Cross-protective vaccine efficacy of the bivalent HPV vaccine against HPV31 is associated with humoral immune responses

Figures & data

Table 1. Comparison of selected enrollment characteristics by case-control status

	Control	31 cases	45 cases	58 cases
	n(%)	n(%)	n(%)	n(%)
Age
18–21	62 (51.67)	45 (58.44)	23 (44.23)	58 (58.00)
22–25	58 (48.33)	32 (41.56)	29 (55.77)	42 (42.00)
Lifetime number of partners
2-Jan	85 (70.83)	49 (63.64)	23 (44.23)	62 (62.00)
3+	35 (29.17)	28 (36.36)	29 (55.77)	38 (38.00)
New partners over follow-up period
None	78 (65)	41 (53.95)	39 (75)	54 (54)
More than 1	42 (35)	35 (46.05)	13 (25)	46 (46)
Enrollment cervical HPV DNA infection
Negative	85 (70.83)	36 (46.75)	20 (38.46)	50 (50.00)
16 or 18 positive	13 (10.83)	16 (20.78)	8 (15.38)	10 (10.00)
Other Carcinogenic*	14 (11.67)	21 (27.27)	20 (38.46)	32 (32.00)
Non-carcinogenic	8 (6.67)	4 (5.19)	4 (7.69)	8 (8.00)
Enrollment 16/18 Serological status
Negative	74 (64.35)	39 (53.42)	20 (40.00)	54 (56.25)
16+ only	12 (10.43)	14 (19.18)	9 (18.00)	15 (15.63)
18+ only	10 (8.70)	5 (6.85)	5 (10.00)	11 (11.46)
16+ or 18+	19 (16.52)	15 (20.55)	16 (32.00)	16 (16.67)
Vaccination window	Dose 1 to dose 2 (days)
Median (IQR)	38 (33 - 50)	35 (32 - 45)	40 (34 - 58)	37 (33 - 50)
	Dose 2 to dose 3 (days)
Median (IQR)	133 (121 - 153)	139 (126 - 162)	134 (121 - 150)	137 (120 - 156)

* By definition does not include 31/45/58 for each of the respective cases.

Table 2. Univariate and multivariate association between markers measured and HPV31 cases and controls

	HPV16 ELISA
Titers (range within quartile)	Controls n(%)	HPV31 Cases n(%)		Univariate OR (95%CI)		Multivariate* OR (95%CI)
Qtl 1 (1–353.67)	79 (26)	57 (30)		1		1
Qtl 2 (≥ 353.67 - 969.05)	72 (23)	53 (27)		1.02 (0.63–1.65)		0.99 (0.61 - 1.61)
Qtl 3 (≥ 969.05 - 2467.08)	80 (26)	40 (21)		0.69 (0.43–1.12)		0.61 (0.38 - 0.97)
Qtl 4 ≥ 2467.08 - 106,096.04	77 (25)	43 (22)		0.77 (0.46–1.31)		0.63 (0.36 - 1.08)
						p trend 0.03
	HPV31 Neutralization
	Controls n(%)		HPV31 Cases n(%)	Univariate OR (95%CI)		Multivariate* OR (95%CI)
Seroconvert: No	138 (45)		100 (52)	1		1
Seroconvert: Yes	170 (55)		93 (48)	0.75 (0.50 - 1.15)		0.68 (0.46 - 1.06)
Positive: Below median < 77.41	95 (31)		35 (18)	0.51 (0.31 - 0.84)		0.52 (0.31 - 0.87)
Positive: Above median ≥ 77.41	75 (24)		58 (30)	1.07 (0.62 - 1.83)		0.89 (0.49 - 1.60)
	HPV16 Avidity
	Controls n(%)		HPV31 Cases n(%)	Univariate OR (95%CI)		Multivariate* OR (95%CI)
Below median: < 1.68	141 (46)		106 (55)	1		1
Above median: ≥ 1.68	167 (54)		87 (45)	0.69 (0.52 - 0.93)		0.72 (0.54 - 0.97)
			Number of markers present**
Positive # of markers	Controls n(%)		HPV31 Cases n(%)	Univariate OR (95%CI)	Multivariate* OR (95%CI)
None	74 (24)		62 (32)	1	1
One marker	67 (22)		43 (22)	0.77 (0.46 - 1.27)	0.73 (0.44 - 1.20)
Two markers	74 (24)		44 (22)	0.71 (0.44 - 1.15)	0.59 (0.36 - 0.96)
Three markers	93 (30)		44 (22)	0.37 (0.48 - 0.87)	0.51 (0.33 - 0.80)
					p trend 0.002

Qtl, quartile. *All models adjusted for age, number of lifetime partners, and enrollment HPV16 DNA and serostatus. **The markers were: HPV16 antibody levels (measured by ELISA, dichotomized on the median), HPV31 neutralization potential (measured by SEAP, positive vs. negative), and HPV16 avidity (dichotomized on the median levels)

Table 3. Univariate and multivariate association between markers measured and HPV45 cases and controls

	HPV18 ELISA
Titers (range within quartile)	Controls n(%)		HPV45 Cases	Univariate OR (95%CI)	Multivariate* OR (95%CI)
			n(%)
Qtl 1 (1–175.11)	71 (23)		51 (22)	1	1
Qtl 2 (≥ 175.11 - 486.26)	82 (27)		24 (22)	0.83 (0.44 - 1.57)	0.76 (0.39 - 1.49)
Qtl 3 (≥ 486.26 - 1214.90)	81 (26)		30 (28)	1.10 (0.58 - 2.06)	0.80 (0.43 - 1.47)
Qtl 4 ≥ 1214.90 - 46,734.13	74 (24)		30 (28)	1.20 (0.61 - 2.35)	0.91 (0.47 - 1.77)
					p trend 0.88
	HPV45 Neutralization
	Controls n(%)	HPV45 Cases n(%)		Univariate OR (95%CI)	Multivariate* OR (95%CI)
Seroconvert: No	152 (49)	57 (53)		1	1
Seroconvert: Yes	156 (51)	50 (47)		0.85 (0.50 - 1.47)	0.79 (0.44 - 1.39)
Positive: Below median < 28.55	78 (25)	27 (25)		0.51 (0.31 - 0.84)	0.92 (0.50 - 1.69)
Positive: Above median ≥ 28.55	78 (25)	23 (22)		1.07 (0.62 - 1.83)	0.79 (0.38 - 1.64)
		Number of markers present**
Positive # of markers	Controls n(%)	HPV45 Cases		Univariate OR (95%CI)	Multivariate* OR (95%CI)
		n(%)
None	98 (32)	32 (30)		1	1
One marker	109 (35)	40 (37)		1.12 (0.64 - 1.97)	1.10 (0.62 - 1.94)
Two markers^¶	101 (33)	35 (33)		1.06 (0.57 - 1.97)	0.82 (0.44 - 1.52)
					p trend 0.50

Qtl, quartile. *All models adjusted for age, number of lifetime partners, and enrollment HPV18 DNA and serostatus. **The markers were: HPV18 antibody levels (measured by ELISA, dichotomized on the median) and HPV45 neutralization potential (measured by SEAP, positive vs. negative). ^¶HPV18 antibody and HPV45 neutralization were evaluated.

Table 4. Univariate and multivariate association between markers measured and HPV58 cases and controls

	HPV16 ELISA
Titers (range within quartile)	Controls n(%)			HPV58 Cases n(%)			Univariate OR (95%CI)	Multivariate* OR (95%CI)
Qtl 1 (1–353.67)	79 (26)			54 (23)			1	1
Qtl 2 (≥ 353.67 - 969.05)	72 (23)			58 (25)			1.18 (0.75 - 1.85)	1.20 (0.75 - 1.89)
Qtl 3 (≥ 969.05 - 2467.08)	80 (26)			60 (26)			1.10 (0.71 - 1.70)	1.05 (0.67 - 1.63)
Qtl 4 (≥ 2467.08 - 106,096.04)	77 (25)			58 (25)			1.10 (0.66 - 1.84)	0.99 (0.59 - 1.66)
								p trend 0.83
	HPV18 ELISA
	Controls n(%)		HPV58 Cases n(%)			Univariate OR (95%CI)		Multivariate* OR (95%CI)
Qtl 1 (1–175.11)	71 (23)		61 (27)			1		1
Qtl 2 (≥ 175.11 - 486.26)	82 (27)		50 (22)			0.71 (0.44 - 1.14)		0.67 (0.42 - 1.09)
Qtl 3 (≥ 486.26 - 1214.90)	81 (26)		60 (26)			0.86 (0.53 - 1.40)		0.78 (0.47 - 1.29)
Qtl 4 (≥ 1214.90 - 46,734.13)	74 (24)		59 (26)			0.93 (0.54 - 1.58)		0.87 (0.50 - 1.50)
								p trend 0.77
	HPV58 Neutralization
	Controls n(%)	HPV58 Cases n(%)				Univariate OR (95%CI)		Multivariate* OR (95%CI)
Seroconvert: No	209 (68)			152 (66)		1		1
Seroconvert: Yes	98 (32)				78 (34)	1.09 (0.68 - 1.78)		1.06 (0.46 - 1.76)
Positive: Below median < 28.74	53 (17)				43 (19)	1.12 (0.64 - 1.94)		1.05 (0.59 - 1.85)
Positive: Above median ≥ 28.74	45 (15)				35 (15)	1.07 (0.55 - 2.07)		1.09 (0.53 - 2.22)
					Number of markers present**
Positive # of markers	Controls n(%)				HPV58 Cases n(%)	Univariate OR (95%CI)		Multivariate* OR (95%CI)
None	72 (23)				61 (27)	1		1
One marker	83 (27)				54 (23)	0.77 (0.49 - 1.20)		0.73 (0.46 - 1.15)
Two markers	117 (38)				80 (35)	0.81 (0.59 - 1.17)		0.75 (0.52 - 1.07)
Three markers	35 (11)				35 (15)	1.18 (0.66 - 2.12)		1.07 (0.59 - 1.96)
								p trend 0.57

Qtl, quartile. *All models adjusted for age, number of lifetime partners, and enrollment HPV16 DNA and serostatus. **The markers were: HPV16 antibody levels (measured by ELISA, dichotomized on the median), HPV58 neutralization potential (measured by SEAP, positive vs. negative), and HPV16 avidity (dichotomized on the median levels)