An assessment of prime-boost vaccination schedules with AS03A -adjuvanted prepandemic H5N1 vaccines: a randomized study in European adults

Abstract

Background: Long-term persistence of immune response and safety of an H5N1 prepandemic influenza vaccine adjuvanted with AS03 (an α-tocopherol oil-in-water emulsion-based adjuvant system) was evaluated using various prime-boost schedules that mimicked potential pandemic scenarios (NCT00430521).

Methods: Five hundred and twelve healthy adults aged 18-60 years received primary vaccination with one or two doses (0, 21 days schedule) of the A/Vietnam/1194/2004 H5N1 vaccine followed by a booster dose (A/Vietnam/1194/2004 or A/Indonesia/05/2005 strain) six or twelve months later across eight randomized groups. Immunogenicity results by hemagglutination inhibition [HI] assay, microneutralization assay, and the cell-mediated immune response (CMI) are reported here for the four groups boosted at Month 12.

Results: A one-dose-adjuvanted primary administration followed 12 months later by a single-adjuvanted booster dose containing a heterologous vaccine strain met or exceeded all US and European criteria for both strains. Increasing the interval between the first and second dose (from 21 days to 12 months) resulted in stronger cross-reactive immune responses against the A/Indonesia/05/2005 strain. The HI antibody response against the two strains persisted for 6 months after the booster dose irrespective of the booster vaccine's strain. The neutralizing antibody responses and the CMI observed in the study population paralleled the HI immune response. Overall, the vaccine had a clinically acceptable safety profile.

Conclusion: The H5N1 vaccine in this study allowed for flexibility in the time interval between primary and booster vaccination and the use of a heterologous strain without impacting the strength of the humoral and cellular immune response to both vaccine strains.

Figure 1

Study design diagram + CONSORT. Explanation for the study design: In the primary study, subjects were randomized into 8 study groups to receive one or two doses (21 days apart) of AS03_A‐adjuvanted H5N1 vaccine with either A/Vietnam/1194/2004 strain (VT) or A/Indonesia/05/2005 strain (IN). A homologous or heterologous booster dose (VT or IN) was administered to 4 study groups at Month 6 and the remaining 4 study groups at Month 12. Blood samples were drawn before vaccination, at Days 21 and 42, Month 6 (+7 and +30 days), Month 12 (+7 and +21 days), and at Month 18. This manuscript presents data from groups that were boosted at Month 12. Group names: VT/VT/M12: A/Vietnam/1194/2004 vaccine at Day 0; A/Vietnam/1194/2004 vaccine at Month 12. VT/IN/M12: A/Vietnam/1194/2004 vaccine at Day 0; A/Indonesia/05/2005 vaccine at Month 12. 2VT/VT/M12: A/Vietnam/1194/2004 vaccine at Days 0 and 21; A/Vietnam/1194/2004 vaccine at Month 12. 2VT/IN/M12: A/Vietnam/1194/2004 vaccine at Days 0 and 21; A/Indonesia/05/2005 vaccine at Month 12.

Figure 2

(A) Reverse cumulative curves for HI antibody response against the A/Vietnam/1194/2004 and A/Indonesia/05/2005 strains at all time points (per‐protocol cohort for immunogenicity). (B) Reverse cumulative curves for neutralizing antibody response against the A/Vietnam/1194/2004 and A/Indonesia/05/2005 strains at all time points (per‐protocol cohort for immunogenicity). For group names see Figure 1.

Figure 3

(A, B) Cell‐mediated immune response at Months 12 and 18 (per‐protocol cohort for immunogenicity). For group names see Figure 1.

Figure 4

(A, B) Split H5N1‐specific memory B cell response against the A/Vietnam/1194/2004 and A/Indonesia/05/2005 strains at all time points (per‐protocol cohort for immunogenicity). For group names see Figure 1.

Figure 5

(A) Solicited local symptoms reported during the 7‐day post‐vaccination follow‐up period after Month 12 booster (total vaccinated cohort). (B) Solicited general symptoms reported during the 7‐day post‐vaccination follow‐up period after Month 12 booster (total vaccinated cohort). Error bars indicate the upper and lower limits of the 95% confidence intervals (CIs). For group names see Figure 1.