new production technologies will be necessary to produce adequate supplies of vaccines for pandemic influenza. One approach is to include adjuvant, which can reduce the amount of antigen required for immunization and stimulate cross-reactive responses to drifted variants of novel viruses. Dose-sparing studies of adjuvant, itself a finite resource, have not previously been reported for H5N1 vaccine development.Methodology/principal findingsA total of 753 healthy 18–40-year-old adults were randomized to one of 12 groups (N ∼ 60/group) to receive two intramuscular doses, 21 days apart, of 3.75, 7.5 or 15 μg of cell culture grown influenza A/H5N1 hemagglutinin (A/Indonesia/5/2005 (H5N1)/PR-8-IBCDC-RG2), each dose level formulated with 0%, 25%, 50% or 100% of the MF59 dose contained in licensed influenza vaccine. 752 subjects actually received one dose, and 695 a second dose. Serum hemagglutination inhibition and neutralizing antibody levels, were determined before and 21 days after each dose. Safety and reactogenicity were assessed by self-completed diary cards. Nonadjuvanted H5N1 formulations were poorly immunogenic, but antibody responses were significantly enhanced by all doses of MF59 for each antigen level. The 3.75 μg H5N1 containing 50% MF59 satisfied the European criteria for pandemic vaccine licensure. All formulations were well tolerated, although MF59 dose-dependent increases in the frequency of injection site pain were observed. The frequencies of injection site and systemic reactions were lower after receipt of the second dose of vaccine. No vaccine-related SAE was reported.ConclusionsDose-sparing of both antigen and adjuvant is possible without compromising immunogenicity, while improving reactogenicity and is a promising strategy that will expand the availability of vaccines for global control of pandemic influenza.