Investigating the potential side effects of the human papillomavirus vaccine: a novel regression discontinuity analysis using the UK Clinical Practice Research Datalink

Date of ISAC Approval: 
Lay Summary: 
The bivalent human papillomavirus (HPV) vaccine for virus types 16&18 (Cervarix) was first introduced in England in 2008, which was replaced by quadrivalent HPV vaccine for virus types 6&11&16&18 (Gardasil) in 2012. It is given to girls aged 12/13 years in order to protect against the human papillomavirus - the leading cause of cervical cancer. Cervical cancer is the most common cancer in women under the age of 35. There have been a number of side effects reported for the type of vaccine used from 2012 (Gardasil). These include complex regional pain syndrome, Guillain-Barre syndrome, postural orthostatic tachycardia syndrome and symptoms associated with autonomous nervous systems (ANS) disorders. However, the evidence from recent systematic reviews suggests that there is no association between these outcomes and the HPV vaccine. The best type of study to examine the effects of a drug on patients are randomised controlled trials (RCTs) where patients are given either the HPV Vaccine or a placebo (a dummy drug that will have no effect) but they do not know which one they are taking. A number of RCTs have been performed before and after the licensing of the vaccine but extensive media attention prevails suggesting adverse effects. RCTs of the vaccine cannot be done now as the vaccine is widely given. It would also need to be very large in size in order to detect differences in rare outcomes, and hence would be expensive and time-consuming. We will be using a statistical method called regression discontinuity analysis (RDA) which allows us to be able to determine whether the vaccine has any potential adverse effect without the need for additional RCTs.
Technical Summary: 
Evidence surrounding the safety of HPV vaccines is reassuring despite extensive media attention suggesting otherwise. We will use a regression discontinuity analysis (RDA) to assess the effect of the HPV vaccine on suggested adverse outcomes. RDA is a statistical technique that allows for causal inference when a decision rule (such as being above or below a cut-off value on a continuous measure) is used to assign treatment. It is a quasi-experimental method that (like RCTs) reduces the effect of confounding of unobserved variables. The assumption being that patients lying just either side of the cut-off value are similar, in terms of observed and unobserved characteristics. Focussing on a small window surrounding the cut-off value should result in treatment assignment being the only difference between patients. Our study sample will be comprised of 12-13-year-old girls born in July through October in each year 2000, 2001, 2002, 2003, 2004 and 2005 who have one year of follow up data. We will use date of birth as exposure, comparing girls in the school year that the vaccine is given with those in the school year prior. Outcomes will include side effects such as complex regional pain syndrome and postural orthostatic tachycardia syndrome. RDA is a novel method and it will provide additional insights into the causal effects of HPV vaccine on side effects.
Health Outcomes to be Measured: 
- Autonomic nervous system (ANS) disorders - Postural orthostatic tachycardia syndrome (POTS) - post-viral fatigue syndrome /myalgic encephalomyelitis - Premature ovarian failure - Alopecia - Demyelinating diseases - chronic fatigue syndrome/ myalgic encephalomyelitis - Complex regional pain syndrome (CRPS) - Venous thromboembolism (VTE) - Myasthenia gravis - Dysautonomias - Number of hospitalisations - Neuropathies - Guillain-Barre syndrome - systemic lupus erythematosus - Thrombocytopenia - Neurogenic bladder and bowel dysfunctions - Number of GP consultations

Dr Kate Northstone - Chief Investigator - University of Bristol
Professor Kate Tilling - Chief Investigator - University of Bristol
Dr Kate Northstone - Corresponding Applicant - University of Bristol
Professor Kate Tilling - Collaborator - University of Bristol
Ruta Margelyte - Collaborator - University of Bristol
Dr Theresa Redaniel - Corresponding Applicant - University of Bristol

HES Admitted;Patient IMD;Practice IMD (Standard)