Currently Approved Prophylactic HPV Vaccines

Diane M Harper

Expert Rev Vaccines. 2009;8(12):1663-1679.

Immunogenicity

The purpose of the prophylactic HPV vaccines is to induce antibodies to the specific vaccine-relevant HPV types that will be sustained for the duration of time the woman is susceptible to HPV infections. Both Cervarix and Gardasil induce antibody titers after three doses that far exceed the titers a natural infection induces in women 16–26 years of age who were seronegative and PCR negative for the vaccine-relevant HPV types at baseline.

The antibody titers, measured in ELISA units/ml, induced by Cervarix remain 13- and 12-fold higher than natural infection titers at 6.4 years for HPV-16 and -18, respectively, with over 98% of the women vaccinated maintaining initial seroconversion through 6.4 years. An increased memory B-cell response has been demonstrated in women 18–30 years of age who were seronegative and PCR negative for HPV-16/18 at the time of vaccination at 1 month after the three doses of Cervarix compared with the HPV-16/18 VLPs adjuvanted with aluminum alone.^[13] The pseudovirion-based neutralization assay (PBNA, ED₅₀ unit) titers for HPV-16 and -18 were likewise high and sustained throughout 6.4 years, and correlated well with the ELISA titers. In addition, the PBNA titers correlated tightly with the measured type-specific cervical mucous antibodies transudating across the basement membrane over 24 months. Antibody titers induced by Cervarix measured in women 15–55 years of age were titers still eightfold higher than natural infection titers for even the oldest 46–55-year-old age cohort after 24 months.^[46] The strong and sustained immunogenic properties of Cervarix offer the possibility of long-term protection for women of many ages.

The neutralization antibody titers induced by Gardasil have been measured by competitive Luminex immunoassay (cLIA) for each HPV type 6, 11, 16 and 18 in milliMerck units/ml. Over 99% of women seroconverted for each HPV type after three doses of vaccine. For HPV-18, however, 28% of women lost their initial seroconversion at 2 years, increasing to 35% of women losing their seroconversion by 3 years. Of those with remaining HPV-18 titers, the levels continued to drop through the studies' end. After an average of 44 months of follow up, 40% of women lost all measurable antibody titers to HPV-18..^[47] In over 14,000 women followed for at least 3 years, there were only 60 cases of HPV-18 infection in the placebo arm for a very low attack rate of less than five infections per 1000 woman-years in an age range of maximal HPV exposure. Such a low attack rate does not allow inferences to be drawn about the duration of the vaccine's efficacy or the immunologic correlate of protection, as there has not been much infectious challenge to the women's waning serostatus. Overall, 10% of women lost their antibody titers to HPV-6 and 5% lost them to HPV-11 within 44 months; of those with remaining seropositivity, the titers dropped to natural infection titers by 24 months, opening the possibility of waning protection. Strong immunogenicity is seen for HPV-16. Over 98% of women maintained seroconversion to HPV-16 and maintained titers tenfold above natural infection titers at 44 months (Figures 2, 3 & 4).

(Enlarge Image)

Figure 2.

Induced anti-HPV-16 titers after Cervarix® and after Gardasil® administration in women 15–26 years of age. These graphs show the subsequent titers for HVP-16 after peak (month 7) responses over time. For Cervarix, the peak titer is 124-fold higher than natural infection titers and remains 11-fold higher 6.4 years later.^[15] For Gardasil, the peak titer is encircled, and is 104-fold higher than natural infection titers and remains tenfold higher 5 years later.
*Denotes when vaccination occurred.
cLIA: Competitive Luminex immunoassay; GMT: Geometric mean titer; HPV: Human papillloma virus; NIT: Natural infection titer; PBNA: Pseudovirion-based neutralization assay (measured in ED₅₀ units).
Redrawn with permission from [50,75].

(Enlarge Image)

Figure 3.

Induced anti-HPV 18 titers after Cervarix® and after Gardasil® administration in women 15–26 years of age. These graphs show the subsequent titers for HVP 18 after peak (month 7) responses over time. For Cervarix, the peak titer is 107-fold higher than natural infection titers and remains fivefold higher 6.4 years later.^[15] For Gardasil, the encircled peak titer is 27-fold higher than natural infection titers and returns to natural infection titer levels at 18 months, with 35% of Gardasil-vaccinated women losing their anti-HPV-18 titers by 3 years. Anti-HPV-18 titers for Gardasil become equivalent to natural infection titers at 18 months and remain equivalent to natural infection titers through 5 years.
*Denotes when vaccination occurred.
cLIA: Competitive Luminex immunoassay; GMT: Geometric mean titer; HPV: Human papilloma virus; NIT: Natural infection titer; PBNA: Pseudovirion-based neutralization assay (measured in ED₅₀ units).
Redrawn with permission from [50,75].

(Enlarge Image)

Figure 4.

Induced anti-HPV-6 and anti-HPV-11 titers after Gardasil® administration in women 16–26 years of age. These graphs show the subsequent titers for HVP-6 and -11 after peak (month 7) responses over time. The encircled peak titer for HPV-6 is 11-fold higher than natural infection titers. The titers for HPV-6 become statistically indistinguishable from the natural infection titers at 18 months, staying at that level over 5 years. The titers for HPV 11 return to baseline natural infection titers at 18 months, dropping slightly lower than natural infection titers over 5 years. cLIA: Competitive Luminex immunoassay; GMT: Geometric mean titer; HPV: Human papilloma virus; NIT: Natural infection titer; PBNA: Pseudovirion-based neutralization assay (measured in ED₅₀ units).
*Denotes when vaccination occurred.
Redrawn with permission from [50].

The neutralizing antibody titers to HPV-16 and -18 have been measured in the same assay in a head-to-head trial of Cervarix and Gardasil^[48] in order to remove the confusion of different proprietary measurement systems. In all circumstances, Cervarix produced significantly higher antibody titers for HPV-16 than did Gardasil (3.7-fold higher) at month 7, the peak titers; and even greater fold higher for HPV-18 (7.3-fold higher). As the duration of vaccine efficacy is the most important public-health parameter of mass vaccination programs, and because antibody titers are the closest surrogate measure to efficacy as evidenced by our use of immunobridging, and despite not having a correlative titer identified, it is likely that Cervarix will have a longer duration of efficacy than will Gardasil. Long-term studies are necessary to prove this (Table 10).

The head-to-head trial also reported cervicovaginal mucous antibody titers present in the vaccinated women. Cervicovaginal secretion mucous antibodies are believed to be central for protection against HPV infection and cervical disease, evidenced by natural history studies in which both IgA and IgG antibodies appear several months after HPV clearance, with the IgG antibody action predominating.^[49] A similar proportion of HPV-specific neutralizing antibodies transudates from the serum to the mucous for both vaccines. The ratios of titers in the serum to titers in the mucous were threefold higher for Cervarix than for Gardasil as measured by the PBNA.

Memory B cells induced after Cervarix and Gardasil were equivalent for HPV-16 measured at 1 month after the series of three vaccinations at nearly 90%. For HPV-18, nearly 90% of the women vaccinated with Cervarix responded with memory B cells, but only 66% of the women vaccinated with Gardasil had so responded at the time of maximal potential response. This is another indicator of the potential necessity for a booster for HPV-18 durability by Gardasil.

An anamnestic response was elicited by an intramuscular injection of a single dose of Gardasil at the end of the 5-year Phase II trial.^[50] Antibodies to HPV-6 were induced in 75% of women who had lost their HPV-6 seropositivity with only a third of the responders mounting titers that exceeded the initial antibody response. Antibodies to HPV-11 were induced in 86% of women who had lost their HPV-11 seropositivity, with 70% of the responders mounting titers that exceeded the initial antibody response. This is worrisome that the boosted titers were not completely regained after only 5 years between the initial series and the booster injection. Antibodies to HPV-18 were induced in 97% of women who had lost their HPV-18 seropositivity, with 73% of the responders mounting titers that exceeded the initial antibody response. It is reassuring to note that the loss of HPV-18 efficacy may be regained by booster shots, certainly within 5 years. The anamnestic studies were not continued to show the rate of decay in the response over time. It is not known how the anamnestic response will behave if the booster is not given until 10 years after the initial vaccination series.

HPV-16 immunogenicity remains strong for Gardasil with anamnestic challenge. There was only one woman who lost her seropositivity to HPV-16 at 60 months, and she responded to the booster shot with titers above the initial antibody response 1 month after the booster. Since no trials of Gardasil have been extended beyond 44 months for the Phase III trials and 5 years for the Phase II trial, the meaning of the loss of antibody titers is unclear for possible future declines in vaccine efficacy.

Both Cervarix and Gardasil were tested in young adolescents 9/10–15 years of age who were seronegative at study entry for the vaccine-relevant HPV types for safety and antibody responses.^[51–54] Both studies showed that young adolescents mounted an antibody response that was significantly higher than the response induced in 16–26-year-old seronegative, PCR-negative women. The concept of immunobridging was invoked to infer a similar efficacy for adolescent females to that seen in the 16–26-year-old female cohort because there was a similar or greater immune response in the young adolescents compared with the 16–26-year-old women.

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Cite this: Currently Approved Prophylactic HPV Vaccines - Medscape - Dec 01, 2009.

Abstract and Introduction
The Two Vaccines
Vaccine Efficacy
Duration of Vaccine Efficacy
Immunogenicity
Seropositive & PCR Negative for HPV-6, -11, -16 & -18
Safety
Expert Commentary
Five-year View
References
Sidebar

Table 1. Vaccine composition.
	Cervarix® (GlaxoSmithKline)	Gardasil® (Merck)
Vaccine type	HPV-16 and HPV-18 VLP L1 capsid component	HPV-6/11/16/18 VLP L1 capsid component
Concentration	20 µg HPV-16 20 µg HPV-18	20 µg HPV-6 40 µg HPV-11 40 µg HPV-16 20 µg HPV-18
Adjuvant	AS04: 500 µg aluminum hydroxide, 50 µg 3-deacylated monophosphoryl lipid A	Alum: 225 µg aluminum hydroxyphosphate sulfate
Recombinant technology substrate system	Baculovirus expression system in Trichoplusia ni insect cells	Yeast expression system in Saccharomyces cerevisiae

HPV: Human papillomavirus; VLP: Virus-like particle.
Data from [16,73].

Table 2. Phase III trial vaccine efficacies by human papillomavirus type causation and by cohort analysis.
Vaccine	CIN 2+ caused by HPV-16/18	CIN 2+ caused by HPV-16/18	CIN 2+ caused by HPV-16/18	CIN 2+ caused by any HPV-type	Ref.
Cervarix^®*	93% (96.1% CI: 80–98), ATP-E n = 14,656	98% (96.1% CI: 88–100), ATP-E^‡ n = 14,656	98% (96.1% CI: 91–100), TVC-E n = 16,120	30% (96.1% CI: 16–42), TVC n = 17,349 70% (96.1% CI: 55–81), TVC-naive n = 10,885	^[26]
Gardasil^®§	98% (95% CI: 94–100), PPSP n = 16,957	95% (95% CI: 85–99), USP^¶ n = 11,728	44% (95% CI: 26–58), ITT^§ n = 12,167	18% (95% CI: 7–28), ITT n = 17,151	^[103]

^*35-months follow-up.^[26]
^‡Those in the ATP-E but HPV type assignment algorithm were used to resolve causation when multiple HPV types were present.
^§44-month close-out analysis.^[103]
^¶36-months follow-up.^[17]
CIN 2+ = CIN 2/3, adenocarcinoma in situ, squamous cell carcinoma and adenocarcinoma.
ATP-E: According to protocol efficacy (efficacy for all women who met eligibility criteria and complied with the protocol, who received three injections, whose baseline Pap was normal, atypical squamous cells of undetermined significance [ASCUS] or low-grade squamous intraepithelial lesion [LSIL]; cases were counted starting the day after the third vaccination); CIN: Cervical intraepithelial neoplasia; HPV: Human papillomavirus; ITT: Intention-to-treat population (regardless of serostatus or HPV DNA PCR status to vaccine-relevant HPV types at study entry, regardless of entry cytology, regardless of timing and number of injections received; cases were counted from day 1 after the first injection); PPSP: Per protocol susceptible population (for those women who were seronegative and PCR negative for the vaccine-related HPV types at study entry regardless of entry cytology results, and remained PCR negative for the vaccine-relevant HPV types through 1 month after receipt of the third injection; cases were counted 1 month after three doses given); TVC: Total vaccinated cohort (women with at least one injection, seropositive or negative, PCR positive or negative for one or more HPV types at baseline, regardless of Pap result; case counting first day after first injection); TVC-E: Total vaccinated cohort for efficacy (women with at least one injection, baseline Pap of normal, ASCUS or LSIL; case counting began the day after the first injection); TVC-naive: Total vaccinated cohort for naive women (women with at least one injection, baseline normal Pap, PCR DNA negative for all 14 oncogenic HPV types and seronegative for HPV-16 and -18; cases counted first day after first injection); USP: Unrestricted susceptible population (for those women who were seronegative and PCR negative for the vaccine-related HPV types at study entry, regardless of entry cytology results, received one or more injections; cases were counted from the first day after the first injection).

Table 3. Duration of efficacy established from Phase II trials.
Vaccine	CIN 1–3 caused by vaccine-relevant HPV type				Vaccine efficacy (%) (95% CI)	Duration of follow-up
Vaccine	Vaccine (n)	Vaccine (cases)	Placebo (n)	Placebo (cases)	Vaccine efficacy (%) (95% CI)	Duration of follow-up
Cervarix®	481	0	470	15	100 (73–100)	6.4 years
Gardasil®	114	0	127	7	100 (31–100)	5 years

Women in these trials were seronegative and DNA-negative at baseline regardless of sexual activity.
Cervarix: population analyzed in this table were seronegative to HPV-16 and -18, and PCR DNA negative to 14 high-risk HPV types at study entry.
Gardasil: population analyzed in this table were seronegative to HPV-6, -11, -16 and -18, and PCR DNA negative to HPV 6, 11, 16 and 18 at study entry.
CIN: Cervical intraepithelial neoplasia; HPV: Human papillomavirus.
Data from [15,16].

Table 4. No vaccine efficacy for viral or lesion clearance by human papillomavirus L1 virus-like particle vaccines in women human papillomavirus DNA PCR positive regardless of serostatus to vaccine relevant HPV types at the time of vaccination.
	Vaccine efficacy (95% CI)			Ref.
	Seropositive baseline status: CIN 1+ caused by HPV-6, -11, -16 or -18	Seronegative baseline status: CIN 1+ caused by HPV-6, -11, -16 -or -18	Seropositive or seronegative baseline status: 12-month persistent HPV-16/18 infection	Ref.
Cervarix®			-7% (-32–13) n = 345	^[24]
Gardasil®	-20% (<0–27) n = 293	19% (<0–54) n = 445		^[18]

Italicized values are not significant.
CIN: Cervical intraepithelial neoplasia; HPV: Human papillomavirus.

Table 5. Vaccine efficacy for CIN 2+ caused by HPV-16/18 in women seropositive, but PCR negative for HPV-16/18 at time of vaccination.
	Placebo cases	Vaccine efficacy	Ref.
Cervarix®	3	100%	^[26]
Gardasil^®*	5	100%	^[17]
Combined vaccines: post hoc analysis	8	100% (95% CI: 63–100)

^*Additional case reported via [Richard Haupt, Merck & Co, USA (2008), Pers. Comm.].
CIN: Cervical intraepithelial neoplasia; HPV: Human papillomavirus.

Table 6. Cross-protection evidence of vaccine efficacy in Phase III trials for oncogenic human papillomavirus types beyond HPV-16/18 in women DNA negative for the cross-protected types at study entry, regardless of serostatus.
	6 months persistent infection		CIN 2+
	Cervarix® 35-month follow-up	Gardasil® 44-month follow-up	Cervarix 35-month follow-up	Gardasil 44-month follow-up
HPV-31	79% (96.1% CI: 70–85) P/V: 215/46	46% (95% CI: 15–66) P/V: 57/31	92% (96.1% CI: 66–99) P/V: 25/2	70% (95% CI: 32–88) P/V: 27/8
HPV-45	76% (96.1% CI: 60–86) P/V: 94/23	8% (95% CI: -67–49) P/V: 26/24	100% (96.1% CI: -68–100) P/V: 4/0	-52% (95% CI: -1718–83) P/V: 2/3
HPV-33	46% (96.1% CI: 25–61) P/V: 123/67	28% (95% CI: -45–66) P/V: 21/15	52% (96.1% CI: -3–79) P/V: 25/12	24% (95% CI: -71–67) P/V: 16/12
HPV-31/-33/-45/-52/-58	30% (96.1% CI: 22–38) P/V:755/534	25% (95% CI: 5–41) P/V: 167/127	53% (96.1% CI: 25–71) P/V: 64/30	33% (95% CI: -0.3–55) P/V: 66/44

For Cervarix: women were DNA PCR negative at baseline for the nonvaccine-relevant HPV types, regardless of DNA PCR status for vaccine-relevant HPV types at study entry, receiving at least one dose of vaccine, with cases counted after month 7. For Gardasil: women were seronegative and DNA PCR negative for the vaccine-relevant HPV types at study entry, were DNA PCR negative for each of the nonvaccine-relevant HPV types, received at least one dose of vaccine, with cases counted after day 1.
Italicized values are not significant.
CIN: Cervical intraepithelial neoplasia; HPV: Human papillomavirus; P/V: Cases occurring in the placebo arm/cases occurring in the vaccinated arm.
Data from [19,26].

Table 7. Estimated maximal cervical cancer reduction accounting for significant cross-protection of additional oncogenic human papillomavirus types.
HPV type	Attributed proportion (%) of cervical cancers by cancer type		Reduction in cases (%) after use of Cervarix®		Reduction in cases (%) after use of Gardasil®
HPV type	Squamous cell carcinoma of the cervix	Adenocarcinoma of the cervix	Squamous cell carcinoma of the cervix	Adenocarcinoma of the cervix	Squamous cell carcinoma of the cervix	Adenocarcinoma of the cervix
16	61.6	47.8	61.6	47.8	61.6	47.8
18	8.2	29.0	8.2	29.0	8.2	29.0
31	4.5	1.2	3.6	0.9	2.1	0.6
33	4.3	1.1	2.0	0.5
45	5.5	12.3	4.2	9.3
Total estimated reduction in cervical cancers attributed to vaccination			79.5%	87.6%	71.9%	77.4%

Assumptions: 100% female coverage, lifetime duration of vaccine efficacy, 100% efficacy for HPV-16- and -18-associated cancers by both Gardasil and Cervarix. For Cervarix, efficacy values were 76, 79 and 46% for HPV-45, -31 and -33 persistent infections, respectively; based on a population of women who were seronegative for the vaccine-relevant HPV types at study entry, were DNA PCR negative at baseline for the 12 nonvaccine-relevant HPV types regardless of DNA PCR status for vaccine relevant HPV types at study entry, receiving at least one dose of vaccine, with cases counted after month 7.^[26] For Gardasil, efficacy against persistent HPV 31 was assumed to be 46% based on a population of women who were seronegative and DNA PCR negative for the vaccine-relevant HPV types at study entry, were DNA PCR negative for each of the ten nonvaccine-relevant HPV types, received at least one dose of vaccine, with cases counted after day 1.^[19] Attributable proportion data taken from [74].
HPV: Human papillomavirus.

Table 8. 3-year reductions in abnormal Pap tests requiring colposcopy referrals and excisional treatments for CIN 2/3, regardless of HPV type causation after human papillomavirus vaccination.
	Cervarix®				Gardasil®
	Vaccine n = 5449	Placebo n = 5436	Reduction (%)	96.1% CI	Vaccine n = 4616	Placebo n = 4679	Reduction (%)	95% CI
Cases (n)	Cases (n)	Cases (n)	Reduction (%)	96.1% CI	Cases (n)		Reduction (%)	95% CI
Reduction in number of colposcopy referrals	354	476	26	15–36%	850	1061	20	21–27
Reduction in number of cervical excisional therapies	26	83	69	50–81%	131	229	42	28–54

Women 15–25 years of age (Cervarix) or 16–23 years of age (Gardasil) negative to 14 oncogenic HPV types with normal cytology at baseline followed on average for 40 and 43 months (Cervarix and Gardasil, respectively).
HPV: Human papillomavirus.
Data from [26,30].

Table 9. Vaccine efficacy summary for Gardasil® for lesions other than cervical disease.
Lesion type	Average duration of study	HPV-type causation	Vaccine efficacy (95% CI)		Ref.
Lesion type	Average duration of study	HPV-type causation	Per protocol	Intent to treat	Ref.
*Condylomas*
Condyloma	44 months	6, 11, 16, 18	99% (96–100) n = 15,802	80% (74–85) n = 17,923	^[103]
Condyloma	44 months	Any	83% (74–89) n = 17,622	63% (54–70) n = 17,389	^[103]
Male condyloma	29 months	6, 11, 16, 18	89% (66–98) n = 2805		^[33]
*VIN 1, VaIN 1*
VIN 1	36 months	6, 11, 16, 18	100% (42–100) n = 15,886	58% (<0–84) n = 17,916	^[104]
VaIN 1	36 months	6, 11, 16, 18	100% (31–100) n = 15,886	76% (28–94) n = 17,916	^[104]
VIN 1 or VaIN 1 or condyloma	36 months	Any		41% (28–51) n = 17,916	^[104]
*VIN 2/3, VaIN 2/3*
VIN 2/3	44 months	16, 18	100% (56–100) n = 15,513	69% (30– 88) n = 17,923	^[103]
VaIN 2/3	44 months	16, 18	100% (50–100) n = 15,516	85% (32–98) n = 17,923	^[103]
VIN 2/3	44 months	Any		50% (9–73) n = 17,389	^[103]
VaIN 2/3	44 months	Any		46% (-7–74) n = 17,389	^[103]

Italicized values are not significant.
Per protocol means women were seronegative at baseline and PCR negative for each type day 1 through month 7, regardless of entry cytology; cases were counted from the first day after 30 days after the third injection. Intent to treat means women were included regardless of serostatus or HPV DNA PCR status to vaccine-relevant HPV types at study entry, regardless of entry cytology, and regardless of timing and number of injections received; cases were counted from day 1 after the first injection.
HPV: Human papillomavirus; VaIN: Vaginal intraepithelial neoplasia; VIN: Vulvar intraepithelial neoplasia.

Table 10. Immunogenicity response of Cervarix® and Gardasil® measured in the same systems for women receiving the complete series of the respective vaccines.
	Peak antibody titer (ED₅₀) at month 7, 18–26-year-old females		Cervicovaginal mucous positivity for neutralizing antibodies (% positivity [95% CI]), 18–45-year-old females		Memory B-cell response (% positivity [95% CI]), 18–45-year-old females		Published years of efficacy ^[15,16]
	HPV-16	HPV-18	HPV-16	HPV-18	HPV-16	HPV-18	Published years of efficacy ^[15,16]
Cervarix	31,715	13,732	81% (67–91)	33% (20–48)	90% (79–96)	89% (78–95)	6.4
Gardasil	8682	1886	51% (37–64)	9% (3–19)	94% (84–99)	66% (53–78)	5
Comparison (fold increase, 95% CI)	3.7-fold (2.7–5.0)	7.3-fold (5.2–10.2)
p-value			Significantly different	Significantly different		p = 0.0041

Antibody titers measured in the PBNA system for serum and cervicovaginal mucous showed statistically higher induced responses at 7 months post vaccine dose 1 for Cervarix than Gardasil. Memory B-cell responses were identical for both vaccines for HPV-16; but were significantly superior for Cervarix for HPV-18.
HPV: Human papillomavirus; PBNA: Pseudovirion-based neutralization assay (measured in ED₅₀ units).
Adapted from [48].

Table 11. Ranked anti-HPV competitive Luminex immunoassay geometric mean titers induced by Gardasil® at end of study for females 16–26 years of age and 9–12 years of age by vaccine-relevant serostatus and PCR status at study entry.
Day 1 serostatus for vaccine-relevant HPV type	Day 1 PCR status for vaccine-relevant HPV type	n	GMT (mMU/ml)	95% CI
*HPV-6*
Positive 16–26-year-olds	Negative 16–26-year-olds	301	376*	329–431
Positive 16–26-year-olds	Positive 16–26-year-olds	95	256	205–319
Negative 9–12-year-olds	Negative 9–12-year-olds	250	180*	160–202
Negative 16–26-year-olds	Positive 16–26-year-olds	121	111	96–130
Negative 16–26-year-olds	Negative 16–26-year-olds	4230	83	80–85
*HPV-11*
Positive 16–26-year-olds	Negative 16–26-year-olds	66	453*	331–619
Positive 16–26-year-olds	Positive 16–26-year-olds	16	239	136–422
Negative 9–12-year-olds	Negative 9–12-year-olds	250	209*	184–238
Negative 16–26-year-olds	Positive 16–26-year-olds	19	187	148–237
Negative 16–26-year-olds	Negative 16–26-year-olds	4231	103	100–106
*HPV-16*
Negative 9–12-year-olds	Negative 9–12-year-olds	248	961^‡	848–1089
Positive 16–26-year-olds	Negative 16–26-year-olds	290	785^‡	679–908
Positive 16–26-year-olds	Positive 16–26-year-olds	204	777	675–895
Negative 16–26-year-olds	Positive 16–26-year-olds	234	423	370–484
Negative 16–26-year-olds	Negative 16–26-year-olds	4088	408	394–422
*HPV-18*
Positive 16–26-year-olds	Positive 16–26-year-olds	51	292*	219–388
Positive 16–26-year-olds	Negative 16–26-year-olds	122	211	162–274
Negative 9–12-year-olds	Negative 9–12-year-olds	251	126*	106–151
Negative 16–26-year-olds	Positive 16–26-year-olds	131	78	63–96
Negative 16–26-year-olds	Negative 16–26-year-olds	4522	38	36–40

End of study was 38–50 months for the 16–26-year-old females. End of study was 30 months for the 9–12-year-old females.
*Seropositive, PCR-negative 16–26-year-old females had significantly higher GMT at the end of study than did the seronegative, PCR-negative 9–12-year-old females.
^‡No significant difference in GMT at the end of the study for HPV-16 for seropositive, PCR-negative 16–26-year-old females and seronegative, PCR-negative 9–12-year-old females.
GMT: Geometric mean titer; HPV: Human papillomavirus; mMU: milliMerck unit.
Adapted from[103].

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