Immunogenicity and safety of a quadrivalent high-dose inactivated influenza vaccine compared with a standard-dose quadrivalent influenza vaccine in healthy people aged 60 years or older: a randomized Phase III trial

Figures & data

Figure 1. Participant disposition.

IIV4-HD, quadrivalent high-dose inactivated influenza vaccine; IIV4-SD, standard-dose quadrivalent influenza vaccine; n, number of participants.

Table 1. Baseline demographics by randomized group – randomized patients

	60–64 y			≥65 y			Overall
	IIV4-HD	IIV4-SD	All	IIV4-HD	IIV4-SD	All	IIV4-HD	II4-SD	All
	(N = 379)	(N = 381)	(N = 760)	(N = 395)	(N = 384)	(N = 779)	(N = 774)	(N = 765)	(N = 1539)
Sex: n (%)
Male	175 (46.2)	192 (50.4)	367 (48.3)	214 (54.2)	183 (47.7)	397 (51.0)	389 (50.3)	375 (49.0)	764 (49.6)
Female	204 (53.8)	189 (49.6)	393 (51.7)	181 (45.8)	201 (52.3)	382 (49.0)	385 (49.7)	390 (51.0)	775 (50.4)
Age (y)
Mean (SD)	62.0 (1.31)	62.0 (1.37)	62.0 (1.34)	71.0 (4.93)	71.3 (5.40)	71.2 (5.17)	66.6 (5.82)	66.6 (6.11)	66.6 (5.97)
Min; Max	60.0; 64.0	60.0; 64.0	60.0; 64.0	65.0; 93.0	65.0; 88.0	65.0; 93.0	60.0; 93.0	60.0; 88.0	60.0; 93.0
Age subgroup: n (%)
<65 y							379 (49.0)	381 (49.8)	760 (49.4)
≥65 y							395 (51.0)	384 (50.2)	779 (50.6)
65 to <75 y				302 (76.5)	278 (72.4)	580 (74.5)	302 (39.0)	278 (36.3)	580 (37.7)
≥75 y				93 (23.5)	106 (27.6)	199 (25.5)	93 (12.0)	106 (13.9)	199 (12.9)
≥75 to <85 y				90 (22.8)	99 (25.8)	189 (24.3)	90 (11.6)	99 (12.9)	189 (12.3)
≥85 y				3 (0.8)	7 (1.8)	10 (1.3)	3 (0.4)	7 (0.9)	10 (0.6)
Racial origin: n (%)
Asian	2 (0.5)	2 (0.5)	4 (0.5)	2 (0.5)	1 (0.3)	3 (0.4)	4 (0.5)	3 (0.4)	7 (0.5)
Black or African American	1 (0.3)	0	1 (0.1)	1 (0.3)	2 (0.5)	3 (0.4)	2 (0.3)	2 (0.3)	4 (0.3)
Native Hawaiian or Other Pacific Islander	4 (1.1)	1 (0.3)	5 (0.7)	0	1 (0.3)	1 (0.1)	4 (0.5)	2 (0.3)	6 (0.4)
White	367 (96.8)	377 (99.0)	744 (97.9)	391 (99.0)	379 (98.7)	770 (98.8)	758 (97.9)	756 (98.8)	1514 (98.4)
Other	5 (1.3)	1 (0.3)	6 (0.8)	1 (0.3)	1 (0.3)	2 (0.3)	6 (0.8)	2 (0.3)	8 (0.5)
History of influenza vaccination, n (%)
Between 01 September 2016 and 31August 2017	130 (34.3)	143 (37.5)	273 (35.9)	229 (58.0)	232 (60.4)	461 (59.2)	359 (46.4)	375 (49.0)	734 (47.7)
Between 01 September 2017 and 31 August 2018	151 (39.8)	157 (41.2)	308 (40.5)	239 (60.5)	241 (62.8)	480 (61.6)	390 (50.4)	398 (52.0)	788 (51.2)
Since 01 September 2018	176 (46.4)	188 (49.3)	364 (47.9)	270 (68.4)	269 (70.1)	539 (69.2)	446 (57.6)	457 (59.7)	903 (58.7)

n: number of participants fulfilling the item listed.

The age of a participant in the study was the calendar age in y only.

IIV4-HD, quadrivalent high-dose inactivated influenza vaccine; IIV4-SD, standard-dose quadrivalent influenza vaccine; SD, standard deviation.

Figure 2. Immunogenicity primary objective: Superiority of IIV4-HD compared with IIV4-SD using GMTs at D 28 after vaccination – Full Analysis Set. (a) Geometric mean titer ratios for each strain in each analysis group. GMTRs calculated as geometric mean of individual ratios at D 28 and 0. Labels GMTR (95% CI). (b) GMTRs for each strain in each analysis group. GMT, geometric mean titer; GMTR, geometric mean titer ratio; IIV4-HD, quadrivalent high-dose inactivated influenza vaccine; IIV4-SD, standard-dose quadrivalent influenza vaccine.

Table 2. Summary of HAI antibody response for each antigen – Full Analysis Set

		60–64 years								≥ 65 years
		IIV4-HD				IIV4-SD				IIV4-HD				IIV4-SD
		A/H1N1 (N=377)	A/H3N2 (N=376)	B1 (N=377)	B2 (N=377)	A/H1N1 (N=377)	A/H3N2 (N=377)	B1 (N=377)	B2 (N=377)	A/H1N1 (N=392)	A/H3N2 (N=392)	B1 (N=392)	B2 (N=392)	A/H1N1 (N=381)	A/H3N2 (N=381)	B1 (N=381)	B2 (N=381)
Pre-dose (Day 1)	N	376	376	377	377	377	377	377	375	392	391	390	388	381	380	380	380
	Geometric mean	50.2	11.5	54.7	80.4	50	12.5	68.7	93.2	47.1	15.2	74.2	99.7	42.8	13.5	80.7	100
	(95% CI)	(42.7; 59.0)	(10.4; 12.8)	(47.4; 63.2)	(68.6; 94.3)	(42.6; 58.8)	(11.2; 14.0)	(59.4; 79.5)	(79.5; 109)	(40.1; 55.2)	(13.5; 17.1)	(64.3; 85.6)	(86.1; 115)	(36.6; 50.0)	(12.1; 15.0)	(70.1; 92.9)	(86.8; 115)
	Participants with titers ≥ 1:10: n (%)	305 (81.1)	196 (52.1)	338 (89.7)	341 (90.5)	305 (80.9)	219 (58.1)	344 (91.2)	341 (90.9)	314 (80.1)	240 (61.4)	360 (92.3)	359 (92.5)	311 (81.6)	222 (58.4)	347 (91.3)	354 (93.2)
	(95% CI)	(76.8; 84.9)	(46.9; 57.3)	(86.1; 92.5)	(87.0; 93.2)	(76.6; 84.7)	(52.9; 63.1)	(87.9; 93.9)	(87.6; 93.6)	(75.8; 83.9)	(56.4; 66.2)	(89.2; 94.8)	(89.4; 94.9)	(77.4; 85.4)	(53.3; 63.4)	(88.0; 93.9)	(90.1; 95.5)
	Participants with titers ≥ 1:40: n (%)	229 (60.9)	59 (15.7)	234 (62.1)	260 (69.0)	234 (62.1)	66 (17.5)	264 (70.0)	272 (72.5)	228 (58.2)	100 (25.6)	272 (69.7)	300 (77.3)	216 (56.7)	78 (20.5)	291 (76.6)	293 (77.1)
	(95% CI)	(55.8; 65.9)	(12.2; 19.8)	(57.0; 67.0)	(64.0; 73.6)	(57.0; 67.0)	(13.8; 21.7)	(65.1; 74.6)	(67.7; 77.0)	(53.1; 63.1)	(21.3; 30.2)	(64.9; 74.3)	(72.8; 81.4)	(51.6; 61.7)	(16.6; 24.9)	(72.0; 80.7)	(72.5; 81.2)
Post-dose (Day 28)	M	377	376	377	377	377	377	377	377	392	392	392	392	381	381	381	381
	Geometric mean	471	303	497	766	248	178	330	433	286	324	405	536	162	151	262	305
	(95% CI)	(416; 533)	(262; 350)	(450; 548)	(690; 849)	(217; 283)	(154; 206)	(297; 367)	(391; 480)	(250; 326)	(281; 374)	(366; 447)	(485; 592)	(139; 190)	(129; 176)	(236; 291)	(274; 340)
	Participants with titers ≥ 1:10: n (%)	377 (100)	376 (100)	377 (100)	377 (100)	375 (99.5)	373 (98.9)	377 (100)	377 (100)	390 (99.5)	387 (98.7)	392 (100)	392 (100)	376 (98.7)	372 (97.6)	381 (100)	381 (100)
	(95% CI)	(99.0; 100)	(99.0; 100)	(99.0; 100)	(99.0; 100)	(98.1; 99.9)	(97.3; 99.7)	(99.0; 100)	(99.0; 100)	(98.2; 99.9)	(97.0; 99.6)	(99.1; 100)	(99.1; 100)	(97.0; 99.6)	(95.6; 98.9)	(99.0; 100)	(99.0; 100)
	Participants with titers ≥ 1:40: n (%)	370 (98.1)	357 (94.9)	377 (100)	376 (99.7)	348 (92.3)	336 (89.1)	375 (99.5)	375 (99.5)	373 (95.2)	363 (92.6)	388 (99.0)	389 (99.2)	322 (84.5)	319 (83.7)	377 (99.0)	370 (97.1)
	(95% CI)	(96.2; 99.3)	(92.2; 96.9)	(99.0; 100)	(98.5; 100)	(89.1; 94.8)	(85.5; 92.1)	(98.1; 99.9)	(98.1; 99.9)	(92.5; 97.1)	(89.5; 95.0)	(97.4; 99.7)	(97.8; 99.8)	(80.5; 88.0)	(79.6; 87.3)	(97.3; 99.7)	(94.9; 98.6)
Post-dose response based on pre-dose (Day 28/Day 1)	M	376	376	377	377	377	377	377	375	392	391	390	388	381	380	380	380
	GMTR	9.36	26.2	9.07	9.52	4.96	14.2	4.8	4.66	6.07	21.4	5.48	5.39	3.8	11.2	3.25	3.06
	(95% CI)	(7.86; 11.1)	(22.8; 30.2)	(7.84; 10.5)	(8.19; 11.1)	(4.20; 5.85)	(12.2; 16.6)	(4.11; 5.60)	(4.03; 5.39)	(5.22; 7.05)	(18.6; 24.7)	(4.78; 6.28)	(4.72; 6.15)	(3.27; 4.41)	(9.66; 13.0)	(2.83; 3.73)	(2.70; 3.46)
	Seroconversion rate: n (%)	250 (66.5)	336 (89.4)	257 (68.2)	266 (70.6)	156 (41.4)	289 (76.7)	180 (47.7)	182 (48.5)	227 (57.9)	340 (87.0)	222 (56.9)	214 (55.2)	141 (37.0)	273 (71.8)	132 (34.7)	132 (34.7)
	(95% CI)	(61.5; 71.2)	(85.8; 92.3)	(63.2; 72.8)	(65.7; 75.1)	(36.4; 46.5)	(72.1; 80.8)	(42.6; 52.9)	(43.4; 53.7)	(52.8; 62.8)	(83.2; 90.1)	(51.8; 61.9)	(50.1; 60.2)	(32.1; 42.1)	(67.0; 76.3)	(30.0; 39.8)	(30.0; 39.8)

A/H1N1 = A/Brisbane/02/2018, A/H3N2 = A/Kansas/14/2017, B1 = B/Maryland/15/2016 BX-69A (B Victoria lineage), B2 = B/Phuket/3073/2013 (B Yamagata lineage)

N: number of participants with available data for the considered endpoint.

Seroconversion is defined as either a pre-vaccination HAI titer <1:10 and a post-vaccination titer ≥1:40 or a pre-vaccination titer ≥1:10 and a ≥4-fold increase in post-vaccination titer.

The two-sided exact 95% CI for the single proportion is based on the Clopper–Pearson method. The two-sided 95% CI for the GM is based on the Student t-distribution.

CI, confidence interval; GM, geometric mean; GMTR: geometric means of individual titer ratios (post-dose over pre-dose); HAI, hemagglutination inhibition; IIV4-HD, quadrivalent high-dose inactivated influenza vaccine; IIV4-SD, standard-dose quadrivalent influenza vaccine.

Figure 3. Summary of neutralizing Ab titers (SN assay) at baseline and at D 28 after vaccination – Full Analysis Set SN Subset. Ab, antibody; IIV4-HD, quadrivalent high-dose inactivated influenza vaccine; IIV4-SD, standard-dose quadrivalent influenza vaccine; SN, seroneutralization.

Figure 4. Summary of anti-NA antibody response (ELLA) at baseline and at D 28 after vaccination – Full Analysis Set-NA Subset. Geometric mean titer ratios calculated from GMT at D 28/GMT at D 0. IIV4-HD, quadrivalent high-dose inactivated influenza vaccine; IIV4-SD, standard-dose quadrivalent influenza vaccine; NA, neuraminidase.

Figure 5. Solicited injection-site reactions after vaccine injection, by maximum intensity during the solicited period (7 d following vaccination) – Safety Analysis Set. (a) 60–64 y IIV4-HD. (b) 60–64 y IIV4-SD. (c) ≥65 y IIV4-HD. (d) ≥65 y IIV4-SD. IIV4-HD, quadrivalent high-dose inactivated influenza vaccine; IIV4-SD, standard-dose quadrivalent influenza vaccine.

Figure 6. Solicited systemic reactions after vaccine injection, by maximum intensity during the solicited period (7 d after vaccination) – Safety Analysis Set. (a) 60–64 y IIV4-HD. (b) 60–64 y IIV4-SD. (c) ≥65 y IIV4-HD. (d) ≥65 y IIV4-SD. IIV4-HD, quadrivalent high-dose inactivated influenza vaccine; IIV4-SD, standard-dose quadrivalent influenza vaccine.

Table 3. Summary of unsolicited AEs within 28 d after vaccine injection – Safety Analysis Set

	60–64 y
	IIV4-HD				IIV4-SD
	(N = 378)				(N = 379)
Participants experiencing at least one:	n	%	(95% CI)	No. of AEs	n	%	(95% CI)	No. of AEs
Immediate unsolicited AE	1	0.3	(0; 1.5)	1	1	0.3	(0; 1.5)	1
Immediate unsolicited AR	1	0.3	(0; 1.5)	1	0	0	(0; 1.0)	0
Unsolicited non-serious AE	95	25.1	(20.8; 29.8)	144	100	26.4	(22.0; 31.1)	147
Unsolicited non-serious AR	25	6.6	(4.3; 9.6)	47	23	6.1	(3.9; 9.0)	33
Unsolicited non-serious injection-site AR	9	2.4	(1.1; 4.5)	10	8	2.1	(0.9; 4.1)	11
Unsolicited non-serious systemic AE	90	23.8	(19.6; 28.4)	134	96	25.3	(21.0; 30.0)	136
Unsolicited non-serious systemic AR	18	4.8	(2.8; 7.4)	37	17	4.5	(2.6; 7.1)	22
SAE	1	0.3	(0; 1.5)	1	2	0.5	(0.1; 1.9)	2
AESI	0	0	(0; 1.0)	0	0	0	(0; 1.0)	0
	≥65 y
	IIV4-HD				IIV4-SD
	(N = 394)				(N = 382)
Participants experiencing at least one:	n	%	(95% CI)	No. of AEs	n	%	(95% CI)	No. of AEs
Immediate unsolicited AE	1	0.3	(0; 1.4)	1	0	0	(0; 1.0)	0
Immediate unsolicited AR	1	0.3	(0; 1.4)	1	0	0	(0; 1.0)	0
Unsolicited non-serious AE	91	23.1	(19.0; 27.6)	135	68	17.8	(14.1; 22.0)	96
Unsolicited non-serious AR	26	6.6	(4.4; 9.5)	32	16	4.2	(2.4; 6.7)	19
Unsolicited non-serious injection-site AR	8	2	(0.9; 4.0)	8	2	0.5	(0.1; 1.9)	2
Unsolicited non-serious systemic AE	84	21.3	(17.4; 25.7)	127	66	17.3	(13.6; 21.4)	94
Unsolicited non-serious systemic AR	18	4.6	(2.7; 7.1)	24	14	3.7	(2.0; 6.1)	17
SAE	4	1	(0.3; 2.6)	4	5	1.3	(0.4; 3.0)	5
AESI	0	0	(0; 0.9)	0	0	0	(0; 1.0)	0

n: number of participants experiencing the endpoint listed in the first column.

N: number of participants with available data for the relevant endpoint.

“AE leading to study discontinuation” includes those participants meeting at least one of the two following criteria:

1. Termination form marked “not completed” due to “adverse event”

2. Any AE of at least Grade 1 within the time period (missing intensity is included) marked “caused study termination/discontinuation.”

Unsolicited non-serious systemic AEs (including SAEs) within 30 min are considered immediate.

Missing relationship (for the definition of AR) was considered at the time of analysis as related to the vaccine.

AE, adverse event; AESI, adverse event of special interest; AR, adverse reaction; IIV4-HD, quadrivalent high-dose inactivated influenza vaccine; IIV4-SD, standard-dose quadrivalent influenza vaccine; SAE, serious adverse event.

Data availability statement

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