Evaluation of safety and immunogenicity of a quadrivalent human papillomavirus vaccine in healthy females between 9 and 26 years of age in Sub-Saharan Africa

Figures & data

Table 1. Subject disposition and summary of exclusions^a from the per-protocol immunogenicity populations

	qHPV vaccine 9 to 12 y n (%)	qHPV vaccine 13 to 15 y n (%)	qHPV vaccine 16 to 26 y n (%)	Placebo 9 to 12 y n (%)
Number randomized	80	30	120	20
Received vaccination 1	80 (100.0)	30 (100.0)	120 (100.0)	20 (100.0)
Received vaccination 2	79 (98.8)	29 (96.7)	119 (99.2)	19 (95.0)
Received vaccination 3	77 (96.3)	28 (93.3)	117 (97.5)	19 (95.0)
Completed Study	61 (76.3)	24 (80.0)	106 (88.3)	15 (75.0)
Discontinued	9 (11.3)	5 (16.7)	10 (8.3)	3 (15.0)
Lost to follow-up	0 (0.0)	1 (3.3)	7 (5.8)	0 (0.0)
Protocol Violation	9 (11.3)	4 (13.3)	2 (1.7)	3 (15.0)
Withdrew	0 (0.0)	0 (0.0)	1 (0.8)	0 (0.0)
Unknown	10 (12.5)	1 (3.3)	4 (3.3)	2 (10.0)
Number excluded from the per-protocol immunogenicity analyses for:
HPV6/11	26	12	45	7
HPV16	23	13	34	6
HPV18	25	12	37	6
Reasons for exclusion^a
Protocol Violation	11	5	5	3
Vaccination series not completed within 6 months^b	0	0	3	0
Missed 2nd and 3rd vaccination	1	1	1	1
Missed 3rd vaccination	2	1	2	0
Missing day 1 swab sample/results^c	0	0	3	0
Missing day 1 serology sample/results^d	9	4	2	3
Missing month 7 swab samples/results^b,d	0	0	3	0
Vaccination 2 or 3 out of acceptable day range	12	7	18	3
Missing month 7 serology sample/results^b,d	9	3	10	3
Positive to HPV6 or 11^e
At day 1	4	2	19	1
At or before month 7	4	2	19	1
Positive to HPV16^e
At day 1	0	2	5	0
At or before month 7	0	2	5	0
Positive to HPV18^e
At day 1	4	1	6	0
At or before month 7	4	1	6	0

^aSubjects are counted once in each applicable exclusion category. A subject may appear in more than one category.

^bAmong subjects who received all 3 vaccinations.

^cIncludes subjects who are missing at least one required swab sample or PCR result.

^dIncludes subjects with a missing serum sample or missing cLIA results for ≥1 HPV type.

^eDay 1 includes seropositivity or PCR positivity. Post-Day 1 includes PCR positivity only. Applies only to the analysis populations for the respective HPV-type(s). PCR positivity is only assessed in 13–26 y olds who are sexually active.

Table 2. Summary of anti-HPV cLIA seropositivity percentages by vaccination group (per-protocol population^a)

		qHPV vaccine (N = 230 )				Placebo (N = 20 )
			Seropositivity				Seropositivity
HPV type	Time Point	# contributing to the analysis	# who seroconverted	Percent (%)	95% CI^b	#. contributing to the analysis	# who seroconverted	Percent (%)	95% CI
HPV6	Day 1	147	0	0.0%	(0%, 2%)	13	0	0.0%	(0%, 25%)
	Month 07	147	147	100%	(98%, 100%)	13	1	7.7%	(0%, 36%)
HPV11	Day 1	147	0	0.0%	(0%, 2%)	13	0	0.0%	(0%, 25%)
	Month 07	147	147	100%	(98%, 100%)	13	1	7.7%	(0%, 36%)
HPV16	Day 1	160	0	0.0%	(0%, 2%)	14	0	0.0%	(0%, 23%)
	Month 07	160	160	100%	(98%, 100%)	14	0	0.0%	(0%, 23%)
HPV18	Day 1	156	0	0.0%	(0%, 2%)	14	0	0.0%	(0%, 23%)
	Month 07	156	156	100%	(98%, 100%)	14	0	0.0%	(0%, 23%)

^aThe per-protocol immunogenicity population includes all subjects who did not violate the protocol, received all 3 vaccinations within acceptable day ranges, were seronegative at day 1 and PCR negative day 1 through month 7 (i.e., one month post-dose 3) for the relevant HPV type(s), and had a month 7 serum sample collected within an acceptable day range.

^bThe hypothesis was that the percentage of subjects receiving qHPV vaccine who seroconvert to each of HPV 6, 11, 16, and 18 at month 7 was acceptable. Each seroconversion rate was declared acceptable if the lower bound of the corresponding 95% confidence interval exceeded 90%.

Percent was calculated as 100*(Number of subjects contributing to the analysis/Number of subjects who seroconverted to the indicated HPV type at the indicated time point). N = Number of subjects randomized to the respective vaccination group who received at least 1 injection; CI = Confidence interval; HPV = Human papillomavirus; mMU = Milli Merck units.

Table 3. Summary of anti-HPV geometric mean titers at 1 month post-dose 3 by vaccination group (per-protocol population^a)

		qHPV vaccine (N = 230)			Placebo (N = 20)
			GMT			GMT
HPV type	Time Point	# contributing to the analysis	(mMU/mL)	95% CI	# contributing to the analysis	(mMU/mL)	95% CI
HPV6	Day 1	147	<10	(<10 , <10)	13	<10	(<10 , <10)
	Month 07	147	602	(526, 689)	13	<10	(<10 , <10)
HPV11	Day 1	147	<7	(<7 , <7)	13	<7	(<7 , <7)
	Month 07	147	626	(545, 718)	13	<7	(<7 , 7)
HPV16	Day 1	160	<9	(<9 , <9)	14	<9	(<9 , <9)
	Month 07	160	3,786	(3,360, 4,265)	14	<9	(<9 , <9)
HPV18	Day 1	156	<15	(<15 , <15)	14	<15	(<15 , <15)
	Month 07	156	811	(708, 928)	14	<15	(<15 , <15)

^aThe per-protocol immunogenicity population includes all subjects who did not violate the protocol, received all 3 vaccinations within acceptable day ranges, were seronegative at day 1 and PCR negative day 1 through month 7 for the relevant HPV type(s), and had a month 7 serum sample collected within an acceptable day range. For samples measuring below the limit of quantification of the assay, a value of half that of the lower limit of quantification was used. The lower limit of quantitation for the cLIA is 11, 8, 11, and 10, for HPV 6, 11, 16 and 18, respectively.

N = Number of subjects randomized to the respective vaccination group who received at least 1 injection.

Table 4. Adverse event summary (days 1 to 15 following any vaccination visit) - all vaccinated subjects by age group

	Placebo 9 to 12 years	qHPV vaccine 9 to 12 years	qHPV vaccine 13 to 15 years	qHPV vaccine 16 to 26 years
	n (%)	n (%)	n (%)	n (%)
Number with follow-up	19	79	29	119
with one or more AE	15 (78.9)	64 (81.0)	23 (79.3)	104 (87.4)
injection-site^a	9 (47.4)^b	54 (68.4)^b	21 (72.4)	88 (73.9)
erythema	1 (5.3)^c	8 (10.1)^c	3 (10.3)	15 (12.6)
size rating (inches)
0 to ≤ 1	1 (5.3)	5 (6.3)	2 (6.9)	15 (12.6)
>1 to ≤ 2	0 (0.0)	3 (3.8)	1 (3.4)	0 (0.0)
pain	9 (47.4)^d	53 (67.1)^d	20 (69.0)	88 (73.9)
mild	6 (31.6)	35 (44.3)	12 (41.4)	52 (43.7)
moderate	2 (10.5)	16 (20.3)	8 (27.6)	33 (27.7)
severe	1 (5.3)	3 (3.8)	0 (0.0)	3 (2.5)
swelling	4 (21.1)^e	23 (29.1)^e	8 (27.6)	31 (26.1)
size rating (inches)
0 to ≤ 1	3 (15.8)	17 (21.5)	8 (27.6)	28 (23.5)
>1 to ≤ 2	1 (5.3)	5 (6.3)	8 (27.6)	1 (0.8)
>2 to ≤ 3	0 (0.0)	1 (1.3)	0 (0.0)	1 (0.8)
unknown	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.8)
systemic^f	11 (57.9)	38 (48.1)	17 (58.6)	73 (61.3)
With incidence >5% among any qHPV vaccine group
abdominal pain	1 (5.3)	7 (8.9)	2 (6.9)	8 (6.7)
pyrexia	5 (26.3)	9 (11.4)	6 (20.7)	9 (7.6)
malaria	1 (5.3)	2 (2.5)	2 (6.9)	2 (1.7)
nasopharyngitis	0 (0.0)	2 (2.5)	1 (3.4)	13 (10.9)
headache	5 (26.3)	27 (34.2)	12 (41.4)	41 (34.5)
dysmenorrhoea	0 (0.0)	0 (0.0)	1 (3.4)	11 (9.2)
vaccine-related systemic^a,f	9 (47.4)	29 (36.7)	15 (51.7)	42 (35.3)
With incidence >5% among any qHPV vaccine group
abdominal pain	0 (0.0)	7 (8.9)	2 (6.9)	3 (2.5)
pyrexia	5 (26.3)	8 (10.1)	6 (20.7)	7 (5.9)
headache	4 (21.1)	21 (26.6)	10 (34.5)	26 (21.8)
with serious AE	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
who died	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Discontinued^g due to an AE	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)

^aDetermined by the investigator to be related to the vaccine.

^bP-Value = 0.11 for vaccine vs placebo in subjects 9 to 12 y old.

^cP-Value = 0.51 for vaccine vs placebo in subjects 9 to 12 y old.

^dP-Value = 0.11 for vaccine vs placebo in subjects 9 to 12 y old.

^eP-Value = 0.48 for vaccine vs placebo in subjects 9 to 12 y old.

^fIncidence >5% among any qHPV vaccination group.

^gStudy medication withdrawn.