Table 1.

Characteristics of studies that evaluated HPV vaccine effectiveness by number of doses

Endpoint/vaccine/authors	Country	Study design	Study population		Vaccination	Case definition	Statistical analyses			Overall risk of bias assessmentb
			Age (years) at Vaccination Outcome		N by dose number		Assignment of dose number	Buffer periodsa (months)	Adjustment or stratification
Vaccine-type HPV infection
Quadrivalent vaccine
Chandler 2018	United States	Cross-sectional study using self-reported data - men	≤26c	14–26	0: 82 1: NA 2: NA 3: NA	HPV 6,11,16, or 18 DNA positivity in self-collected penile and perianal/anal swabsd	Final status	0	None	Serious (2/3)
Widdice 2019	United States	Cross-sectional study using self-reported data - men	16.2 wave 1 (mean); 15.1 wave 2 (mean)	13–26	0: 471 1: 58 2: 37 3: 143	HPV 6,11,16, or 18 DNA positivity in genital and perianal/anal swabsd	Final status	0	Age at vaccination, sexual initiation before or after vaccination	Serious (1/3)
Sonawane 2019	United States	Cross-sectional study of a nationally representative sample	<26b	18–26	0: 1,004 1: 106 2: 126 3: 384	HPV 6,11,16, or 18 DNA positivity in self-collected cervicovaginal samplesd	Final status	0	Attained age, race/ethnicity, age at sexual debut, lifetime number of male sexual partners	Serious (2/3)
Markowitz 2020	United States	Cross-sectional study of women enrolled in an integrated health-care delivery system	<29b	20–29	0: 1,052 1: 303 2: 304 3: 2,610	HPV 6,11,16, or 18 DNA positivity in liquid-based cytology samplesd	Final status	1	Age at vaccination, screening year, race/ethnicity, attained age	Moderate (2/3)
Batmunkh 2020	Mongolia	Cross-sectional study of women	11–17	16–26	0: 357 1: 118	HPV 16 or 18 DNA positivity in self-collected swabse	Final status	0	Attained age at assessment, sexual behavior, education, income, employment status, tobacco and alcohol use, pregnancy	Moderate (2/3)
Bivalent vaccine
Kavanagh 2014	Scotland	Cross-sectional study using screening registry data	15–17	20–21	0: 3,418 1: 55 2: 106 3: 1,100	HPV 16 or 18 DNA positivity in liquid-based cytology samplesf	Final status	0	Birth year cohort, deprivation score	Serious (1/3)
Cuschieri 2016	Scotland	Cross-sectional study using screening registry data with additional sampling of those with <3 doses	15–>18	20–21	0: 3,619 1: 177 2: 300 3: 1,853	HPV 16 or 18 DNA positivity in liquid-based cytology samplesg	Final status	0	Birth year cohort, deprivation score, age at first dose	Serious (1/3)
Kavanagh 2017	Scotland	Cross-sectional study using screening registry data	12–>18	20–21	0: 4,008 1: 223 2: 391 3: 3,962	HPV 16 or 18 DNA positivity in liquid-based cytology samplesg	Final status	0	Age at vaccination, birth year cohort, deprivation score	Moderate (2/3)
Hoes 2021	Netherlands	Prospective cohort study	12–13	14–17	0: 929 2: 1098h	HPV 16 or 18 incident DNA positivity in self-collected vaginal swabsi	Final status	0	Attained age, ethnicity, ever had sex, ever used contraception	Moderate (1/3)
Anogenital warts
Quadrivalent vaccine
Herweijer2014	Sweden	Retrospective cohort study using population-based health registries	10–19	10–24	0: 1,045,157 1: 115,197 2: 107,338 3: 89,836	First observed diagnosis: ICD-10 code A63.0 or podophyllotoxin / imiquimod prescription	Time-dependent Final status	0 to 12	Age at first vaccination, age at outcome, parental education	Serious (1/3)
Blomberg 2015	Denmark	Retrospective cohort study using population-based health national registries	12–27	12–27	0: 188,956 1: 55,666 2: 93,519 3: 212,549	First diagnosis: ICD-10 code A63.0 or podophyllotoxin prescription	Time-dependent	1	Attained age, age at vaccination, maternal education disposable income, calendar year	Serious (2/3)
Dominiak-Felden 2015	Belgium	Retrospective cohort study using sick-fund/insurance reimbursement database	10–21	16–23	0: 63,180 1: 4,020 2: 3,587 3: 35,792	First prescription of imiquimod and reimbursement	Time-dependent	1	Age at first dose	Serious (2/3)
Perkins 2017	United States	Retrospective cohort study using commercial claims database	9–25	9–25	0: 201,933 1: 30,438 2: 36,583 3: 118,962	ICD-9 and CPT codes and prescriptionsj	Final status	0, 12	Age at start of exposure period, regions, SES indicators, calendar year, differential observation periods	Serious (1/3)
Navarro-Illana 2017	Spain	Retrospective cohort study using national registries	14	14–19	0: 607,006 1: 18,142 2: 31,420 3: 153,296 (person-yrs)	First diagnosis of ICD-9-CM code 078.11	Time-dependent	0	Attained age (time varying), calendar year, health department	Serious (1/3)
Lamb 2017	Sweden	Retrospective cohort study using national registries	10–19	10–27	2: 79,042 3: 185,456	First diagnosis of ICD-10 code A63.0 or podophyllotoxin / imiquimod prescription	Time-dependent	0	Attained age at outcome, age at vaccination time between doses	Serious (1/3)
Hariri 2018	United States	Retrospective cohort study in integrated health-care delivery systems	16–17 (mean)	11–28	0: 31,563 1: 5,864 2: 5,459 3: 21,631	ICD-9 code (078.10, 078.11, 078.19), specialty of diagnosing provider, and STI tests ordered	Final status	6 from last dose 12 from first dose	Race/ethnicity, health plan, age at enrollment in health plan, age at beginning of study period, evidence of sexual activity (as defined by composite measure), age at first evidence of sexual activity, age at first dose, continuous enrollment indicator, months enrolled in health plan, Medicaid enrollment	Moderate (3/3)
Zeybek 2018	United States	Matched retrospective cohort study using health insurance claims databases (males and females)	9–26	10–31	0: 286,963 1: 54,280 2: 55,632 3: 177,051	ICD-9-CM or 10 code 078.11 or A63.0	Final status	3	Age group (based on age at last dose) sex, region of residence, history of STDs, enrollment history.	Serious (1/3)
Willows 2018	Canada	Matched retrospective cohort study using linked vaccine registry and claims and population-based databases	9–26	10–33	0: 94,327 1: 3,521 2: 6,666 3: 21,277	ICD-9-CM or 10 code 078.11 or A63.0 and related procedure code	Final status	0	Age at vaccination, place of residence, area-level income, birth date, previous hospitalizations and physician visits, history of chronic diseases, sexual activity (based on evidence using a composite measure)	Serious (2/3)
Baandrup, 2021	Denmark	Retrospective cohort study using population-based health national registries	12–30	12–30	0: 1,904,895 1: 235,653 2: 460,978 3: 1,934,589 (person-yrs)	First diagnosis: ICD-10 code A63.0 or podophyllotoxin prescription	Time-dependent	1	Attained age, age at vaccination, maternal education, calendar time	Serious (1/3)
Cervical abnormalities
Quadrivalent vaccine
Gertig 2013	Australia	Retrospective cohort study using linked data from registries	12–19	12–21	0: 14,085 1: 1,422 2: 2,268 3: 21,151	Histology: CIN3/AIS, CIN2, CIN1, any high grade Cytology: low grade and high grade	Time-dependent Final status	0	Age at first screen, remoteness area, SES	Serious (2/3)
Crowe 2014	Australia	Case control study using linked data from registries	12–26	11–31	0: 60,282 1: 10,879 2: 12,073 3: 25,119	Histology: CIN2+/AIS	Final status	0, 1, 6, 12	Year of birth, remoteness area, SES, follow-up time	Serious (2/3)
Brotherton 2015	Australia	Retrospective cohort study using linked regional data registries	12–26	12–30	0: 133,055 1: 20,659 2: 27,500 3: 108,264	Histology: CIN3/AIS, CIN2, any high grade Cytology: low grade and high grade	Final status	0, 1, 6, 12, 24	Age in 2007, remoteness, SES, screening start (before or after vaccination)	Serious (1/3)
Hofstetter 2016	United States	Retrospective cohort study using medical center records	11–20	11–27	0: 1,632 1: 695 2: 604 3: 1,196	Cytology: any abnormal and high gradej	Final status	1	Age at vaccination initiation or first missed opportunity for vaccination for unvaccinated, insurance, language, clinic type, CT screening, and baseline cytology	Serious (2/3)
Kim 2016	Canada	Nested case-control study using linked data from registries	10–15	18–21	0: 5,712 1: 327 2: 490 3: 3,675	Cytology: low grade and high gradek	Final status	0	Attained age, urban/rural, laboratory site, neighborhood income	Serious (2/3)
Silverberg 2018	United States	Nested case-control study of women enrolled in an integrated health-care delivery system	14–26	18–34	0: 23,293 1: 756 2: 554 3: 1,527	Histology: CIN2+/AIS	Final status	6	Smoking, parity, recent outpatient visits, race/ethnicity, STDs, hormonal contraceptives, immunosuppression	Serious (2/3)
Dehlendorff 2018	Denmark& Sweden	Retrospective cohort study using linked national registry data	13–29	13–30	0: 2,091,579 1: NA 2: NA 3: NA	Histology: CIN2+/AIS	Time-dependent	0	Attained age, age at vaccination, maternal education	Serious (1/3)
Brotherton 2019	Australia	Retrospective cohort study using linked regional data registries	≤13–22	15–22	0: 48,845 1: 8,618 2: 18,190 3: 174, 995	Histology: CIN2+CIN3+	Final status (time-varying as a sensitivity analysis)	0, 12, 24	Birth cohort, age at study entry, area of residence, socioeconomic status, attained age (time varying)	Serious (1/3)
Verdoodt 2020	Denmark	Retrospective cohort study using linked national registry data	12–16	17–25	0: 374,327 1: 10,480 2: 30,259 3: 174,532	Histology: CIN2+CIN3+	Time-dependent (final status for the comparison between doses)	0 6 in secondary analysis	Attained age, maternal education	Serious (1/3)
Johnson Gargano 2020	United States	Case control study using medical records data from 5 US sites; test negative design	12–26	18–39	0: 2,731 1: 136 2: 108 3: 325	Histology: HPV type-specific CIN2+	Final status	1, 12, 24, 36	Birth cohort, geographic site, race/ethnicity, insurance status, age at vaccination	Moderate (3/3)
Rodriguez 2020	United States	Retrospective matched cohort study using health insurance claims database	9–26	9–31	0: 66,541 1: 13,630 2: 14,088 3: 38,823	Histology: CIN2/3 Cytology: HSIL/ASC-H	Final status	12	Age at vaccination, region, history of STDs and pregnancy, length of enrollment, history and results of pap test, US census region, age at beginning of follow-up	Serious (1/3)
Innes 2020	New Zealand	Retrospective cohort study using linked national registry data	14–21	20–24	0: 47,283 1 or 2: 8,317 3: 48,713	Histology: CIN1 CIN2+	Final status	0	Age at first dose, birth year cohort	Serious (1/3)
Bivalent vaccine
Pollock 2014	Scotland	Retrospective cohort study using linked national registry data	15->18	20–21	0: 76,114 1: 1,315 2: 2,725 3: 25,898	Histology: CIN1, CIN2, CIN3	Final status	0	Attained age, birth year cohort year, deprivation score	Serious (2/3)
Cameron 2017	Scotland	Retrospective cohort study using linked national registry data	14->18	20–21	0: 75,683 1: 2,258 2: 4,462 3: 55,303	Histology: CIN1, CIN2, CIN3	Final status	0	Deprivation score, birth year cohort	Serious (2/3)
Palmer 2019	Scotland	Retrospective cohort study using linked national registry data	12->18	20	0: 64,026 1: 2,051 2: 4,135 3: 68,480	Histology: CIN1, CIN2, CIN3 Cytology: Low grade, moderate grade, severe grade	Final status	0	Age at vaccination, deprivation score, rurality	Serious (2/3)
Acuti Martellucci 2021 l	Italy	Retrospective cohort study using administrative data	14->30	17–32	0: 7,394 1: 212 2: 83 3: 96	Cytology: Any abnormal cytology, low and high grade	Final status	1, 6, 12	Year of birth, residential area, country of birth, screening test kit, number of screens	Serious (2/3)

Abbreviations: CT, chlamydia trachomatis; SES, socioeconomic status, STD, sexually transmitted disease or infection; CIN, cervical intraepithelial neoplasia; CIN2+, CIN grade 2 or worse; AIS, adenocarcinoma in situ; ICD-9, International Classification of Disease, ninth revision; ICD-10, International Classification of Disease, tenth revision; NA, not available

Note: Crowe et al (2014) reported on an additional outcome defined using cytology and histology data for classification, results are not included in this paper

^aBuffer period is the lag time between vaccination and counting of outcomes.

^bOverall risk of bias assessment considers 3 categories: selection, information bias and confounding (ratings are low, moderate, serious, critical) and is based on the worst rating. If different objectives have different overall assessments, this table includes the bias rating for 1 vs 0 doses when available. In parentheses is number of categories of bias (out of 3) with the worst rating. More information is provided in supplementary material.

^cnot explicitly stated in paper.

^dBy Roche Linear Array assay detecting 37 types.

^eBy Xpert HPV assay and Anypex II detecting 28 types.

^fBy multimetrix HPV assay detecting 24 types.

^gBy Optiplex HPV assay detecting 24 types.

^hNumbers in first study year;

ⁱBy HPV-LIPA25 detecting 25 types.

^jThree possible scenarios: a) ≥ 1 diagnosis of ICD-9 code 078.1; b) ≥ 1 diagnosis of ICD-9 code 078.1, 078.10, 078.19 plus destruction/excision procedure or ICD-9 code 211.4, 216.5, 221.8, 222.9; c) ≥ 1 prescription for anogenital warts plus destruction/excision procedure or ICD-9 code 211.4, 216.5, 221.8, 222.9.

^kLow-grade cytology defined as atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. High-grade cytology defined as atypical squamous cells, cannot rule out a high-grade lesion, or high-grade squamous intraepithelial lesion.

^lEither bivalent or quadrivalent HPV vaccine.