Scolaris Content Display Scolaris Content Display

Flow diagram summarising the retrieval, inclusion and exclusion of relevant reports of randomised trials assessing the safety and effects of prophylactic HPV vaccines.
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Figure 1

Flow diagram summarising the retrieval, inclusion and exclusion of relevant reports of randomised trials assessing the safety and effects of prophylactic HPV vaccines.

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
 V1 = Random sequence generation; V2 = Allocation concealment; V3 = Blinding participants & personnel; V4 = Blinding of outcome assessment; V5 = Incomplete outcomes; V6 = Selective reporting.
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Figure 2

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
V1 = Random sequence generation; V2 = Allocation concealment; V3 = Blinding participants & personnel; V4 = Blinding of outcome assessment; V5 = Incomplete outcomes; V6 = Selective reporting.

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.
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Figure 3

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
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Figure 4

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.

Protection against CIN2+ irrespective of presence of HPV types in women, aged 15‐26 years, regardless of their HPV DNA status at baseline, who received at least one dose.
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Figure 5

Protection against CIN2+ irrespective of presence of HPV types in women, aged 15‐26 years, regardless of their HPV DNA status at baseline, who received at least one dose.

Summary of vaccine efficacy estimates, by age group, outcome and HPV DNA status at enrolment (for women who received at least one dose). [REFS BETWEEN SQUARE BRACKETS MUST BE ADAPTED][
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Figure 6

Summary of vaccine efficacy estimates, by age group, outcome and HPV DNA status at enrolment (for women who received at least one dose). [REFS BETWEEN SQUARE BRACKETS MUST BE ADAPTED][

Summary of vaccine efficacy estimates by age group, outcome and number of received doses (for women who were HPV16/18 DNA negative at enrolment). [REFS BETWEEN SQUARE BRACKETS MUST BE ADAPTED][
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Figure 7

Summary of vaccine efficacy estimates by age group, outcome and number of received doses (for women who were HPV16/18 DNA negative at enrolment). [REFS BETWEEN SQUARE BRACKETS MUST BE ADAPTED][

Modified Cates plot: Number of cases of CIN2+ associated with HPV16/18 occurring in women who were all hrHPV DNA negative at baseline. 16 out of 1000 non‐vaccinated women developed the lesion (left) whereas fewer than one (0.2) out 1000 vaccinated women developed the lesion (right). Relative risk= 0.01 (95% CI: 0.01 to 0.05).
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Figure 8

Modified Cates plot: Number of cases of CIN2+ associated with HPV16/18 occurring in women who were all hrHPV DNA negative at baseline. 16 out of 1000 non‐vaccinated women developed the lesion (left) whereas fewer than one (0.2) out 1000 vaccinated women developed the lesion (right). Relative risk= 0.01 (95% CI: 0.01 to 0.05).

Modified Cates plot: Number of cases of CIN2+ irrespective of HPV types occurring in women who were all hrHPV DNA negative at baseline. 28 out of 1000 non‐vaccinated women developed the lesion (left) whereas 11 out 1000 vaccinated women developed the lesion (right). Relative risk= 0.37 (95% CI: 0.25 to 0.55).
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Figure 9

Modified Cates plot: Number of cases of CIN2+ irrespective of HPV types occurring in women who were all hrHPV DNA negative at baseline. 28 out of 1000 non‐vaccinated women developed the lesion (left) whereas 11 out 1000 vaccinated women developed the lesion (right). Relative risk= 0.37 (95% CI: 0.25 to 0.55).

Sensitivity analysis of Analysis 7.6 on severe adverse effects restricting to data extracted from publications in peer‐reviewed journals.
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Figure 10

Sensitivity analysis of Analysis 7.6 on severe adverse effects restricting to data extracted from publications in peer‐reviewed journals.

Sensitivity analysis of Analysis 7.7 on deaths restricting to data extracted from publications in peer‐reviewed journals.
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Figure 11

Sensitivity analysis of Analysis 7.7 on deaths restricting to data extracted from publications in peer‐reviewed journals.

Protection against CIN2+ associated with HPV16/18 in women, aged 15‐26 years, who were HPV DNA 16/18 negative at baseline, by number of doses.
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Figure 12

Protection against CIN2+ associated with HPV16/18 in women, aged 15‐26 years, who were HPV DNA 16/18 negative at baseline, by number of doses.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 1 CIN2+ associated with HPV16/18, at least 1 dose.
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Analysis 1.1

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 1 CIN2+ associated with HPV16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 2 CIN2+ associated with HPV6/11/16/18, at least 1 dose.
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Analysis 1.2

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 2 CIN2+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 3 CIN3+ associated with HPV16/18, at least 1 dose.
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Analysis 1.3

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 3 CIN3+ associated with HPV16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 4 CIN3+ associated with HPV6/11/16/18, at least 1 dose.
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Analysis 1.4

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 4 CIN3+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 5 AIS associated with HPV16/18, at least 1 dose.
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Analysis 1.5

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 5 AIS associated with HPV16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 6 AIS associated with HPV6/11/16/18, at least 1 dose.
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Analysis 1.6

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 6 AIS associated with HPV6/11/16/18, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 7 Any CIN2+ irrespective of HPV types, at least 1 dose.
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Analysis 1.7

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 7 Any CIN2+ irrespective of HPV types, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 8 Any CIN3+ irrespective of HPV types, at least 1 dose.
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Analysis 1.8

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 8 Any CIN3+ irrespective of HPV types, at least 1 dose.

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 9 Any AIS irrespective of HPV types, at least 1 dose.
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Analysis 1.9

Comparison 1 High‐grade cervical lesions in hrHPV DNA negative women at baseline, Outcome 9 Any AIS irrespective of HPV types, at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 1 CIN2+ associated with HPV16/(18), 3 doses.
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Analysis 2.1

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 1 CIN2+ associated with HPV16/(18), 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 2 CIN2+ associated with HPV16/(18), at least 1 dose.
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Analysis 2.2

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 2 CIN2+ associated with HPV16/(18), at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 3 CIN2+ associated with HPV16/(18), 1 or 2 doses (post hoc analysis).
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Analysis 2.3

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 3 CIN2+ associated with HPV16/(18), 1 or 2 doses (post hoc analysis).

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 4 CIN2+ associated with HPV6/11/16/18, 3 doses.
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Analysis 2.4

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 4 CIN2+ associated with HPV6/11/16/18, 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 5 CIN2+ associated with HPV6/11/16/18, at least 1 dose.
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Analysis 2.5

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 5 CIN2+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 6 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses (post hoc analysis).
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Analysis 2.6

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 6 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses (post hoc analysis).

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 7 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 3 doses.
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Analysis 2.7

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 7 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 8 CIN3+ associated with HPV 16/18 or HPV6/11/16/18, at least 1 dose.
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Analysis 2.8

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 8 CIN3+ associated with HPV 16/18 or HPV6/11/16/18, at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 9 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis).
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Analysis 2.9

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 9 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis).

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 10 AIS associated with HPV16/18 or HPV6/11/16/18, 3 doses.
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Analysis 2.10

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 10 AIS associated with HPV16/18 or HPV6/11/16/18, 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 11 AIS associated with HPV16/18 or 6/11/16/18, at least 1 dose.
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Analysis 2.11

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 11 AIS associated with HPV16/18 or 6/11/16/18, at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 12 AIS associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis).
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Analysis 2.12

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 12 AIS associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis).

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 13 Any CIN2+ irrespective of HPV types, 3 doses.
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Analysis 2.13

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 13 Any CIN2+ irrespective of HPV types, 3 doses.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 14 Any CIN2+ irrespective of HPV types, at least 1 dose.
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Analysis 2.14

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 14 Any CIN2+ irrespective of HPV types, at least 1 dose.

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 15 Any CIN2+ irrespective of HPV types, 1 or 2 doses (post hoc analysis).
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Analysis 2.15

Comparison 2 High‐grade cervical lesions in HPV16/18 DNA negative women at baseline, Outcome 15 Any CIN2+ irrespective of HPV types, 1 or 2 doses (post hoc analysis).

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 1 CIN2+ associated with HPV16/18, at least 1 dose.
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Analysis 3.1

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 1 CIN2+ associated with HPV16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 2 CIN2+ associated with HPV6/11/16/18, at least 1 dose.
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Analysis 3.2

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 2 CIN2+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 3 CIN3+ associated with HPV16/18, at least 1 dose.
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Analysis 3.3

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 3 CIN3+ associated with HPV16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 4 CIN3+ associated with HPV6/11/16/18, at least 1 dose.
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Analysis 3.4

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 4 CIN3+ associated with HPV6/11/16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 5 AIS associated with HPV16/18, at least 1 dose.
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Analysis 3.5

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 5 AIS associated with HPV16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 6 AIS associated with HPV6/11/16/18, at least 1 dose.
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Analysis 3.6

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 6 AIS associated with HPV6/11/16/18, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 7 Any CIN2+ irrespective of HPV types, at least 1 dose.
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Analysis 3.7

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 7 Any CIN2+ irrespective of HPV types, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 8 Any CIN3+ HPV type, at least 1 dose.
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Analysis 3.8

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 8 Any CIN3+ HPV type, at least 1 dose.

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 9 Any AIS irrespective of HPV types, at least 1 dose.
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Analysis 3.9

Comparison 3 High‐grade cervical lesions in women regardless of baseline HPV DNA status, Outcome 9 Any AIS irrespective of HPV types, at least 1 dose.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 1 Incident HPV16/18 infection, 3 doses.
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Analysis 4.1

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 1 Incident HPV16/18 infection, 3 doses.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 2 Persistent HPV16/18 infection (6M), 3 doses.
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Analysis 4.2

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 2 Persistent HPV16/18 infection (6M), 3 doses.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 3 Persistent HPV16/18 infection (6M), at least 1 dose.
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Analysis 4.3

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 3 Persistent HPV16/18 infection (6M), at least 1 dose.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 4 Persistent HPV16/18 infection(12M), 3 doses.
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Analysis 4.4

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 4 Persistent HPV16/18 infection(12M), 3 doses.

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 5 Persistent HPV16/18 infection (12M), at least 1 dose.
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Analysis 4.5

Comparison 4 Infection with HPV vaccine types in hrHPV DNA negative women at baseline, Outcome 5 Persistent HPV16/18 infection (12M), at least 1 dose.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 1 Incident HPV16/18 infection, 3 doses.
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Analysis 5.1

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 1 Incident HPV16/18 infection, 3 doses.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 2 Incident HPV16/18 infection, at least 1 dose.
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Analysis 5.2

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 2 Incident HPV16/18 infection, at least 1 dose.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 3 Incident HPV16/18 infection, 1 or 2 doses (post hoc analysis).
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Analysis 5.3

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 3 Incident HPV16/18 infection, 1 or 2 doses (post hoc analysis).

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 4 Persistent HPV16/18 infection (6M), 3 doses.
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Analysis 5.4

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 4 Persistent HPV16/18 infection (6M), 3 doses.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 5 Persistent HPV16/18 infection (6M), at least 1 dose.
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Analysis 5.5

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 5 Persistent HPV16/18 infection (6M), at least 1 dose.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 6 Persistent HPV16/18 infection (6M), 1 or 2 doses (post hoc analysis).
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Analysis 5.6

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 6 Persistent HPV16/18 infection (6M), 1 or 2 doses (post hoc analysis).

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 7 Persistent HPV6/11/16/18 infection (6M), 3 doses.
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Analysis 5.7

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 7 Persistent HPV6/11/16/18 infection (6M), 3 doses.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 8 Persistent HPV6/11/16/18 infection (6M), at least 1 dose.
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Analysis 5.8

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 8 Persistent HPV6/11/16/18 infection (6M), at least 1 dose.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 9 Persistent HPV16/18 infection (12M), 3 doses.
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Analysis 5.9

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 9 Persistent HPV16/18 infection (12M), 3 doses.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 10 Persistent HPV16/18 infection (12M), at least 1 dose.
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Analysis 5.10

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 10 Persistent HPV16/18 infection (12M), at least 1 dose.

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 11 Persistent HPV16/18 infection (12M), 1 or 2 doses (post hoc analysis).
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Analysis 5.11

Comparison 5 HPV16/18 infection in HPV16/18 DNA negative women at baseline, Outcome 11 Persistent HPV16/18 infection (12M), 1 or 2 doses (post hoc analysis).

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 1 Incident HPV16/18 infection, at least 1 dose.
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Analysis 6.1

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 1 Incident HPV16/18 infection, at least 1 dose.

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 2 Persistent HPV16/18 infection (6M), at least 1 dose.
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Analysis 6.2

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 2 Persistent HPV16/18 infection (6M), at least 1 dose.

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 3 Persistent HPV6/11/16/18 infection (6M), at least 1 dose.
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Analysis 6.3

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 3 Persistent HPV6/11/16/18 infection (6M), at least 1 dose.

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 4 Persistent HPV16/18 infection (12M), at least 1 dose.
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Analysis 6.4

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 4 Persistent HPV16/18 infection (12M), at least 1 dose.

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 5 Persistent HPV16/18 infection (12M) by dose (post hoc analysis).
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Analysis 6.5

Comparison 6 Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline, Outcome 5 Persistent HPV16/18 infection (12M) by dose (post hoc analysis).

Comparison 7 Adverse events, Outcome 1 Overall local/injection site adverse events.
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Analysis 7.1

Comparison 7 Adverse events, Outcome 1 Overall local/injection site adverse events.

Comparison 7 Adverse events, Outcome 2 Pain at injection site.
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Analysis 7.2

Comparison 7 Adverse events, Outcome 2 Pain at injection site.

Comparison 7 Adverse events, Outcome 3 Swelling at injection site.
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Analysis 7.3

Comparison 7 Adverse events, Outcome 3 Swelling at injection site.

Comparison 7 Adverse events, Outcome 4 Redness at injection site.
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Analysis 7.4

Comparison 7 Adverse events, Outcome 4 Redness at injection site.

Comparison 7 Adverse events, Outcome 5 Overall systemic event and general symptoms.
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Analysis 7.5

Comparison 7 Adverse events, Outcome 5 Overall systemic event and general symptoms.

Comparison 7 Adverse events, Outcome 6 Serious adverse events.
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Analysis 7.6

Comparison 7 Adverse events, Outcome 6 Serious adverse events.

Comparison 7 Adverse events, Outcome 7 Deaths.
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Analysis 7.7

Comparison 7 Adverse events, Outcome 7 Deaths.

Comparison 8 Pregnancy outcomes, Outcome 1 Normal infant.
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Analysis 8.1

Comparison 8 Pregnancy outcomes, Outcome 1 Normal infant.

Comparison 8 Pregnancy outcomes, Outcome 2 Spontaneous abortion/miscarriage.
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Analysis 8.2

Comparison 8 Pregnancy outcomes, Outcome 2 Spontaneous abortion/miscarriage.

Comparison 8 Pregnancy outcomes, Outcome 3 Elective termination/induced abortion.
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Analysis 8.3

Comparison 8 Pregnancy outcomes, Outcome 3 Elective termination/induced abortion.

Comparison 8 Pregnancy outcomes, Outcome 4 Stillbirth.
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Analysis 8.4

Comparison 8 Pregnancy outcomes, Outcome 4 Stillbirth.

Comparison 8 Pregnancy outcomes, Outcome 5 Abnormal infant.
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Analysis 8.5

Comparison 8 Pregnancy outcomes, Outcome 5 Abnormal infant.

Summary of findings for the main comparison. HPV vaccine effects on cervical lesions in adolescent girls and women negative for hrHPV DNA at baseline

HPV vaccine effects on cervical lesions in adolescent girls and women who are hrHPV DNA negative at baseline

Patient or population: adolescent girls and women aged 15 to 26 years who are hrHPV negative before vaccination

Setting: Europe, Asia Pacific countries, South & North America
Intervention: HPV vaccines (at least one dose of bivalent or quadrivalent vaccines)

Comparison: Placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with HPV vaccination1

Cervical cancer ‐ not measured

CIN2+ associated with HPV16/18.

Follow‐up: 3 to 5 years

164 per 10,000

2 per 10,000
(0 to 8)

RR 0.01
(0.00 to 0.05)

23,676
(3 RCTs)

⊕⊕⊕⊕
HIGH

CIN3+ associated with HPV16/18

Follow‐up: 3 to 5 years

70 per 10,000

0 per 10,000
(0 to 7)

RR 0.01
(0.00 to 0.10)

20,214
(2 RCTs)

⊕⊕⊕⊕
HIGH

Continuity correction

AIS associated with HPV16/18

Follow‐up: 3 to 5 years

9 per 10,000

0 per 10,000
(0 to 7)

RR 0.10
(0.01 to 0.82)

20,214
(2 RCTs)

⊕⊕⊕⊝
MODERATE 2

Continuity correction

Any CIN2+ irrespective of HPV type, bivalent or quadrivalent vaccine

Follow‐up: 2 to 6 years

287 per 10,000

106 per 10,000
(72 to 158)

RR 0.37
(0.25 to 0.55)

25,180
(5 RCTs)

⊕⊕⊕⊕
HIGH

Substantial subgroup heterogeneity was observed (I2= 84.3%) for bi‐ and quadrivalent vaccines. So results are reported separately for the 2 vaccines (see next 2 rows).

Any CIN2+ irrespective of HPV type

Follow‐up (bivalent): 3.5 to 6 years

Follow‐up (quadrivalent): 3.5 years

Bivalent vaccine

RR 0.33

(0.25 to 0.43)

15,884

(4 RCTs)

⊕⊕⊕⊕
HIGH

285 per 10,000

94 per 10,000

(71 to 122)

Quadrivalent vaccine

RR 0.57

(0.44 to 0.76)

9296

(1 RCT)

⊕⊕⊕⊝
MODERATE3

291 per 10,000

166 per 10,000

(128 to 221)

Any CIN3+ irrespective of HPV type, bivalent or quadrivalent vaccine

Follow‐up: 3.5 to 4 years

109 per 10,000

23 per 10,000
(4 to 120)

RR 0.21
(0.04 to 1.10)

20,719
(3 RCTs)

⊕⊕⊕⊝
MODERATE 3

Substantial subgroup heterogeneity was observed (I2 = 84.3%) for bi‐ and quadrivalent vaccines. So results are reported separately for the 2 vaccines (see next 2 rows).

Any CIN3+ irrespective of HPV type

Follow‐up (bivalent): 4 years

Follow‐up (quadrivalent): 3.5 years

Bivalent vaccine

RR 0.08

(0.03 to 0.23)

11,423

(2 RCTs)

⊕⊕⊕⊕
HIGH

81 per 10,000

6 per 10,000

(3 to 19)

Quadrivalent vaccine

RR 0.54

(0.36 to 0.82)

9296

(1 RCT)

⊕⊕⊕⊝
MODERATE3

143 per 10,000

77 per 10,000

(51 to 117 )

Any AIS irrespective of HPV type

Follow‐up: 3 to 5 years

10 per 10,000

0 per 10,000
(0 to 8)

RR 0.10
(0.01 to 0.76)

20,214
(2 RCTs)

⊕⊕⊕⊝
MODERATE 2

Continuity correction

1The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). When risk in vaccine group is zero, the 95% CI is computed using an exact binomial method.

AIS: adenocarcinoma in situ; CI: Confidence interval; CIN: cervical intraepithelial neoplasia; RR: Risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Assumed risk calculated from the sum of control group event rates.

2 Downgraded due to serious imprecision in effect estimate (width 95% CI around RR > 0.6).

3 Downgraded one level due to serious imprecision. Few events observed in the two studies (9 in placebo arms and 0 in vaccination arms for the outcome of AIS HPV16/18 and 7 in placebo arms and 0 in vaccination arms for outcome of AIS of any type).

Figures and Tables -
Summary of findings for the main comparison. HPV vaccine effects on cervical lesions in adolescent girls and women negative for hrHPV DNA at baseline
Summary of findings 2. HPV vaccine effects on cervical lesions in adolescent girls and women negative for HPV16/18 DNA at baseline

HPV vaccine effects on cervical lesions in adolescent girls and women negative for HPV16/18 DNA at baseline

Patient or population: adolescent girls and women aged 15 to 45 years who were HPV16/18 negative before vaccination
Setting: Europe, Asia Pacific countries, South & North America
Intervention: HPV vaccines (at least one dose of bivalent or quadrivalent vaccines)
Comparison: Placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with HPV vaccination1

Cervical cancer ‐ not measured

CIN2+ associated with HPV16/18

Follow‐up (age 15 to 26 years): 1 to 8.5 years

Follow‐up (age 24 to 45 years): 4 to 6 years

15 to 26 years

RR 0.05
(0.03 to 0.10)

34,478
(6 RCTs)

⊕⊕⊕⊕
HIGH

113 per 10,000

6 per 10,000
(3 to 11)

24 to 45 years

RR 0.30

(0.11 to 0.81)

7552

(2 RCTs)

⊕⊕⊕⊝

MODERATE 2

45 per 10,000

14 per 10,000

(5 to 37)

CIN3+ associated with HPV16/18 (age 15 to 26 years)

Follow‐up: 3 years

57 per 10,000

3 per 10,000

(1 to 8)

RR 0.05

(0.02 to 0.14)

33,199

(3 studies)

⊕⊕⊕⊕
HIGH

AIS associated with HPV16/18 or 6/11/16/18 (age 15 to 26 years)

Follow‐up: 3 years

12 per 10,000

0 per 10,000
(0 to 8)

RR 0.09
(0.01 to 0.72)

17,079
(2 RCTs)

⊕⊕⊕⊝

MODERATE 2

Continuity

correction

Any CIN2+ irrespective of HPV type (age 15 to 26 years)

Follow‐up: 2 to 6.5 years

231 per 10,000

95 per 10,000
(74 to 120)

RR 0.41
(0.32 to 0.52)

19,143
(3 RCTs)

⊕⊕⊕⊕
HIGH

Any CIN3+ irrespective of HPV type ‐ not measured

Any AIS irrespective of HPV type ‐ not measured

1The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Exception: when risk in vaccine group is zero, the 95% CI is computed using an exact binomial method..

AIS: adenocarcinoma in situ; CI: Confidence interval; CIN: cervical intraepithelial neoplasia; RR: Risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Assumed risk calculated from the sum of control group event rates.

2 Downgraded due to serious imprecision in effect estimate (width 95% CI around RR > 0.6).

Figures and Tables -
Summary of findings 2. HPV vaccine effects on cervical lesions in adolescent girls and women negative for HPV16/18 DNA at baseline
Summary of findings 3. HPV vaccine effects in adolescent girls and women regardless of HPV DNA status at baseline

HPV vaccine effects on cervical lesions in adolescent girls and women unselected for HPV DNA status at baseline

Patient or population: adolescent girls and women aged 15 to 45 years regardless of HPV DNA status at baseline
Setting: Europe, Asia Pacific countries, South & North America and Africa
Intervention: HPV vaccines (at least one dose of bivalent or quadrivalent vaccines)
Comparison: Placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with HPV vaccination1

Cervical cancer ‐ not measured

CIN2+ associated with HPV16/18

Follow‐up (age 15 to 26 years): 3.5 to 8.5 years

Follow‐up (age 24 to 45 years): 3.5 years

15 to 26 years

RR 0.46

(0.37 to 0.57

34,852
(3 RCTs)

⊕⊕⊕⊕
HIGH

341 per 10,000

157 per 10,000
(126 to 194)

24 to 45 years

RR 0.74

(0.52 to 1.05)

9200

(2 studies)

⊕⊕⊕⊝
MODERATE 2

145 per 10,000

107 per 10,000

(76 to 152)

CIN3+ associated with HPV16/18

Follow‐up: 3.5 years

165 per 10,000

91 per 10,000

(74 to 127)

RR 0.55

(0.45 to 0.67)

34,562

(2 RCTs)

⊕⊕⊕⊕
HIGH

Adeno carcinoma in situ (AIS) associated with HPV16/18

Follow‐up: 3.5 years

14 per 10,000

5 per 10,000
(3 to 11)

RR 0.36
(0.17 to 0.78)

34,562
(2 RCTs)

⊕⊕⊕⊕
HIGH

Any CIN2+ irrespective of HPV type

Follow‐up (age 15 to 26 years): 3.5 to 8.5 years

Follow‐up (age 24 to 45 years): 3.5 to 6 years

15 to 26 years

RR 0.70
(0.58 to 0.85)

35,779
(4 RCTs)

⊕⊕⊕⊕
HIGH

559 per 10,000

391 per 10,000
(324 to 475)

24 to 45 years

RR 1.04
(0.83 to 1.30)

9287
(2 RCTs)

⊕⊕⊕⊝
MODERATE 2

343 per 10,000

356 per 10,000
(284 to 445)

Any CIN3+ irrespective of HPV type (age 15 to 26 years)

Follow‐up: 3.5 to 4 years

266 per 10,000

178 per 10,000

(231 to 247)

RR 0.67

(0.49 to 0.93)

35,489

(3 RCTs)

⊕⊕⊕⊝
MODERATE

Substantial subgroup heterogeneity was observed (I2 = 84.3%) for bivalent and quadrivalent vaccines. So results are reported separately for two vaccines.

Any CIN3+ irrespective of HPV type (age 15 to 26 years),

Follow‐up (bivalent): 3.5 to 4 years

Follow‐up (quadrivalent): 3.5 years

Bivalent vaccine

RR 0.55

(0.43 to 0.71)

18,329

(2 RCTs)

⊕⊕⊕⊕
HIGH

188 per 10,000

104 per 10,000

(81 to 134)

Quadrivalent vaccine

0.81

(0.69 to 0.96)

17,160

(1 RCT)

⊕⊕⊕⊝
MODERATE 3

349 per 10,000

283 per 10,000

(241 to 335)

Any AIS irrespective of HPV type (age 15 to 26 years)

Follow‐up: 3.5 years

17 per 10,000

5 per 10,000
(3 to 11)

RR 0.32
(0.15 to 0.67)

34,562
(2 RCTs)

⊕⊕⊕⊕
HIGH

Serious adverse events

Follow‐up: 6 months to 7 years

669 per 10,000

656 per 10,000
(616 to 703)

RR 0.98
(0.92 to 1.05)

71,597
(23 RCTs)

⊕⊕⊕⊕
HIGH

Deaths

Follow‐up: 7 months to 10 years. Most of the information in the analysis comes from studies with follow‐up ranging from 5‐10 years.

11 per 10,000

14 per 10,000
(9 to 22)

RR 1.29
(0.85 to 1.98)

71,176
(23 RCTs)

⊕⊕⊝⊝
LOW 4 5

Older women had higher fatality rate (RR 2.36, 95% CI 1.10 to 5.03). Assessment of the deaths in the studies has not been able to identify a pattern in the cause or timing of death.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

AIS: adenocarcinoma in situ; CI: Confidence interval; CIN: cervical intraepithelial neoplasia; RR: Risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Assumed risk calculated from the sum of control group event rates for all outcomes unless otherwise stated.

2 Downgraded due to serious imprecision. Confidence interval is wide and includes large decrease and small increase in lesions with vaccination group in the older age group.

3 Downgraded one level due to serious inconsistency. Reduction in lesions was greater in younger women than in older women (RR 0.46 in 15 to 26 years versus RR 0.74 in 24 to 45 years; P = 0.02 for interaction).

4 Downgraded one level due to serious imprecision. Confidence interval includes potentially meaningful increase in risk of mortality.

5 Downgraded one level due to serious inconsistency. Despite limited evidence of statistical variation, sub grouping studies by age showed higher fatality rate with vaccines in older age group. There is no clear pattern in causes or timing of deaths.

Figures and Tables -
Summary of findings 3. HPV vaccine effects in adolescent girls and women regardless of HPV DNA status at baseline
Summary of findings 4. HPV vaccine effects on pregnancy outcomes

HPV vaccine adverse pregnancy outcomes (regardless of DNA status and age)

Patient or population: adolescent girls and women aged 15 to 45 years who became pregnant during the study
Setting: Europe, Asia Pacific, North, Central and South America
Intervention: HPV vaccines (bivalent or quadrivalent vaccines)
Comparison: Placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with HPV vaccines

Spontaneous abortion/miscarriage

Follow‐up: 1 to 7 years

Study population

RR 0.88
(0.68 to 1.14)

8618
(9 RCTs)

⊕⊕⊕⊕
HIGH

1618 per 10,000

1,424 per 10,000
(1,100 to 1844)

Elective termination/induced abortion

Follow‐up: 1 to 7 years

Study population

RR 0.90
(0.80 to 1.02)

10,909
(9 RCTs)

⊕⊕⊕⊕
HIGH 1

931 per 10,000

838 per 10,000
(745 to 950)

Stillbirth

Follow‐up: 1 to 3.5 years

Study population

RR 1.12
(0.68 to 1.83)

8754
(6 RCTs)

⊕⊕⊕⊝
MODERATE 2

70 per 10,000

78 per 10,000
(48 to 128)

Babies born with congenital malformations

Follow‐up: 3 to 7 years

Study population

RR 1.22
(0.88 to 1.69)

9252
(5 RCTs)

⊕⊕⊕⊝
MODERATE 2

205 per 10,000

250 per 10,000
(180 to 346)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Confidence interval rules out an increased risk of termination so there is no downgrade for imprecision.

2 Downgraded one level due to serious imprecision. Confidence intervals for both outcomes include meaningful increase and reduction in risk of stillbirth or abnormal infants following vaccination.

Figures and Tables -
Summary of findings 4. HPV vaccine effects on pregnancy outcomes
Table 1. Listing of included trials

Valency

Phase

Number of trials

Appelation

N

Outcomes

Main References

Monovalent

II

1

Phase2 trial (ph2,1v)

2392

Efficacy, safety

Koutsky 2002

Mao 2006

Rowhani‐Rahbar 2009

Bivalent

II

2

Japanese trial (ph2,2v)

1040

Efficacy, safety

Konno 2010

Konno 2010a

Konno 2014

Phase2 trial (ph2,2v)

1113

Efficacy, safety

Harper 2004

Harper 2006

The GSK Study Group 2009

De Carvalho 2010

III

16

African_2 country trial (ph3,2v)

676

Safety

Sow 2013

Chinese trial (ph3,2v)_young

6051

Efficacy, safety

Zhu 2014

Chinese trial (ph3,2v)_ adolescent

750

Safety

Zhu 2014a

Chinese trial (ph3,2v)_mid‐adult

1212

Safety

Zhu 2014a

Co‐vaccination_dTpa_IPV trial (ph3,2v)

494

Safety

Garcia‐Sicilia 2010

Co‐vaccination_HAB trial (Ph3, 2v)

494

Safety

Pedersen 2012

Co‐vaccination_HepB trial (ph3, 2v)

541

Safety

Schmeink 2011

CVT (ph3,2v)

7466

Efficacy, safety

Herrero 2011

Kreimer 2011

Hong Kong trial (ph3,2v)

294

Safety

Ngan 2010

Immunobridging(ph3,2v)

2067

Safety

Medina 2010

Indian trial (ph3,2v)

354

Safety

Bhatla 2010

Korean trial (ph3,2v)

208

Safety

Kim 2010

Korean trial (ph3b,2v)

321

Safety

Kim 2011

Malaysian trial (ph3,2v)

271

Safety

Lim 2014

PATRICIA trial (ph3,2v)

18,644

Efficacy, safety

Paavonen 2007

Paavonen 2009

Szarewski 2011

Wheeler 2011

Lehtinen 2012

VIVIANE trial (ph3,2v)

5752

Efficay, safety,

Skinner 2014

Wheeler 2016

Quadrivalent

II

3

Japanese trial (ph2,4v)

1021

Safety

Yoshikawa 2013

Korean trial (ph2,4v)

176

Safety

Kang 2008

Phase2 trial (ph2,4v)

552

Efficacy, safety

Villa 2005

Villa 2006

Villa 2006a

Olsson 2009

III

4

African_3 country trial (ph3,4v)

98

Safety

Mugo 2015

FUTURE I trial (ph3,4v)

5455

Efficacy, safety

Garland 2007

FUTURE II trial (ph3,4v)

12,167

Efficacy, safety

FUTURE‐II 2007

FUTURE III trial (ph3,4v)

3819

Efficacy, safety

Munoz 2009

Castellsagué 2011

Total

26

73,428

Figures and Tables -
Table 1. Listing of included trials
Table 2. Results of all the efficacy outcomes

Outcomes and exposure subgroups

Absolute risk / per 10,000

Relative risk
(95% CI)

Vaccine

efficacy

(95% CI)

Risk difference/ per 10,000

(95% CI)

No of Participants
(studies)

Certainty of evidence
(GRADE)*

Placebo

Vaccinated

1. High‐grade cervical lesions in women who were hrHPV DNA negative at baseline

Analysis 1.1 CIN2+ associated with HPV16/18, at least 1 dose, age 15‐26 years

164

2

0.01

(0.00 to 0.05)

99%

(95% to 100%)

162

(157 to 164)

23,676
(3 studies)

⊕⊕⊕⊕

high

Analysis 1.2 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 15‐26 years

197

2

0.01

(0.00 to 0.09)

99%

(91% to 100%)

195

(179 to 197)

9296

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 1.3 CIN3+ associated with HPV16/18, at least 1 dose, age 15‐26 years

70

0*

0.01

(0.00 to 0.10)

99%

(90% to 100%)

70

(63 to 70)

20,214

(2 studies)

⊕⊕⊕⊕

high

Analysis 1.4 CIN3+ associated with HPV6/11/16/18, at least 1 dose, age 15‐26 years

94

0*

0.01

(0.00 to 0.18)

99%

(82% to 100%)

94

(77 to 94)

9296

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 1.5 AIS associated with HPV16/18, at least 1 dose, age 15‐26 years

9

0*

0.10

(0.01 to 0.82)

90%

(18% to 99%)

9

(2 to 9)

20,214
(2 studies)

⊕⊕⊕⊝
moderate4

Analysis 1.6 AIS associated with HPV6/11/16/18m at least 1 dose, age 15‐26 years

6

0*

0.14

(0.01 to 2.8)

86%

(‐180% to 99%)

6

(‐12 to 6)

9296

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 1.7.1 Any CIN2+ irrespective of HPV types, at least 1 dose of the bivalent vaccine, age 15‐26 years

285

94

0.33

(0.25 to 0.43)

67%

(57% to 75%)

191

(163 to 214)

15,884

(4 studies)

⊕⊕⊕⊕

high

Analysis 1.7.2 Any CIN2+ irrespective of HPV types, at least 1 dose of the quadrivalent vaccine, age 15‐26 years

291

166

0.57

(0.44 to 0.76)

43%

(24 to 56%)

125

(70 to 163)

9296

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 1.8.1 Any CIN3+ irrespective of HPV types, at least 1 dose of the bivalent vaccine, age 15‐26 years

81

6

0.08

(0.03 to 0.23)

92%

(77% to 97%)

74

(62 to 78)

11,423

(2 studies)

⊕⊕⊕⊕
high

Analysis 1.8.2 Any CIN3+ irrespective of HPV types, at least 1 dose of the quadrivalent vaccine, age 15‐26 years

143

77

0.54

(0.36 to 0.82)

46%

(17% to 64%)

66

(26 to 92)

9296

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 1.9 Any AIS irrespective of HPV types, at least 1 dose

10

0*

0.10

(0.01 to 0.76)

90%

(24% to 99%)

10

(2 to 10)

20,214
(2 studies)

⊕⊕⊕⊝
moderate4

2. High‐grade cervical lesions in women who were HPV16/18 negative at baseline

Analysis 2.1.1 CIN2+ associated with HPV16/18, 3 doses, age 15‐26 years

74

5

0.07

(0.03 to 0.15)

93%

(85% to 97%)

69

(63 to 72)

36,579

(6 studies)

⊕⊕⊕⊕

high

Analysis 2.1.2 CIN2+ associated with HPV16/18, 3 doses, 24‐45 years

36

6

0.16

(0.04 to 0.74)

84%

(26% to 96%)

30

(9 to 34)

6797

(2 studies)

⊕⊕⊕⊝
moderate4

Analysis 2.2.1 CIN2+ associated with HPV16/18, at least 1 dose, 15‐26 years

113

6

0.05

(0.03 to 0.10)

95%

(90% to 97%)

107

(102 to 110)

34,478

(6 studies)

⊕⊕⊕⊕

high

Analysis 2.2.2 CIN2+ associated with HPV16/18, at least 1 dose, age 24‐45 years

45

14

0.30

(0.11 to 0.81)

70%

(19% to 89%)

32

(9 to 40)

7552

(2 studies)

⊕⊕⊕⊝
moderate4

Analysis 2.3.1 CIN2+ associated with HPV16/18, 1 or 2 doses, 15‐26 years***

436

44

0.10

(0.04 to 0.26)

90%

(74% to 96%)

392

(323 to 418)

2958

(5 studies)

⊕⊕⊝⊝

low1$

Analysis 2.3.2 CIN2+ associated with HPV16/18, 1 or 2 doses, age 24‐45 years***

134

82

0.61

(0.14 to 2.67)

39%

(‐167% to 86%)

52

(‐2245 to 115)

755

(2 studies)

⊕⊝⊝⊝
very low1$,4

Analysis 2.4 CIN2+ associated with HPV6/11/16/18, 3 doses, age 15‐45 years

99

6

0.06

(0.01 to 0.61)

94%

(39% to 99%)

93

(39 to 98)

7664

(2 studies)

⊕⊕⊕⊝
moderate4

Analysis 2.4.1 CIN2+ associated with HPV6/11/16/18, 3 doses, age 15‐26 years

142

0*

0.02

(0.00 to 0.25)

98%

(75% to 100%)

142

(93 to 190)

4499

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 2.4.2 CIN2+ associated with HPV6/11/16/18, 3 doses, age 24‐45 years

38

6

0.17

(0.02 to 1.39)

83%

(‐39% to 98%)

32

(‐1 to 32)

3165

(1 study)

⊕⊕⊝⊝
low3,4

Analysis 2.5.1 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 15‐26 years

160

0*

0.01

(0.00 to 0.19)

99%

(81% to 100%)

160

(130 to 159)

5351

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 2.5.2 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 24‐45 years

44

16

0.37

(0.10 to 1.41)

63%

(‐41% to 90%)

28

(‐18 to 40)

3629

(1 study)

⊕⊕⊕⊝
moderate3,4

Analysis 2.6 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses, age 15‐45 years***

199

48

0.24

(0.01 to 5)

76%

(‐400% to 99%)

151

(‐795 to 197)

1316

(2 studies)

⊕⊝⊝⊝
very low1$,4

Analysis 2.6.1 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses, age 15‐26 years***

258

0*

0.04

(0.00 to 0.74)

96%

(26% to 100%))

258

(108 to 409)

852

(1 study)

⊕⊝⊝⊝
very low1$,3,4

Analysis 2.6.2 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses, age 24‐45 years***

88

85

0.97

(0.14 to 6.80)

3%

(‐580% to 86%)

3

(‐165 to 171)

464

(1 study)

⊕⊝⊝⊝
very low1$,3,4

Analysis 2.7 CIN3+ associated with HPV16/18, 3 doses, age 15‐26 years

40

3

0.07

(0.02 to 0.29)

93%

(71% to 98%)

37

(28 to 39)

29,720

(3 studies)

⊕⊕⊕⊕
high

Analysis 2.8 CIN3+ associated with HPV16/18, at least 1 dose, age 15‐26 years

57

3

0.05

(0.02 to 0.14)

95%

(86% to 98%)

54

(49 to 56)

33,199

(3 studies)

⊕⊕⊕⊕

high

Analysis 2.9 CIN3+ associated with HPV16/18, 1 or 2 doses, age 15‐26 years***

200

12

0.06

(0.01 to 0.24)

94%

(26% to 100%)

188

(152 to 198)

3479

(3 studies)

⊕⊕⊝⊝

low1$

Analysis 2.10 AIS+ associated with HPV16/18, 3 doses, age 15‐26 years

8

0*

0.12

(0.02 to 0.70)

88%

(36% to 99%)

8

(2 to 8)

29,707

(3 studies)

⊕⊕⊕⊝
moderate4

Analysis 2.11 AIS+ associated with HPV16/18, at least 1 dose, age 15‐26 years

12

0*

0.09

(0.01 to 0.72)

81%

(28% to 99%)

12

(3 to 12)

17,079

(2 studies)

⊕⊕⊕⊝
moderate4

Analysis 2.12 AIS+ associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses, age 15‐26 years***

29

0*

0.15

(0.01 to 2.97)

85%

(‐197% to 99%)

29

(‐57 to 29)

2015

(2 studies)

⊕⊝⊝⊝
very low1$,4

Analysis 2.13 CIN2+ irrespective of HPV types, 3 doses, age 15‐26 years

166

66

0.40

(0.25 to 0.64)

60%

(36% to 75%)

99

(60 to 124)

7320

(3 studies)

⊕⊕⊕⊕

high

Analysis 2.14 CIN2+ irrespective of HPV types, at least 1 dose, age 15‐26 years

231

95

0.41

(0.32 to 0.52)

58%

(46% to 67%)

136

(111 to 157)

19,143

(3 studies)

⊕⊕⊕⊕

high

Analysis 2.15 CIN2+ irrespective of HPV types, 1 or 2 doses, age 20‐25 years***

1000

710

0.71

(0.15 to 3.38)

29%

(‐238% to 85%)

290

(‐2,380 to 850)

34

(1 study)

⊕⊝⊝⊝
very low1$,3,4

3. High‐grade cervical lesions in all women regardless of HPV DNA status at baseline**

Analysis 3.1.1 CIN2+ associated with HPV16/18, at least 1 dose, age 15‐26 years

341

157

0.46

(0.37 to 0.57)

54%

(43% to 63%)

184

(147 to 215)

34,852
(3 studies)

⊕⊕⊕⊕

high

Analysis 3.1.2 CIN2+ associated with HPV16/18, at least 1 dose, age 24‐45 years

157

116

0.74

(0.52 to 1.05)

26%

(‐5% to 48%)

41

(‐8 to 75)

9200

(2 studies)

⊕⊕⊕⊝

moderate4

Analysis 3.2.1 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 15‐26 years

436

217

0.50

(0.42 to 0.59)

50%

(41% to 58%)

219

(166 to 272)

17,160

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 3.2.2 CIN2+ associated with HPV6/11/16/18, at least 1 dose, age 24‐45 years

145

113

0.78

(0.44 to 1.37)

22%

(‐37% to 56%)

143

(72 to 204

3723

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 3.3 CIN3+ associated with HPV16/18, at least 1 dose, age 15‐26 years

165

91

0.55

(0.43 to 0.68)

74%

(55% to 91%)

74

(55 to 91)

34,562
(2 studies)

⊕⊕⊕⊕

high

Analysis 3.4 CIN3+ associated with HPV16/18, 1 or 2 doses, age 15‐26 years***

230

124

0.54

(0.43 to 0.68)

46%

(32% to 57%)

106

(74 to 131)

17,160

(1 study)

⊕⊕⊝⊝
low1,3

Analysis 3.5 AIS associated with HPV16/18, at least 1 dose, age 15‐26 years

14

5

0.36

(0.17 to 0.78)

64%

(22% to 83%)

9

(3 to 12)

34,562
(2 studies)

⊕⊕⊕⊕

high

Analysis 3.6 AIS associated with HPV6/11/16/18, at least 1 dose, age 15‐45 years

15

6

0.40

(0.16 to 0.98)

60%

(2% to 84%)

9

(0 to 13)

20,830

(1 study)

⊕⊕⊕⊝
moderate3,4

Analysis 3.7.1 Any CIN2+ irrespective of HPV types, at least 1 dose, age 15‐26 years

559

391

0.70

(0.58 to 0.85)

30%

(15% to 42%)

168

(84 to 235)

35,779
(4 studies)

⊕⊕⊕⊕

high

Analysis 3.7 2 Any CIN2+ irrespective of HPV types, at least 1 dose, age 24‐45 years

342

356

1.04

(0.83 to 1.30)

‐4%

(‐30% to 17%)

‐14

(‐103 to 58)

9287

(2 studies)

⊕⊕⊝⊝
moderate4

Analysis 3.8 Any CIN3+ irrespective of HPV types, at least 1 dose, age 18‐26 years, bivalent vaccine

188

103

0.55

(0.43 to 0.71)

45%

(29% to 57%)

84

(54 to 1107)

18,329

(2 studies)

⊕⊕⊕⊕

high

Analysis 3.8 Any CIN3+ irrespective of HPV types, at least 1 dose, age 15‐26 years, quadrivalent vaccine

349

283

0.81

(0.69 to 0.96)

19%

(4% to 31%)

66

(14 to 108)

17,160

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 3.9 Any AIS irrespective of HPV types, at least 1 dose, age 15‐26 years

17

5

0.32

(0.15 to 0.67)

68%

(33% to 0.85%)

11

(6 to 14)

34,562
(2 studies)

⊕⊕⊕⊕

high

4. HPV16/18 infection in women who were hrHPV DNA negative at baseline

Analysis 4.1 Incident HPV16/18 infection, 3 doses, age 18‐26 years

2,457

147

0.06

(0.02 to 0.20)

94%

(80% to 98%)

2,310

(1,966 to 2,408)

368

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 4.2 Persistent HPV16/18 infection(6M), 3 doses, age 15‐26 years

971

29

0.02

(0.00 to 0.35)

97%

(57% to 100%)

942

(554 to 971)

368

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 4.3 Persistent HPV16/18 infection(6M), at least 1 dose, age 18‐25 years

96

7

0.07

(0.05 to 0.09)

93%

(81% to 95%)

90

(88 to 91)

10,826

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 4.4 Persistent HPV16/18 infection(12M), 3 doses, age 15‐26 years

571

23

0.04

(0.00 to 0.73)

96%

(27% to 100%)

549

(154 to 571)

368

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 4.5 Persistent HPV16/18 infection(12M), at least 1 dose, age 15‐26 years

462

37

0.08

(0.05 to 0.12)

92%

(88% to 95%)

425

(406 to 439)

14,153

( 2 studies)

⊕⊕⊕⊕

high

5. HPV16/18 infection in women who were HPV16/18 negative at baseline

Analysis 5.1 Incident HPV16/18 infection, 3 doses, age 15‐26 years

474

81

0.17

(0.10 to 0.31)

87%

(78% to 92%)

412

(369 to 436)

8,034

(4 studies)

⊕⊕⊕⊕

high

Analysis 5.2 Incident HPV16/18 infection, at least 1 dose, age 15‐26 years

1,326

305

0.23

(0.14 to 0.37)

81%

(71% to 88%)

1,074

(941 to 1,167)

23,872

(5 studies)

⊕⊕⊕⊕

high

Analysis 5.3 Incident HPV16/18 infection, 1 or 2 dose, age 15‐26 years***

2,568

1207

0.47

(0.26 to 0.84)

74%

(31% to 90%)

1,901

(796 to 2,311)

331

(3 studies)

⊕⊕⊕⊝

moderate1

Analysis 5.4.1 Persistent HPV16/18 infection (6M), 3 doses, age 15‐26 years

581

35

0.06

(0.05 to 0.08)

94%

(91% to 95%)

546

(534 to 552)

27,385

(6 studies)

⊕⊕⊕⊕

high

Analysis 5.4.2 Persistent HPV16/18 infection (6M), 3 doses, age 24‐45 years

350

38

0.11

(0.06 to 0.20)

89%

(80% to 94%)

311

(280 to 329)

6728

(2 studies)

⊕⊕⊕⊝
moderate4

Analysis 5.5.1 Persistent HPV16/18 infection (6M), at least 1 dose, age 15‐26 years

657

66

0.10

(0.08 to 0.13)

90%

(87% to 92%)

591

(572 to 605)

22,803

(4 studies)

⊕⊕⊕⊕

high

Analysis 5.5.2 Persistent HPV16/18 infection (6M), at least 1 dose, age 24‐45 years

441

75

0.17

(0.10 to 0.29)

83%

(71% to 90%)

366

(313 to 397)

7520

(2 studies)

⊕⊕⊕⊕

high

Analysis 5.6.1 Persistent HPV16/18 infection (6M), 1 or 2 doses, age 15‐26 years***

996

119

0.12

(0.03 to 0.42)

88%

(58% to 97%)

876

(577 to 966)

437

(2 studies)

⊕⊕⊝⊝
low1,4

Analysis 5.6.2 Persistent HPV16/18 infection (6M), 1 or 2 doses, age 24‐45 years***

1,221

379

0.31

(0.18 to 0.54)

69%

(46% to 82%)

843

(562 to 1002)

792

(2 studies)

⊕⊕⊕⊝

moderate1

Analysis 5.7 Persistent HPV6/11/16/18 infection (6M), 3 doses

518

62

0.12

(0.06 to 0.21)

88%

(79% to 94%)

456

(409 to 487)

4008

(2 studies)

⊕⊕⊕⊕

high

Analysis 5.8 Persistent HPV6/11/16/18 infection (6M), at least 1 dose

907

118

0.13

(0.05 to 0.37)

87%

(63% to 95%)

789

(571 to 862)

4129

(2 studies)

⊕⊕⊕⊕

high

Analysis 5.9 Persistent HPV16/18 infection (12M), 3 doses

297

27

0.09

(0.06 to 0.13)

91%

(87% to 94%)

270

(258 to 279)

22,267

(4 studies)

⊕⊕⊕⊕

high

Analysis 5.10 Persistent HPV16/18 infection (12M), at least 1 dose

365

58

0.16

(0.01 to 0.13)

84%

(87% to 99%)

306

(292 to 361)

29,464

(5 studies)

⊕⊕⊕⊕

high

Analysis 5.11 Persistent HPV16/18 infection (12M), 1 or 2 doses***

205

27

0.13

(0.06 to 0.33)

87%

(67% to 94%)

178

(137 to 193)

3912

(3 studies)

⊕⊕⊕⊝

moderate1

6. HPV16/18 infection regardless of HPV DNA status at baseline**

Analysis 6.1 Incident HPV16/18 infection, at least 1 dose, age 15‐26 years

807

194

0.24

(0.17 to 0.33)

76%

(67% to 83%)

613

(541 to 670)

4210

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 6.2.1 Persistent HPV16/18 infection (6M), at least 1 dose, age 15‐26 years

1,359

598

0.44

(0.38 to 0.51)

56%

(49% to 62%)

761

(666 to 842)

25,199

(2 studies)

⊕⊕⊕⊕

high

Analysis 6.2.2 Persistent HPV16/18 infection (6M), at least 1 dose, age 24‐45 years

642

366

0.57

(0.47 to 0.69)

43%

(31% to 53%)

276

(199 to 341)

8648

(2 studies)

⊕⊕⊕⊕

high

Analysis 6.3 Persistent HPV6/11/16/18 infection (6M), at least 1 dose, age 24‐45 years

1,136

591

0.52

(0.42 to 0.65)

48%

(35% to 58%)

545

(398 to 659)

3713

(1 study)

⊕⊕⊕⊝
moderate3

Analysis 6.4 Persistent HPV16/18 infection (12M), at least 1 dose, age 15‐26 years

861

396

0.46

(0.40 to 0.54)

54%

(46% to 60%)

465

(396 to 516)

24,785

(2 studies)

⊕⊕⊕⊕

high

CI: Confidence interval; RR: Risk Ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect. *The attribution of "high quality" depends on the following conditions: well‐conducted randomised trials, with consistent findings, direct outcome, precise estimates (narrow confidence intervals), absence of reporting bias (Guyatt 2008).

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1In case of study flaws as assessed by the Cochrane Collaboration's tool for assessing risk of bias in randomised trials (Higgins 2011b), not observed but calculated outcome;

2 Substantial heterogeneity defined as I2 >30%, when multiple studies were available for the considered outcome;

3When only one study was retrieved for the outcome;

4Imprecision, when the width of the 95% confidence interval around RR >0.60.

0* When zero events occurred in the vaccine group a continuity correction was applied to compute the RR and its confidence interval. Nevertheless, in this case the absolute risks in the vaccine arms in Table 2 were computed considering an exact binomal distribution.

** Relative and absolute effects in women regardless of HPV DNA status at baseline (headings 3 and 6) must be interpreted with care since influenced by the prevalence of HPV infection at enrolment in the respective trials.

*** Post hoc analysis for women who received <3 doses.

$ For the precancer endpoints (CIN2/3 and AIS),a higher risk in the placebo arms was observed if <3 doses were received compared to those who received 3 doses Therefore the quality of evidence was downgraded to low or very low.

Figures and Tables -
Table 2. Results of all the efficacy outcomes
Table 3. Number needed to vaccinate (NNV) to prevent one outcome event (in young women aged 15‐26 years)

Outcome

Initial HPV status at enrolment

hrHPV negative

Regardless of HPV status

Lesions associated with HPV16/18

NNV (95% CI)

NNV (95% CI)

CIN2+

62 (61 to 64)

54 (46 to 68)

CIN3+

204 (149 to 333)

135 (110 to 263)

AIS+

1111 (714 to 5000)

1111 (625 to 3333)

Lesions irrespective of HPV types

NNV (95% CI)

NNV (95% CI)

CIN2+

60 (50 to 76)

68 (52 to 97)

CIN3+

141 (106 to 208)

133 (94 to 227)

AIS+

1000 (556 to 10,000)

833 (526 to 2000)

AIS: adenocarcinoma in situ, CIN: cervical intraepithelial neoplasia, CIN2+: CIN of degree II or worse, CIN3+: CIN of degree 3 or worse, hrHPV: high‐risk human papillomavirus types, NNV: number needed to vaccinate.

Figures and Tables -
Table 3. Number needed to vaccinate (NNV) to prevent one outcome event (in young women aged 15‐26 years)
Table 4. Results of all the safety outcomes (adverse events, pregnancy outcomes)

Outcomes

Absolute risk/ per 10,000

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

placebo

vaccinated

Analysis 7.1Overall local/injection site adverse events

6847

8080

1.18

(1.16 to 1.20)

18,113
(8 studies)

⊕⊕⊕⊝
moderate2

Analysis 7.2Pain at injection site

6505

8782

1.35

(1.23 to 1.49)

25,691
(13 studies)

⊕⊕⊕⊝
moderate2

Analysis 7.3Swelling at injection site

1582

2737

1.73

(1.32 to 2.27)

22,106
(9 studies)

⊕⊕⊕⊝
moderate2

Analysis 7.4Redness at injection site

1938

3333

1.72

(1.50 to 1.97)

19,996
(6 studies)

⊕⊕⊕⊝
moderate2

Analysis 7.5Overall systematic event and general symptoms

6102

6224

1.02

(0.98 to 1.07)

18,191
(8 studies)

⊕⊕⊕⊝
moderate2

Analysis 7.6Serious adverse events

605

611

1.01

(0.95 to 1.07)

6978
(21studies)

⊕⊕⊕⊕
high

Analysis 7.7Deaths

11

13

1.25

(0.81 to 1.93)

71,452

(23 studies)

⊕⊕⊝⊝
low2,4,†

Analysis 8.1Normal infant

7171

7171

1.00

(0.97 to 1.02)

8782
(8 studies)

⊕⊕⊕⊕
high

Analysis 8.2Spontaneous abortion/miscarriage

1618

1424

0.88

(0.68 to 1.14)

8618
(9 studies)

⊕⊕⊕⊕
high

Analysis 8.3Elective termination/induced abortion

931

838

0.90

(0.80 to 1.02)

10.909
(9 studies)

⊕⊕⊕⊕
high

Analysis 8.4Stillbirth

70

78

1.12

(0.68 to 1.83)

8754
(6 studies)

⊕⊕⊕⊝4
moderate

Analysis 8.5Abnormal infant

205

250

1.22

(0.88 to 1.69)

9252
(5 studies)

⊕⊕⊕⊝4
moderate

CI: Confidence interval; RR: Risk Ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect. *The attribution of "high quality" depends on the following conditions: well‐conducted randomized trials, with consistent findings, direct outcome, precise estimates (narrow confidence intervals), absence of reporting bias (Guyatt 2008).

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1In case of study flaws as assessed by Cochrane's tool for assessing risk of bias in randomised trials (Higgins 2011b), not observed but calculated outcome

2 Substantial heterogeneity defined as I2 > 30%, when multiple studies were available for the considered outcome

3When only one study was retrieved for the outcome

4Imprecision, when the width of the 95% confidence interval around RR > 0.60

† inter‐age group heterogeneity, absence of pattern in causes of deaths

Figures and Tables -
Table 4. Results of all the safety outcomes (adverse events, pregnancy outcomes)
Table 5. Deaths observed in the FUTURE III trial (quadrivalent vaccine, phase 3, women aged 24‐45 years)

ID

Group

Death causes

1

C

Pulmonary thromboembolism with background of acute lymphoblastic leukaemia

2

V

Breast cancer

3

V

Pulmonary tuberculosis

4

V

Thyrotoxicosis

5

V

Cerebral haemorrhage subsequent to hypertension

6

V

Pericarditis on a background of lupus erythematosus

7

V

Nasopharyngeal cancer with metastases to brain

8

V

Pulmonary embolism after intervention for uterine myoma

RR of deaths in vaccine vs placebo arm (7 over 1,890 vs 1 over 1888): RR = 6.99 (95% CI 0.86 to 56.78), 2‐sided pexact=0.070.

The age at death varied between 29 and 45 years, seven of the deaths occurred in the Philippines and one in Columbia.

All participants received three doses of HPV vaccine or placebo except one who received only two doses of vaccine. The time interval between last dose and date at death ranged between 6 and 37 months.

Group:V = vaccinated against HPV, C = control group.

Source: end‐of‐study analysis after a median follow‐up of four years (Castellsagué 2011) and personal communication with Alfred Saah (MSD, 6/05/2016).

Figures and Tables -
Table 5. Deaths observed in the FUTURE III trial (quadrivalent vaccine, phase 3, women aged 24‐45 years)
Table 6. Deaths observed in the VIVIANE trial (bivalent vaccine, phase 3 trial, women aged >25 years)

Patient

Cause of death

Group

Age

Country

Source

1

Breast cancer metastatic

V

47

Canada

1

2

Suicide

V

47

Mexico

1

3

Lower respiratory tract infection and sepsis*

C

55

Mexico

1

4

Cervix cancer metastatic**

V

45

Mexico

1

5

Interstitial lung disease

V

41

Mexico

1

6

Breast cancer

***

32

Mexico

1***

7

Suicide

V

41

Mexico

1

8

Cardiac valve disease and liver disorder*

C

38

Mexico

1

9

Drug hypersensitivity and acute renal failure*

V

46

Peru

1

10

Cardiorespiratory arrest

C

44

Phillipines

1

11

Acute myocardial infarction

V

31

Phillipines

1

12

Multiple myeloma and pulmonary embolism*

V

50

Phillipines

1

13

Homicide

V

32

Phillipines

1

14

Bronchopneumonia

V

40

Singapore

1

15

Lung neoplasm malignant

V

41

Thailand

1

16

Suicide

V

28

USA

1

17

Glioblastoma multiforme

V

45

USA

1

18

Anaplastic astrocytoma

C

43

****

2

19

Nasopharyngeal cancer

C

41

****

2

Remarks

*

Multiple death causes

**

This woman had normal cytology but was HPV‐18 DNA‐positive at study entry (May 2006). At the next scheduled cytology testing at Month 12 (April 2007), the cytology finding was atypical squamous cells cannot exclude high‐grade squamous intraepithelial lesion. She was diagnosed with metastatic cervical cancer in May 2007 (approximately 7 months after receiving the third dose of vaccine or control) and died in July 2008

***

One case of death due to breast cancer reported in the 48 month report (Skinner 2014) had to be excluded from the analysis (Wheeler 2016).

****

Two additional cases of death occurring in the control arm were reported in the 84‐month report (Wheeler 2016). The country for these two cases was not reported.

Source: 1) interim analysis after 48 months of follow‐up (Skinner 2014); 2) report at 84 months of follow‐up (Wheeler 2016)

The 84‐month follow‐up report revealed 13 deaths in the HPV arm (N = 2877) versus 5 (N = 2870), with death causes allocated to the trial arms (vaccine versus placebo arm) the RR was 2.59 (95% CI 0.93 to 7.27), 2‐sided pexact=0.0957. No pattern was noticed which could indicate a causal role attributed to HPV vaccination.

Figures and Tables -
Table 6. Deaths observed in the VIVIANE trial (bivalent vaccine, phase 3 trial, women aged >25 years)
Table 7. Trials for which vaccine efficacy is reported by smaller age subgroups

Trial

Target age group

Age category

Reported age sub‐groups

Phase2 trial (ph2,1v)

16‐23

younger

none

Phase2 trial (ph2,2v)

15‐25

younger

none

Phase2 trial (ph2,4v)

16‐23

younger

none

Japanese trial (ph2,2v)

20‐25

younger

none

PATRICIA trial (ph3,2v)

15‐25

younger

15‐17, 18‐20, 21‐25

CVT (ph3,2v)

18‐25

younger

18‐19, 20‐21, 22‐23, 24‐25

VIVIANE trial (ph3,2v)

26+

older

26‐35, 36‐45, 46+

FUTURE I trial (ph3,4v)

16‐24

younger

none

FUTURE II trial (ph3,4v)

15‐26

younger

none

FUTURE III trial (ph3,4v)

25‐45

older

none

Figures and Tables -
Table 7. Trials for which vaccine efficacy is reported by smaller age subgroups
Table 8. Influence of age (PATRICIA trial)

Outcome

Age

Event/N

Vaccine

Event/N

Placebo

Relative risk

(95% CI)

Vaccine efficacy

% (95% CI)

P value for linear effect of age

In women with hrHPV DNA negative status at baseline

CIN2+ associated with HPV16/18

15‐17

1/1997

53/2022

0.02 (0.00 to 0.14)

98% (86 to 100%)

0.995

18‐20

0/1096

27/1144

0.02 (0.00 to 0.32)

98% (68 to 100%)

21‐25

0/2363

17/2281

0.03 (0.00 to 0.47)

97% (53 to 100%)

CIN2+ irrespective of HPV types

15‐17

34/1997

101/2022

0.34 (0.23 to 0.50)

66% (50 to 77%)

0.355

18‐20

10/1096

38/1144

0.27 (0.14 to 0.55)

73% (45 to 86%)

21‐25

17/2363

33/2281

0.50 (0.28 to 0.89)

50% (11 to 72%)

CIN3+ associated with HPV16/18

15‐17

0/1997

14/2022

0.04 (0.00 to 0.61)

96% (39 to100%)

1.000

18‐20

0/1096

8/1144

0.07 (0.00 to 1.13)

93% (‐13 to 100%)

21‐25

0/2363

5/2281

0.10 (0.00 to 1.74)

90%(‐74 to 100%)

CIN3+ irrespective of HPV types

15‐17

2/1997

24/2022

0.08 (0.02 to 0.36)

92% (64 to 98%)

0.488

18‐20

1/1096

11/1144

0.09 (0.01 to 0.73)

91% (27 to 99%)

21‐25

0/2363

9/2281

0.05 (0.00 to 0.92)

95% (8 to 100%)

Persistent HPV16/18 infection (6M)

15‐17

14/1989

303/2020

0.05 (0.03 to 0.08)

95% (92 to 97%)

0..042

18‐20

9/1090

110/1125

0.08 (0.04 to 0.17)

92%(83 to 96%)

21‐25

12/2338

108/2249

0.11 (0.06 to 0.19)

89% (81 to 94%)

Regardless of women’s baseline HPV DNA status

CIN2+ associated with HPV16/18

15‐17

21/2882

100/2892

0.21 (0.13 to 0.24)

79% (66 to 87%)

0.000

18‐20

23/1871

66/1908

0.36 (0.22 to 0.57)

64% (43 to 78%)

21‐25

46/3929

62/3898

0.74 (0.50 to 1.08)

26% (‐8 to 50%)

CIN2+ irrespective of HPV types

15‐17

112/2882

200/2892

0.56 (0.45 to 0.70)

44% (30 to 55%)

0.006

18‐20

62/1871

105/1908

0.60 (0.44 to 0.82)

40% (18 to 56%)

21‐25

113/3929

123/3898

0.91 (0.09 to 1.17)

9% (‐17 to 29%)

CIN3+ associated with HPV16/18

15‐17

7/2882

36/2892

0.20 (0.09 to 0.44)

80% (56 to 91%)

0.000

18‐20

13/1871

30/1908

0.44 (0.23 to 0.84)

56% (16 to 77%)

21‐25

31/3929

28/3898

1.10 (0.66 to 1.83)

‐10% (‐83 to 34%)

CIN3+ irrespective of HPV types

15‐17

21/2882

61/2892

0.35 (0.21 to 0.57)

65% (43 to 79%)

0.008

18‐20

22/1871

44/1908

0.51 (0.31 to 0.85)

49% (15 to 69%)

21‐25

43/3929

53/3898

0.80 (0.54 to 1.20)

20% (‐20 to 46%)

Persistent HPV16/18 infection (6M)

15‐17

167/2916

588/2920

0.28 (0.24 to 0.34)

72% (66 to 76%)

0.000

18‐20

143/1925

283/1961

0.51 (0.43 to 0.62)

49% (38 to 57%)

21‐25

194/4009

356/3979

0.54 (0.46 to 0.64)

46% (36 to 54% )

Source: Lehtinen 2012.

CIN: cervical intraepithelial neoplasia, CIN2+: CIN of degree II or worse, CIN3+: CIN of degree 3 or worse, HPV: human papillomavirus types..

Figures and Tables -
Table 8. Influence of age (PATRICIA trial)
Table 9. Influence of age (CVT trial)

Outcome

Age

Vaccine

Placebo

Relative risk

(95% CI)

Vaccine efficacy

(95% CI)

P value for linear effect of age

In women with HPV16/18 DNA negative status at baseline cohort

Persistent HPV16/18 infection (6M)

18‐19

1/825

51/870

0.02 (0.00 to 0.10)

98% (90% to 100%)

0.145

20‐21

3/659

36/649

0.08 (0.02 to 0.24)

92% (76% to 98%)

22‐23

2/588

36/625

0.06 (0.00 to 0.20)

94% (80% to 100%)

24‐25

3/563

20/533

0.14 (0.03 to 0.44)

86% (56% to 97%)

Regardless if women’s baseline HPV DNA status

Persistent HPV16/18 infection (6M)

18‐19

47/1193

165/1,244

0.30 (0.21 to 0.41)

70% (59% to 79%)

0.000

20‐21

64/946

134/905

0.46 (0.34 to 0.61)

54% (39% to 66%)

22‐23

59/818

112/848

0.55 (0.40 to 0.75)

45% (25% to 60%)

24‐25

61/770

75/742

0.78 (0.56 to 1.99)

22 %(‐9.9 to 44%)

Source: Herrero 2011.

Figures and Tables -
Table 9. Influence of age (CVT trial)
Table 10. Influence of age (VIVIANE trial)

Outcome

Age

Event/NVaccine

Event/NPlacebo

Relative risk

(95% CI)

Vaccine efficacy

(95% CI)

P value for linear effect of age

In women with HPV16/18 DNA negative status at baseline cohort

Persistent HPV16/18 infection (6M)

26‐35

3/834

22/800

0.13 (0.04 to 0.44)

87% (56% to 96%)

0.532

36‐45

3/816

12/809

0.25 (0.07 to 0.88)

75%(12% to 93%)

46+

0/219

0/213

N.A.

N.A.

Regardless if women’s baseline HPV DNA status

Persistent HPV16/18 infection (6M)

26‐35

48/1221

78/1242

0.63 (0.44 to 0.89)

37% (11% to 56%)

0.177

36‐45

19/1244

43/1228

0.44 (0.26 to 0.74)

56% (26% to 74%)

46+

4/300

11/306

0.37 (0.12 to 1.15)

63% (‐15% to 88%)

Source: Skinner 2014.

Figures and Tables -
Table 10. Influence of age (VIVIANE trial)
Table 11. Influence of the initial serological status on vaccine efficacy against cervical lesions associated with HPV16/18

Initial HPV DNA/ status

Serology

status

Vaccine

Placebo

Relative Risk

(95% CI)

Relative Risk ratio

FUTURE I trial (ph3,4v) (Garland 2007)*

DNA(‐)

Sero‐

0/2,241

32/2258

0.00 (0.02 to 0.26)

15.93

Sero+

0/377

2/379

0.25 (0.01 to 5.20)

DNA(+)

Sero‐

27/232

31/213

0.80 (0.49 to 1.29)

1.50

Sero+

41/156

30/137

1.20 (0.80 to 1.81)

FUTURE II trial (ph3,4v) (FUTURE‐II 2007)**

DNA(‐)

Sero‐

0/5,305

28/5260

0.02(0.00 to 0.14)

7.41

Sero+

0/498

4/524

0.13 (0.01 to 2.43)

DNA(+)

Sero‐

33/423

35/402

0.90 (0.57 to 1.41)

1.12

Sero+

47/298

52/332

1.01 (0.70 to 1.45

PATRICIA trial (ph3,2v) (Paavonen 2009)**

DNA(‐)

Sero‐

5/8709

92/8112

0.05 (0.02 to 0.12)

6.16

Sero+

3/1710

10/1777

0.31 (0.09 to 1.13)

DNA(+)

Sero‐

20/309

29/293

0.65 (0.38 to 1.13)

1.70

Sero+

53/333

44/307

1.11 (0.77 to 1.61)

Pooled results for CIN2+ associated with HPV16/18

(FUTURE II trial (ph3,4v) and PATRICIA trial (ph3,2v)***

DNA(‐)

Sero‐

5/14,014

120/13,372

0.03 (0.02 to 0.09)

5.85

(0.53 to 65.10)

Sero+

3/2205

14/2301

0.19 (0.09 t0 o.77)

DNA(+)

Sero‐

53/679

64/695

0.79 (0.60 to 1.05

1.37

(0.97 to 1.93)

Sero+

100/531

96/639

1.10 (0.88 to 1.36)

*RR against HPV 6/11/16/18 related cervical lesions

** RR against HPV16/18 related CIN2+

*** Pooled only for FUTURE II and PATRIACIA, since, in the FUTURE I trial, the endpoints were cervical lesions and not CIN2+ associated with HPV16/18

Figures and Tables -
Table 11. Influence of the initial serological status on vaccine efficacy against cervical lesions associated with HPV16/18
Table 12. Influence of the study quality and the involvement of vaccine manufacturers

Outcome

P value

V1

V2

V3

V4

V5

V6

V7

Persistent HPV16/18 infection (6M), in women being baseline HPV16/18 negative 3 doses

0.70

0.60

np

np

0.90

np

0.42

Persistent HPV16/18 infection (6M), in women being baseline HPV16/18 negative at least 1 dose

0.56

0.56

np

np

np

np

np

Persistent HPV16/18 infection (12M), in women being baseline HPV16/18 negative 3 doses

0.94

0.94

np

np

np

np

0.73

Persistent HPV16/18 infection (12M), in women being baseline HPV16/18 negative at least 1 dose

0.67

0.67

np

np

np

np

np

Influence of study quality (items V1‐V6) and independence of the research team towards the vaccine manufacturer (V7) on protection against persistent HPV16/18 infection assessed by meta‐regression.

The P values correspond with the statistical significance of the incorporation of each item in the meta‐regression.

V1: Random sequence generation; V2: Allocation concealment; V3: Blinding participants and personnel; V4: Blinding of outcome; V5: Incomplete outcomes; V6: Selective reporting; V7: Involvement of manufacturer,

np: meta‐regression not possible because of collinearity.

Figures and Tables -
Table 12. Influence of the study quality and the involvement of vaccine manufacturers
Table 13. Influence of the number of administered doses: one, two or three in two RCTs with four years of follow‐up

Outcome

No. of doses

Vaccine

arm

Placebo

arm

Relative Risk

(95%CI)

P value for linear

dose‐effect relation

12‐month

persistent HPV16/18

infection

in women being

HPV16/18 negative at baseline

3

84/11,104

627/11,203

0.135 (0.108 to 0.169)

0.303

2

3/611

26/574

0.108 (0.033 to 0.356)

1

1/292

17/249

0.050 (0.007 to 0.374)

6‐month

persistent HPV16/18

infection

in women being

HPV16/18 negative at baseline

3

114/11,104

1000/11,209

0.115 (0.095 to 0.139)

0.269

2

4/611

35/574

0.107 (0.038 to 0.300)

1

1/292

24/250

0.036 (0.005 to 0.261)

Incident HPV16/18 infection

in women being HPV16/18

negative at baseline

3

529/11,110

2172/11,217

0.246 (0.224 to 0.269)

0.337

2

22/611

82/574

0.252 (0.160 to 0.398)

1

8/292

45/251

0.153 (0.073 to 0.318)

12‐month

persistent HPV16/18

infection

in women being

hrHPV negative at baseline

3

27/6634

351/6656

0.077 (0.052 to 0.114)

0.996

2

2/273

12/276

0.168 (0.038 to 0.746)

1

0/138

5/99

0.071 (0.004 to 1.289)

6‐month

persistent HPV16/18

infection

in women being

hrHPV negative at baseline

3

38/6634

567/6660

0.067 (0.049 to 0.093)

0.809

2

2/273

16/276

0.126 (0.029 to 0.544)

1

0/138

8/100

0.045 (0.003 to 0.774)

Incident HPV16/18 infection

in women being hrHPV

negative at baseline

3

38/6634

567/6660

0.067 (0.049 to 0.093)

0.809

2

2/273

16/276

0.126 (0.029 to 0.544)

1

0/138

8/100

0.045 (0.003 to 0.774)

Figures and Tables -
Table 13. Influence of the number of administered doses: one, two or three in two RCTs with four years of follow‐up
Table 14. Influence of the number of administered doses in the CVT trial (seven years of follow‐up)

Outcome

No. of doses

n events

N vaccinated

% (95%CI)

P* for difference with 3 doses

Cumulative

incidence

HPV16/18

infections

3

88

2023

4.3 (3.5 to 5.3)

2 (at months 0 & 6)

3

78

3.8 (1.0 to 10.1)

1.00

2 (at months 0 & 1)

7

192

3.6 (1.6 to 7.1)

0.85

1

2

133

1.5 (0.3 to 4.9)

0.17

Source: Safaeian 2018.

* two‐sided exact test for difference between proportions.

Figures and Tables -
Table 14. Influence of the number of administered doses in the CVT trial (seven years of follow‐up)
Table 15. Influence of the number of administered doses: all three versus less than three doses

Outcomes

Age

Group

(years)

Studies

RR if 3 doses

(95% CI)

RR if 1‐2 doses

(95% CI)

CIN2+

due to HPV16/18

15‐26

5 (FUTURE II trial (ph3,4v); Japanese trial (ph2,2v);

PATRICIA trial (ph3,2v); Phase2 trial (ph2,1v); Chinese trial (ph3,2v)_young)

0.07 (0.03 to 0.14)*

0.10 (0.04 to 0.26)*

24‐45

2 (FUTURE III trial (ph3,4v); VIVIANE trial (ph3,2v))

0.14 (0.03 to 0.79)*

0.98 (0.20 to 4.83)

CIN3+

due to HPV16/18

15‐26

1 (PATRICIA trial (ph3,2v))

0.20 (0.04 to 0.91)*

0.04 (0.01 to 0.74)*

Incident HPV16/18 infection

15‐26

3 (Japanese trial (ph2,2v); Phase2 trial (ph2,1v);Chinese trial (ph3,2v)_young)

0.20 (0.10 to 0.41)*

0.47 (0.26 to 0.84)*

6‐month persistent HPV16/18 infection

15‐26

2 (Japanese trial (ph2,2v);Chinese trial (ph3,2v)_young)

0.05 (0.01 to 0.27)*

0.12 (0.03 to 0.42)*

24‐45

2 (FUTURE III trial (ph3,4v);VIVIANE trial (ph3,2v))

0.15 (0.09 to 0.27)*

0.34 (0.19 to 0.61)*

12‐month persistent HPV16/18 infection

15‐26

3 (Japanese trial (ph2,2v);CVT (ph3,2v); Chinese trial (ph3,2v)_young)

0.09 (0.05 to 0.19)*

0.13 (0.06 to 0.33)*

*Vaccine efficacy in women being HPV16/18 DNA negative at enrolment and having received all three or less than three doses (computed from trials where per‐protocol [all doses administered] and intention‐to‐treat analyses [at least one dose administered] are reported).

Figures and Tables -
Table 15. Influence of the number of administered doses: all three versus less than three doses
Table 16. Influence of follow‐up time

Outcomes

Study

Report

(duration of follow‐up)

Vaccine

Placebo

Relative Risk

(95%CI)

P value for linear difference

of follow‐up time effect

CIN2+ associated with HPV16/18

in women being HPV negative at baseline

PATRICIA

Paavonen 2007

14.8 moths

2/7788

21/7838

0.096 (0.007 to 0.466)

0.512

Paavonen 2009

34.9 months

5/8040

91/8080

0.054 (0.016 to 0.137)

Szarewski 2011

39.4 months

5/8079

92/8112

0.054 (0.016 to 0.137)

Lehtinen 2011

43.7 months

5/7338

97/7305

0.051 (0.016 to 0.123)

FUTURE

The FUTURE II study group 2007

36 months

3/5865

87/5836

0.039 (0.011 to 0.109)

0.994

Munoz 2010*

43 months

0/4616

89/4680

0.006 (0.000 to 0.092)

CIN2+ irrespective of HPV types

regardless of women’s initial HPV DNA status

PATRICIA

Paavonen 2009

34.9 months

224/8667

322/8682

0.696 (0.579 to 0.8369)

0.750

Lehtinen 2011

43.7 months

287/8694

428/8708

0.669 (0.574 to 0.778)

FUTURE

The FUTURE II study group 2007

36 months

281/6087

361/6080

0.780 (0.668 to 0.905)

0.665

Munoz 2010

43 months

421/8562

520/8598

0.807 (0.690 to 0.943)

Assessment of the influence of duration of follow‐up on study outcomes using meta‐regression. p‐values correspond with the statistical significance of incorporating average follow‐up time as a continuous variable.

Figures and Tables -
Table 16. Influence of follow‐up time
Table 17. Influence of the number of sexual partners

Number of sex partners

Vaccine

Placebo

Relative Risk

(95% CI)

P value of number of sexual partners effect

In women being HPV16/18 DNA negative at baseline cohort

Virgin

1/566

17/615

0.064 (0.003 to 0.352)

0.7448

1 partner

3/904

27/915

0.112 (0.007 to 0.335)

2 partners

1/544

17/519

0.056 (0.003 to 0.309)

3+ partners

3/621

28/628

0.108 (0.026 to 0.321)

Regardless of women’s baseline HPV DNA status

Virgin

4/733

21/819

0.202 (0.059 to 0.551)

< 0.0001

1 partner

40/1237

83/1256

0.489 (0.333 to 0.711)

2 partners

38/777

81/753

0.455 (0.307 to 0.665)

3+ partners

71/940

116/911

0.593 (0.440 to 0.796)

The influence of the number of lifetime sexual partners on vaccine efficacy was assessed by Poisson regression. The P value corresponds with the likelihood ratio test comparing a Poisson model with and without inclusion of the sexual history with 3 possible categories.

Source: CVT (ph3,2v) (Herrero 2011).

Figures and Tables -
Table 17. Influence of the number of sexual partners
Table 18. Influence of the study size

Outcomes

Study

Number of

participants

Study size

Vaccine

Placebo

Relative

Risk

(95%CI)

P value

CIN2+ associated with

HPV16/18

in women being

HPV16/18 negative at baseline

Phase2 trial (V1)

2392

S

0/126

8/127

0.062*

(0.004 to 1.071)

0.598

Phase2 trial (V2)

1113

S

0/219

3/212

0.161*

(0.008 to 3.091)

Japanese trial (ph2,2v)

1040

S

0/422

2/427

0.252*

(0.012 to 5.241)

PATRICIA trial (ph3,2v)

18,644

L

5/8040

91/8080

0.055

(0.022 to 0.136)

FUTURE II trial (ph3, 4v)

12,167

L

3/5865

87/5863

0.034

(0.011 to 0.109)

Chinese trial (ph3,2V)

6051

L

0/2543

4/2554

0.125

(0.001 to 8.681)

CIN2+ irrespective of

HPV types and

regardless of women’s

initial HPV DNA status

FUTURE I/II trial (ph3,4v)

17,622

L

421/8562

520/8598

0.813

(0.718 to 0.921)

0.703

PATRICIA trial (ph3,2v)

18,644

L

287/8694

428/8708

0.672

(0.582 to 0.778)

Phase2 trial (v1)

2392

S

8/148

12/142

0.640

(0.269 to 1.568)

Assesment of the influence of the study size on the protection against CIN2+ associated with HPV16/18 according to study size (S = small, < 3000 participants, L = large >= 3000 participants) in women aged 15‐26 years and received at least 1 dose.

* P values correspond with the statistical significance of a meta‐regression with vs without study size category.

Figures and Tables -
Table 18. Influence of the study size
Table 19. Vaccine efficacy endpoints derived from phase 2 trials with longest follow‐up time

Analysis

Endpoint

Initial HPV status

Doses

Relative Risk

Monovalent vaccine (Rowhani‐Rahbar, 2009): 102 months of follow‐up

3.1

CIN2+ associated with HPV16

HPV16‐

3

0.00

3.2

CIN2+ associated with HPV16

HPV16‐

>= 1

0.00

3.3

CIN2+ associated with HPV16

HPV16‐

1‐2

0.00

4.1

Incident HPV16 infection

HPV16‐

3

0.05

4.3

Incident HPV16 infection

HPV16‐

>= 1

0.11

4.3

Incident HPV16 infection

HPV16‐

1‐2

0.25

5.1

CIN2+ associated with HPV16

regardless of HPV infection

>= 1

0.36

5.3

CIN2+ irrespective of HPV types

regardless of HPV infection

>= 1

0.64

Bivalent vaccine (De Calvaho, 2012): 88 months of follow‐up

2.2

6M persistent HPV16/18 infection

hrHPV‐

3

0.00

2.4

12M persistent HPV16/18 infection

hrHPV‐

3

0.00

3.2

CIN2+ associated with HPV16/18

HPV16/18‐

>= 1

0.00

Quadrivalent vaccine (Villa, 2006): 60 months of follow‐up

4.8

Persistent HPV6/11/16/18 infection

HPV16/18‐

>= 1

0.07

Figures and Tables -
Table 19. Vaccine efficacy endpoints derived from phase 2 trials with longest follow‐up time
Table 20. Cross‐protective efficacy of the bivalent and quadrivalent vaccine

Trials

Ref

Endpoint

Relative Risk (95% CI)

P value for

difference in VE

Bivalent

Quadrivalent

FUT I/II trials (ph3,4v)

Malagon 2012

6‐month persistent HPV31 infection

0.229 (0.156 to 0.228)

0.538 (0.336 to 0.847)

0.003

PATRICIA trial (ph3,2v)

6‐month persistent HPV45 infection

0.210 (0.106 to 0.387)

0.922 (0.507 to 1.670)

0.0003

Phase2 trial (ph2,2v)

CIN2+ associated with HPV33

0.177 (0.053 to 0.466)

0.760 (0.328 to 1.712)

0.02

Phase2 trial (ph2,4v)

CIN2+ associated with HPV45

0.000 (0.000 to 0.583)

0.481 (0.174 to 1.177)

0.04

CVT (ph3,2v)

Hildesheim 2014

CIN2+ associated with other hrHPV

0.401 (0.192 to 0.793)

VIVIANE trial (ph3,2v)

Skinner 2014

6‐month persistent HPV31 infection

0.209 (0.041 to 0.724)

6‐month persistent HPV45 infection

0.221 (0.044 to 0.914)

Figures and Tables -
Table 20. Cross‐protective efficacy of the bivalent and quadrivalent vaccine
Table 21. Relative risk ratio of adverse effects associated with the bivalent versus the quadrivalent vaccine, adjusted for age group and products administered in the control group

Adverse effect

Relative risk

Relative risk ratio

p value

Quadrivalent vs placebo

Bivalent/Quadrivalent

1

Overall adverse effects at injection site

1.19 (0.89 to 1.59)

1.69 (0.96 to 2.96)

0.061

2

Pain at injection site

1.20 (0.78 to 1.85)

1.19 (0.67 to 2.12)

0.501

3

Swelling at injection site

2.72 (0.77to 9.61)

0.62 (0.16 to 2.41)

0.427

4

Redness at injection site

1.46 (1.23 to 1.74)

1.08 (0.88 to 1.32)

0.307

5

Overall systemic events

0.99 (0.91 to 1.07)

1.06 (0.95 to 1.19)

0.210

6

Serious adverse events

0.94 (0.70 to 1.26)

1.08 (0.80 to 1.45)

0.583

7

Deaths

1.18 (0.25 to 5.62)

0.84 (0.14 to 4.91)

0.775

Relative risks of the quadrivalent vaccine versus placebo and the relative risk ratios were computed by meta‐regression including vaccine, age group and type of product injected in the control group (aluminium adjuvants alone or other vaccine such as Hepatitis A vaccine) as covariate. The relative risk ratio reflects how much more an adverse effect is observed after vaccination with the bivalent versus the quadrivalent vaccine.

Figures and Tables -
Table 21. Relative risk ratio of adverse effects associated with the bivalent versus the quadrivalent vaccine, adjusted for age group and products administered in the control group
Comparison 1. High‐grade cervical lesions in hrHPV DNA negative women at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 CIN2+ associated with HPV16/18, at least 1 dose Show forest plot

3

23676

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.05]

2 CIN2+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

1

9296

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.09]

3 CIN3+ associated with HPV16/18, at least 1 dose Show forest plot

2

20214

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.10]

4 CIN3+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

1

9296

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.18]

5 AIS associated with HPV16/18, at least 1 dose Show forest plot

2

20214

Risk Ratio (IV, Random, 95% CI)

0.10 [0.01, 0.82]

6 AIS associated with HPV6/11/16/18, at least 1 dose Show forest plot

1

9296

Risk Ratio (IV, Random, 95% CI)

0.14 [0.01, 2.80]

7 Any CIN2+ irrespective of HPV types, at least 1 dose Show forest plot

5

25180

Risk Ratio (IV, Random, 95% CI)

0.37 [0.25, 0.55]

7.1 Bivalent vaccine

4

15884

Risk Ratio (IV, Random, 95% CI)

0.33 [0.25, 0.43]

7.2 Quadrivalent vaccine

1

9296

Risk Ratio (IV, Random, 95% CI)

0.57 [0.44, 0.76]

8 Any CIN3+ irrespective of HPV types, at least 1 dose Show forest plot

3

20719

Risk Ratio (IV, Random, 95% CI)

0.21 [0.04, 1.10]

8.1 Bivalent vaccine

2

11423

Risk Ratio (IV, Random, 95% CI)

0.08 [0.03, 0.23]

8.2 Quadrivalent vaccine

1

9296

Risk Ratio (IV, Random, 95% CI)

0.54 [0.36, 0.82]

9 Any AIS irrespective of HPV types, at least 1 dose Show forest plot

2

20214

Risk Ratio (IV, Random, 95% CI)

0.10 [0.01, 0.76]

Figures and Tables -
Comparison 1. High‐grade cervical lesions in hrHPV DNA negative women at baseline
Comparison 2. High‐grade cervical lesions in HPV16/18 DNA negative women at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 CIN2+ associated with HPV16/(18), 3 doses Show forest plot

8

43376

Risk Ratio (IV, Random, 95% CI)

0.08 [0.04, 0.16]

1.1 Age group 15‐26 years

6

36579

Risk Ratio (IV, Random, 95% CI)

0.07 [0.03, 0.15]

1.2 Age group 24‐45 years

2

6797

Risk Ratio (IV, Random, 95% CI)

0.16 [0.04, 0.74]

2 CIN2+ associated with HPV16/(18), at least 1 dose Show forest plot

8

42030

Risk Ratio (IV, Random, 95% CI)

0.10 [0.05, 0.20]

2.1 Age group 15‐26 years

6

34478

Risk Ratio (IV, Random, 95% CI)

0.05 [0.03, 0.10]

2.2 Age group 24‐45 years

2

7552

Risk Ratio (IV, Random, 95% CI)

0.30 [0.11, 0.81]

3 CIN2+ associated with HPV16/(18), 1 or 2 doses (post hoc analysis) Show forest plot

7

3713

Risk Ratio (IV, Random, 95% CI)

0.19 [0.07, 0.51]

3.1 women age 15‐26 years

5

2958

Risk Ratio (IV, Random, 95% CI)

0.10 [0.04, 0.26]

3.2 women age 24‐45 years

2

755

Risk Ratio (IV, Random, 95% CI)

0.61 [0.14, 2.67]

4 CIN2+ associated with HPV6/11/16/18, 3 doses Show forest plot

2

7664

Risk Ratio (IV, Random, 95% CI)

0.06 [0.01, 0.61]

4.1 Age group 15‐26 years

1

4499

Risk Ratio (IV, Random, 95% CI)

0.02 [0.00, 0.25]

4.2 Age group 24‐45 years

1

3165

Risk Ratio (IV, Random, 95% CI)

0.17 [0.02, 1.39]

5 CIN2+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

2

8980

Risk Ratio (IV, Random, 95% CI)

0.08 [0.00, 2.41]

5.1 Age group 15‐26 years

1

5351

Risk Ratio (IV, Random, 95% CI)

0.01 [0.00, 0.19]

5.2 Age group 24‐45 years

1

3629

Risk Ratio (IV, Random, 95% CI)

0.37 [0.10, 1.41]

6 CIN2+ associated with HPV6/11/16/18, 1 or 2 doses (post hoc analysis) Show forest plot

2

1316

Risk Ratio (IV, Random, 95% CI)

0.24 [0.01, 5.00]

6.1 Age group 15‐26 years

1

852

Risk Ratio (IV, Random, 95% CI)

0.04 [0.00, 0.74]

6.2 Age group 24‐45 years

1

464

Risk Ratio (IV, Random, 95% CI)

0.97 [0.14, 6.80]

7 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 3 doses Show forest plot

3

29720

Risk Ratio (IV, Random, 95% CI)

0.07 [0.02, 0.29]

8 CIN3+ associated with HPV 16/18 or HPV6/11/16/18, at least 1 dose Show forest plot

3

33199

Risk Ratio (IV, Random, 95% CI)

0.05 [0.02, 0.14]

9 CIN3+ associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis) Show forest plot

3

3479

Risk Ratio (IV, Random, 95% CI)

0.06 [0.01, 0.24]

10 AIS associated with HPV16/18 or HPV6/11/16/18, 3 doses Show forest plot

3

29707

Risk Ratio (IV, Random, 95% CI)

0.12 [0.02, 0.70]

11 AIS associated with HPV16/18 or 6/11/16/18, at least 1 dose Show forest plot

2

17079

Risk Ratio (IV, Random, 95% CI)

0.09 [0.01, 0.72]

12 AIS associated with HPV16/18 or HPV6/11/16/18, 1 or 2 doses (post hoc analysis) Show forest plot

2

2015

Risk Ratio (IV, Random, 95% CI)

0.15 [0.01, 2.97]

13 Any CIN2+ irrespective of HPV types, 3 doses Show forest plot

3

7320

Risk Ratio (IV, Random, 95% CI)

0.40 [0.25, 0.64]

14 Any CIN2+ irrespective of HPV types, at least 1 dose Show forest plot

3

19143

Risk Ratio (IV, Random, 95% CI)

0.41 [0.32, 0.52]

15 Any CIN2+ irrespective of HPV types, 1 or 2 doses (post hoc analysis) Show forest plot

1

34

Risk Ratio (IV, Random, 95% CI)

0.71 [0.15, 3.38]

Figures and Tables -
Comparison 2. High‐grade cervical lesions in HPV16/18 DNA negative women at baseline
Comparison 3. High‐grade cervical lesions in women regardless of baseline HPV DNA status

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 CIN2+ associated with HPV16/18, at least 1 dose Show forest plot

5

44052

Risk Ratio (IV, Random, 95% CI)

0.52 [0.41, 0.67]

1.1 Age group 15‐26 years

3

34852

Risk Ratio (IV, Random, 95% CI)

0.46 [0.37, 0.57]

1.2 Age group 24‐45 years

2

9200

Risk Ratio (IV, Random, 95% CI)

0.74 [0.52, 1.05]

2 CIN2+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

2

20883

Risk Ratio (IV, Random, 95% CI)

0.57 [0.38, 0.86]

2.1 Age group 15‐26 years

1

17160

Risk Ratio (IV, Random, 95% CI)

0.50 [0.42, 0.59]

2.2 Age group 24‐45 years

1

3723

Risk Ratio (IV, Random, 95% CI)

0.78 [0.44, 1.37]

3 CIN3+ associated with HPV16/18, at least 1 dose Show forest plot

2

34562

Risk Ratio (IV, Random, 95% CI)

0.55 [0.45, 0.67]

4 CIN3+ associated with HPV6/11/16/18, at least 1 dose Show forest plot

1

17160

Risk Ratio (IV, Random, 95% CI)

0.54 [0.43, 0.68]

5 AIS associated with HPV16/18, at least 1 dose Show forest plot

2

34562

Risk Ratio (IV, Random, 95% CI)

0.36 [0.17, 0.78]

6 AIS associated with HPV6/11/16/18, at least 1 dose Show forest plot

2

20830

Risk Ratio (IV, Random, 95% CI)

0.40 [0.16, 0.98]

7 Any CIN2+ irrespective of HPV types, at least 1 dose Show forest plot

6

45066

Risk Ratio (IV, Random, 95% CI)

0.79 [0.65, 0.97]

7.1 Age group 15‐26 years

4

35779

Risk Ratio (IV, Random, 95% CI)

0.70 [0.58, 0.85]

7.2 Age group 24‐45 years

2

9287

Risk Ratio (IV, Random, 95% CI)

1.04 [0.83, 1.30]

8 Any CIN3+ HPV type, at least 1 dose Show forest plot

3

35489

Risk Ratio (IV, Random, 95% CI)

0.67 [0.49, 0.93]

8.1 Bivalent vaccine

2

18329

Risk Ratio (IV, Random, 95% CI)

0.55 [0.43, 0.71]

8.2 Quadrivalent vaccine

1

17160

Risk Ratio (IV, Random, 95% CI)

0.81 [0.69, 0.96]

9 Any AIS irrespective of HPV types, at least 1 dose Show forest plot

2

34562

Risk Ratio (IV, Random, 95% CI)

0.32 [0.15, 0.67]

Figures and Tables -
Comparison 3. High‐grade cervical lesions in women regardless of baseline HPV DNA status
Comparison 4. Infection with HPV vaccine types in hrHPV DNA negative women at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incident HPV16/18 infection, 3 doses Show forest plot

1

368

Risk Ratio (IV, Random, 95% CI)

0.06 [0.02, 0.20]

2 Persistent HPV16/18 infection (6M), 3 doses Show forest plot

1

368

Risk Ratio (IV, Random, 95% CI)

0.02 [0.00, 0.35]

3 Persistent HPV16/18 infection (6M), at least 1 dose Show forest plot

1

10826

Risk Ratio (IV, Random, 95% CI)

0.07 [0.05, 0.09]

4 Persistent HPV16/18 infection(12M), 3 doses Show forest plot

1

368

Risk Ratio (IV, Random, 95% CI)

0.04 [0.00, 0.73]

5 Persistent HPV16/18 infection (12M), at least 1 dose Show forest plot

2

14153

Risk Ratio (IV, Random, 95% CI)

0.08 [0.05, 0.12]

Figures and Tables -
Comparison 4. Infection with HPV vaccine types in hrHPV DNA negative women at baseline
Comparison 5. HPV16/18 infection in HPV16/18 DNA negative women at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incident HPV16/18 infection, 3 doses Show forest plot

4

8034

Risk Ratio (IV, Random, 95% CI)

0.17 [0.10, 0.31]

2 Incident HPV16/18 infection, at least 1 dose Show forest plot

5

23872

Risk Ratio (IV, Random, 95% CI)

0.23 [0.14, 0.37]

3 Incident HPV16/18 infection, 1 or 2 doses (post hoc analysis) Show forest plot

3

331

Risk Ratio (IV, Random, 95% CI)

0.47 [0.26, 0.84]

4 Persistent HPV16/18 infection (6M), 3 doses Show forest plot

8

34113

Risk Ratio (IV, Random, 95% CI)

0.07 [0.06, 0.09]

4.1 Age group 15‐26 years

6

27385

Risk Ratio (IV, Random, 95% CI)

0.06 [0.05, 0.08]

4.2 Age group 24‐45 years

2

6728

Risk Ratio (IV, Random, 95% CI)

0.11 [0.06, 0.20]

5 Persistent HPV16/18 infection (6M), at least 1 dose Show forest plot

6

30323

Risk Ratio (IV, Random, 95% CI)

0.12 [0.08, 0.17]

5.1 Age group 15‐26 years

4

22803

Risk Ratio (IV, Random, 95% CI)

0.10 [0.08, 0.12]

5.2 Age group 24‐45 years

2

7520

Risk Ratio (IV, Random, 95% CI)

0.17 [0.10, 0.29]

6 Persistent HPV16/18 infection (6M), 1 or 2 doses (post hoc analysis) Show forest plot

4

1229

Risk Ratio (IV, Random, 95% CI)

0.26 [0.16, 0.44]

6.1 Age group 15‐26 years

2

437

Risk Ratio (IV, Random, 95% CI)

0.12 [0.03, 0.42]

6.2 Age group 24‐45 years

2

792

Risk Ratio (IV, Random, 95% CI)

0.31 [0.18, 0.54]

7 Persistent HPV6/11/16/18 infection (6M), 3 doses Show forest plot

2

4008

Risk Ratio (IV, Random, 95% CI)

0.12 [0.06, 0.21]

8 Persistent HPV6/11/16/18 infection (6M), at least 1 dose Show forest plot

2

4129

Risk Ratio (IV, Random, 95% CI)

0.13 [0.05, 0.37]

9 Persistent HPV16/18 infection (12M), 3 doses Show forest plot

4

22267

Risk Ratio (IV, Random, 95% CI)

0.09 [0.06, 0.13]

10 Persistent HPV16/18 infection (12M), at least 1 dose Show forest plot

5

29464

Risk Ratio (IV, Random, 95% CI)

0.16 [0.12, 0.20]

11 Persistent HPV16/18 infection (12M), 1 or 2 doses (post hoc analysis) Show forest plot

3

3912

Risk Ratio (IV, Random, 95% CI)

0.13 [0.06, 0.33]

Figures and Tables -
Comparison 5. HPV16/18 infection in HPV16/18 DNA negative women at baseline
Comparison 6. Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incident HPV16/18 infection, at least 1 dose Show forest plot

1

4210

Risk Ratio (IV, Random, 95% CI)

0.24 [0.17, 0.33]

2 Persistent HPV16/18 infection (6M), at least 1 dose Show forest plot

4

33847

Risk Ratio (IV, Random, 95% CI)

0.48 [0.41, 0.57]

2.1 Age group 15‐26 years

2

25199

Risk Ratio (IV, Random, 95% CI)

0.44 [0.38, 0.51]

2.2 Age group 24‐45 years

2

8648

Risk Ratio (IV, Random, 95% CI)

0.57 [0.47, 0.69]

3 Persistent HPV6/11/16/18 infection (6M), at least 1 dose Show forest plot

1

3713

Risk Ratio (IV, Random, 95% CI)

0.52 [0.42, 0.65]

4 Persistent HPV16/18 infection (12M), at least 1 dose Show forest plot

2

24785

Risk Ratio (IV, Random, 95% CI)

0.46 [0.40, 0.54]

5 Persistent HPV16/18 infection (12M) by dose (post hoc analysis) Show forest plot

1

7153

Risk Ratio (IV, Random, 95% CI)

0.18 [0.12, 0.27]

Figures and Tables -
Comparison 6. Infection with HPV types included in the vaccine in women regardless of HPV DNA status at baseline
Comparison 7. Adverse events

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall local/injection site adverse events Show forest plot

8

18113

Risk Ratio (IV, Fixed, 95% CI)

1.18 [1.16, 1.20]

1.1 Bivalent vaccine

2

6503

Risk Ratio (IV, Fixed, 95% CI)

1.29 [1.26, 1.33]

1.2 Quadrivalent vaccine

6

11610

Risk Ratio (IV, Fixed, 95% CI)

1.14 [1.12, 1.16]

2 Pain at injection site Show forest plot

13

25691

Risk Ratio (IV, Random, 95% CI)

1.35 [1.23, 1.49]

2.1 Monovalent vaccine

1

2280

Risk Ratio (IV, Random, 95% CI)

1.05 [1.01, 1.09]

2.2 Bivalent vaccine

8

16897

Risk Ratio (IV, Random, 95% CI)

1.49 [1.26, 1.75]

2.3 Quadrivalent vaccine

4

6514

Risk Ratio (IV, Random, 95% CI)

1.13 [1.07, 1.19]

3 Swelling at injection site Show forest plot

9

22106

Risk Ratio (IV, Random, 95% CI)

1.73 [1.32, 2.27]

3.1 Bivalent vaccine

7

16603

Risk Ratio (IV, Random, 95% CI)

1.62 [1.15, 2.29]

3.2 Quadrivalent vaccine

2

5503

Risk Ratio (IV, Random, 95% CI)

2.79 [0.85, 9.15]

4 Redness at injection site Show forest plot

6

19996

Risk Ratio (IV, Random, 95% CI)

1.72 [1.50, 1.97]

4.1 Quadrivalent vaccine

1

5345

Risk Ratio (IV, Random, 95% CI)

1.46 [1.32, 1.63]

4.2 Bivalent vaccine

5

14651

Risk Ratio (IV, Random, 95% CI)

1.80 [1.53, 2.11]

5 Overall systemic event and general symptoms Show forest plot

8

18191

Risk Ratio (IV, Random, 95% CI)

1.02 [0.98, 1.07]

5.1 Bivalent vaccine

2

6503

Risk Ratio (IV, Random, 95% CI)

1.07 [0.97, 1.19]

5.2 Quadrivalent vaccine

6

11688

Risk Ratio (IV, Random, 95% CI)

1.01 [0.98, 1.04]

6 Serious adverse events Show forest plot

23

71597

Risk Ratio (IV, Random, 95% CI)

0.98 [0.92, 1.05]

6.1 Monovalent vaccine

1

2387

Risk Ratio (IV, Random, 95% CI)

0.95 [0.51, 1.78]

6.2 Bivalent vaccine

15

46231

Risk Ratio (IV, Random, 95% CI)

1.01 [0.96, 1.07]

6.3 Quadrivalent vaccine

7

22979

Risk Ratio (IV, Random, 95% CI)

0.81 [0.65, 1.02]

7 Deaths Show forest plot

23

71176

Risk Ratio (IV, Random, 95% CI)

1.29 [0.85, 1.98]

7.1 Monovalent vaccine

1

2280

Risk Ratio (IV, Random, 95% CI)

0.0 [0.0, 0.0]

7.2 Bivalent vaccine

15

46231

Risk Ratio (IV, Random, 95% CI)

1.21 [0.66, 2.22]

7.3 Quadrivalent vaccine

7

22665

Risk Ratio (IV, Random, 95% CI)

1.54 [0.73, 3.23]

Figures and Tables -
Comparison 7. Adverse events
Comparison 8. Pregnancy outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Normal infant Show forest plot

8

8782

Risk Ratio (IV, Random, 95% CI)

1.00 [0.97, 1.02]

2 Spontaneous abortion/miscarriage Show forest plot

9

8618

Risk Ratio (IV, Random, 95% CI)

0.88 [0.68, 1.14]

3 Elective termination/induced abortion Show forest plot

9

10909

Risk Ratio (IV, Random, 95% CI)

0.90 [0.80, 1.02]

4 Stillbirth Show forest plot

6

8754

Risk Ratio (IV, Random, 95% CI)

1.12 [0.68, 1.83]

5 Abnormal infant Show forest plot

5

9252

Risk Ratio (IV, Random, 95% CI)

1.22 [0.88, 1.69]

Figures and Tables -
Comparison 8. Pregnancy outcomes