Safety and immunogenicity of a quadrivalent influenza vaccine in adults 65 y of age and older

Figures & data

Figure 1. Participant disposition and study flow in the randomized cohort (adults ≥ 65 y of age). A total of 675 adults ≥ 65 y of age were randomly assigned 1:1:1 to receive the quadrivalent split-virion influenza vaccine (IIV4), the licensed trivalent split-virion influenza vaccine containing the B Victoria-lineage strain (IIV3–1), or an investigational split-virion IIV3 containing the B Yamagata-lineage strain (IIV3–2). AE, adverse event; n, number of participants in the group.

Table 1. Participant characteristics in the randomized cohort (≥ 65 years).

	IIV4	IIV3–1	IIV3–2
Characteristic	N = 225	N = 225	N = 225
Sex, n (%)
Male	96 (42.7)	99 (44.0)	104 (46.2)
Female	129 (57.3)	126 (56.0)	121 (53.8)
Age (y)
Mean ± standard deviation	72.4 ± 5.7	72.8 ± 5.3	72.8 ± 5.6
Range	65.1–92.2	65.0–94.6	65.1–92.3
Race/Ethnicity, n (%)
Caucasian	197 (87.6)	202 (89.8)	205 (91.1)
Black	9 (4.0)	4 (1.8)	2 (0.9)
Hispanic	19 (8.4)	17 (7.6)	14 (6.2)
Other	0 (0.0)	2 (0.9)	4 (1.8)
Received 2009–2010 seasonal influenza vaccine, n (%)
Yes	183 (81.3)	180 (80.0)	167 (74.2)
No	41 (18.2)	42 (18.7)	52 (23.1)
Unknown	1 (0.4)	3 (1.3)	6 (2.7)
Received 2009 H1N1 monovalent influenza vaccine, n (%)
Yes	72 (32.0)	69 (30.7)	52 (23.1)
No	141 (62.7)	135 (60.0)	152 (67.6)
Unknown	12 (5.3)	21 (9.3)	21 (9.3)

Values are for all participants vaccinated. Abbreviations: IIV3–1, licensed split-virion trivalent influenza vaccine containing the B Victoria-lineage strain; IIV3–2, investigational split-virion trivalent influenza vaccine containing the B Yamagata-lineage strain; IIV4, quadrivalent split-virion inactivated influenza vaccine.

Table 2. Immunogenicity comparisons in the randomized cohort (≥ 65 years).

Measure/comparison	Strain/lineage	Comparator	Ratio of GMT and difference in seroconversion rate (95% CI)	Criteria met?
			–Ratio of GMTs–
HAI GMT	A/H1N1	Pooled IIV3s^a	0.85 (0.67, 1.09)	Yes
Non-inferiority^b	A/H3N2	Pooled IIV3s^a	1.55 (1.25, 1.92)	Yes
	B Victoria	IIV3–1	1.11 (0.90, 1.37)	Yes
	B Yamagata	IIV3–2	1.27 (1.05, 1.55)	Yes
Superiority^c	B Victoria	IIV3–2	1.75 (1.43, 2.14)	No
	B Yamagata	IIV3–1	2.14 (1.74, 2.65)	Yes
Seroconversion rate (%)			–Seroconversion difference–
Non-inferiority^d	A/H1N1	Pooled IIV3s	−3.86 (−11.50, 3.56)	No
	A/H3N2	Pooled IIV3s	9.77 (1.96, 17.20)	Yes
	B Victoria	IIV3–1	1.96 (−6.73, 10.60)	Yes
	B Yamagata	IIV3–2	9.91 (1.96, 17.70)	Yes
Superiority^e	B Victoria	IIV3–2	20.04 (12.90, 27.00)	Yes
	B Yamagata	IIV3–1	24.05 (16.60, 31.20)	Yes

Values are for all participants who completed the study according to protocol and had valid serology results. Abbreviations: CI, confidence interval; GMT, geometric mean titer; HAI, hemagglutination inhibition titer; IIV3–1, the licensed split-virion trivalent inactivated influenza vaccine containing the B Victoria-lineage strain; IIV3–2, an investigational split-virion trivalent inactivated influenza vaccine containing the B Yamagata-lineage strain; IIV4, split-virion quadrivalent inactivated influenza vaccine

^a Includes participants vaccinated with either IIV3–1 or IIV3–2

^b Non-inferiority for HAI GMT was defined as a lower limit of the 2-sided 95% CI > 0.66 for the ratio of GMT for IIV4 vs. the GMT for IIV3

^c Superiority for HAI GMT was defined as a lower limit of the 2-sided 95% CI > 1.5 for the ratio of the GMT for IIV4 vs. the GMT for IIV3

^d Non-inferiority for seroconversion rate was defined as a lower limit of the 2-sided 95% CI > −10% for the difference in seroconversion rate for IIV4 vs. IIV3

^e Superiority for seroconversion was defined as a the lower limit of the 2-sided 95% CI > 10% for the difference in seroconversion rate for IIV4 vs. IIV3

Table 3. Immunogenicity measures in the randomized cohort (≥ 65 years).

Vaccine	Measure	A/H1N1	A/H3N2	B Victoria	B Yamagata
IIV4 (N = 220)	HAI GMT (95% CI)
	Day 0	21.7 (17.9, 26.3)	52.3 (42.1, 65.0)	27.1 (23.3, 31.5)	20.2 (17.5, 23.3)
	Day 21	231 (188, 283)	501 (422, 593)	73.8 (63.9, 85.3)	61.1 (52.5, 71.2)
	Day 21/day 0 GMTR (95% CI)	8.81 (7.06, 11.0)	8.72 (7.13, 10.7)	2.46 (2.16, 2.80)	2.65 (2.33, 3.03)
	Seroprotection, % (95% CI)
	Day 0	31.7 (25.6, 38.2)	53.8 (47.0, 60.6)	48.9 (42.1, 55.7)	30.3 (24.3, 36.8)
	Day 21	91.4 (56.8, 94.7)	100.0 (98.3, 100.0)	77.7 (71.6, 83.0)	73.2 (66.8, 78.9)
	Seroconversion, % (95% CI)	65.9 (59.2, 72.1)	69.1 (62.5, 75.1)	28.6 (22.8, 35.1)	33.2 (27.0, 39.8)
IIV3–1 (N = 219)	HAI GMT (95% CI)
	Day 0	24.8 (20.4, 30.1)	48.3 (40.0, 58.4)	29.0 (25.0, 33.7)	18.7 (16.4, 21.3)
	Day 21	269 (221, 328)	291 (243, 347)	57.9 (50.6, 66.4)	28.5 (24.6, 33.0)
	Day 21/day 0 GMTR (95% CI)	9.18 (7.33, 11.5)	5.65 (4.65, 6.86)	1.83 (1.62, 2.07)	1.40 (1.27, 1.54)
	Seroprotection, % (95% CI)
	Day 0	45.8 (32.7, 59.2)	45.8 (32.7, 59.2)	35.6 (23.6, 49.1)	30.5 (19.2, 43.9)
	Day 21	91.3 (86.8, 94.7)	95.4 (91.8, 97.8)	71.7 (65.2, 77.6)	46.1 (39.4, 53.0)
	Seroconversion, % (95% CI)	66.7 (60.0, 72.9)	55.7 (48.9, 62.4)	18.7 (13.8, 24.5)	9.1 (5.7, 13.8)
IIV3–2 (N = 221)	HAI GMT (95% CI)
	Day 0	21.1 (17.5, 25.5)	42.3 (34.9, 51.4)	28.5 (24.2, 33.6)	19.7 (17.2, 22.6)
	Day 21	271 (221, 331)	360 (302, 429)	42.2 (36.5, 48.7)	54.8 (47.5, 63.3)
	Day 21/day 0 GMTR (95% CI)	10.6 (8.60, 13.0)	7.73 (6.38, 9.36)	1.34 (1.25, 1.45)	2.47 (2.18, 2.80)
	Seroprotection, % (95% CI)
	Day 0	45.8 (32.7, 59.2)	45.8 (32.7, 59.2)	35.6 (23.6, 49.1)	30.5 (19.2, 43.9)
	Day 21	91.9 (87.4, 95.1)	95.9 (92.4, 98.1)	60.2 (53.4, 98.1)	67.4 (60.8, 73.6)
	Seroconversion, % (95% CI)	72.9 (66.5, 78.6)	62.9 (56.2, 69.3)	8.6 (5.3, 13.1)	31.2 (25.2, 37.8)
Pooled IIV3s^a (N = 440)	Day 21 HAI GMT (95% CI)	270 (234, 311)	324 (285, 267)	—	—
	Day 21 Seroconversion, % (95% CI)	69.8 (62.3, 74.0)	59.3 (54.6, 64.0)	—	—

Hemagglutinin inhibition (HAI) geometric mean titers (GMTs) were calculated at baseline (day 0) and 21 d post-vaccination. The geometric mean titer ratio (GMTR) was calculated as the geometric mean of the individual post-vaccination/pre-vaccination titer ratios. Seroprotection was defined as a HAI titer ≥ 40. Seroconversion was defined as a pre-vaccination titer < 10 and post-vaccination titer ≥ 40 or a pre-vaccination titer ≥ 10 and a ≥ 4-fold increase in post-vaccination titer. Values are for all participants vaccinated with valid results. Abbreviations: CI, confidence interval; IIV3–1, the licensed split-virion trivalent inactivated influenza vaccine containing the B Victoria-lineage strain; IIV3–2, an investigational split-virion trivalent inactivated influenza vaccine containing the B Yamagata-lineage strain; IIV4, split-virion quadrivalent inactivated influenza vaccine.

^a Includes participants vaccinated with either IIV3–1 or IIV3–2

Table 4. Proportions reporting solicited reactions in the randomized cohort (≥ 65 years).

		IIV4	IIV3–1	IIV3–2
		(N = 225)	(N = 225)	(N = 225)
Event	Maximum intensity	% (95% CI)	% (95% CI)	% (95% CI)
Any solicited reaction	Any	43.8 (37.2; 50.5)	38.4 (32.0; 45.1)	33.3 (27.2; 39.9)
	grade 3	0.9 (0.1; 3.2)	0.0 (0.0; 1.6)	1.3 (0.3; 3.8)
Solicited injection site reaction	Any	33.5 (27.3; 40.1)	29.5 (23.6; 35.9)	24.0 (18.6; 30.1)
	grade 3	0.9 (0.1; 3.2)	0.0 (0.0; 1.6)	0.0 (0.0; 1.6)
Solicited systemic reaction	Any	24.6 (19.1; 30.7)'	24.1 (18.7; 30.3)	20.9 (15.8; 26.8)
	grade 3	0.4 (0.0; 2.5)	0.0 (0.0; 1.6)	1.3 (0.3; 3.8)
Injection-site pain	Any	32.6 (26.5; 39.2)	28.6 (22.8; 35.0)	23.1 (17.8; 29.2)
	grade 3	0.9 (0.1; 3.2)	0.0 (0.0; 1.6)	0.0 (0.0; 1.6)
Injection-site erythema	Any	2.7 (1.0; 5.7)	1.3 (0.3; 3.9)	1.3 (0.3; 3.9)
	grade 3	0.0 (0.0; 1.6)	0.0 (0.0; 1.6)	0.0 (0.0; 1.6)
Injection-site swelling	Any	1.8 (0.5; 4.5)	1.3 (0.3; 3.9)	0.0 (0.0; 1.6)
	grade 3	0.0 (0.0; 1.6)	0.0 (0.0; 1.6)	0.0 (0.0; 1.6)
Fever	Any	1.3 (0.3; 3.9)	0.0 (0.0; 1.6)	0.9 (0.1; 3.2)
	grade 3	0.4 (0.0; 2.5)	0.0 (0.0; 1.6)	0.4 (0.0; 2.5)
Headache	Any	13.4 (9.2; 18.6)	11.6 (7.7; 16.5)	11.6 (7.7; 16.5)
	grade 3	0.4 (0.0; 2.5)	0.0 (0.0; 1.6)	0.4 (0.0; 2.5)
Malaise	Any	10.7 (7.0; 15.5)	6.3 (3.5; 10.3)	11.6 (7.7; 16.5)
	grade 3	0.4 (0.0; 2.5)	0.0 (0.0; 1.6)	0.9 (0.1; 3.2)
Myalgia	Any	18.3 (13.5; 24.0)	18.3 (13.5; 24.0)	14.2 (9.9; 19.5)
	grade 3	0.4 (0.0; 2.5)	0.0 (0.0; 1.6)	0.4 (0.0; 2.5)

Swelling and erythema were graded based on the diameter of the reaction as any for ≥ 25 mm and grade 3 for > 100 mm. Fever was graded as any for ≥ 38.0°C and grade 3 for ≥ 39.0°C. All other solicited reactions were graded as any for no interference or at least some interference with daily activity and grade 3 for significant interference preventing daily activity. Abbreviations: IIV3–1, the licensed split-virion trivalent inactivated influenza vaccine containing a B strain of the Victoria lineage; IIV3–2, an investigational split-virion trivalent inactivated influenza vaccine containing a B strain of the Yamagata lineage; IIV4, split-virion quadrivalent inactivated influenza vaccine.

Table 5. Proportions reporting unsolicited adverse events in the randomized cohort (≥ 65 years).

	IIV4	IIV3–1	IIV3–2
	N = 224	N = 224	N = 225
Event	n (%)	n (%)	n (%)
Immediate unsolicited AE (< 20 min)	0 (0.0)	0 (0.0)	0 (0.0)
Unsolicited AE	28 (12.4)	24 (10.7)	23 (10.2)
Vaccine-related	6 (2.7)	6 (2.7)	4 (1.8)
SAE	0 (0)	2 (0.9)	1 (0.4)
Vaccine-related	0 (0.0)	0 (0.0)	0 (0.0)
Death	0 (0.0)	0 (0.0)	0 (0.0)

Values are for all participants randomized and for whom safety data were available. Abbreviations: AE, adverse event; IIV3–1, the licensed split-virion trivalent inactivated influenza vaccine containing a B strain of the Victoria lineage; IIV3–2, an investigational split-virion trivalent inactivated influenza vaccine containing a B strain of the Yamagata lineage; IIV4, split-virion quadrivalent inactivated influenza vaccine; SAE, serious adverse event.