title: Methodological challenges in measuring vaccine effectiveness using population cohorts in low resource settings.
abstract: Post-licensure real world evaluation of vaccine implementation is important for establishing evidence of vaccine effectiveness (VE) and programme impact, including indirect effects. Large cohort studies offer an important epidemiological approach for evaluating VE, but have inherent methodological challenges. Since March 2012, we have conducted an open prospective cohort study in two sites in rural Malawi to evaluate the post-introduction effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) against all-cause post-neonatal infant mortality and monovalent rotavirus vaccine (RV1) against diarrhoea-related post-neonatal infant mortality. Our study sites cover a population of 500,000, with a baseline post-neonatal infant mortality of 25 per 1000 live births. We conducted a methodological review of cohort studies for vaccine effectiveness in a developing country setting, applied to our study context. Based on published literature, we outline key considerations when defining the denominator (study population), exposure (vaccination status) and outcome ascertainment (mortality and cause of death) of such studies. We assess various definitions in these three domains, in terms of their impact on power, effect size and potential biases and their direction, using our cohort study for illustration. Based on this iterative process, we discuss the pros and cons of our final per-protocol analysis plan. Since no single set of definitions or analytical approach accounts for all possible biases, we propose sensitivity analyses to interrogate our assumptions and methodological decisions. In the poorest regions of the world where routine vital birth and death surveillance are frequently unavailable and the burden of disease and death is greatest We conclude that provided the balance between definitions and their overall assumed impact on estimated VE are acknowledged, such large scale real-world cohort studies can provide crucial information to policymakers by providing robust and compelling evidence of total benefits of newly introduced vaccines on reducing child mortality.
authors.affiliation: Institute for Global Health, University College London, 30 Guilford Street, London WC1N 1EH, United Kingdom. Electronic address: c.king@ucl.ac.uk.
authors.forename: C
authors.initials: C
authors.lastname: King
authors.affiliation: Institute for Global Health, University College London, 30 Guilford Street, London WC1N 1EH, United Kingdom; London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Beard
authors.affiliation: London School of Hygiene and Tropical Medicine, London, United Kingdom; Karonga Prevention Study, Karonga, Malawi.
authors.forename: A C
authors.initials: AC
authors.lastname: Crampin
authors.affiliation: Institute for Global Health, University College London, 30 Guilford Street, London WC1N 1EH, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Costello
authors.affiliation: MaiMwana Project Mchinji, Parent and Child Health Initiative, Lilongwe, Malawi; Ministry of Health, Lilongwe, Malawi.
authors.forename: C
authors.initials: C
authors.lastname: Mwansambo
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
authors.forename: N A
authors.initials: NA
authors.lastname: Cunliffe
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi; Liverpool School of Tropical Medicine, Liverpool, United Kingdom; Division of Infection & Immunity, University College London, London, United Kingdom.
authors.forename: R S
authors.initials: RS
authors.lastname: Heyderman
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom; Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi.
authors.forename: N
authors.initials: N
authors.lastname: French
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom; Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi.
authors.forename: N
authors.initials: N
authors.lastname: Bar-Zeev
mesh_terms: D003906:Developing Countries; D004812:Epidemiologic Methods; D006801:Humans; D008295:Malawi; D022242:Pneumococcal Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D011446:Prospective Studies; D022243:Rotavirus Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D016019:Survival Analysis; D016896:Treatment Outcome; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology
chemical_list: C538862:13-valent pneumococcal vaccine; D022242:Pneumococcal Vaccines; C492457:RIX4414 vaccine; D022243:Rotavirus Vaccines; D014613:Vaccines, Attenuated
keywords: Children; Cohort; Diarrhoea; Methodology; PCV13; Pneumococcal disease; Pneumonia; RV1; Survival analysis; Vaccine effectiveness