Safety and persistence of immunological response 6 months after intramuscular vaccination with an AS03-adjuvanted H1N1 2009 influenza vaccine

Figures & data

Figure 1. Study design diagram. Total vaccinated cohort (TVC): all subjects with at least one documented vaccine dose with available immunogenicity results. According-to-protocol (ATP) cohort for immunogenicity: all evaluable subjects (i.e., those meeting all eligibility criteria, with no elimination criteria during the relevant analysis interval), who received two vaccine doses and for whom assay results were available at Day 42 and Day 182. Group 1.9µgHA: Subjects aged 6 mo-9 y received two doses of 1.9µg HA+AS03_B (5.93mg α-tocopherol) vaccine, 21 d apart. Group 3.75µgHA: Subjects aged 10–17 y received two doses of 3.75µg HA+AS03_A (11.86mg α-tocopherol) vaccine, 21 d apart.

Table 1. Immune response in terms of haemagglutination inhibition antibodies against vaccine homologous A/California/7/2009 strain [CBER^c/CHMP^d criteria] (ATP cohort for immunogenicity)

Measure	Time point	Group 1.9µgHA 6 mo−9 y						Group 3.75µgHA 10–17 y
		N^a	Overall	Age sub-strata				N	Overall
				N	6–35 mo	N	3–9 y
		Value or Point estimate (95% CI^b)
Seroprotection rates	PRE^#^	29	3.4% (0.1–17.8)	10	0.0% (0.0–30.8)	19	5.3% (0.1–26.0)	30	26.7% (12.3–45.9)
	Day 21^	29	100% (88.1–100)	10	100% (69.2-100)	19	100% (82.4–100)	30	96.7% (82.8–99.9)
	Day 42	28	100% (85.5–100)*	9	100% (66.4-100)	19	100% (82.4–100)	30	100% (86.4–100)*
	Day 182	28	100% (87.7–100)	9	100% (66.4-100)	19	100% (82.4–100)	29	100% (88.1–100)
Seroconversion rates	Day 21^	29	100% (88.1–100)	10	100% (69.2–100)	19	100% (82.4–100)	30	90% (73.5–97.9)
	Day 42^	28	100% (85.5–100)*	9	100% (66.4–100)	19	100% (82.4–100)	30	100% (86.4–100)*
	Day 182	28	96.4% (81.7–99.9)	9	100% (66.4–100)	19	94.7% (74.0–99.9)	29	89.7% (72.6–97.8)
Geometric Mean Fold Rise	Day 21^	29	27.1 (20.4–36.1)	10	23.5 (14.4–38.2)	19	29.3 (19.9–42.9)	30	22.1 (13.6–35.9)
	Day 42	28	146.8 (99.6–216.4)*	9	256.0 (161.4–406.1)	19	112.8 (74.6–170.5)	30	57.1 (33.5–97.3)*
	Day 182	28	25.3 (18.4–34.7)	9	30.8 (20.1–47.3)	19	23.1 (14.9–35.8)	29	23.5 (14.9–37.1)
Geometric Mean Titers	PRE^#^	29	6.3 (5.0–8.1)	10	5.0 (5.0–5.0)	19	7.2 (5.0–10.3)	30	15.3 (9.5–24.6)
	Day 21^	29	172 (130.1–227.6)	10	117.3 (72.2–190.8)	19	210.4 (150.4–294.5)	30	339 (238.8–481.2)
	Day 42	28	939.3 (722.9–1220.6)*	9	1279.9 (806.9–2030.4)	19	811.3 (628.4–1047.4)	30	874.3 (717.4–1065.4)*
	Day 182	28	161.9 (133.7–196.1)	9	154.0 (100.3–236.5)	19	165.8 (131.9–208.5)	29	347.9 (254.0–476.5)
Seropositivity rates	PRE^#^	29	17.2% (5.8–35.8)	10	0.0 (0.0–30.8)	19	26.3% (9.1–51.2)	30	60.0% (40.6–77.3)
	Day 21^	29	100% (88.1–100)	10	100% (69.2–100)	19	100% (82.4–100)	30	100% (88.4–100)
	Day 42	28	100% (85.5–100)*	9	100% (66.4–100)	19	100% (82.4–100)	30	100% (86.4–100)*
	Day 182	28	100% (87.7–100)	9	100% (66.4–100)	19	100% (82.4–100)	29	100% (88.1–100)

Group 1.9µgHA: Subjects aged 6 mo-9 y received two doses of 1.9µg HA+AS03_B (5.93mg α-tocopherol) vaccine, 21 d apart. Group 3.75µgHA: Subjects aged 10–17 y received two doses of 3.75µg HA+AS03_A (11.86mg α-tocopherol) vaccine, 21 d apart. ^aN: Number of subjects with available results. ^bCI: Confidence Interval. ^cCBER: Center for Biologics Evaluation and Research [Lower limit of 95% CI: SPR: ≥ 70%; SCR: ≥ 40%]. ^dCHMP: Committee for Medicinal Products for Human Use [Point estimate: SPR: > 70%; SCR: > 40%; GMFR: > 2.5].^#PRE: Pre-vaccination antibody titers for ATP cohort for immunogenicity at Day 21.*As per pre-defined primary co-objectives of this study, Day 42 immune response was calculated with 97.5% CI as per the CBER criteria for Group A (age 6 mo to 9 y), Group B (age 10–17 y), while at the other time points 95% CI was used. BOLD: Values of SPR and Geometric mean fold rise that did not meet the pre-specified criteria. ^PRE and Day 21 data have been presented previously in the primary manuscript [ref. 21: Saitoh A, et al. J Japan Pediatr Soc 2011]

Table 2. Immune response in terms of neutralising antibodies against the A/Netherlands/602/2009 strain (ATP immunogenicity cohort)

Measure	Time point		Group 1.9µgHA 6 mo−9 y						Group 3.75µgHA 10–17 y
		N^a	Overall	Age sub-strata				N	Overall
				N	6–35 mo	N	3–9 y
			Value or Point estimate (95% CI^b)
Seropositivity rates	PRE^#	29	10.3% (2.2–27.4)	10	10.0% (0.3–44.5)	19	10.5% (1.3–33.1)	30	46.7% (28.3–65.7)
	Day 21	29	96.6% (82.2–99.9)	10	100% (69.2–100)	19	94.7% (74–99.9)	29	96.6 (82.2–99.9)
	Day 42	28	100% (87.7–100)	9	100% (66.4–100)	19	100% (82.4–100)	30	100% (88.4–100)
	Day 182	28	100% (87.7–100)	9	100% (66.4–100)	19	100% (82.4–100)	29	100% (88.1–100)
Geometric Mean Titers	PRE^#	29	4.9 (3.7–6.5)	10	4.7 (3.3–6.6)	19	5.0 (3.3–7.5)	30	11.3 (6.8–18.9)
	Day 21	29	53.8 (31.2–92.7)	10	42.5 (24.4–73.9)	19	60.8 (27–137.2)	29	121.2 (68.4–214.9)
	Day 42	28	551.1 (417–728.5)	9	623.4 (369.4–1052.1)	19	519.9 (362.3–745.5)	30	702.4 (433.5–1138)
	Day 182	28	149.6 (104.7–213.6)	9	161 (85.5–303.2)	19	144.4 (90–231.7)	29	213.3 (141.7–321)
Vaccine Response Rate	Day 21	29	51.7% (32.5–70.6)	10	60% (26.2–87.8)	19	47.4% (24.4–71.1)	29	58.6% (38.9–76.5)
	Day 42	28	100% (87.7–100)	9	100% (66.4–100)	19	100% (82.4–100)	30	100% (88.4–100)
	Day 182	28	96.4% (81.7–99.9)	9	100% (66.4–100)	19	94.7% (74–99.9)	29	82.8% (64.2–94.2)

Group 1.9µgHA: Subjects aged 6 mo-9 y received two doses of 1.9µg HA+AS03_B (5.93mg α-tocopherol) vaccine, 21 d apart. Group 3.75µgHA: Subjects aged 10–17 y received two doses of 3.75µg HA+AS03_A (11.86mg α-tocopherol) vaccine, 21 d apart. ^aN: Number of subjects with available results. ^bCI: Confidence interval. ^#PRE: Pre-vaccination antibody titers for ATP cohort for immunogenicity at Day 21. Vaccine response rate defined as percentage of subjects with either a pre-vaccination titer < 1:8 and a post-vaccination titer ≥ 1:32, or a pre-vaccination titer ≥ 1:8 and at least a 4-fold increase in post-vaccination titer.

Table 3. Solicited local symptoms reported during the 7 d post-vaccination follow-up period after each vaccine dose (Total vaccinated cohort)

		Group 1.9µgHA						Group 3.75µgHA
		6–35 mo		3–5 y		6–9 y		10–17 y
		Dose 1	Dose 2	Dose 1	Dose 2	Dose 1	Dose 2	Dose 1	Dose 2
		N^a = 10	n = 10	n = 14	n = 13	n = 6	n = 6	n = 30	n = 30
		Point estimate (95% CI^b)
Pain	Any	60.0 (26.2–87.8)	50.0 (18.7–81.3)	92.9 (66.1–99.8)	84.6 (54.6–98.1)	83.3 (35.9–99.6)	83.3 (35.9–99.6)	100 (88.4–100)	100 (88.4–100)
	Grade 3	0 (0–30.8)	0 (0–30.8)	7.1 (0.2–33.9)	7.7 (0.2–36.0)	0 (0–45.9)	0 (0–45.9)	10.0 (2.1–26.5)	6.7 (0.8–22.1)
Redness	Any	0 (0–30.8)	10.0 (0.3–44.5)	0 (0–23.2)	7.7 (0.2–36.0)	16.7 (0.4–64.1)	0 (0–45.9)	23.3 (9.9–42.3)	16.7 (5.6–34.7)
	Grade 3	0 (0–30.8)	0 (0–30.8)	0 (0–23.2)	0 (0–24.7)	0 (0–45.9)	0 (0–45.9)	0 (0–11.6)	0 (0–11.6)
Swelling	Any	30.0 (6.7–65.2)	10.0 (0.3–44.5)	14.3 (1.8–42.8)	23.1 (5.0–53.8)	33.3 (4.3–77.7)	33.3 (4.3–77.7)	46.7 (28.3–65.7)	50.0 (31.3–68.7)
	Grade 3	0 (0–30.8)	0 (0–30.8)	0 (0–23.2)	0 (0–24.7)	0 (0–45.9)	0 (0–45.9)	3.3 (0.1–17.2)	3.3 (0.1–17.2)

Group 1.9µgHA: Subjects aged 6 mo-9 y received two doses of 1.9µg HA+AS03_B (5.93mg α-tocopherol) vaccine, 21 d apart. Group 3.75µgHA: Subjects aged 10–17 y received two doses of 3.75µg HA+AS03_A (11.86mg α-tocopherol) vaccine, 21 d apart. ^aN: Number of subjects with available results. ^bCI: Confidence interval

Table 4. Solicited general symptoms reported during the 7-d post-vaccination follow-up period after each vaccine dose (Total vaccinated cohort)

					Group 1.9µgHA				Group 3.75µgHA
			6–35 mo		3–5 y		6–9 y		10–17 y
			Dose 1	Dose 2	Dose 1	Dose 2	Dose 1	Dose 2	Dose 1	Dose 2
			N^a = 10	n = 10	n = 14	n = 13	n = 6	n = 6	n = 30	n = 30
			Point estimate (95% CI^b)
Drowsiness		Any	10.0 (0.3–44.5)	30.0 (6.7–65.2)	28.6 (8.4–58.1)	30.8 (9.1–61.4)	–	–	–	–
		Grade 3	0 (0–30.8)	0 (0–30.8)	0 (0–23.2)	0 (0–24.7)	–	–	–	–
Irritability		Any	30.0 (6.7–65.2)	40.0 (12.2–73.8)	21.4 (4.7–50.8)	15.4 (1.9–45.4)	–	–	–	–
		Grade 3	10.0 (0.3–44.5)	0 (0–30.8)	0 (0–23.2)	0 (0–24.7)	–	–	–	–
Loss of appetite		Any	10.0 (0.3–44.5)	30.0 (6.7–65.2)	28.6 (8.4–58.1)	15.4 (1.9–45.4)	–	–	–	–
		Grade 3	0 (0–30.8)	10.0 (0.3–44.5)	0 (0–23.2)	0 (0–24.7)	–	–	–	–
Fever		Any	0 (0–30.8)	40.0 (12.2–73.8)	21.4 (4.7–50.8)	15.4 (1.9–45.4)	33.3 (4.3–77.7)	0 (0–45.9)	13.3 (3.8–30.7)	23.3 (9.9–42.3)
		Grade 3	0 (0–30.8)	20.0 (2.5–55.6)	0 (0–23.2)	0 (0–24.7)	0 (0–45.9)	0 (0–45.9)	6.7 (0.8–22.1)	0 (0–11.6)
Fatigue		Any	–	–	–	–	16.7 (0.4–64.1)	16.7 (0.4–64.1)	36.7 (19.9–56.1)	36.7 (19.9–56.1)
		Grade 3	–	–	–	–	0 (0–45.9)	0 (0–45.9)	3.3 (0.1–17.2)	3.3 (0.1–17.2)
Gastrointestinal		Any	–	–	–	–	16.7 (0.4–64.1)	16.7 (0.4–64.1)	10.0 (2.1–26.5)	10.0 (2.1–26.5)
		Grade 3	–	–	–	–	0 (0–45.9)	0 (0–45.9)	0 (0–11.6)	0 (0–11.6)
Headache		Any	–	–	–	–	33.3 (4.3–77.7)	16.7 (0.4–64.1)	40.0 (22.7–59.4)	33.3 (17.3–52.8)
		Grade 3	–	–	–	–	0 (0–45.9)	0 (0–45.9)	0 (0–11.6)	6.7 (0.8–22.1)
Joint pain at other location		Any	–	–	–	–	0 (0–45.9)	0 (0–45.9)	16.7 (5.6–34.7)	23.3 (9.9–42.3)
		Grade 3	–	–	–	–	0 (0–45.9)	0 (0–45.9)	0 (0–11.6)	0 (0–11.6)
Muscle aches		Any	–	–	–	–	0 (0–45.9)	0 (0–45.9)	23.3 (9.9–42.3)	30.0 (14.7–49.4)
		Grade 3	–	–	–	–	0 (0–45.9)	0 (0–45.9)	0 (0–11.6)	0 (0–11.6)
Shivering		Any	–	–	–	–	16.7 (0.4–64.1)	0 (0–45.9)	23.3 (9.9–42.3)	26.7 (12.3–45.9)
		Grade 3	–	–	–	–	0 (0–45.9)	0 (0–45.9)	0 (0–11.6)	0 (0–11.6)
Sweating		Any	–	–	–	–	33.3 (4.3–77.7)	0 (0–45.9)	6.7 (0.8–22.1)	10.0 (2.1–26.5)
		Grade 3	–	–	–	–	0 (0–45.9)	0 (0–45.9)	3.3 (0.1–17.2)	0 (0–11.6)

Group 1.9µgHA: Subjects aged 6 mo-9 y received two doses of 1.9µg HA+AS03_B (5.93mg α-tocopherol) vaccine, 21 d apart. Group 3.75µgHA: Subjects aged 10–17 y received two doses of 3.75µg HA+AS03_A (11.86mg α-tocopherol) vaccine, 21 d apart. ^aN: Number of subjects with available results. ^bCI: Confidence interval

Saitoh A, Tamura S, Nagai A, Tsuchida N, Sako M, Maekawa T, et al. Clinical evaluation of an AS03-adjuvanted pandemic influenza H1N1 2009 vaccine in children (Preliminary report). [Japanese.] J Jap Pediatr Soc 2011; 115:578 - 84

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