Immunogenicity and safety of quadrivalent and 9-valent human papillomavirus vaccines in Indian clinical trial participants

Figures & data

Table 1. Overview of qHPV and 9vHPV vaccine clinical trials in India.

Trial	Population	n	Design	Vaccine	Key endpoints
Study V501–029 [NCT00380367]	Girls aged 9–15 years from seven sites in India	110	Open-label, single-arm immunogenicity and safety study	qHPV vaccine (three doses^a)	Immunogenicity: Anti-HPV6/11/16/18 GMTs and seroconversion percentages at Month 7 (by HPV-4 cLIA) Safety: Injection site AEs, systemic AEs, and SAEs within 15 days of vaccination; vaccine-related SAEs and deaths at any time
Study V501–125	Females aged 9–45 years vaccinated in routine clinical practice at eight sites in India	188	Post-marketing safety surveillance study	qHPV vaccine (three doses recommended)	Safety: SAEs within 30 days of any qHPV vaccine dose
Study V503–002 [NCT00943722]	Indian participants from the study (girls/boys aged 9–15 years and women aged 16–26 years from 7 sites in India)	225^b	Subgroup analysis of a global immunogenicity and safety study	9vHPV vaccine (three doses^a)	Immunogenicity: Anti-HPV6/11/16/18/31/33/45/52/58 GMTs and seropositivity at Months 7, 12, 24 and 36 (by HPV-9 cLIA) Safety: Injection-site and systemic AEs within 15 days of vaccination; SAEs through 6 months after the last vaccine dose; vaccine-related SAEs and deaths at any time

^aDoses administered at Day 1, Month 2, Month 6.

^bNumber of participants at sites in India (global study, N = 3074).

Abbreviations: 9vHPV, 9-valent human papillomavirus; AE, adverse event; cLIA, competitive Luminex immunoassay; GMT, geometric mean titer; HPV, human papillomavirus; qHPV, quadrivalent human papillomavirus; SAE, serious adverse event.

Figure 1. Participant disposition for Indian participants in the qHPV vaccine (Study V501–029) (a) and 9vHPV vaccine (Study V503–002) (b) clinical trials.

Abbreviations: 9vHPV, 9-valent human papillomavirus; qHPV, quadrivalent human papillomavirus; y, years.

Table 2. Participant baseline characteristics for Study V501–029 and V503–002 (Indian participants).

	qHPV vaccine study (V501–029)	9vHPV vaccine study (V503–002)
	Girls aged 9–15 y (N = 110)	Girls/boys aged 9–15 y (N = 200)	Women aged 16–26 y (N = 25)
Gender, n (%)
Male	0 (0.0)	75 (37.5)	0 (0.0)
Female	110 (100.0)	125 (62.5)	25 (100.0)
Age
9–12 y, n (%)	79 (71.8)	137 (68.5)	0 (0.0)
13–15 y, n (%)	31 (28.2)	63 (31.5)	0 (0.0)
16–26 y, n (%)	0 (0.0)	0 (0.0)	25 (100.0)
Mean (SD)	11.5 (1.7)	11.5 (1.8)	22.7 (2.6)
Median (range)	11.0 (9, 15)	11.0 (9, 15)	23.0 (17, 26)
Weight, kg
Mean (SD)	34.9 (8.8)	36.8 (9.8)	51.3 (7.8)
Median (range)	34.0 (20.0, 60.0)	36.0 (19.0, 72.0)	53.0 (35.0, 65.0)
BMI, kg/m^2
Mean (SD)	16.8 (2.8)	17.7 (3.0)	21.5 (3.3)
Median (range)	16.4 (11.7, 24.7)	17.4 (10.1, 29.8)	21.6 (15.8, 28.1)

Abbreviations: 9vHPV, 9-valent human papillomavirus; BMI, body mass index; qHPV, quadrivalent human papillomavirus; SD, standard deviation; y, years.

Table 3. Summary of anti-HPV6/11/16/18 GMTs and seroconversion at Month 7 in Indian girls receiving qHPV vaccine in Study V501–029 and the overall population of young women from Study V501–015 (per-protocol immunogenicity population^a).

	qHPV vaccine India registration study (V501–029)		qHPV vaccine historic international efficacy study (V501–015)^b
	Girls aged 9–15 y (N = 110)		Women aged 16–23 y (N = 6082)
Assay	n	GMT (95% CI), mMU/mL	n	GMT (95% CI), mMU/mL
Anti-HPV6	99	408.7 (297.1, 562.3)	1056	528.8 (504.2, 554.5)
Anti-HPV11	105	941.1 (759.8, 1165.7)	1057	732.8 (694.6, 773.1)
Anti-HPV16	105	2877.6 (2209.7, 3747.4)	1017	2388.7 (2215.8, 2575.1)
Anti-HPV18	105	900.9 (688.5, 1178.8)	1140	451.6 (425.4, 479.4)
Assay	m	Seropositive^c (95% CI), %	m	Seropositive^c (95% CI), %
Anti-HPV6	96	97.0 (93.6, 100.4)	1054	99.8 (99.3, 100.0)
Anti-HPV11	104	99.0 (97.2, 100.9)	1054	99.7 (99.2, 99.9)
Anti-HPV16	104	99.0 (97.2, 100.9)	1014	99.7 (99.1, 99.9)
Anti-HPV18	104	99.0 (97.2, 100.9)	1133	99.4 (98.7, 99.8)

^aThe per-protocol immunogenicity population included participants who had no protocol violations that could interfere with the evaluation of immunogenicity, received all three vaccinations within acceptable day ranges, were seronegative at Day 1 and (for participants 16–26 years of age only) PCR-negative to the appropriate HPV type from Day 1 through Month 7 for the relevant HPV type(s) and had a Month 7 serum sample collected within an acceptable day range.

^bClinicaltrials.gov identifier: NCT00092534.²³

^cSeropositive defined as anti‐HPV serum cLIA levels ≥20, 16, 20, and 24 mMU/mL for HPV types 6, 11, 16, and 18, respectively.

N, number of participants who received at least one vaccine dose.

n, number of participants evaluable for immunogenicity (per‐protocol) for each HPV type.

m, number of seropositive participants at Month 7.

Abbreviations: CI, confidence interval; cLIA, competitive Luminex Immunoassay; GMT, geometric mean titer; HPV, human papillomavirus; mMU, milli-Merck units; qHPV, quadrivalent human papillomavirus; y, years.

Table 4. Summary of anti-HPV6/11/16/18/31/33/45/52/58 GMTs through Month 36 in Indian girls and boys receiving 9vHPV vaccine in Study V503–002 versus young women from the pivotal 9vHPV vaccine efficacy study (Study V503–001) (per-protocol immunogenicity population^a).

	Indian participants from 9vHPV vaccine immunogenicity study (Study V503–002)				9vHPV vaccine efficacy study (Study V503–001)^b
	Girls aged 9–15 y (N = 125)		Boys aged 9–15 y (N = 75)		Women aged 16–26 y (N = 6792)
Assay	n	GMT (95% CI), mMU/mL	n	GMT (95% CI), mMU/mL	n	GMT (95% CI), mMU/mL
Anti-HPV6
Month 7	105	1552.0 (1300.2, 1852.6)	65	1796.3 (1499.9, 2151.4)	3993	893.1 (871.7, 915.1)
Month 12	33	587.4 (458.7, 752.3)	58	528.1 (425.4, 655.6)	800	330.6 (312.2, 350.1)
Month 24	30	341.8 (275.8, 423.5)	52	320.1 (263.1, 389.5)	715	208.6 (195.5, 222.7)
Month 36	30	279.2 (215.6, 361.6)	47	290.1 (229.0, 367.4)	685	163.9 (153.0, 175.6)
Anti-HPV11
Month 7	105	1152.9 (962.4, 1381.1)	65	1225.1 (1017.4, 1475.2)	3995	666.3 (649.6, 683.4)
Month 12	33	452.2 (338.9, 603.3)	58	361.2 (288.5, 452.3)	810	212.4 (200.1, 225.6)
Month 24	30	219.1 (161.6, 297.0)	52	174.4 (141.4, 215.2)	763	123.3 (115.8, 131.2)
Month 36	30	173.2 (125.7, 238.7)	48	160.0 (122.4, 208.9)	690	89.6 (83.3, 96.3)
Anti-HPV16
Month 7	107	6767.9 (5640.9, 8120.1)	68	7549.3 (6316.6, 9022.5)	4032	3131.1 (3057.1, 3206.9)
Month 12	33	2360.0 (1850.4, 3009.8)	61	2296.4 (1862.9, 2830.8)	819	1041.7 (979.9, 1107.4)
Month 24	30	1261.0 (973.4, 1633.7)	55	1014.5 (798.8, 1288.3)	778	520.7 (484.7, 559.4)
Month 36	30	991.0 (747.8, 1313.3)	50	981.2 (747.4, 1288.1)	695	386.5 (356.3, 419.4)
Anti-HPV18
Month 7	110	1957.0 (1589.9, 2408.8)	68	2408.6 (1930.0, 3005.8)	4539	804.6 (782.7, 827.1)
Month 12	34	566.7 (401.5, 800.0)	61	588.9 (466.1, 744.1)	929	198.6 (184.9, 213.4)
Month 24	31	265.9 (186.2, 379.7)	55	289.7 (230.7, 363.8)	886	86.0 (79.0, 93.6)
Month 36	31	192.1 (134.0, 275.5)	50	258.4 (199.9, 334.2)	789	78.5 (71.9, 85.6)
Anti-HPV31
Month 7	105	1731.6 (1454.4, 2061.7)	66	1566.8 (1278.7, 1919.7)	4466	658.4 (636.7, 680.9)
Month 12	32	556.8 (378.3, 819.6)	59	479.6 (386.6, 594.9)	909	196.5 (183.5, 210.4)
Month 24	29	290.0 (199.1, 422.6)	53	232.8 (181.3, 299.1)	863	101.9 (94.9, 109.5)
Month 36	29	242.3 (158.2, 371.0)	48	232.8 (175.6, 308.7)	772	72.7 (67.5, 78.4)
Anti-HPV33
Month 7	108	812.6 (672.4, 982.1)	67	927.9 (761.0, 1131.5)	4702	415.9 (405.6, 426.4)
Month 12	32	271.4 (204.2, 360.6)	60	278.6 (221.0, 351.2)	958	126.2 (119.9, 132.9)
Month 24	29	126.1 (93.7, 169.6)	54	116.2 (89.6, 150.7)	909	65.3 (61.7, 69.0)
Month 36	29	99.7 (73.3, 135.7)	50	110.3 (82.6, 147.4)	813	46.8 (44.0, 49.8)
Anti-HPV45
Month 7	111	717.5 (579.6, 888.3)	68	783.7 (623.3, 985.5)	4792	252.8 (246.2, 259.6)
Month 12	34	255.8 (164.7, 397.3)	61	217.0 (164.9, 285.5)	976	69.2 (65.4, 73.3)
Month 24	31	114.3 (73.7, 177.4)	55	100.1 (73.6, 136.2)	928	33.0 (31.0, 35.0)
Month 36	31	90.4 (56.5, 144.6)	50	88.2 (61.5, 126.6)	835	22.9 (21.4, 24.4)
Anti-HPV52
Month 7	108	851.2 (698.0, 1038.0)	68	790.0 (645.8, 966.4)	4455	379.7 (371.6, 388.0)
Month 12	33	325.4 (240.1, 440.9)	61	240.1 (190.2, 303.1)	916	118.9 (113.0, 125.0)
Month 24	30	171.8 (127.1, 232.2)	55	111.3 (89.7, 138.1)	867	57.9 (54.7, 61.2)
Month 36	30	127.5 (95.4, 170.2)	50	95.6 (71.0, 128.7)	777	47.9 (45.0, 50.9)
Anti-HPV58
Month 7	106	1168.6 (963.5, 1417.4)	67	1246.3 (1026.4, 1513.2)	4486	482.5 (469.9, 495.3)
Month 12	34	515.3 (377.1, 704.3)	60	415.2 (339.8, 507.3)	905	153.3 (145.5, 161.6)
Month 24	31	240.0 (174.2, 330.6)	54	189.3 (153.7, 233.0)	852	80.3 (75.7, 85.3)
Month 36	31	204.2 (143.3, 290.8)	50	172.6 (134.4, 221.6)	765	55.0 (51.4, 58.8)

^aThe per-protocol immunogenicity population included participants who had no protocol violations that could interfere with the evaluation of immunogenicity, received all three vaccinations within acceptable day ranges, were seronegative at Day 1 and (for participants 16–26 years of age only) PCR-negative to the appropriate HPV type from Day 1 through Month 7 for the relevant HPV type(s) and had a Month 7 serum sample collected within an acceptable day range.

^bData published previously.¹³

N, number of participants who received at least one vaccine dose.

n, number of participants evaluable for immunogenicity (per‐protocol) for each HPV type.

Abbreviations: 9vHPV, 9-valent human papillomavirus; CI, confidence interval; GMT, geometric mean titer; HPV, human papillomavirus; mMU, milli-Merck units; PCR, polymerase chain reaction; y, years.

Table 5. Summary of anti-HPV6/11/16/18/31/33/45/52/58 GMTs and seroconversion at Month 7 in Indian young women versus the entire cohort of young women in Study V503–002 (per-protocol immunogenicity population^a).

	Women aged 16–26 y from the 9vHPV vaccine immunogenicity study (Study V503–002)
	Indian women (N = 25)		Entire cohort of women (N = 468)
Assay	n	GMT (95% CI), mMU/mL	n	GMT (95% CI), mMU/mL
Anti-HPV6	15	1155.4 (793.8, 1681.9)	328	900.8 (822.3, 986.9)
Anti-HPV11	15	980.2 (665.8, 1442.9)	332	706.6 (645.2, 773.8)
Anti-HPV16	15	6207.9 (4247.2, 9073.7)	329	3522.6 (3223.5, 3849.5)
Anti-HPV18	15	1422.2 (887.4, 2279.1)	345	882.7 (795.4, 979.5)
Anti-HPV31	15	1476.4 (964.0, 2261.0)	340	753.9 (682.5, 832.7)
Anti-HPV33	14	751.1 (486.7, 1159.2)	354	466.8 (426.9, 510.3)
Anti-HPV45	15	485.0 (297.8, 790.0)	368	272.2 (243.8, 303.9)
Anti-HPV52	15	688.0 (447.9, 1056.6)	337	419.6 (381.4, 461.5)
Anti-HPV58	14	913.2 (597.3, 1396.1)	332	590.5 (538.2, 647.9)
Assay	m	Seropositive^b (95% CI), %	m	Seropositive^b (95% CI), %
Anti-HPV6	15	100 (78.2, 100)	327	99.7 (98.3, 100)
Anti-HPV11	15	100 (78.2, 100)	332	100 (98.9, 100)
Anti-HPV16	15	100 (78.2, 100)	329	100 (98.9, 100)
Anti-HPV18	15	100 (78.2, 100)	344	99.7 (98.4, 100)
Anti-HPV31	15	100 (78.2, 100)	339	99.7 (98.4, 100)
Anti-HPV33	14	100 (76.8, 100)	353	99.7 (98.4, 100)
Anti-HPV45	15	100 (78.2, 100)	366	99.5 (98.1, 99.9)
Anti-HPV52	15	100 (78.2, 100)	336	99.7 (98.4, 100)
Anti-HPV58	14	100 (76.8, 100)	332	100.0 (98.9, 100)

^aThe per-protocol immunogenicity population included participants who had no protocol violations that could interfere with the evaluation of immunogenicity, received all three vaccinations within acceptable day ranges, were seronegative at Day 1 and (for participants 16–26 years of age only) PCR-negative to the appropriate HPV type from Day 1 through Month 7 for the relevant HPV type(s) and had a Month 7 serum sample collected within an acceptable day range.

^bSeropositive defined as anti-HPV serum levels ≥30, 16, 20, 24, 10, 8, 8, 8, and 8 mMU/mL for HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, respectively.

N, number of participants who received at least one vaccine dose.

n, number of participants evaluable for immunogenicity (per‐protocol) for each HPV type.

m, number of seropositive participants at Month 7.

Abbreviations: 9vHPV, 9-valent human papillomavirus; CI, confidence interval; GMT, geometric mean titer; HPV, human papillomavirus; mMU, milli-Merck units; PCR, polymerase chain reaction; y, years.

Table 6. Summary of AEs in Indian girls (aged 9–15 years) from the qHPV vaccine study (Study V501–029) (Safety population).

	qHPV vaccine India registration study (V501–029)
n, (%) participants	Girls aged 9–15 y (N = 108)
Participants with ≥1 AE, n (%)^a	63 (58.3)
Injection-site AE, n (%)^a,b	50 (46.3)
Injection-site pain	46 (42.6)
Mild	37 (34.3)
Moderate	7 (6.5)
Severe	2 (1.9)
Injection-site tenderness	25 (23.1)
Mild	19 (17.6)
Moderate	6 (5.6)
Injection-site erythema	13 (12.0)
Mild (0 to ≤2.5 cm)	13 (12.0)
Injection-site swelling	10 (9.3)
Mild (0 to ≤2.5 cm)	9 (8.3)
Moderate (>2.5 to ≤5.0 cm)	1 (0.9)
Systemic AE, n (%)^a,b	35 (32.4)
Pyrexia	25 (23.1)
Nasopharyngitis	8 (7.4)
Vaccine-related^c systemic AE, n (%)^a	26 (24.1)
Serious AE, n (%)	0 (0.0)
Vaccine-related^c serious AE	0 (0.0)
Death	0 (0.0)
Discontinuation^d due to AE, n (%)	0 (0.0)
Maximum temperature (oral)^e
≥37.8°C and <38.9°C	19 (17.6)
≥38.9°C and <39.9°C	4 (3.7)
≥39.9°C	0 (0.0)

N, number of participants with follow-up.

^aAEs that were reported within 1 to 15 days after any vaccination.

^bA specific AE appears on this table only if its incidence is ≥5%.

^cDetermined by the investigator to be possibly, probably, or definitely related to the vaccine.

^dStudy vaccination withdrawn. 

^eMaximum temperature within 1 to 5 days after any vaccination.

Abbreviations: qHPV, quadrivalent human papillomavirus; AE, adverse event; y, years.

Table 7. Summary of AEs in Indian girls (aged 9–15 years), boys (aged 9–15 years), and young women (aged 16–26 years) from the 9vHPV vaccine study (Study V503–002) (Safety population).

	Indian participants from 9vHPV vaccine study (V503–002)
n, (%) participants	Girls aged 9–15 y (N = 122)	Boys aged 9–15 y (N = 72)	Women aged 16–26 y (N = 25)
Participants with ≥1 AE, n (%)^a	85 (69.7)	42 (58.3)	14 (56.0)
Injection-site AE, n (%)^a,b	81 (66.4)	40 (55.6)	14 (56.0)
Injection-site pain^c	80 (65.6)	37 (51.4)	13 (52.0)
Mild	37 (30.3)	25 (34.7)	9 (36.0)
Moderate	34 (27.9)	12 (16.7)	3 (12.0)
Severe	9 (7.4)	0 (0.0)	1 (4.0)
Injection-site erythema^c	25 (20.5)	11 (15.3)	4 (16.0)
Mild (0 to ≤2.5 cm)	20 (16.4)	11 (15.3)	4 (16.0)
Moderate (>2.5 to ≤5.0 cm)	4 (3.3)	0 (0.0)	0 (0.0)
Severe (>5.0 cm)	1 (0.8)	0 (0.0)	0 (0.0)
Injection-site swelling^c	33 (27.0)	13 (18.1)	7 (28.0)
Mild (0 to ≤2.5 cm)	24 (19.7)	11 (15.3)	5 (20.0)
Moderate (>2.5 to ≤5.0 cm)	7 (5.7)	1 (1.4)	2 (8.0)
Severe (>5.0 cm)	2 (1.6)	1 (1.4)	0 (0.0)
Systemic AE, n (%)^a,b	25 (20.5)	9 (12.5)	7 (28.0)
Pyrexia	14 (11.5)	8 (11.1)	5 (20.0)
Vaccine-related^d systemic AE, n (%)^a	14 (11.5)	7 (9.7)	5 (20.0)
Serious AE, n (%)	0 (0.0)	0 (0.0)	1 (4.0)
Vaccine-related^d serious AE	0 (0.0)	0 (0.0)	0 (0.0)
Death	0 (0.0)	0 (0.0)	0 (0.0)
Discontinuation^e due to AE, n (%)	0 (0.0)	0 (0.0)	0 (0.0)
Maximum temperature (oral)^c
≥37.8°C and <38.9°C	13 (10.7)	7 (9.7)	4 (16.0)
≥38.9°C and <39.9°C	0 (0.0)	0 (0.0)	1 (4.0)
≥39.9°C	0 (0.0)	0 (0.0)	0 (0.0)

N, number of participants with follow-up.

^aAEs that were reported within 1 to 15 days after any vaccination.

^bA specific AE appears on this table only if its incidence is ≥5%.

^cReported within 1 to 5 days after any vaccination.

^dDetermined by the investigator to be possibly, probably, or definitely related to the vaccine.

^eStudy vaccination withdrawn.

Abbreviations: 9vHPV, 9-valent human papillomavirus; AE, adverse event; y, years.

The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356(19):1915–1927. doi:10.1056/NEJMoa061741.

 PubMed Web of Science ®Google Scholar

Huh WK, Joura EA, Giuliano AR, Iversen O-E, de Andrade RP, Ault KA, Bartholomew D, Cestero RM, Fedrizzi EN, Hirschberg AL et al. Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16–26 years: a randomised, double-blind trial. Lancet. 2017;390(10108):2143–2159. doi:10.1016/S0140-6736(17)31821-4.

 PubMed Web of Science ®Google Scholar