A dose-ranging study in older adults to compare the safety and immunogenicity profiles of MF59®-adjuvanted and non-adjuvanted seasonal influenza vaccines following intradermal and intramuscular administration

Figures & data

Table 1. Study groups and vaccine formulations

Vaccine group/ formulation	Route of administration	A/H1N1 antigen per dose (µg)	A/H3N2 antigen per dose (µg)	B strain antigen per dose (µg)	MF59 per dose (%)	Volume per dose (mL)
ID1 (n = 47)	ID	6	6	6	0	0.2
ID2 (n = 46)	ID	6	12	6	0	0.2
A (n = 44)	IM	15	15	15	0	0.5
B (n = 43)	IM	15	30	15	0	0.5
C (n = 45)	IM	15	15	15	25	0.5
D (n = 46)	IM	15	30	15	25	0.5
E (n = 46)	IM	15	15	15	50	0.5
F (n = 43)	IM	15	30	15	50	0.5
G (n = 47)	IM	15	15	15	100	0.5
H (n = 43)	IM	15	30	15	100	0.5

ID, intradermal; IM, intramuscular. This paper focuses on groups ID1 and ID2 (low-dose non-adjuvanted ID); groups A and B (full-dose non-adjuvanted IM); and groups G and H (full-dose MF59-adjuvanted IM).

Table 2. Study population demographics

	Group ID1 (n = 47)	Group ID2 (n = 46)	Group A (n = 44)	Group B (n = 43)	Group G (n = 47)	Group H (n = 43)
A/H3N2 antigen per dose (µg)	6	12	15	30	15	30
MF59 per dose (%)	0	0	0	0	100	100
Age (years, SD)	68.3 ± 3.5	69.6 ± 5.1	69.2 ± 3.6	69.2 ± 4.0	68.5 ± 3.1	69.0 ± 3.5
Male (%)	49	48	40	56	42	46
Weight (kg, SD)	78.6 ± 15.5	77.1 ± 10.5	74.8 ± 13.5	77.1 ± 14.7	76.6 ± 14.3	73.0 ± 13.3
Height (cm, SD)	168.4 ± 9.0	167.7 ± 8.2	167.0 ± 8.0	167.0 ± 9.0	167.0 ± 8.0	165.0 ± 10.0
Previously vaccinated (%)	70	74	74	73	76	76
Caucasian (%)	100	100	100	98	100	100
Asian (%)	0	0	0	2	0	0

SD, standard deviation. The demographic data for IM subject groups C, D, E, and F are published elsewhere.³⁶

Table 3. Geometric mean titers (GMTs) and geometric mean ratios (GMRs) at baseline (day 1), 1 wk (day 8), and 3 wk (day 22) after vaccination (95% CI)

	GMT			GMR
A/H3N2	Group ID1 (6 µg H3N2) (0% MF59)	Group A (15 µg H3N2) (0% MF59)	Group G (15 µg H3N2) (100% MF59)	Groups A: ID1	Groups G: ID1
Day 1	14 (9.9-21) n = 43	17 (12-25) n = 43	18 (13–26) n = 46	1.2 (0.7–2.0)	1.3 (0.8–2.1)
Day 8	84 (56–128) n = 43	81 (54–123) n = 43	94 (63–141) n = 46	1.0 (0.5–1.7)	1.1 (0.6–2.0)
Day 22	236 (157–353) n = 43	158 (106–237) n = 43	252 (169–374) n = 45	0.7 (0.4–1.2)	1.1 (0.6–1.9)
A/H3N2	Group ID2 (12 µg H3N2) (0% MF59)	Group B (30 µg H3N2) (0% MF59)	Group H (30 µg H3N2) (100% MF59)	Groups B: ID2	Groups H: ID2
Day 1	15 (10–21) n = 43	17 (12–26) n = 41	16 (11–24) n = 42	1.2 (0.7–2.1)	1.1 (0.7–1.9)
Day 8	73 (48–110) n = 43	48 (31–74) n = 41	158 (103–242) n = 41	0.7 (0.4–1.2)	2.2 (1.2–3.9)*
Day 22	195 (129–293) n = 42	122 (80–184) n = 41	333 (220–503) n = 41	0.6 (0.4–1.1)	1.7 (1.0–3.1)
A/H1N1	Groups ID1+ID2 (low-dose) (0% MF59)	Groups A+B (full-dose) (0% MF59)	Groups G+H (full-dose) (100% MF59)	Groups A+B: ID1+ID2	Groups G+H: ID1+ID2
Day 1	20 (15–25) n = 86	23 (18–30) n = 84	21 (16–27) n = 88	1.2 (0.8–1.7)	1.1 (0.7–1.5)
Day 8	56 (44–72) n = 86	46 (36–60) n = 84	99 (77–126) n = 87	0.8 (0.6–1.2)	1.8 (1.2–2.5)**
Day 22	96 (74–123) n = 85	65 (50–83) n = 84	152 (118–196) n = 86	0.7 (0.5–1.0)*	1.6 (1.1–2.3)*
B Strain	Groups ID1+ID2 (low-dose) (0% MF59)	Groups A+B (full-dose) (0% MF59)	Groups G+H (full-dose) (100% MF59)	Groups A+B: ID1+ID2	Groups G+H: ID1+ID2
Day 1	12 (10–14) n = 86	12 (10–14) n = 84	11 (9.4–13) n = 88	1.0 (0.8–1.3)	0.9 (0.7–1.2)
Day 8	22 (18–27) n = 86	20 (16–24) n = 84	33 (27–39) n = 87	0.9 (0.7–1.2)	1.5 (1.1–1.9)**
Day 22	34 (28–43) n = 85	29 (23–36) n = 84	47 (38–58) n = 86	0.8 (0.6–1.1)	1.4 (1.0–1.8)*

Antibody titers at day 8 and 22 are baseline adjusted. Asterisks indicate significant differences between groups: *P < 0.05; **P < 0.01.

Table 4. Immunogenicity analyses against A/H3N2, A/H1N1, and B strain vaccine antigens according to the European (CHMP) licensure criteria for influenza vaccines for older adults

A/H3N2	Group ID1 (6 µg H3N2) (0% MF59)		Group A (15 µg H3N2) (0% MF59)		Group G (15 µg H3N2) (100% MF59)
	Day 8 (n = 43)	Day 22 (n = 43)	Day 8 (n = 43)	Day 22 (n = 43)	Day 8 (n = 46)	Day 22 (n = 46)
SC (%)	47	77	56	70	59	87
SP (%)	67	88	74	93	74	96
GMR	5.7	16	4.6	9.0	5.7	15
A/H3N2	Group ID2 (12 µg H3N2) (0% MF59)		Group B (30 µg H3N2) (0% MF59)		Group H (30 µg H3N2) (100% MF59)
	Day 8 (n = 43)	Day 22 (n = 43)	Day 8 (n = 41)	Day 22 (n = 41)	Day 8 (n = 42)	Day 22 (n = 42)
SC (%)	51	71	32	63	66	95
SP (%)	74	90	66	80	90	100
GMR	4.9	13	2.9	7.3	8.9	19
A/H1N1	Groups ID1+ID2 (low-dose) (0% MF59)		Groups A+B (full-dose) (0% MF59)		Groups G+H (full-dose) (100% MF59)
	Day 8 (n = 86)	Day 22 (n = 86)	Day 8 (n = 84)	Day 22 (n = 84)	Day 8 (n = 87)	Day 22 (n = 87)
SC (%)	35	44	20	30	51	62
SP (%)	69	84	68	77	91	95
GMR	3.1	5.1	2.0	2.8	4.5	7.1
B Strain	Groups ID1+ID2 (low-dose) (0% MF59)		Groups A+B (full-dose) (0% MF59)		Groups G+H (full-dose) (100% MF59)
	Day 8 (n = 86)	Day 22 (n = 86)	Day 8 (n = 84)	Day 22 (n = 84)	Day 8 (n = 87)	Day 22 (n = 87)
SC (%)	15	36	15	30	36	49
SP (%)	36	61	32	49	51	66
GMR	1.9	3.0	1.7	2.5	2.8	4.1

SC, seroconversion (>30% with HI titer ≥ 40); GMR, geometric mean ratio (>2.0); SP, seroprotection (>60% with HI titer ≥ 40). Day 8 GMR values describe ratio of day 8 to day 1 HI GMTs. Day 22 GMR values describe ratio of day 22 to day 1 HI GMTs. Bold text indicates that CHMP licensure criterion was met.

Figure 1. Percentages of subjects experiencing any solicited local and systemic adverse reactions within 1 wk (days 1−7) of vaccination.

Figure 2. Percentages of subjects experiencing solicited local (A) and systemic (B) adverse reactions following vaccination. Bars show percentages of subjects experiencing reactions after vaccination in the low-dose non-adjuvanted ID groups (groups ID1+ID2) (black bars); in the full-dose non-adjuvanted IM groups (groups A+B) (open bars); and in the full-dose MF59-adjuvanted IM groups (groups G+H) (gray bars). Numbers in parentheses above bars indicate numbers of subjects experiencing severe reactions. Asterisks indicate significant differences between groups: ∗ 2 sided P < 0.01; ∗∗ 2 sided P < 0.0001.

Table 5. Percentages of subjects experiencing unsolicited adverse events within 3 wk (day 1 to day 22) of vaccination

	Group ID1 (n = 47)	Group ID2 (n = 46)	Group A (n = 44)	Group B (n = 41)	Group G (n = 47)	Group H (n = 43)
A/H3N2 antigen per dose (µg)	6	12	15	30	15	30
MF59 per dose (%)	0	0	0	0	100	100
Any AEs (%)	64	59	25	16	26	19
Vaccine-related AEs (%)	53	52	7	7	11	5
SAEs (%)	0	0	2	0	0	0
AEs leading to withdrawal (%)	0	0	0	0	0	0

AEs, adverse events; SAEs, serious adverse events.

Della Cioppa G, Nicolay U, Lindert K, Leroux-Roels G, Clement F, Castellino F, Galli G, Groth N, Del Giudice G. Superior immunogenicity of seasonal influenza vaccines containing full dose of MF59 (®) adjuvant: results from a dose-finding clinical trial in older adults. Hum Vaccin Immunother 2012; 8:216 - 27; http://dx.doi.org/10.4161/hv.18445; PMID: 22426371

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