The “Performance of Rotavirus and Oral Polio Vaccines in Developing Countries” (PROVIDE) Study: Description of Methods of an Interventional Study Designed to Explore Complex Biologic Problems

Beth D. Kirkpatrick Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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E. Ross Colgate Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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Josyf C. Mychaleckyj Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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Rashidul Haque Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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Dorothy M. Dickson Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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Marya P. Carmolli Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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Uma Nayak Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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Mami Taniuchi Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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Caitlin Naylor Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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Firdausi Qadri Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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Jennie Z. Ma Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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Masud Alam Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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Mary Claire Walsh Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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Sean A. Diehl Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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the PROVIDE Study Teams Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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William A. Petri Jr. Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, Vermont; Departments of Medicine, The University of Virginia, Charlottesville, Virginia; The icddr,b, Dhaka, Bangladesh

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Oral vaccines appear less effective in children in the developing world. Proposed biologic reasons include concurrent enteric infections, malnutrition, breast milk interference, and environmental enteropathy (EE). Rigorous study design and careful data management are essential to begin to understand this complex problem while assuring research subject safety. Herein, we describe the methodology and lessons learned in the PROVIDE study (Dhaka, Bangladesh). A randomized clinical trial platform evaluated the efficacy of delayed-dose oral rotavirus vaccine as well as the benefit of an injectable polio vaccine replacing one dose of oral polio vaccine. This rigorous infrastructure supported the additional examination of hypotheses of vaccine underperformance. Primary and secondary efficacy and immunogenicity measures for rotavirus and polio vaccines were measured, as well as the impact of EE and additional exploratory variables. Methods for the enrollment and 2-year follow-up of a 700 child birth cohort are described, including core laboratory, safety, regulatory, and data management practices. Intense efforts to standardize clinical, laboratory, and data management procedures in a developing world setting provide clinical trials rigor to all outcomes. Although this study infrastructure requires extensive time and effort, it allows optimized safety and confidence in the validity of data gathered in complex, developing country settings.

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Author Notes

* Address correspondence to Beth D. Kirkpatrick, University of Vermont College of Medicine, Vaccine Testing Center, 89 Beaumont Avenue, Burlington, VT 05405. E-mail: beth.kirkpatrick@med.uvm.edu

Financial support: Support for this work was from the Bill and Melinda Gates Foundation.

Authors' addresses: Beth D. Kirkpatrick, E. Ross Colgate, Dorothy M. Dickson, Marya P. Carmolli, Mary Claire Walsh, and Sean A. Diehl, Department of Medicine and Vaccine Testing Center, The University of Vermont College of Medicine, Burlington, VT, E-mails: beth.kirkpatrick@med.uvm.edu, ross.colgate@med.uvm.edu, marya.carmolli@med.uvm.edu, dorothy.dickson@med.uvm.edu, mary-claire.walsh@med.uvm.edu, and sean.diehl@med.uvm.edu. Josyf C. Mychaleckyj, Uma Nayak, Mami Taniuchi, Caitlin Naylor, Jennie Z. Ma, and William A. Petri Jr., Department of Medicine, The University of Virginia, Charlottesville, VA, E-mails: jcm6t@virginia.edu, un8x@eservices.virginia.edu, mt2f@cms.mail.virginia.edu, cgn5q@virginia.edu, jzm4h@eservices.virginia.edu, and wap3g@cms.mail.virginia.edu. Rashidul Haque, Firdausi Qadri, Masud Alam, the PROVIDE study teams, the ICDDRB, Dhaka, Bangladesh, E-mails: rhaque@icddrb.org, fqadri@icddrb.org, and masud@icddrb.org.

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