The logistics of delivering a mass immunization program are considerable, and concurrent administration of vaccines would be efficient for providers and more appealing to vaccinees than a requirement to make multiple visits to a healthcare provider. During the influenza A(H1N1)pmd09 pandemic, considerable variability in administration of TIV and pandemic vaccines occurred, with some authorities recommending co-administration, and others recommending that TIV be given a month or more after the pandemic vaccine. Of course, concurrent administration of vaccines is desirable only when immunogenicity is not adversely effected, and safety is similar or improved.
Although regulatory criteria for A(H1N1)pmd09 strain immunogenicity were met in all vaccine groups at 21 days after the first H1N1 dose and up to six months later, the HI antibody response against the pandemic strain following co-administration or sequential administration of TIV and A(H1N1)pmd09 vaccines was decreased compared to when A(H1N1)pmd09 vaccine was administered alone. Co-administration of TIV with the first dose of pandemic vaccine, or TIV administration 21 days prior to pandemic vaccination, appeared to negatively influence the immune response to the non-adjuvanted 15 μg HA A(H1N1)pmd09 vaccine and the AS03-adjuvanted 3.75 μg HA A(H1N1)pmd09 vaccine to a similar degree (range of GMT decrement 30.6% to 46.9%). This effect was similar at Day 63 and Day 182. This finding contrasts with data from studies of concurrent TIV and monovalent A(H1N1)pmd09 vaccination which reported that sequential and simultaneous administration of A(H1N1)pmd09 influenza vaccine and seasonal influenza vaccine did not influence the immune responses to either vaccine antigens
[3, 5–7] . In contrast to our study, participants in these cited studies could have received TIV in previous seasons compared to our population of TIV-naive subjects. As well an older age range of adults was included in other studies compared to our population of 18 to 40 year olds, and different study designs were used.
In a study in elderly adults (>64 years) using a similar AS03-adjuvanted dose-sparing vaccine, evidence of modest influence was also observed, though again with strong immune responses against the vaccine homologous A(H1N1)pmd09 strain when TIV was co-administered or sequentially administered with A(H1N1)pmd09 vaccine (GMTs: 227.5−309.8; SCRs: 64.2−97.6%)
. In a study of adults including persons over 60 years, co-administration of whole virion inactivated TIV and 6 μg HA inactivated whole virion H1N1 2009 vaccine adjuvanted with aluminium phosphate gel elicited strong immune responses against both H1N1 strains and seasonal influenza strains (GMFR: ~8.0 and 2.7−3.8; SCRs: ~81.0% and 40.3−70.7%, respectively)
Interestingly, TIV vaccination prior to pandemic vaccine in these TIV-naïve study participants increased, moderately, A(H1N1)pmd09 specific HI titres in subjects on Day 21 even before they received adjuvanted and non-adjuvanted pandemic vaccines. Other studies also suggest that prior TIV vaccination is associated with increased pandemic specific antibody responses
[9, 10]. The mechanism of this phenomenon is not known, but could be explained by lack of specificity of HI antibody testing or cross-reactive antibody responses despite lack of epitope similarity. Since up to 25% of subjects across groups in the present study were seroprotected at baseline, likely due to natural infection during the first wave of the pandemic, many of these vaccine-naive participants could have had A(H1N1)pmd09 infection without it being physician-diagnosed.
Immunogenicity to the TIV strains was unaffected by co- or sequential administration with the AS03-adjuvanted and non-adjuvanted H1N1 2009 vaccines; the CHMP and CBER criteria were met in all groups, 21 days after TIV administration (Day 42 or Day 63) and up to at least six months following the first TIV dose, except in Group F against A/Brisbane/59/2007.
As has been previously demonstrated, use of an oil-in-water adjuvant was associated with more robust immune pandemic influenza A(H1N1)pmd09 responses at all time points compared to use of non-adjuvanted 15 μg HA A(H1N1)pmd09 vaccine (to be noted: 11 μg instead of 15 μg HA was delivered). This observation has been documented in all age groups tested and for influenza antigen doses of 3.75 μg and 1.9 μg HA
The high frequency of injection site pain with the AS03-adjuvanted vaccine, is a consistent finding and in agreement with other reports
[10–12]. Grade 3 injection site pain was uncommon. The incidence of general symptoms between adjuvanted and unadjuvanted vaccine recipients were comparable.
There are several limitations to our study. The sample included TIV-naïve subjects, that is, adults less than 40 years of age without a history of receiving TIV or the pandemic vaccine, in order to increase the likelihood that subjects had little or no prior exposure to influenza and reduce age-based immunogenicity-variation and allowing for a smaller sample size. About 10.5 to 25% of subjects were not naïve to the pandemic strain. Thus, these results may not be generalizable to older adults or those with prior influenza vaccine exposure. Also, the pandemic virus was circulating during the trial, and may have confounded vaccine immunogenicity. However this is not likely to have affected one or more of the vaccine groups disproportionately.