The number of doses of H1N1 2009 pandemic influenza vaccine required to induce an optimal immune response in the elderly adult population (a population at lower risk for H1N1 disease)5
continues to be a topic of discussion. In this assessment of an AS03-adjuvanted H1N1 2009 pandemic influenza vaccine, a single dose induced strong HI immune responses 21 days later that met all three CHMP criteria for pandemic influenza vaccines in elderly adults; the CBER criterion for SCR was also met at day 21 but not the criterion for the percentage of subjects with HI antibody titers ≥ 1:40. In a study conducted in the UK, where 71 elderly subjects ≥ 65 years of age were enrolled in a larger study, a two dose regimen with an AS03-adjuvanted 3.75 µg HA formulated as split virion vaccine (n = 37) or unadjuvanted 7.5 µg HA formulated as whole-virion vaccine (n = 34) was recommended for elderly adults as European regulatory criteria were not met in this age stratum following one dose of 3.75 μg HA adjuvanted with AS03.22
A study in the US in which 257 subjects ≥ 65 years of age received the AS03-adjuvanted 3.75 µg HA vaccine, 21 days following a single vaccine dose, European and US regulatory criteria were met.23
In another study in the ≥ 65 years population, a single dose of unadjuvanted 7.5 µg HA vaccine also induced potentially protective immune responses.24
The HI antibody response in the elderly study population in the present study persisted to six months after vaccination though at lower levels than at day 21, as evident from the high seropositivity rates (81.6%). The CHMP criteria for SCR and GMFR were still met at month 6. This is in agreement with observations made in two separate studies in the US and UK, which reported that in subjects ≥ 65 years of age two doses of the AS03-adjuvanted 3.75 µg HA H1N1) 2009 vaccine were necessary to induce long-term persistence of HI antibody.22,23
The evidence for an effective immune response induced by this AS03-adjuvanted H1N1 2009 vaccine in the elderly population is not well-established in Japan. However, data for Japanese adults under age 65 years is available from studies conducted just before the mass vaccination programs with adjuvanted and non-adjuvanted formulations of H1N1 2009 vaccine.21,25
These studies reported that the immune response after two doses of AS03-adjuvanted 3.75 µg HA H1N1 2009 vaccine in Japanese adults was much higher than that observed after two doses of non-adjuvanted 15 µg HA H1N1 2009 vaccine, although the immune response after a single dose of either the adjuvanted or the non-adjuvanted formulations was comparable. The above studies suggested that two doses of AS03-adjuvanted vaccine may improve the persistence of immune response in the elderly Japanese population.
The vaccine induced a strong neutralizing antibody response in the elderly Japanese population in the present study, as evident from the VRRs at day 21. The neutralizing antibody response decreased at month 6, similar to HI antibody persistence, as the VRR at month 6 was lower than that at day 21, as was the observation for the SPR and SCR for HI antibody response at month 6.
Overall, no safety concerns related to vaccination were identified in this study population ≥ 65 years of age. The majority of the solicited symptoms reported were of mild nature (< 2.0% were of Grade 3 intensity). A comparable observation was made in a previous study in Japanese adults 20−64 years of age using a similar vaccine.21
The incidence of solicited adverse events, especially fever in the present study population of elderly adults was lower than that observed in previous studies in younger adults and children.21,28,29
In a previous study in children 6 months to 10 years of age, following two doses of an AS03-adjuvanted H1N1 pandemic influenza vaccine, the HI antibody titers were found to be the highest in children with fever ≥ 38.0₫C, which indicated a possible correlation between the immunogenicity and reactogenicity profiles of the vaccine.30
In contrast, post hoc exploratory analyses in this study indicated that there was no apparent correlation between GMT (for HI or neutralizing antibodies) and injection site pain (data not shown).
This study had certain drawbacks. First, it was a single-center study and the sample size was modest, which could be a plausible reason for not meeting the CBER regulatory guidance criteria following a single dose of the study vaccine. However, this relatively small sample size was proposed in the absence of a suitable reference study in the elderly Japanese population and taking into consideration the commitment to provide timely clinical evidence on the H1N1 2009 vaccine to the regulatory agencies at the time of the ensuing pandemic. And second, in the absence of a non-adjuvanted control group, no direct comparisons of immunogenicity or reactogenicity may be made between adjuvanted and non-adjuvanted vaccine formulations.
Since 2001, mass vaccination programs in Japan focused on two target groups – the ≥ 65 year-old population and those 60−64 years of age with chronic disorders of heart, kidney and lung.31
In this context, long-term persistence data in the elderly population from this study will complement existing literature on immune response immediately following primary vaccination.