Immunogenicity and safety of two quadrivalent influenza vaccines in healthy adult and elderly participants in India - A phase III, active-controlled, randomized clinical study

Figures & data

Figure 1. Participant disposition.

Table 1. Demographics and baseline characteristics of participants

	Test Vaccine(N = 240) n (%)	Reference Vaccine (N = 240) n (%)	All Participants(N = 480) n (%)
Age (years), Mean (SD)	51.5 (18.2)	51.7 (18.0)	51.6 (18.1)
Age Categorical (Years)
≥18 and = <60 years	120 (50.0%)	122 (50.8%)	242 (50.4%)
≥61 years	120 (50.0%)	118 (49.2%)	238 (49.6%)
Gender
Male	113 (47.1%)	132 (55.0%)	245 (51.0%)
Female	127 (52.9%)	108 (45.0%)	235 (49.0%)
Comorbidities
Number of Participants With at Least One Medical History Finding	71 (29.6%)	69 (28.8%)	140 (29.2%)
Hypertension	36 (15.0%)	30 (12.5%)	66 (13.8%)
Diabetes mellitus (incl subtypes)	20 (8.3%)	19 (7.9%)	39 (8.1%)
Age related issues	14 (5.8%)	19 (7.9%)	33 (6.9%)
Post menopause	13 (5.4%)	19 (7.9%)	32 (6.7%)
Menopause	1 (0.4%)	0	1 (0.2%)

Abbreviations: SD: Standard deviation, Percentages are based on the number of participants in the all participants randomized sample

Table 2. Geometric mean hemagglutination inhibition (HI) Titer by strain and geometric mean fold increase in HI titer by strain

	A(H3N2)-strain		A(H1N1)-strain		B-strain Victoria lineage		B-strain Yamagata lineage
Statistic	Test Vaccine(N = 236)	Reference Vaccine(N = 237)	Test Vaccine(N = 236)	Reference Vaccine(N = 237)	Test Vaccine(N = 236)	Reference Vaccine(N = 237)	Test Vaccine(N = 236)	Reference Vaccine(N = 237)
Overall (All participants)
Pre-vaccination (Visit 1)
GMT (GSD)	52.8 (6.3)	42.8 (6.4)	20.7 (5.2)	18.3 (4.8)	6.3 (2.3)	6.9 (2.6)	6.2 (2.2)	7.4 (2.8)
95% CI	(41.7, 66.8)	(33.7, 54.3)	(16.7, 25.5)	(15.0, 22.4)	(5.7, 7.0)	(6.1, 7.8)	(5.6, 6.8)	(6.5, 8.4)
Post-vaccination (Visit 2)
GMT (GSD)	735.3 (4.9)	844.4 (3.2)	451.6 (5.4)	395.9 (4.9)	31.7 (7.4)	41.3 (6.9)	26.4 (6.0)	26.9 (6.0)
95% CI	(599.4, 902.0)	(727.8, 979.6)	(363.4, 561.0)	(322.6, 485.7)	(24.5, 41.0)	(32.3, 52.9)	(21.0, 33.2)	(21.4, 33.9)
GMFI (GSD)	13.9 (9.7)	19.7 (9.4)	22.7 (8.3)	21.6 (8.8)	5.0 (7.2)	6.0 (6.7)	4.3 (5.8)	3.7 (6.5)
95% CI	(10.4, 18.6)	(14.8, 26.3)	(17.3, 29.8)	(16.4, 28.5)	(3.9, 6.5)	(4.7, 7.6)	(3.4, 5.4)	(2.9, 4.6)
Adults (18–60 years)
Pre-vaccination (Visit 1)
GMT (GSD)	44.9 (6.2)	45.8 (6.3)	20.8 (5.0)	21.6 (5.1)	6.2 (2.1)	6.6 (2.3)	6.3 (2.1)	7.5 (2.9)
95% CI	(32.2, 62.7)	(32.9, 63.8)	(15.5, 28.0)	(16.1, 29.0)	(5.4, 7.1)	(5.7, 7.7)	(5.4, 7.2)	(6.2, 9.1)
Post-vaccination (Visit 2)
N	118	121	118	121	118	121	118	121
GMT (GSD)	766.7 (4.5)	781.0 (2.9)	492.1 (4.7)	457.8 (4.4)	32.8 (7.0)	43.4 (6.6)	31.0 (5.8)	30.3 (5.9)
95% CI	(583.4, 1007.6)	(642.8, 948.8)	(371.1, 652.4)	(350.8, 597.3)	(23.0, 46.8)	(30.9, 60.9)	(22.5, 42.7)	(22.0, 41.6)
GMFI (GSD)	17.1 (9.1)	17.0 (8.0)	25.4 (6.9)	21.2 (9.7)	5.3 (6.6)	6.6 (6.3)	5.0 (5.7)	4.0 (6.1)
95% CI	(11.4, 25.5)	(11.7, 24.8)	(17.8, 36.3)	(14.1, 31.9)	(3.8, 7.5)	(4.7, 9.2)	(3.6, 6.8)	(2.9, 5.6)
Elderly adults (≥61 years)
Pre-vaccination (Visit 1)
N	118	116	118	116	118	116	118	116
GMT (GSD)	62.1 (6.3)	39.9 (6.6)	20.5 (5.4)	15.4 (4.4)	6.4 (2.5)	7.3 (2.9)	6.1 (2.4)	7.2 (2.7)
95% CI	(44.3, 86.9)	(28.2, 56.5)	(15.1, 27.9)	(11.8, 20.2)	(5.5, 7.6)	(6.0, 8.9)	(5.2, 7.1)	(6.0, 8.7)
Post-vaccination (Visit 2)
N	118	116	118	116	118	116	118	116
GMT (GSD)	705.1 (5.4)	916.0 (3.5)	414.4 (6.2)	340.2 (5.5)	30.6 (7.9)	39.3 (7.3)	22.5 (6.0)	23.9 (6.1)
95% CI	(518.3, 959.3)	(729.4, 1150.3)	(296.9, 578.4)	(248.5, 465.8)	(21.0, 44.6)	(27.3, 56.6)	(16.2, 31.2)	(17.1, 33.2)
GMFI (GSD)	11.4 (10.2)	23.0 (10.9)	20.2 (9.8)	22.1 (7.9)	4.8 (8.0)	5.4 (7.1)	3.7 (5.8)	3.3 (6.8)
95% CI	(7.4, 17.4)	(14.8, 35.7)	(13.4, 30.7)	(15.1, 32.3)	(3.3, 7.0)	(3.8, 7.7)	(2.7, 5.1)	(2.3, 4.7)

Abbreviations: CI: Confidence Interval, GMT: Geometric mean titer, GMFI = Geometric Mean Fold Increase, GSD: Geometric Standard Deviation

Note. n: Number of participants with non-missing data

Table 3. Seroprotection and seroconversion rates based on hemagglutination inhibition titer by strain

	A(H3N2)-strain		A(H1N1)-strain		B-strain Victoria lineage		B-strain Yamagata lineage
Statistic	Test Vaccine(N = 236)	Reference Vaccine(N = 237)	Test Vaccine(N = 236)	Reference Vaccine(N = 237)	Test Vaccine(N = 236)	Reference Vaccine(N = 237)	Test Vaccine(N = 236)	Reference Vaccine(N = 237)
Seroprotection Rates
Overall (All participants)
Pre-vaccination (Visit 1)
m (%)	152 (64.4)	141 (59.5)	101 (42.8)	91 (38.4)	17 (7.2)	25 (10.5)	15 (6.4)	23 (9.7)
95% CI	(57.9, 70.5)	(52.9, 65.8)	(36.4, 49.4)	(32.2, 44.9)	(4.3, 11.3)	(6.9, 15.2)	(3.6, 10.3)	(6.3, 14.2)
Post-vaccination (Visit 2)
m (%)	226 (95.8)	236 (99.6)	217 (91.9)	219 (92.4)	117 (49.6)	137 (57.8)	114 (48.3)	113 (47.7)
95% CI	(92.3, 97.9)	(97.7,100.0)	(87.7, 95.1)	(88.3, 95.4)	(43.0, 56.1)	(51.2, 64.2)	(41.8, 54.9)	(41.2, 54.2)
Adults 18–60 years
Pre-vaccination (Visit 1)
N	118	121	118	121	118	121	118	121
m (%)	73 (61.9)	76 (62.8)	53 (44.9)	53 (43.8)	9 (7.6)	12 (9.9)	9 (7.6)	13 (10.7)
95% CI	(52.5,70.6)	(53.6, 71.4)	(35.7, 54.3)	(34.8, 53.1)	(3.5, 14.0)	(5.2, 16.7)	(3.5, 14.0)	(5.8, 17.7)
Post-vaccination (Visit 2)
N	118	121	118	121	118	121	118	121
m (%)	114 (96.6)	121 (100.0)	112 (94.9)	115 (95.0)	61 (51.7)	73 (60.3)	63 (53.4)	62 (51.2)
95% CI	(91.5, 99.1)	(97.0, 100.0)	(89.3, 98.1)	(89.5, 98.2)	(42.3, 61.0)	(51.0, 69.1)	(44.0, 62.6)	(42.0, 60.4)
Elderly adults ≥ 61 years
Pre-vaccination (Visit 1)
N	118	116	118	116	118	116	118	116
m (%)	79 (66.9)	65 (56.0)	48 (40.7)	38 (32.8)	8 (6.8)	13 (11.2)	6 (5.1)	10 (8.6)
95% CI	(57.7, 75.3)	(46.5, 65.2)	(31.7, 50.1)	(24.3, 42.1)	(3.0, 12.9)	(6.1, 18.4)	(1.9, 10.7)	(4.2, 15.3)
Post-vaccination (Visit 2)
N	118	116	118	116	118	116	118	116
m (%)	112 (94.9)	115 (99.1)	105 (89.0)	104 (89.7)	56 (47.5)	64 (55.2)	51 (43.2)	51 (44.0)
95% CI	(89.3, 98.1)	(95.3, 100.0)	(81.9, 94.0)	(82.6, 94.5)	(38.2, 56.9)	(45.7, 64.4)	(34.1, 52.7)	(34.8, 53.5)
Seroconversion Rates
Overall (All subjects)
Post-vaccination (Visit 2)
m* (%)	168 (71.2)	178 (75.1)	186 (78.8)	183 (77.2)	107 (45.3)	121 (51.1)	105 (44.5)	98 (41.4)
95% CI	(65.0,76.9)	(69.1,80.5)	(73.0,83.8)	(71.3,82.4)	(38.9,51.9)	(44.5,57.6)	(38.0,51.1)	(35.0,47.9)
Adults aged 18–60 years
Post-vaccination (Visit 2)
N	118	121	118	121	118	121	118	121
m* (%)	89 (75.4)	90 (74.4)	99 (83.9)	91 (75.2)	57 (48.3)	66 (54.5)	57 (48.3)	56 (46.3)
95% CI	(66.6,82.9)	(65.6,81.9)	(76.0,90.0)	(66.5,82.6)	(39.0,57.7)	(45.2,63.6)	(39.0,57.7)	(37.2,55.6)
Elderly adults aged ≥ 61 years
Post-vaccination (Visit 2)
N	118	116	118	116	118	116	118	116
m* (%)	79 (66.9)	88 (75.9)	87 (73.7)	92 (79.3)	50 (42.4)	55 (47.4)	48 (40.7)	42 (36.2)
95% CI	(57.7,75.3)	(67.0,83.3)	(64.8,81.4)	(70.8,86.3)	(33.3,51.8)	(38.1,56.9)	(31.7,50.1)	(27.5,45.6)

Abbreviations: CI: confidence interval

Notes. n: Number of participants with non-missing data; m: Number of seroprotected participants, m*: Number of seroconverted subjects

Seroprotection defined as an HI titer≥40

Seroconversion defined as a pre vaccination titer <10 and a post-vaccination titer ≥ 40 or a pre vaccination titer ≥10 and at least a 4 fold post-vaccination increase

95% CI was calculated using Clopper-Pearson method

Figure 2. Reverse cumulative distribution (RCD) curves.

Table 4. Overall summary of adverse events

	Statistics	Test Vaccine(N = 240)	Reference Vaccine(N = 240)	Total(N = 480)
Number of Participants Without Any TEAE	n (%)	238 (99.2%)	239 (99.6%)	477 (99.4%)
Number of Participants With at Least One TEAE	n (%) E	2 (0.8%) 2	1 (0.4%) 1	3 (0.6%) 3
Number of Participants With at Least One Severe TEAE	n (%) E	0	0	0
Number of Participants With at Least One TEAE with a Reasonable Possibility for a Causal Relationship	n (%) E	0	0	0
Number of Participants With at Least One SAE	n (%) E	0	0	0
Number of Participants With at Least One TEAE Leading to Study Termination	n (%) E	0	0	0
Number of Participants With at Least One TESAE	n (%) E	0	0	0
Number of Deaths	n (%) E	0	0	0
Number of TE Deaths	n (%) E	0	0	0

Abbreviation:TE: Treatment emergent, TEAE: Treatment emergent adverse event

Notes: n: Number of participants, E: Number of events

Percentages are based on the number of participants in the safety participant sample.

A TEAE is defined as an AE that started or worsened in severity on or after the first study vaccination.

TEAEs leading to study termination are TEAEs reported on the Adverse Event Case report form (CRF) with “Led to Study Termination” = ‘yes’.

Severe = severity reported as severe or missing.

Reasonable possibility for a causal relationship = drug-event relationship reported as possible, probable or missing.

[TE] Death is defined as a fatal outcome of a [TE](S)AE.

Table 5. Summary of treatment emergent adverse events

	Test(N = 240) n (%)	Reference(N = 240) n (%)	Total(N = 480) n (%)
Ligament sprain	1 (0.4%)	0	1 (0.2%)
Musculoskeletal and connective tissue pain and discomfort	1 (0.4%)	0	1 (0.2%)
Back pain	1 (0.4%)	0	1 (0.2%)
Headache	0	1 (0.4%)	1 (0.2%)

Table

PI Name & Designation	Institution/Site Name and Address	EC Name/Location
Dr. Pravin Supe	Supe Heart and Diabetes Hospital and Research Center Opp. Adharashram,Gharpure Ghat, Nearrungtha School, Ashok Sthambh,Nasik422002,Maharashtra	Supe Hospital Ethics Committee
Dr. Peersab Pinjar	S.S Institute of Medical Sciences and Research Center Nh 4, Bypass Road, Davangere- 577005, Karnataka.	Institutional Ethics Review Board, S.S Institute of Medical Sciences and Research Center
Dr K.V Giriraja	Saptagiri Institute of Medical Science And Research Center No 15 Chikkasandra Hessaraghatta Main Road Bangalore560090, Karnataka	Institutional Ethics Committee Saptageri Institute of Medical Science and Research Center
Dr D Anil Kumar	Gandhi Hospitalgandhi Hospital, Musheerabad, Secunderabad- 500003, Hyderabad Andhra Pradesh	Institutional Ethics Committee Gandhi Medical College Secunderabad
Dr Vijay Shukla	Ajanta Research Centreajanta Hospital and Ivf Center,765, Abc Complex, Kanpur Road, Alambagh Lucknow 226005, Uttar Pradesh	Ethics Committee Ajanta Hospital and IVF Center
Dr Indraneel Basu	Popular Hospitaln-10/60, A-2, D.L.Wroad, Near Flyover, Kakarmatta, Varanasi, 221004, Uttar Pradesh	Popular Hospital Ethics Committee
Dr Pradeep Kumar Mishra	Yashoda Hospital Yashoda Hospital Behind Harihara, Kala Bhawan, Secunderabad- 500007, Hyderabad, Andhra Pradesh	Yashoda Hospital EC
Dr Sunil Prem Chand Masand	Maharaja Agrasen Hospital Punjabi Bagh, New Delhi	Maharaja Agrasen Hospital EC
Dr Sunil Naik	Rajiv Gandhi Institute of Medical Sciences Srikakulam & Rims Government General Hospital Situated at Srikakulam-532001, Andhra Pradesh	Institutional Ethics Committee,Rajiv Gandhi Institute of Medical Sciences
Dr Sujaya Menon	Psg Institute Of Medical Sciences And Research Post Box No. 1674, Peelamedu, Coimbatore – 641004, Tamil Nadu	Institutional Ethics Committee, PSG institute of Medical Sciences and Research
Dr Vikram Vardhan Remella	King George Hospital Vishakhapatnam- 5300 02, Andhra Pradesh	IECKGH
Dr Ranjith V	Krishna Rajendra Hospital Irwin Road, Mysuru, 570001, Karnataka	IEC Krishna Rajendra Hospital
Dr Manish Agarwal	Medilink Hospital & Research Center Basement Medilink Hospital, Near Shyamal Cross Road,132, Ft, Ring Road, Satellite, Ahmedabad – 380015, Gujarat.	EC, Medilink Hospital and Research Center
Dr Shishir Joshi	Sahyadri Hospital Plot No. 13 S, Swami Vivekanand Road, Survey No. 573, City No 281, Bibvewadi, Pune, 411037, Maharashtra	Sahyadri Hospital EC
Dr Viral Shah	Panchshil Hospital Nr. Sabarmati Police Station,High-Way, Ramnagar, Sabarmati, Ahmedabad-380005, Gujarat	Panchshil Hospital EC
Dr Falguni Parikh	Kokilaben Dhirubhai Ambani Hospital & Medical Research Institute 2nd Floor, Medical Research Department Four Bungalows, Andheri [W], Mumbai, 400053, Maharashtra	EC, Kokilaben Dhirubhai Ambani Hospital & Medical Research Institute
Anupam Mandal	Ipgmerand SSKM Hospital 244 A.J.C. Bose Road, Kolkata, 70002 Kolkata, West Bengal	IPGMER
Dr Arpit Jain	Artemis Hospitals Artemis Hospitals Sector 51, Gurgoan122001, Haryana	IEC, Artemis Health Science
Dr Arun Narayan	Ms Ramaiah Memorial Hospital Msrit Post, Bangalore 560954, Karnataka	MS Ramaiah Memorial Hospital EC
Dr.Manoj Kumar Srivastava	Om Research Center Om Surgical Center & Maternity Home, Shri Krishna Nagar Colony, Ashapur, Varanasi, 221007, Uttar Pradesh	IEC Om Surgical Center