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Using Existing Data Sources for Assessment of Vaccine Safety: a Focus on Methods Using existing data sources for assessment of vaccine safety: a focus on methods Het gebruik van bestaande gegevensbronnen ter beoordeling van de veiligheid van vaccins: een focus op methodiek. Thesis to obtain the degree of Doctor from the Erasmus University Rotterdam by command of the rector magnificus Prof. dr. R.C.M.E. Engels and in accordance with the decision of the Doctorate Board The public defense shall be held on 26 June 2019 at 15:30 hrs by Caitlin Nora Dodd Born in Duluth, Minnesota, USA. Doctoral Committee PROMOTER Prof. dr. M.C.J.M. Sturkenboom OTHER MEMBERS Prof. S. Black Prof. dr. E.P. van Puyenbroek Prof. dr. M. Koopmans COPROMOTERS Dr. M.A.J. de Ridder Dr. D.M. Weibel Using existing data sources for assessment of vaccine safety: A focus on methods CAITLIN NORA DODD Cover design by Caitlin Dodd Layout by Caitlin Dodd This work described in this thesis was carried out at the Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands For Nora and Millie. CONTENTS Chapter 1. General Introduction .................................................................................................................................. 14 Chapter 2. Methods for signal detection in spontaneous reporting system databases ...................................... 25 2.1 Drug safety monitoring in children: Performance of signal detection algorithms and impact of age stratification ............................................................................................................................................................. 27 2.2 Masking by vaccines in pediatric signal detection: A study in the EudraVigilance database ..................... 47 2.3 Pediatric vaccine safety signal detection in VAERS and EudraVigilance using disproportionality analysis, time to onset, and their combination ...................................................................................................................... 65 Chapter 3. Methods for rapid assessment ................................................................................................................... 93 3.1 Incidence rates of narcolepsy diagnoses in Taiwan, Canada, and Europe: methods for assessment of potential safety issues on a population level in the SOMNIA study ........................................................................................ 95 Chapter 4. Single database studies for the assessment of vaccine effects ................................................................ 115 4.1. Bell’s palsy and influenza(H1N1)pdm09 containing vaccines: a self-controlled case series ........................... 117 4.2 The impact and longevity of measles-associated immune suppression: a matched cohort study using data from the THIN general practice database in the United Kingdom ......................................................................... 133 Chapter 5 Collaborative studies to assess vaccine effects .................................................................................... 159 5.1 International collaboration to assess the risk of Guillain-Barré Syndrome following influenza A (H1N1) 2009 monovalent vaccines ..................................................................................................................................... 161 5.2 Narcolepsy and adjuvanted pandemic influenza A (H1N1) 2009 vaccines: a Multi-country assessment ........ 183 5.3 Enhancing global vaccine pharmacovigilance: Proof-of-concept study on aseptic meningitis and immune thrombocytopenic purpura following measles-mumps containing vaccination.................................................... 207 Chapter 6 Methods for dealing with heterogeneity and bias ............................................................................... 233 6.1 Pandemic Influenza vaccine & Narcolepsy: Simulations on the potential impact of bias ........................ 235 6.2 Quantifying outcome misclassification in multi-database studies: the case study of pertussis in the ADVANCE project ................................................................................................................................................... 257 Abstract ...................................................................................................................................................................... 258 6.3 Estimating the incidence of adverse events following vaccination in observational databases with incomplete exposure data ..................................................................................................................................... 283 Chapter 7. General Discussion ................................................................................................................................... 297 General Discussion ................................................................................................................................................. 298 Summary .................................................................................................................................................................... 312 Samenvatting in het Nederlands ................................................................................................................................ 315 List of Publications ..................................................................................................................................................... 318 Acknowledgements .................................................................................................................................................... 322 About the author ....................................................................................................................................................... 324 PhD Portfolio .............................................................................................................................................................. 325 CHAPTER 1. GENERAL INTRODUCTION Using existing data-sources for assessment of vaccine safety: a focus on methods Vaccines as a public health intervention Vaccination is widely accepted as one of the foremost public health achievements of the last century, with the United States Centers for Disease Control reporting in 2014 that vaccines have prevented 322 million illnesses, 21 million hospitalizations, and 732,000 deaths over the lifespan of children born between 1984 and 2014 (1) . Vaccines confer this degree of protection only when a large enough proportion of the population is vaccinated to produce herd immunity, or protection of the unvaccinated by the vaccinated (2). Because vaccines serve as a primary prevention measure, they are principally administered to healthy individuals. This means that public expectations for measurement of the safety and effectiveness of vaccines may be more stringent in terms of timeliness and accuracy than those for drugs which treat illness. The vaccine product life cycle Vaccines are rigorously tested for safety and effectiveness in clinical trials before receiving market authorization (3). Because clinical trials are limited in size and scope, however, adverse events and unexpected benefits may go undetected in trials and arise only when the vaccine is administered to large populations. Chen et al, in their paper describing the then newly-initiated Vaccine Adverse Events Reporting System (VAERS), displayed the cycle of vaccine confidence in an often-cited figure (figure 1). The figure displays how increasing vaccination coverage is paired with decreasing incidence of the vaccine-preventable disease but also potentially with increasing reports of vaccine-associated (either causally or temporally) adverse events. This increased reporting of adverse events following vaccination can lead to decreased confidence in the vaccine and associated decreases in coverage and effectiveness. The Vaccine Confidence Project, led by the London School of Hygiene and Tropical Health, has found that concern about vaccine safety is the primary cause of vaccine hesitancy in Europe (4). It is of utmost importance to public health that any adverse reactions or deficiencies in efficacy are detected and addressed quickly and accurately in order to maintain public confidence in vaccines(5). The phases of vaccine development, pharmacovigilance, and communication can be described using figure 1. Period one (Prevaccine) represents all phases of development and testing prior to market authorization of a vaccine while period two (Increasing Coverage) represents post-authorization vaccination of targeted populations. I focus in this thesis on time periods three (Loss of Confidence) and four (Resumption of Confidence) during which safety signals may be detected and verified, additional hypotheses regarding safety and efficacy may be tested, public health implications are assessed, and scientists, public health agencies, and healthcare providers communicate with the public about the benefits and risks of vaccines. Period five (Eradication), or complete elimination of the vaccine preventable disease, will not be addressed in this thesis. 8 Figure 1. Potential stages in the evolution of immunization program, showing the dynamics of the interaction between vaccine coverage, disease incidence and vaccine adverse events, as the program matures from pre- vaccine to disease eradication (6, 7) Methodological challenges of assessing vaccine safety There are many methodological challenges inherent to the assessment of vaccine safety.
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