A phase II study of an investigational tetravalent influenza vaccine formulation combining MF59^®

Figures & data

Table 1. Demographics of the study population. Group A: Tetravalent vaccine and placebo on Day 1, A/H5N1 vaccine on Day 22; Group B: A/H5N1 vaccine and placebo on Day 1, tetravalent vaccine on Day 22; Group C: A/H5N1 and seasonal influenza vaccines on Day 1, A/H5N1 vaccine on Day 22

	Group A (n = 199)	Group B (n = 203)	Group C (n = 199)
Age (years, SD)	28.3 ± 8.0	30.6 ± 9.8	31.0 ± 9.6
Male (%)	36	36	42
Weight (kg, SD)	69.7 ± 15.7	69.4 ± 14.1	72.1 ± 15.3
Height (cm, SD)	172.2 ± 8.3	172.6 ± 8.2	172.8 ± 9.5
BMI (kg/m^2, SD)	23.4 ± 4.4	23.2 ± 3.9	24.0 ± 4.2
Previous influenza vaccination (%)	24	28	30
Asian (%)	0	0	2
Black (%)	1	0	0
Caucasian (%)	97	98	97
Hispanic (%)	2	2	1

SD, standard deviation; BMI, body mass index.

Table 2. Immunogenicity analyses against the pre-pandemic vaccine strain, A/Vietnam/1194/2004 (H5N1)

	Vaccine groups (95% CI)			Vaccine group ratios (96.7% CI)
	A	B	C	A: B	A: C	B: C
SRH Assay
GMA Day 1	4.6 (4.2–5.2) n = 194	4.1 (3.7–4.6) n = 202	4.6 (4.1–5.1) n = 198	1.1 (1.0–1.3)	1.0 (0.9–1.1)	0.9 (0.8–1.0)
GMA Day 22	14 (10–19) n = 31	12 (8.5–16) n = 31	16 (12–23) n = 30	1.2 (0.7–1.9)	0.9 (0.5–1.4)	0.7 (0.4–1.2)
GMA Day 43	41 (36–47) n = 181	35 (31–40) n = 189	39 (34–44) n = 189	1.1 (1.0–1.3)	1.1 (0.9–1.2)	0.9 (0.8–1.0)
GMR Days 22: 1	3.1 (2.2–4.2)	2.5 (1.8–3.4)	3.2 (2.3–4.5)	1.2 (0.8–2.0)	1.0 (0.6–1.6)	0.8 (0.5–1.3)
GMR Days 43: 1	8.8 (7.4–10)	8.6 (7.3–10)	8.3 (7.0–9.8)	1.0 (0.8–1.2)	1.1 (0.9–1.3)	1.0 (0.9–1.2)
HI Assay
GMT Day 1	5.9 (5.5–6.4) n = 192	5.6 (5.2–6.0) n = 198	5.9 (5.4–6.3) n = 193	1.1 (1.0–1.1)	1.0 (0.9–1.1)	1.0 (0.9–1.0)
GMT Day 22	8.4 (5.8–12) n = 31	6.8 (4.7–9.8) n = 31	9.7 (6.7–14) n = 30	1.2 (0.7–2.2)	0.9 (0.5–1.5)	0.7 (0.4–1.2)
GMT Day 43	46 (30–70) n = 181	33 (22–50) n = 187	49 (32–75) n = 186	1.4 (0.9–2.1)	0.9 (0.6–1.4)	0.7 (0.5–1.0)
GMR Days 22: 1	1.5 (1.0–2.2)	1.4 (0.9–2.1)	1.9 (1.3–2.9)	1.1 (0.6–2.0)	0.8 (0.4–1.4)	0.7 (0.4–1.3)
GMR Days 43: 1	7.9 (5.1–12)	6.1 (4.0–9.2)	8.8 (5.7–13)	1.3 (0.9–2.0)	0.9 (0.6–1.4)	0.7 (0.5–1.0)
MN Assay
GMT Day 1	10 (9.3–11) n = 194	10 (9.7–11) n = 202	10 (9.6–11) n = 198	1.0 (0.9–1.0)	1.0 (0.9–1.1)	1.0 (0.9–1.1)
GMT Day 22	14 (11–19) n = 31	16 (12–22) n = 31	17 (13–23) n = 30	0.9 (0.7–2.2)	0.8 (0.5–1.5)	0.9 (0.4–1.2)
GMT Day 43	141 (110–180) n = 181	111 (87–141) n = 189	133 (105–169) n = 189	1.4 (0.9–2.1)	0.9 (0.6–1.4)	0.7 (0.5–1.0)
GMR Days 22: 1	1.5 (1.1–1.9)	1.6 (1.2–2.2)	1.6 (1.2–2.2)	0.9 (0.6–1.4)	0.9 (0.6–1.4)	1.0 (0.6–1.6)
GMR Days 43: 1	14 (11–18)	11 (8.4–14)	13 (10–16)	1.3 (1.0–1.7)	1.1 (0.9–1.4)	0.8 (0.7–1.0)

Geometric mean titers (GMT), geometric mean areas (GMA), and geometric mean ratios (GMRs) determined by SRH, HI, and MN assays (95% CI). Group A: Tetravalent vaccine and placebo on Day 1, A/H5N1 vaccine on Day 22; Group B: A/H5N1 vaccine and placebo on Day 1, tetravalent vaccine on Day 22; Group C: A/H5N1 and seasonal influenza vaccines on Day 1, A/H5N1 vaccine on Day 22.

Figure 1. (A) Seroprotection rates (95% CI) against the pre-pandemic vaccine strain, A/Vietnam/1194/2004 (H5N1), after two vaccine doses (Day 43) as measured by SRH and HI assays; (B) seroprotection rates (95% CI) against the seasonal vaccine strains, A/Solomon Islands/3/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 (B strain) after two vaccine doses (Day 43) as measured by HI assay. Dotted lines represent the CHMP licensure criterion for seroprotection (70%). Group A: Tetravalent vaccine and placebo on Day 1, A/H5N1 vaccine on Day 22; Group B: A/H5N1 vaccine and placebo on Day 1, tetravalent vaccine on Day 22; Group C: A/H5N1 and seasonal influenza vaccines on Day, A/H5N1 vaccine on Day 22.

Table 3. Immunogenicity analysis by HI assay (95% CI) against the seasonal vaccine strains, A/Solomon Islands/3/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 (B strain)

	Group A H1N1	Group B H1N1	Group C H1N1	Group A H3N2	Group B H3N2	Group C H3N2	Group A B Strain	Group B B Strain	Group C B Strain
GMT (Day 1)	45 (29–68) n = 194	38 (26–58) n = 202	54 (36–82) n = 198	45 (32–63) n = 194	37 (27–52) n = 202	44 (32–63) n = 198	11 (9.1–14) n = 194	13 (11–16) n = 202	13 (11–16) n = 198
GMT (Day 22)	541 (360–815) n = 31	58 (38–87) n = 31	618 (408–937) n = 30	414 (273–628) n = 31	35 (23–54) n = 31	368 (241–562) n = 30	98 (71–135) n = 31	13 (9.1–17) n = 31	104 (75–145) n = 30
GMT (Day 43)	702 (536–920) n = 181	687 (529–891) n = 189	565 (434–735) n = 189	425 (331–544) n = 181	451 (355–573) n = 189	292 (229–371) n = 189	116 (89–149) n = 181	113 (88–145) n = 189	110 (85–141) n = 189
GMR (Day 1: 22)	21 (12–36) n = 31	1.6 (0.9–2.7) n = 31	15 (8.9–27) n = 30	17 (11–28) n = 31	1.4 (0.9–2.3) n = 31	10 (6.3–17) n = 30	15 (10–20) n = 31	1.5 (1.1–2.1) n = 31	14 (10–20) n = 30
GMR (Day 1: 43)	16 (10–24) n = 181	17 (11–26) n = 189	9.9 (6.4–15) n = 189	9.4 (6.6–13) n = 181	11 (8.2–16) n = 189	6.1 (4.3–8.7) n = 189	9.9 (7.3–13) n = 181	7.9 (5.9–11) n = 189	8.0 (5.9–11) n = 189
SP % (Day 1)	51 (44–58) n = 194	52 (45–59) n = 202	57 (49–64) n = 198	54 (46–61) n = 194	48 (40–55) n = 202	56 (48–63) n = 198	8 (5–13) n = 194	13 (9–19) n = 202	12 (8–17) n = 198
SP % (Day 22)	97 (83–100) n = 31	81 (63–93) n = 31	100 (88–100) n = 30	97 (83–100) n = 31	58 (39–75) n = 31	100 (88–100) n = 30	97 (83–100) n = 31	16 (5–34) n = 31	90 (73–98) n = 30
SP % (Day 43)	99 (97–100) n = 181	99 (96–100) n = 189	99 (96–100) n = 189	99 (96–100) n = 181	100 (98–100) n = 189	98 (95–100) n = 189	88 (83–93) n = 181	85 (79–90) n = 189	89 (84–93) n = 189
SC % (Day 22)	87 (70–96) n = 31	13 (4–30) n = 31	73 (54–88) n = 30	84 (66–95) n = 31	3.0 (0.1–17) n = 31	73 (54–88) n = 30	87 (70–96) n = 31	3.0 (0.1–17) n = 31	87 (69–96) n = 0
SC % (Day 43)	79 (72–85) n = 181	80 (74–86) n = 189	72 (65–78) n = 189	80 (73–85) n = 181	78 (72–84) n = 189	71 (64–78) n = 189	81 (75–87) n = 181	71 (64–78) n = 189	78 (71–83) n = 189

Group A: Tetravalent vaccine and placebo on Day 1, A/H5N1 vaccine on Day 22; Group B: A/H5N1 vaccine and placebo on Day 1, tetravalent vaccine on Day 22; Group C: A/H5N1 and seasonal influenza vaccines on Day 1, A/H5N1 vaccine on Day 22. GMT, geometric mean titer; GMR, geometric mean ratio; SC, seroconversion or significant increase; SP, seroprotection.

Table 4. Percentages of subjects experiencing mild to moderate (and severe) solicited local adverse reactions within one week of receiving first (two doses, one in each arm) and second vaccine doses

	Group A 1st Dose		Group B 1st Dose		Group C 1st Dose		Group A 2nd Dose	Group B 2nd Dose	Group C 2nd Dose
	Tetravalent (n = 195)	Placebo (n = 194)	A/H5N1 (n = 201)	Placebo (n = 201)	A/H5N1 (n = 197)	Seasonal (n = 196)	A/H5N1 (n = 188)	Tetravalent (n = 192)	A/H5N1 (n = 192)
Erythema	5 (0)	0 (0)	2 (0)	0 (0)	3 (0)	3 (0)	1 (0)	3 (1)	3 (0)
Induration	11 (0)	1 (0)	2 (0)	0 (0)	5 (0)	2 (0)	4 (0)	4 (1)	4 (0)
Swelling	10 (0)	1 (0)	3 (0)	0 (0)	4 (0)	2 (0)	3 (0)	3 (1)	3 (0)
Ecchymosis	1 (0)	1 (0)	1 (0)	0 (0)	1 (0)	1 (0)	2 (0)	2 (0)	1 (0)
Pain	83 (1)	15 (0)	69 (< 1)	16 (0)	66 (0)	41 (< 1)	52 (0)	69 (2)	46 (1)

Group A: Tetravalent vaccine and placebo on Day 1, A/H5N1 vaccine on Day 22; Group B: A/H5N1 vaccine and placebo on Day 1, tetravalent vaccine on Day 22; Group C: A/H5N1 and seasonal influenza vaccines on Day, A/H5N1 vaccine on Day 22.

Table 5. Percentages of subjects experiencing mild to moderate (and severe) solicited systemic reactions within one week of vaccination

	Group A 1st Dose (n = 195)	Group B 1st Dose (n = 201)	Group C 1st Dose (n = 196)	Group A 2nd Dose (n = 187)	Group B 2nd Dose (n = 192)	Group C 2nd Dose (n = 192)
Chills	10 (2)	4 (< 1)	4 (1)	2 (1)	5 (1)	2 (0)
Malaise	29 (3)	14 (< 1)	13 (1)	7 (1)	17 (3)	7 (1)
Myalgia	32 (3)	23 (0)	20 (1)	11 (1)	26 (2)	14 (0)
Arthralgia	14 (3)	7 (0)	5 (1)	2 (1)	7 (1)	2 (1)
Headache	34 (2)	26 (< 1)	21 (1)	17 (1)	23 (3)	13 (1)
Sweating	5 (2)	8 (< 1)	4 (1)	2 (1)	7 (0)	4 (0)
Fatigue	37 (4)	29 (0)	26 (1)	16 (1)	28 (3)	16 (2)
Nausea	11 (1)	8 (< 1)	4 (0)	3 (1)	7 (1)	3 (0)
Coughing	7 (0)	8 (< 1)	8 (0)	7 (0)	5 (1)	6 (1)
Fever (≥38°C)	4	< 1	2	1	3	0
Stayed home	4	3	1	1	4	1
Analgesic/Antipyretic	14	10	8	3	8	3

Group A: Tetravalent vaccine and placebo on Day 1, A/H5N1 vaccine on Day 22; Group B: A/H5N1 vaccine and placebo on Day 1, tetravalent vaccine on Day 22; Group C: A/H5N1 and seasonal influenza vaccines on Day, A/H5N1 vaccine on Day 22.