A total of 1359 subjects (see ), were enrolled and 1357 subjects received either TIV or placebo from 12 June 2006 to 01 August 2006. A total of 823 subjects received the multi-dose lots (Lot 1 n=273, Lot 2 n=275, Lot 3 n=275); 266 subjects received the pre-filled, thimerosal-free syringes, and 268 subjects received placebo. demonstrates that the subjects were randomly distributed between the different vaccine formulations by age, gender, and race. All subjects who received any study vaccine or placebo were included in the safety assessment.
Flow Chart of Subject Disposition
Demographic characteristics of vaccinated subjects
A total of 1351 subjects (99.5%) completed the study, and 8 subjects (0.6%) were withdrawn: five subjects were lost to follow-up, one subject withdrew from the study voluntarily, and two subjects were randomized but not vaccinated (). There were no withdrawals due to vaccine-associated adverse events.
Subjects without paired pre- and post-vaccination blood samples and individuals who received either steroids or immunomodulating agents after enrollment were excluded, leaving a total evaluable population of 1341 subjects: 814 subjects receiving vaccine from the multi-dose vials (Lot 1 n=270 [98.9%], Lot 2 n=275 [100%], Lot 3 n=269 [97.8%]); 263 subjects (98.9%) receiving vaccine from the pre-filled syringes, and 264 subjects (97.8%) receiving placebo (see ).
presents the immunogenicity data on the 1341 subjects in the evaluable population. The proportion of subjects who achieved seroprotection (post-vaccination titer ≥ 40) was 97.8% (95% CI 96.7%, 98.6%) for the A/New Caledonia strain, 99.9% (95% CI 99.5%, 100.0%) for the A/New York strain, and 94.2% (95% CI 92.7%, 95.6%) for the B/Malaysia strain. All presentations of vaccine yielded comparable immune responses.
Co-primary immunogenicity endpoint* results by presentation, lot, placebo and for all active vaccine formulations
displays post-vaccination sero-protection rates based on age groups of subjects at the time of enrollment. Sero-protection rates were similar in all age groups for the H1N1 and H3N2 strains, but were slightly lower with age for the B strain. Subjects last vaccinated in the previous year were more likely to have had pre-vaccination seroprotective titres compared with subjects who were last vaccinated either 2 years or more ago (). Pre-vaccination seroprotection rates were generally much lower for the B strain than the other strains.
Percentage of subjects with seroprotective levels of antibodies by influenza strain and age group.
Percent of subjects with prevaccination seroprotective titers by influenza strain and year of the last influenza vaccine received
The solicited adverse events of induration, erythema, pain, tenderness, bruising and myalgia were reported more often after vaccine than placebo (). In general the solicited adverse event profile was comparable between the thimerosal-free and thimerosal-containing preparations. However, injection site pain (47% vs 37.4%, p=0.0031), and tenderness (68.0% vs 57.1%, p=0.0007) were more frequently seen with the thimerosal-free than the thimerosal-containing preparation. P values were not adjusted for multiple comparisons.
Proportion of subjects reporting solicited adverse events on Days 0–4
Of those subjects who reported AEs, most symptoms were mild to moderate in intensity. During the 20-days post-vaccination period the majority of unsolicited AEs were mild (350) or moderate (191) with induration, erythema, and pain seen significantly more often after vaccine than placebo. A smaller percentage of subjects had unsolicited AEs that were considered severe in intensity (1.9% in the placebo group, 1.1% thimerosal-free preparation, and 0.9% in the thimerosal-containing vials). No severe intensity unsolicited AEs were judged to be associated with vaccine.
One subject, a health care worker who had been previously vaccinated on multiple occasions without adverse events, experienced generalized urticaria, arthralgias, and dermatographism beginning 24 hours after immunization, which has persisted for at least one year and has been diagnosed as serum sickness syndrome. The subject had no prior history of reaction to vaccines, thimerosal or egg protein, nor a family history of allergy. The event was assessed as vaccine associated (Lot 3 multi-dose vial, thimerosal-containing presentation). Another subject became pregnant at approximately the time of vaccination and delivered a healthy baby. There were no vaccine related serious adverse events during the study.