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KSR Number: KSRA73811

Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors

  • Cochrane Database Syst Rev 2018, 5, CD009069, 10.1002/14651858.CD009069.pub3
  • Full report

Risk of Bias Assessment

Overall summary: Low risk of bias in the review

Bottom Line

HPV vaccines protect against cervical precancer in adolescent girls and women vaccinated between 15 and 26 years of age. The protection is lower when a part of the population is already infected with HPV. Longer-term follow-up is needed to assess the impact on cervical cancer. There are limited data from trials on the effect of vaccines on deaths, stillbirth and babies born with malformations. However, no increased risk of serious adverse effects, miscarriage or pregnancy termination was found. These findings are likely to be reliable.

Risk of Bias Assessment

Overall summary Low risk of bias in the review

Low

All domains were considered at low concern. A range of comments were made about the review which can be found or are cited in the comments section of the review in the Cochrane Library.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? Probably yes
B. Was the relevance of identified studies to the review's research question appropriately considered? Probably yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Probably yes
Risk of bias in the review Low

Details of Review

Number of studies 26
Number of participants 73428
Last search date 15 June 2017
Review type Intervention
Objective To evaluate the harms and protection of prophylactic human papillomaviruses (HPV) vaccines against cervical precancer and HPV16/18 infection in adolescent girls and women.
Population Female participants with no evidence of baseline infection with high-risk human papillomaviruses (hrHPV) and HPV types and regardless of baseline infection with HPV.
Interventions Prophylactic human papillomaviruses (HPV) vaccines containing virus-like particles composed of the L1 capsid protein of HPV16 (monovalent vaccine), HPV16 and HPV18 (bivalent vaccine), or HPV6, HPV11, HPV16 and HPV18 (quadrivalent vaccine).
Comparator Placebo containing no active product or only the adjuvant of the human papillomaviruses (HPV) vaccine, without L1 virus-like particles (VLPs), or another non-HPV vaccine.
Outcome Primary outcomes: Histologically-confirmed high-grade cervical intraepithelial neoplasia (High-grade cervical intraepithelial neoplasia [CIN]2, CIN3 and adenocarcinoma in situ) or worse, associated with the HPV types invasive cervical cancer, safety or occurrence of adverse effects such as local adverse effects [redness, swelling, pain, itching at the injection site], mild systemic effects, serious systemic effects, mortality and pregnancy outcomes observed during the trials, in particular occurrence of congenital anomalies.

Secondary outcomes: Incident infection with vaccine HPV types (HPV16 and HPV18, jointly and HPV6, HPV11, HPV16 and HPV18 jointly), persistent infection (persisting during at least six months or at least 12 months) with vaccine HPV types.
Study design Randomised controlled trials.

Results

At follow up of 3-5 years, HPV vaccines reduced risk of cervical intraepithelial neoplasia grade 2 and above (CIN2+) associated with HPV16/18 (risk ratio [RR] 0.01, 95% confidence interval [CI] 0 to 0.05, N =23676, 3 RCTs).

At follow up of 3-5 years, HPV vaccines reduced risk of CIN3+ associated with HPV16/18 (risk ratio [RR] 0.01, 95% confidence interval [CI] 0 to 0.10, N =20214, 2 RCTs).

At follow up of 3-5 years, HPV vaccines reduced risk of adenocarcinoma in situ associated with HPV16/18 (risk ratio [RR] 0.10, 95% confidence interval [CI] 0.01 to 0.82, N =20214, 2 RCTs).

At follow-up of 3.5 to 4 years, a RR of 0.21 (95% CI 0.04 to 1.10) was reported for any CIN3+ irrespective of HPV type, bivalent or quadrivalent vaccine.

At follow-up of 3 to 5 years, a RR of 0.10 (95% CI 0.01 to 0.76) was reported for any adenocarcinoma in situ, irrespective of HPV type.

The risk of adverse events in women of all ages was 656/10,000 compared with 669 (RR 0.98, 95% CI 0.92 to 1.05, N =71597, 23 RCTs) and mortality was 11/10,000 in control groups compared with 14/10,000 (9 to 22) with HPV vaccine (RR 1.29, 95% CI 0.85 to 1.98, N =71176, 23 RCTs). There is a higher number of deaths in older women, whereas overall death was low.

The pooled analysis found no evidence of increased risk of miscarriage (RR 0.88, 95% CI 0.68 to 1.14, N =8,618, 9 RCTs), termination (RR 0.90, 95% CI 0.80 to 1.02, N =10,909, 9 RCTs) and congenital abnormalities and stillbirths (RR 1.22, 95% CI 0.88 to 1.69, N =9252, 5 RCTs) in women with no infection with high-risk human papillomavirus or HPV types.

Full Risk of Bias Assessment

The research objective was clearly stated and appropriate inclusion criteria were defined. No restrictions were applied to eligibility criteria based on study characteristics and sources of information. There were some minor issues with including and excluding trials that used other vaccines than mono-, bi- or quadrivalent.

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Probably no
1.2 Were the eligibility criteria appropriate for the review question? Probably yes
1.3 Were eligibility criteria unambiguous? Yes
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? Yes
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? Yes
Concerns regarding specification of study eligibility criteria Low

Cochrane Central Register of Controlled Trials (CENTRAL 2002 to 2017, Issue 5), MEDLINE (2002 to June Week 1 2017), and Embase (2002 to 2017 week 24) were searched for relevant articles. In addition, reference lists of included studies, www.clinicaltrials.gov, www.isrctn.com, and www.cancer.gov/clinicaltrials, www.gskclinicalstudyregister.com/, the World Health Organization (WHO, Geneva), the US Centers for Disease Control and Prevention (CDC, Atlanta), the European Centre for Disease Prevention and Control (ECDC, Stockholm), and the International Agency for Research on Cancer (IARC, Lyon), abstracts of the latest conferences of relevant scientific societies related to vaccination, virology (in particular the International Papillomavirus Society), paediatrics, and gynaecology were searched for additional findings. The search strategy was reported in full and appeared adequate. No restrictions were reported based on date, publication format, or language. Three reviewers were independently involved in study selection and disagreements were resolved by discussion. If no consensus could be reached another review author was consulted.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? Yes
2.2 Were methods additional to database searching used to identify relevant reports? Yes
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? Probably yes
2.4 Were restrictions based on date, publication format, or language appropriate? Probably yes
2.5 Were efforts made to minimise error in selection of studies? Yes
Concerns regarding methods used to identify and/or select studies Low

Three reviewers were independently involved in the data extraction process and disagreements were resolved by discussion or by appeal to a third reviewer. Sufficient study characteristics appear to have been extracted to allow interpretation of results. Relevant study results appear to have been extracted. Methodological quality assessment of included studies was performed by using Cochrane Risk of Bias Tool.

3.1 Were efforts made to minimise error in data collection? Yes
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? Probably yes
3.3 Were all relevant study results collected for use in the synthesis? Probably yes
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? Yes
3.5 Were efforts made to minimise error in risk of bias assessment? Yes
Concerns regarding methods used to collect data and appraise studies Low

The synthesis included all relevant studies. Analyses pre-defined in the methodology section were performed appropriately. Significant heterogeneity was found between the studies in cervical intraepithelial neoplasia grade 2+ and cervical intraepithelial neoplasia grade 3+ outcomes. Subgroup analyses and meta-regression analysis was performed to address the between-study heterogeneity. Publication bias using funnel plot was planned but could not be performed due to the low number of studies. The quality of the individual studies was considered in the synthesis.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Yes
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Probably yes
4.4 Was between-study variation minimal or addressed in the synthesis? Probably yes
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably yes
4.6 Were biases in primary studies minimal or addressed in the synthesis? Probably yes
Concerns regarding synthesis and findings Low

Abstract

Abstract - Background Persistent infection with high‐risk human papillomaviruses (hrHPV) types is causally linked with the development of cervical precancer and cancer. HPV types 16 and 18 cause approximately 70% of cervical cancers worldwide. Objectives To evaluate the harms and protection of prophylactic human papillomaviruses (HPV) vaccines against cervical precancer and HPV16/18 infection in adolescent girls and women. Search methods We searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase (June 2017) for reports on effects from trials. We searched trial registries and company results' registers to identify unpublished data for mortality and serious adverse events. Selection criteria Randomised controlled trials comparing efficacy and safety in females offered HPV vaccines with placebo (vaccine adjuvants or another control vaccine). Data collection and analysis We used Cochrane methodology and GRADE to rate the certainty of evidence for protection against cervical precancer (cervical intraepithelial neoplasia grade 2 and above [CIN2+], CIN grade 3 and above [CIN3+], and adenocarcinoma‐in‐situ [AIS]), and for harms. We distinguished between the effects of vaccines by participants' baseline HPV DNA status. The outcomes were precancer associated with vaccine HPV types and precancer irrespective of HPV type. Results are presented as risks in control and vaccination groups and risk ratios (RR) with 95% confidence intervals in brackets. Main results We included 26 trials (73,428 participants). Ten trials, with follow‐up of 1.3 to 8 years, addressed protection against CIN/AIS. Vaccine safety was evaluated over a period of 6 months to 7 years in 23 studies. Studies were not large enough or of sufficient duration to evaluate cervical cancer outcomes. All but one of the trials was funded by the vaccine manufacturers. We judged most included trials to be at low risk of bias. Studies involved monovalent (N = 1), bivalent (N = 18), and quadrivalent vaccines (N = 7). Most women were under 26 years of age. Three trials recruited women aged 25 and over. We summarize the effects of vaccines in participants who had at least one immunisation. Efficacy endpoints by initial HPV DNA status hrHPV negative HPV vaccines reduce CIN2+, CIN3+, AIS associated with HPV16/18 compared with placebo in adolescent girls and women aged 15 to 26. There is high‐certainty evidence that vaccines lower CIN2+ from 164 to 2/10,000 (RR 0.01 (0 to 0.05)) and CIN3+ from 70 to 0/10,000 (RR 0.01 (0.00 to 0.10). There is moderate‐certainty evidence that vaccines reduce the risk of AIS from 9 to 0/10,000 (RR 0.10 (0.01 to 0.82). HPV vaccines reduce the risk of any CIN2+ from 287 to 106/10,000 (RR 0.37 (0.25 to 0.55), high certainty) and probably reduce any AIS lesions from 10 to 0/10,000 (RR 0.1 (0.01 to 0.76), moderate certainty). The size of reduction in CIN3+ with vaccines differed between bivalent and quadrivalent vaccines (bivalent: RR 0.08 (0.03 to 0.23), high certainty; quadrivalent: RR 0.54 (0.36 to 0.82), moderate certainty). Data in older women were not available for this comparison. HPV16/18 negative In those aged 15 to 26 years, vaccines reduce CIN2+ associated with HPV16/18 from 113 to 6 /10,000 (RR 0.05 (0.03 to 0.10). In women 24 years or older the absolute and relative reduction in the risk of these lesions is smaller (from 45 to 14/10,000, (RR 0.30 (0.11 to 0.81), moderate certainty). HPV vaccines reduce the risk of CIN3+ and AIS associated with HPV16/18 in younger women (RR 0.05 (0.02 to 0.14), high certainty and RR 0.09 (0.01 to 0.72), moderate certainty, respectively). No trials in older women have measured these outcomes. Vaccines reduce any CIN2+ from 231 to 95/10,000, (RR 0.41 (0.32 to 0.52)) in younger women. No data are reported for more severe lesions. Regardless of HPV DNA status In younger women HPV vaccines reduce the risk of CIN2+ associated with HPV16/18 from 341 to 157/10,0 0 (RR 0.46 (0.37 to 0.57), high certainty). Similar reductions in risk were observed for CIN3+ associated with HPV16/18 (high certainty). The number of women with AIS associated with HPV16/18 is reduced from 14 to 5/10,000 with HPV vaccines (high certainty). HPV vaccines reduce any CIN2+ from 559 to 391/10,000 (RR 0.70 (0.58 to 0.85, high certainty) and any AIS from 17 to 5/10,000 (RR 0.32 (0.15 to 0.67), high certainty). The reduction in any CIN3+ differed by vaccine type (bivalent vaccine: RR 0.55 (0.43 to 0.71) and quadrivalent vaccine: RR 0.81 (0.69 to 0.96)). In women vaccinated at 24 to 45 years of age, there is moderate‐certainty evidence that the risks of CIN2+ associated with HPV16/18 and any CIN2+ are similar between vaccinated and unvaccinated women (RR 0.74 (0.52 to 1.05) and RR 1.04 (0.83 to 1.30) respectively). No data are reported in this age group for CIN3+ or AIS. Adverse effects The risk of serious adverse events is similar between control and HPV vaccines in women of all ages (669 versus 656/10,000, RR 0.98 (0.92 to 1.05), high certainty). Mortality was 11/10,000 in control groups compared with 14/10,000 (9 to 22) with HPV vaccine (RR 1.29 [0.85 to 1.98]; low certainty). The number of deaths was low overall but there is a higher number of deaths in older women. No pattern in the cause or timing of death has been established. Pregnancy outcomes Among those who became pregnant during the studies, we did not find an increased risk of miscarriage (1618 versus 1424/10,000, RR 0.88 (0.68 to 1.14), high certainty) or termination (931 versus 838/10,000 RR 0.90 (0.80 to 1.02), high certainty). The effects on congenital abnormalities and stillbirths are uncertain (RR 1.22 (0.88 to 1.69), moderate certainty and (RR 1.12 (0.68 to 1.83), moderate certainty, respectively). Authors' conclusions There is high‐certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and young women aged 15 to 26. The effect is higher for lesions associated with HPV16/18 than for lesions irrespective of HPV type. The effect is greater in those who are negative for hrHPV or HPV16/18 DNA at enrolment than those unselected for HPV DNA status. There is moderate‐certainty evidence that HPV vaccines reduce CIN2+ in older women who are HPV16/18 negative, but not when they are unselected by HPV DNA status. We did not find an increased risk of serious adverse effects. Although the number of deaths is low overall, there were more deaths among women older than 25 years who received the vaccine. The deaths reported in the studies have been judged not to be related to the vaccine. Increased risk of adverse pregnancy outcomes after HPV vaccination cannot be excluded, although the risk of miscarriage and termination are similar between trial arms. Long‐term of follow‐up is needed to monitor the impact on cervical cancer, occurrence of rare harms and pregnancy outcomes. Plain language summary HPV vaccination to prevent cancer and pre‐cancerous changes of the cervix Background 
 Human papillomaviruses (HPV) are sexually transmitted and are common in young people. Usually they are cleared by the immune system. However, when high‐risk (hr) types persist, they can cause the development of abnormal cervical cells, which are referred to as cervical precancer if at least two thirds of the surface layer of the cervix is affected. Precancer can develop into cervical cancer after several years. Not everyone who has cervical precancer goes on to develop cervical cancer, but predicting who will is difficult. There are a number of different hrHPV types which can cause cervical precancer and cancer. HPV16 and 18 are the most important high‐risk types, since they cause about 70% of cervical cancers worldwide. Preventive vaccination, by injection of HPV virus‐like particles in the muscle, triggers the production of antibodies which protect against future HPV infections. Review question 
 Does H V vaccination prevent the development of cervical precancer or cancer and what are the harms? Main results 
 We included 26 studies involving 73,428 adolescent girls and women. All trials evaluated vaccine safety over a period 0.5 to 7 years and ten trials, with follow‐up 3.5 to 8 years, addressed protection against precancer. Cervical cancer outcomes are not available. Most participants enrolled were younger than 26 years of age. Three trials recruited women between 25 to 45 years. The studies compared HPV vaccine with a dummy vaccine. We assessed protection against precancer in individuals who were free of hrHPV, free of HPV16/18 or those with or without HPV infection at the time of vaccination. We separately assessed precancer associated with HPV16/18 and any precancer. Protection against cervical precancer 1) Women free of hrHPV Outcomes were only measured in the younger age group for this comparison (15 to 25 years). HPV vaccines reduce the risk of cervical precancer associated with HPV16/18 from 164 to 2/10,000 women (high certainty). They reduce also any precancer from 287 to 106/10,000 (high certainty). 2) Women free of HPV16/18 The effect of HPV vaccines on risk of precancer differ by age group. In younger women, HPV vaccines reduce the risk of precancer associated with HPV16/18 from 113 to 6/10,000 women (high certainty). HPV vaccines lower the number of women with any precancer from 231 to 95/10,000 (high certainty). In women older than 25, the vaccines reduce the number with precancer associated with HPV16/18 from 45 to 14/10,000 (moderate certainty). 3) All women with or without HPV infection In those vaccinated between 15 to 26 years of age, HPV vaccination reduces the risk of precancer associated with HPV16/18 from 341 to 157/10,000 (high certainty) and any precancer from 559 to 391/10,000 (high certainty). In older women, vaccinated between 25 to 45 years of age, the effects of HPV vaccine on precancer are smaller, which may be due to previous exposure to HPV. The risk of precancer associated with HPV16/18 is probably reduced from 145/10,000 in unvaccinated women to 107/10,000 women following HPV vaccination (moderate certainty). The risk of any precancer is probably similar between unvaccinated and vaccinated women (343 versus 356/10,000, moderate certainty). Adverse effects The risk of serious adverse events is similar in HPV and control vaccines (placebo or vaccine against another infection than HPV (high certainty). The rate of death is similar overall (11/10,000 in control group, 14/10,000 in HPV vaccine group) (low certainty). The number of deaths overall is low although a higher number of deaths in older women was observed. No pattern in the cause or timing of death has been established. Pregnancy outcomes HPV vaccines did not increase the risk of miscarriage or termination of pregnancy. We do not have enough data to be certain about the risk of stillbirths and babies born with malformations (moderate certainty). Conclusion 
 There is high‐certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and women who are vaccinated between 15 and 26 years of age. The protection is lower when a part of the population is already infected with HPV. Longer‐term follow‐up is needed to assess the impact on cervical cancer. The vaccines do not increase the risk of serious adverse events, miscarriage or pregnancy termination. There are limited data from trials on the effect of vaccines on deaths, stillbirth and babies born with malformations.