Safety and immunogenicity of influenza A H5 subunit vaccines: effect of vaccine schedule and antigenic variant

Abstract

Background: The current US national stockpile of influenza H5 vaccine was produced using the antigen from the strain A/Vietnam/1203/2004 (a clade 1 H5 virus). Recent H5 disease has been caused by antigenically divergent H5 viruses, including A/Indonesia/05/2005 (a clade 2 H5 virus).

Methods: The influence of schedule on the antibody response to 2 doses of H5 vaccines (one a clade 1 hemagglutinin protein [HA] vaccine and one a clade 2 HA vaccine) containing 90 μg of antigen was evaluated in healthy adults 18-49 years of age.

Results: Two doses of vaccine were required to induce antibody titers ≥ 1:10 in most subjects. Accelerated schedules were immunogenic, and antibody developed after vaccinations on days 0 and 7, 0 and 14, and 0 and 28, with the day 0 and 7 schedule inducing lower titers than those induced with the other schedules. With mixed vaccine schedules of clade 1 followed by clade 2 vaccine administration, the first vaccination primed for a heterologous boost. The heterologous response was improved when the second vaccination was given 6 months after the first, compared with the response when the second vaccination was given after an interval of 1 month.

Conclusions: An accelerated vaccine schedule of injections administered at days 0 and 14 was as immunogenic as a vaccine schedule of injections at days 0 and 28, but both schedules were inferior to a vaccine schedule of injections administered at 0 and 6 months for priming for heterologous vaccine boosting. Clinical Trial Registry Number: NCT00703053.

Figures

Figure 1.

Occurrence of any adverse reaction after vaccination dose 1 (A) or vaccination dose 2 (B) among all groups. Severity of reactions is also indicated. Mild, does not interfere with daily activity; moderate, interferes with daily activity; severe, prevents daily activity. Vac, vaccination.

Figure 2.

Occurrence of 6 types of systemic reactions and any systemic reactions, as well as 6 types of local reactions and any local reactions, among all subjects in all groups after vaccination dose 1 (A) or vaccination dose 2 (B). Mild, does not interfere with daily activity; moderate, interferes with daily activity; severe, prevents daily activity. For redness (mm) and swelling (mm), mild, moderate, and severe refer to small (<20-mm), medium (20–50-mm), or large (>50-mm) diameter, respectively, of the indicated sign of adverse event. Elev, elevated; Temp, temperature; Vac, vaccination.

Figure 3.

Geometric mean titer (GMT) plots of serum hemagglutinating inhibiting (HI) antibody to A/Vietnam/04 antigen among the 9 vaccine groups are shown. Symbols on the x-axis of each subpanel indicate the day of vaccination with A/Vietnam/04 vaccine (V), A/Indonesia/05 vaccine (I), or both (B). Statistical comparisons (a) to assess vaccine schedule in group 4 versus group 2 (P = .99) and group 4 versus group 3 (P = .94), (b) to assess monovalent vaccine versus bivalent vaccine in group 4 versus group 7 (P = .61), (c) to assess heterologous boosting in group 4 versus group 6 (P = .37), (d) to assess heterologous boosting after a long rest in group 4 versus group 9 (P = .31) and group 6 versus group 9 (P = .009), and (e) to assess heterologous boost versus bivalent vaccine in group 6 versus group 7 (P >.99).

Figure 4.

Geometric mean titer (GMT) plots of serum hemagglutinating inhibiting (HI) antibody to A/Indonesia/05 antigen among the 9 vaccine groups are shown. Symbols on the x-axis of each subpanel indicate the day of vaccination with A/Vietnam/04 vaccine (V), A/Indonesia/05 vaccine (I), or both (B). Statistical comparisons (a) to assess long-interval vaccine schedule in group 5 versus group 8 (P = .03), (b) to assess monovalent vaccine versus bivalent vaccine in 5 versus group 7 (P >.99),= (c) to assess heterologous boost after a 1-month interval in group 5 versus group 6 (P = .001), (d) to assess heterologous boost after a long rest interval in group 5 versus group 9 (P = .59) and group 8 versus group 9 (P = .72), and (e) to assess interval of heterologous boost in group 6 versus group 9 (P≤.001).

Figure 5.

Geometric mean titer (GMT) plots of serum microneutralizing (Neut) antibody to A/Vietnam/04 antigen among the 9 vaccine groups are shown. Symbols on the x-axis of each subpanel indicate the day of vaccination with A/Vietnam/04 vaccine (V), A/Indonesia/05 vaccine (I), or both (B). Statistical comparisons (a) to assess vaccine schedule in group 4 versus group 2 (P = .03) and in group 4 versus group 3 (P = .74), (b) to assess monovalent vaccine versus bivalent vaccine in group 4 versus group 7 (P = .006), (c) to assess heterologous boosting in group 4 versus group 6 (P = .01), (d) to assess heterologous boosting after a long rest group 4 versus group 9 (P≤.001; and group 6 versus group 9 (P≤.001), and (e) to assess heterologous boost versus bivalent vaccine in group 6 versus group 7 (P <.99).

Figure 6.

Geometric mean titer (GMT) plots of serum microneutralizing (Neut) antibody to A/Indonesia/05 antigen among the 9 vaccine groups are shown. Symbols on the x-axis of each subpanel indicate the day of vaccination with A/Vietnam/04 vaccine (V), A/Indonesia/05 vaccine (I), or both (B). Statistical comparisons (a) to assess long-interval vaccine schedule in group 5 versus group 8 (P≤.001), (b) to assess monovalent vaccine versus bivalent vaccine in group 5 versus group 7 (P>.99), (c) to assess heterologous boost after a 1-month interval in group 5 versus group 6 (P≤.001), (d) to assess heterologous boost after a long rest interval in group 5 versus group 9 (P = .93) and group 8 versus group 9 (P = .002), and (e) to assess interval of heterologous boost in group 6 versus group 9 (P≤.001).