Serious adverse events associated with HPV vaccination

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A systematic literature review was undertaken to investigate serious adverse events associated with
human papillomavirus (HPV) vaccination. The HPV vaccine comes in two types: a bivalent (HPV
16/18, Cervarix™, GlaxoSmithKline) and a quadrivalent (HPV 6/11/16/18, Gardasil® or Silgard, Merck)
This review considered all primary and secondary (systematic review, SR) research evidence. Despite
a large number of studies that pooled (metaanalysed) primary research evidence, none of these
were conducted as formal SRs and so were not included. SRs are characterised by a research
question, a comprehensive search for evidence, a protocol for study selection and critical appraisal of
the included research, and synthesis of that research. This approach limits the likelihood that the
presented results are biased or inaccurate. We found one SR that was eligible, according to our
review protocol; however, most of the trials included in this SR had since been updated, and so it was
excluded in favour of incorporating the more uptodate primary research evidence that was
There is a considerable amount of randomised controlled trial (RCT) evidence reporting on the safety
and efficacy of HPV vaccines. Indeed, the total pool of subjects in this review was over 77 000, and
there were several individual trials with large numbers of participants. Although the trials all
considered vaccine safety, it was not the primary outcome in the vast majority of cases, and only
afforded a small portion of the published reports. Serious adverse events (SAE) were rarely defined.
It is clear that many of the trial investigators interpreted SAEs and the other outcomes new onset of
chronic diseases and medically significant conditions in very different ways; the reporting rates
varied widely across studies. Rates of SAEs were reported as low as <1% and as high as 25% in one
comparison. When appraising these studies, using GRADE methodology, the individual outcomes
were downgraded for indirectness because of this issue; but the appraisal was also upgraded
because the trials were large and had long followup times. Thus, on balance, these trials received a
high quality rating after being appraised.
Most of the trials assessed whether SAEs were associated with vaccination, but only one trial
explained how causality was assessed. The majority of SAEs were deemed to be not vaccinerelated.
Likewise, most trials reported deaths, but trials that reported causality found no associated between
the reported deaths and HPV vaccination.
A number of cohort studies also investigated the association between HPV vaccination and specific
adverse events, in particular autoimmune diseases. These studies were generally very well designed
and used appropriate methods to minimise confounding. The results from both the trial evidence
and from the cohort studies is very consistent in finding that there is no relationship between any
serious adverse event and HPV vaccination. The main results are summarised in
Table 1.

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