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Risk ratio (RR) estimates were pooled using random-effects meta-analysis.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Outcomes<\/jats:title>\n<jats:p>Clinically relevant outcomes in intention to treat populations\u2014including HPV-related cancer precursors irrespective of involved HPV types, treatment procedures and serious and general harms.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Twenty-four of 50 eligible clinical study reports were obtained with 58,412 pages of 22 trials and 2 follow-up studies including 95,670 participants: 79,102 females and 16,568 males age 8\u201372; 393,194 person-years; and 49\u2009months mean weighted follow-up. We judged all 24 studies to be at high risk of bias. Serious harms were incompletely reported for 72% of participants (68,610\/95,670). Nearly all control participants received active comparators (48,289\/48,595, 99%). No clinical study report included complete case report forms. At 4\u00a0years follow-up, the HPV vaccines reduced HPV-related carcinoma in situ (367 in the HPV vaccine group vs. 490 in the comparator group, RR 0.73 [95% confidence interval, CI, 0.53 to 1.00], number needed to vaccinate [NNV] 387, <jats:italic>P<\/jats:italic>\u2009=\u20090.05, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u200967%) and HPV-related treatment procedures (1018 vs. 1416, RR 0.71 [95% CI 0.63 to 0.80], NNV 75, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.00001, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u200945%). The HPV vaccines increased serious nervous system disorders (exploratory analysis: 72 vs. 46, RR 1.49 [1.02 to 2.16], number needed to harm [NNH] 1325, <jats:italic>P<\/jats:italic>\u2009=\u20090.040, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u20090%) and general harms (13,248 vs. 12,394, RR 1.07 [95% CI 1.03 to 1.11], NNH 51, <jats:italic>P<\/jats:italic>\u2009=\u00a00.0002, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u200977%) but did not significantly increase fatal harms (45 vs. 38, RR 1.19 [95% CI 0.65 to 2.19], <jats:italic>P<\/jats:italic>\u2009=\u20090.58, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u200930%) or serious harms (1404 vs. 1357, RR 1.01 [95% CI 0.94 to 1.08], <jats:italic>P<\/jats:italic>\u2009=\u20090.79, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u20090%).<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>At 4\u00a0years follow-up, the HPV vaccines decreased HPV-related cancer precursors and treatment procedures but increased serious nervous system disorders (exploratory analysis) and general harms. As the included trials were primarily designed to assess benefits and were not adequately designed to assess harms, the extent to which the HPV vaccines\u2019 benefits outweigh their harms is unclear. Limited access to clinical study reports and trial data with case report forms prevented a thorough assessment.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Systematic review registration<\/jats:title>\n<jats:p>CRD42017056093. Our systematic review protocol was registered on PROSPERO in January 2017: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.crd.york.ac.uk\/PROSPEROFILES\/56093_PROTOCOL_20170030.pdf\">https:\/\/www.crd.york.ac.uk\/PROSPEROFILES\/56093_PROTOCOL_20170030.pdf<\/jats:ext-link>. Two protocol amendments were registered on PROSPERO on November 2017: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.crd.york.ac.uk\/PROSPEROFILES\/56093_PROTOCOL_20171116.pdf\">https:\/\/www.crd.york.ac.uk\/PROSPEROFILES\/56093_PROTOCOL_20171116.pdf<\/jats:ext-link>. Our index of the HPV vaccine studies was published in Systematic Reviews in January 2018: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"https:\/\/doi.org\/10.1186\/s13643-018-0675-z\">10.1186\/s13643-018-0675-z<\/jats:ext-link>. A description of the challenges obtaining the data was published in September 2018: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"https:\/\/doi.org\/10.1136\/bmj.k3694\">10.1136\/bmj.k3694<\/jats:ext-link>.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s13643-019-0983-y","type":"journal-article","created":{"date-parts":[[2020,2,28]],"date-time":"2020-02-28T00:08:18Z","timestamp":1582848498000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Benefits and harms of the human papillomavirus (HPV) vaccines: systematic review with meta-analyses of trial data from clinical study reports"],"prefix":"10.1186","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9737-0555","authenticated-orcid":false,"given":"Lars","family":"J\u00f8rgensen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C.","family":"G\u00f8tzsche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Jefferson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,28]]},"reference":[{"issue":"19","key":"983_CR1","first-page":"241","volume":"92","author":"World Health Organization","year":"2017","unstructured":"World Health Organization. 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LJ declares no support from any organisation for the submitted work, no financial relationships with any organisations that might have an interest in the submitted work, no other relationships or activities that could appear to have influenced the submitted work. PCG spoke by video link about the HPV vaccines at the IFICA (International Federation for Injured Children and Adults, ) conference in 2018 but received no fee or reimbursement for this. PCG and TJ were co-signatories of a complaint to the European Ombudsman on maladministration in relation to the EMA investigation of possible harms from HPV vaccines. PCG does not regard this as a competing interest. TJ was a co-recipient of a UK National Institute for Health Research grant (HTA\u201310\/80\/01 update and amalgamation of two Cochrane Reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children\u2014). TJ is also in receipt of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. TJ is occasionally interviewed by market research companies about phase I or II pharmaceutical products. In 2011\u20132014, TJ acted as an expert witness in a litigation case related to the antiviral oseltamivir, in two litigation cases on potential vaccine-related damage and in a labour case on influenza vaccines in healthcare workers in Canada. He has acted as a consultant for Roche (1997\u20131999), GSK (2001\u20132002), Sanofi-Synthelabo (2003) and IMS Health (2013). In 2014\u20132016, TJ was a member of three advisory boards for Boehringer Ingelheim. TJ was a member of an independent data monitoring committee for a Sanofi Pasteur clinical trial on an influenza vaccine.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Publisher\u2019s Note"}}],"article-number":"43"}}