A high immune response in terms of HI antibodies, neutralizing antibodies, and cell-mediated immunity was induced by 2 injections of a single dose of 3.75 μg HA AS03A-adjuvanted vaccine given 3 weeks apart to participants aged >60 years. All CHMP requirements for influenza vaccines in the elderly population were met for this regimen. The more stringent CHMP criteria for vaccination of younger adults (>40% for SCR and >70% for SPR) were also achieved. The benefit of the AS03A adjuvant system was demonstrated since the nonadjuvanted vaccine groups showed markedly lower immune responses that failed to meet regulatory acceptance criteria. Persistence of the immune response was also high 6 months after vaccination. The SCR was still above the postvaccination licensure criterion with both adjuvanted formulations, and the SPR was above the criterion for the double-dose adjuvanted formulation. Although the specified sample size was not reached, adequate statistical power was achieved. Originally, a sample size of 170 subjects per group was estimated to have 86% power to detect a 1.7-fold difference between GMTs in the 2 AS03-adjuvanted groups. In fact, there was a 1.87-fold difference between GMTs in the 2 groups, and the reestimated power based on this difference was calculated to be 94.1%.
Assessment of a double-dose vaccine regimen was motivated by the well-recognized lower immune response in elderly persons [12
]. Accordingly, the single-dose regimen induced lower immune responses after 2 vaccinations than usually observed in adults aged 18-60 years [5
]. However, although the double dose of the AS03A
-adjuvanted vaccine produced a higher immune response, licensing criteria were easily met with the single vaccine dose following a 2-vaccination administration schedule. This supports the use of the single dose in both the elderly population and among adults aged 18-60 years, as has been recognized by regulatory authorities with the recent extension of the vaccine licence to all adults aged >18 years [4
When the overall study population was considered, only 1 dose of AS03A
-adjuvanted vaccine (either single or double) seemed sufficient to reach both CHMP SCR and SPR criteria. However, further exploratory analysis showed that this effect was mainly driven by the HI immune response in initially seropositive individuals, who represented 38% of the ATP cohort for immunogenicity. In initially seronegative individuals, the response was lower, and all CHMP criteria were only met after 2 vaccinations with both the single- and double-dose regimens, indicating that a majority of elderly subjects will benefit from a 2-vaccination administration schedule, with doses given 21 days apart. The proportion of initially seropositive participants was higher than previously observed in younger adult populations [5
] and may have occurred as a result of previous seasonal influenza vaccination or natural infection, as several studies have demonstrated cross-reactivity between avian and human strains for cell-mediated immunity and neutralizing antibody response [20
]. More recently, cross-reactivity for an HA-specific antibody response was demonstrated in a study in which a seasonal influenza vaccine containing H1 and H3 antigens produced antibodies that cross-reacted with H5 HA [23
]. Alternatively, the high seropositivity may reflect false-positive assay results, and it is possible that the microneutralization assay may have captured some N1 response. However, the HI assay used corresponds to international standards [14
], and we are confident that the antibody activity measured is specific to H5N1. Thus, we believe that cross-reactivity between seasonal and avian influenza strains is a more likely explanation of the high levels of prevaccination seropositivity. Antibody titers may have limitations as the sole indicator of influenza vaccine efficacy in elderly persons, and it has been suggested that measures of the cell-mediated immune response should be included in evaluations of vaccines in this population [24
]. Measurement of cell-mediated immunity was therefore included in the present study to gain a better understanding of the overall immune response induced by the vaccine and, thus, a better evaluation of its protective potential. The study showed that the pattern of the immune response to the AS03A
-adjuvanted H5N1 vaccine was similar in terms of HI antibodies, neutralizing antibodies, and cell-mediated immunity (CD4 T cell responses). No CD8 T cell responses were observed. This may be due to the assay method or the protein content of the vaccine, although the possibility that the vaccine does not induce CD8 T cell responses cannot be excluded.
It is interesting to note that the kinetics of the immune response to the AS03A
-adjuvanted H5N1 vaccine in elderly subjects seemed different from those observed in younger adults: 3 weeks after the first dose of vaccine was administered, HI antibody titers against the vaccine strain in the present study were higher than those in younger adults [5
]. In contrast, 3 weeks after the second dose of vaccine was administered, titers were higher in the younger individuals. Although there was some decline, the immune response persisted up to 6 months after first vaccination, consistent with results seen in younger adults [8
The safety and reactogenicity profile of the AS03A-adjuvanted H5N1 vaccine in elderly subjects was similar to that in younger adults (data shown in safety supplement), and no safety concerns were raised. Although there were more local and general symptoms reported with the adjuvanted vaccine than the nonadjuvanted vaccine, they were mainly mild-to-moderate and transient in nature, and reactogenicity was clinically acceptable.
In conclusion, 2 single 3.75-μg HA doses of the AS03A-adjuvanted H5N1 vaccine administered 21 days apart induced a high immune response in an elderly population. The study indicates that elderly persons do not require a higher vaccine dose than younger adults and the vaccine can be administered according to the same schedule. This will support a dose-sparing strategy, because elderly persons are an important target for vaccination in a pandemic situation.