Adverse events associated with human papillomavirus vaccines: a protocol for systematic review with network meta-analysis incorporating all randomised controlled trials comparing with placebo, adjuvants and other vaccines

Abstract

IntroductionAdverse events following the injection (AEFIs) of human papillomavirus vaccine (HPVv) among female adolescents are still a major public health concern.MethodsAccording to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension statement for systematic reviews incorporating network meta-analyses, all prospective randomised trials will be included. The primary outcome for adverse events is topical pain during the observation period.We will mainly search 17 electronic databases from January 2000 through September 2019 with suitable Medical Subject Headings and text words for PubMed. Two reviewers will independently check the reports at the title/abstract level and identify potentially applicable studies. Then we will obtain their full texts and decide whether to include them based on the same eligible criteria.We will compare HPVv with placebo, HPVv with adjuvant and HPVv with other vaccines. Interstudy heterogeneity, publication biases or small study effects will be evaluated using conventional meta-analysis methods. The consistency of the network will be checked using tests for local and global inconsistency and the side-splitting method. To address the heterogeneity of treatment effects among the studies, we will use the multivariable random effect model.Ethics and disseminationThis pairwise or network meta-analysis does not require ethics approval. The data used here are not individual nor private. We will be able to determine which component of the vaccine induces adverse events, especially topical pain. This systematic review with network meta-analysis will provide valid answers regarding AEFIs for HPVv.PROSPERO registration numberCRD42018109265

Adjuvant-containing control arms in pivotal quadrivalent human papillomavirus vaccine trials: restoration of previously unpublished methodology

“…We are unaware of any randomised trial directly evaluating AAHS against placebo; a network meta-analysis is underway that aims to use extant randomised controlled trial (RCT) data to determine the safety profile of the AAHS component of qHPV vaccine. 39 Moreover, while other vaccines contain AAHS (e.g., Recombivax and VAQTA), such vaccines cannot be used to characterise AAHS safety as 'it cannot be assumed that an adjuvant that is safe in one vaccine with a given antigen will be safe when added to another vaccine' . 40 The unknown consequences of aluminum-containing adjuvants, more generally, is concerning.…”