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.
Overall summary Low risk of bias in the review
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|
|Number of studies||26|
|Number of participants||73428|
|Last search date||15 June 2017|
|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.|
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.
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. However, it can be improved with better search logic. They search for: HPV + (vaccination OR named vaccines); it should be: (HPV + vaccination) OR named vaccines (e.g. gardasil). The Embase strategy includes an out-dated Emtree term which was replaced in 2015: exp Papilloma virus/. The correct Emtree is: Exp Papillomaviridae/. 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 no|
|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|