Real-world impact and effectiveness assessment of the quadrivalent HPV vaccine: a systematic review of study designs and data sources

Figures & data

Figure 1. PRISMA diagram with details of the literature search and extraction process for the period 01–01-2007 – 31-03-2020, on all outcomes.

Table 1. Criteria for study inclusion/exclusion

Population(s)	4vHPV and/or 9vHPV vaccinated or non-vaccinated females and males of any age from any country.
Interventions	Vaccination with 4vHPV vaccine and/or 9vHPV vaccine
Comparator	Vaccine effectiveness: vaccinated vs. vaccine-naive subjects from the same or a similar population Vaccine impact: pre-vaccination period vs. post-vaccination period, or time trend analyses after the start of vaccination.
Outcomes	HPV genital, anal or oral infections Anogenital warts Recurrent respiratory papillomatosis Cervical or anal lesions Anal, cervical, oropharyngeal, penile, vaginal or vulvar cancer
Time	1 January 2007–31 March 2020
Study design	Observational studies aiming to evaluate ‘real-world benefit’ on: Vaccine effectiveness – the proportion of infection or disease prevented among vaccinated individuals, estimated by comparing the frequency of outcomes in vaccinated vs unvaccinated individuals within similar populations. Vaccine impact – the population-prevented fraction of infection or disease, assessed by comparing prevalence or incidence in the vaccine era to a comparable population from the pre-vaccine era or by measuring population-level trends over time. Included: Observational studies (including cohort, cross-sectional, case-control), on 4vHPV and/or 9vHPV vaccine effectiveness and impact in any language aiming to evaluate ‘real-world benefit’ Excluded: Burden of disease studies with no concurrent vaccine uptake, health-economic studies, modeling/simulation/extrapolation studies, awareness, knowledge, and/or acceptability studies, results of long-term follow-up studies of clinical trial populations, studies exclusively reporting data on 2vHPV vaccine, literature review articles, conference abstracts

Figure 2. Trend in publications of vaccine impact and effectiveness studies.

Table 2. Study characteristics

Study details	Outcomes
	Anogenital warts		Cervical lesions		Genital infection		Anal infection or lesion		Oral infection		JO-RRP		Total
	I	VE	I	VE	I	VE	I	VE	I	VE	I	VE	I	VE
	37	13	28	31	31	37	1	4	1	10	1		99*	95*
Study design
Cohort	22 ^A1	12 ^B1	16 ^C1	24 ^D1	-	4 ^F1	-	3 ^H1	-	2 ^J1	-	-	38	45
Cross-sectional	2 ^A2	1 ^B2	2 ^C2	1 ^D2	3 ^E2	8 ^F2	-	-	1 ^I1	4 ^J2	-	-	8	14
Repeated Cross-sectional	13 ^A3	-	10 ^C3	2 ^D3	28 ^E3	24 ^F3	1^G3	1 ^H3	-	4 ^J3	1 ^K3	-	53	31
Case-control	-	-	-	4 ^D4	-	1 ^F4	-	-	-	-	-	-	-	5
Population
Female	6 ^A5	10 ^B5	28 ^C5	31 ^D5	24 ^E5	33 ^F5	-	2 ^H5	-	3 ^J5	-	-	58	79
Male	-	1 ^B6	-	-	5 ^E6	3 ^F6	1 ^G6	2 ^H6	-	7 ^J6	-	-	6	13
Female and male	31 ^A7	2 ^B7	-	-	2 ^E7	1 ^F7	-	-	1 ^I7	-	1 ^K7	-	35	3
Outcome data source
Claims database	12 ^A8	5 ^B8	3 ^C8	3 ^D8	-	-	-	-	-	-	-	-	15	8
Electronic health record	11 ^A9	3 ^B9	8 ^C9	6 ^D9	1 ^E9	1 ^F9	-	-	-	-	1 ^K9	-	21	10
Registry	13 ^A10	4 ^B10	13 ^C10	18 ^D10	4 ^E10	3 ^F10	-	-	-	-	-	-	30	25
Survey	1 ^A11	1 ^B11	4 ^C11	4 ^D11	26 ^E11	33 ^F11	1 ^G11	4 ^H11	1 ^I11	10 ^J11	-	-	33	52
Exposure data source
Claims database	3 ^A12	3 ^B12	-	1 ^D12	-	-	-	1 ^H12	-	-	-	-	3	5
Electronic health record	-	2 ^B13	1 ^C13	2 ^D13	1 ^E13	-	-	-	-	-	-	-	2	4
Registry	3 ^A14	7 ^B14	4 ^C14	16 ^D14	8 ^E14	7 ^F14	-	-	-	1 ^J14	-	-	15	31
Survey	-	1 ^B15	2 ^C15	8 ^D15	15 ^E15	22 ^F15	1 ^G15	1 ^H15	-	6 ^J15	1 ^K15	-	19	38
Not described	31 ^A16	-	21 ^C16	2 ^D16	7 ^E16	5 ^F16	-	-	1 ^I16	1 ^J16	-	-	60	8
Other^#	-	-	-	2 ^D17	-	3 ^F17	-	2 ^H17	-	2 ^J17	-	-	-	9

^aIncluding 18 studies that performed both impact and effectiveness. I – impact; JO-RRP – juvenile-onset recurrent respiratory papillomatosis; VE – vaccine effectiveness

^#Other includes combinations of listed data sources, or a study-specific database.

Number as in reference list:

A1: 86, 89, 90, 93, 95, 100, 110, 112, 115, 117, 122, 125, 130, 132, 134, 139, 140, 148, 152, 153, 159, 161; A2: 84, 97; A3: 79, 81, 82, 83, 87, 88, 98, 102, 106, 116, 119, 129, 143; A5: 86, 93, 98, 116, 159, 161; A7: 79, 81, 82, 83, 84, 87, 88, 89, 90, 95, 97, 100, 102, 106, 110, 112, 115, 117, 119, 122, 125, 129, 130, 132, 134, 139, 140, 143, 148, 152, 153; A8: 84, 90, 93, 95, 115, 125, 130, 132, 139, 148, 159, 161; A9: 79, 81, 82, 83, 87, 106, 116, 122, 129, 140, 143; A10: 86, 88, 89, 97, 100, 102, 110, 112, 117, 119, 134, 152, 153; A11: 98; A12: 125, 132, 159; A14: 152, 153, 161; A16: 79, 81, 82, 83, 84, 86, 87, 88, 89, 90, 93, 95, 97, 98, 100, 102, 106, 110, 112, 115, 116, 117, 119, 122, 129, 130, 134, 139, 140, 143, 148; B1: 16, 18, 22, 24, 26, 41, 43, 52, 57, 58; B2: 8; B5: 16, 18, 22, 26, 41, 43, 52, 57, 159, 161; B6: 24; B7: 48, 58; B8: 43, 57, 58, 159, 161; B9: 24, 41, 52; B10: 16, 18, 22, 26; B11: 48; B12: 43, 58, 159; B13: 24, 52; B14: 16, 18, 22, 26, 41, 57, 161; B15: 48; C1: 80, 96, 104, 105, 113, 114, 120, 127, 142, 155, 156, 158, 161, 166, 167, 172; C2: 91, 133; C3: 94, 109, 123, 128, 145, 146, 150, 151, 154, 157; C5: 80, 91, 94, 96, 104, 105, 109, 113, 114, 120, 123, 127, 128, 133, 142, 145, 146, 150, 151, 154, 155, 156, 157, 158, 161, 166, 167, 172; C8: 114, 161, 167; C9: 109, 141, 145, 146, 150, 151, 157, 172; C10: 80, 91, 96, 104, 105, 113, 120, 123, 128, 133, 154, 155, 156, 158; C11: 94, 127, 142, 166; C13: 145; C14: 151, 155, 161, 167; C15: 166, 172; C16: 80, 91, 94, 96, 104, 105, 109, 113, 114, 120, 123, 127, 128, 133, 142, 146, 150, 154, 156, 157, 158; D1: 17, 19, 23, 27, 32, 33, 36, 37, 42, 44, 49, 59, 61, 64, 69, 72, 74, 75, 76, 78, 161, 166, 167, 172; D2: 30; D3: 28, 68; D4: 20, 34, 55, 67; D5: 17, 19, 20, 23, 27, 28, 30, 32, 33, 34, 36, 37, 42, 44, 49, 55, 59, 61, 64, 67, 68, 69, 72, 74, 75, 76, 78, 161, 166, 167, 172; D8: 75, 161, 167; D9: 28, 33, 36, 67, 76, 172; D10: 17, 19, 20, 23, 27, 32, 34, 37, 42, 44, 49, 55, 61, 64, 69, 72, 74, 78; D11: 30, 59, 68, 166; D12: 75; D13: 55, 64; D14: 161, 167; D15: 30, 36, 42, 44, 68, 76, 166, 172; D16: 28, 37; D17: 59, 67; E2: 131, 165, 173; E3: 62, 85, 92, 99, 101, 103, 107, 108, 111, 118, 121, 123, 124, 126, 135, 136, 137, 144, 147, 149, 162, 163, 164, 168, 169, 170, 171, 174; E5: 85, 92, 99, 103, 107, 108, 111, 118, 121, 124, 131, 135, 136, 137, 144, 147, 162, 164, 165, 168, 170, 171, 173, 174; E6: 123, 126, 149, 163, 169; E7: 62, 101; E9: 124; E10: 103, 108, 131, 144; E11: 62, 85, 92, 99, 101, 107, 111, 118, 121, 123, 126, 135, 136, 137, 147, 149, 162, 163, 164, 165, 168, 169, 170, 171, 173, 174; E13: 108; E14: 85, 101, 131, 137, 144, 162, 165, 174; E15: 62, 118, 121, 123, 124, 135, 136, 147, 149, 164, 168, 169, 170, 171, 173; E16: 92, 99, 103, 107, 111, 126, 163; F1: 13, 36, 59, 60; F2: 30, 31, 39, 51, 53, 65, 165, 173; F3: 12, 15, 21, 25, 35, 38, 45, 50, 54, 56, 62, 66, 70, 71, 73, 77, 162, 163, 164, 168, 169, 170, 171, 174; F4: 11; F5: 11, 12, 13, 15, 21, 25, 30, 31, 35, 36, 39, 45, 50, 51, 53, 54, 56, 59, 60, 65, 66, 70, 71, 73, 77, 162, 164, 165, 168, 170, 171, 173, 174; F6: 38, 163, 169; F7: 62; F9: 36; F10: 12, 45, 73; F11: 11, 13, 15, 21, 25, 30, 31, 35, 38, 39, 50, 51, 53, 54, 56, 59, 60, 62, 65, 66, 70, 71, 77, 162, 163, 164, 165, 168, 169, 170, 171, 173, 174; F14: 45, 56, 65, 77, 162, 165, 174; F15: 11, 15, 25, 30, 31, 36, 38, 39, 45, 50, 51, 53, 54, 56, 62, 65, 66, 70, 71, 77, 162, 164, 165, 168, 169, 170, 171, 173, 174; F16: 12, 13, 21, 35, 163; F17: 59, 60, 73; G3: 149; G6: 149; G11: 149; G15: 149; H1: 13, 24, 36; H3: 46; H5: 13, 36; H6: 24, 46; H11: 13, 24, 36, 46; H12: 24; H15: 46; H17: 13, 36; I1: 160; I7: 160; I11: 160; I16: 160; J1: 13, 36; J2: 29, 62, 65, 160; J3: 40, 47, 63, 195; J5: 13, 36, 65; J6: 29, 40, 47, 62, 63, 160, 195; J11: 13, 29, 36, 40, 47, 62, 63, 65, 160, 195; J14: 65; J15: 29, 40, 47, 62, 63, 195; J16: 160; J17: 13, 36; K3: 138; K7: 138; K9: 138; K15: 138;

Table 3. Considerations for study design

Impact	Vaccine Effectiveness
Study design
Preferred design: Repeated cross-sectional study, large population at low cost. Best suited to assess the total effect. Disease incidence is the preferred to disease prevalence as outcome. Stratification for potential confounders (e.g. age at first sexual intercourse, condom use, positive history of STI) is possible but can be subject to recall bias.	Preferred design: Cohort study provides highest level of confidence; alternative: repeated cross-sectional study with knowledge of vaccination status. Case–control studies will be more useful for long term and more infrequent outcomes such as cancer. Disease incidence is preferred to disease prevalence as outcome. Stratification for potential confounders (e.g. age at first sexual intercourse, condom use, positive history of STI) is possible but can be subject to recall bias.
Study population
The study population is not necessary to be of age eligible for vaccination. Inclusion of males or unvaccinated female could show herd protection. With increasing GNV, preferably both women and men are included in the study population.	The vaccinated cohort should be of age eligible for vaccination. To reduce bias, controls should be selected within the same age range. In NIPs with GNV preferably both women and men are included, to assess effectiveness in both genders.
Outcome data source
AGW: as most people with AGW will be treated at some point, claims databases are good data sources. CL: cervical cancer screening registries, linked to pathology databases, have been used successfully. * INF: if HPV-based screening is performed, cervical cancer screening registries provide very useful data, although HPV type information may not be available. Anal and oral INF: no routine sample collection is available, making surveys the only option to collect data.	Outcome data need to be linked to exposure data to determine effectiveness. INF: in the absence of HPV-based screening, surveys provide the best data. Anal and oral INF: no routine sample collection is available, making surveys the only option to collect data.
Exposure data source
Vaccination status at the individual level is not necessary for impact studies, as pre- and post-vaccination periods are compared. Knowledge of the vaccination coverage at population level is important.	Vaccination registries/immunization information systems with strong organization are preferred as sources of exposure data where available, as date of immunization and number of doses are generally more reliable than self-reported vaccination status (avoiding exposure misclassification bias).
Time since start vaccination program
AGW and INF (so-called short incubation outcomes) are most likely to show early impact. CL may take longer to develop and is most easily detected in populations eligible for cervical cancer screening in an established, organized cervical cancer screening program, including appropriate registration of outcomes. Evidence of an effect on cervical cancer, as well as JO-RRP, will take relatively longer, as it concerns an outcome with a long delay or an outcome among the children of vaccinated women.
Vaccination coverage rate
Essentially, the higher the vaccination coverage rate, the more likely impact can be observed. However, for AGW and INF, a low but significant impact has been demonstrated with coverage rates as low as 30%.	Not necessary to have a high VCR. With a high VCR, unvaccinated controls may not be available. Use of other control groups (e.g. older [non-eligible] age) may impact confounders (e.g. sexual activity).
Source material for HPV detection
The drive toward HPV-based cervical cancer screening will likely result in the HPV status being recorded in the EHR. Increasingly, self-collected cervicovaginal material is considered a valid source for HPV detection, simplifying survey studies on genital infection. First-void urine may be considered as a noninvasive replacement for women.

AGW – anogenital warts; CL – cervical lesions; EHR – electronic health records; GNV – gender-neutral vaccination; INF – infection; JO-RRP – juvenile-onset recurrent respiratory papillomatosis; STI – sexually transmitted infection; VCR – vaccine coverage rate