PROVIDE Randomized Controlled Trial

Background: Oral vaccines have been shown to be less effective in low-income and developing countries, limiting the optimal benefits of vaccination in populations with the greatest disease burden. There are several plausible biologic explanations for the observation of vaccine underperformance, including environmental enteropathy (EE), malnutrition, and breast milk interference. PROVIDE study was designed to evaluate factors that could interfere with oral vaccine efficacy in an environment characterized by poverty, urban overcrowding, poor sanitary conditions, and environmental enteropathy.

Objectives:

Primary Objectives:

Investigate the efficacy of a 2-dose Rotarix® oral rotavirus vaccine (given at 10 and 17 weeks of age) to prevent rotavirus diarrhea in the first year of life
Investigate OPV efficacy when a single inactivated polio vaccine (IPV) boost replaced the fourth dose (at 39 weeks of age) of trivalent OPV (tOPV)

Secondary Objectives: Determine whether EE, measured by lactulose/mannitol testing, was associated with reduced efficacy of oral vaccines for polio and rotavirus among infants. Multiple exploratory objectives included exploration of variables that might impact oral vaccine function, including socioeconomic status (SES), micronutrient deficiency, the presence of enteric co-pathogens, other measures of EE, and interference of transplacental maternal or breast milk antibodies.

Methodology:

Geographic Location/Study Sites: Dhaka, Bangladesh

Dates of Data Collection: May 2011 - November 2014

Study Design: Randomized controlled trial with two vaccine interventions

Eligibility Criteria: Mothers and infants were enrolled in the study if they met the following criteria

Inclusion Criteria:

Infant aged 0 to 7 days old
Infant has no obvious congenital abnormalities or birth defects
Infant has not had abnormal (frequency and consistency) stools since birth
Household planning to remain in the area for the next 2 years

Exclusion Criteria:

Parents unwilling to have baby vaccinated at ICDDR,B field clinic
Parents unwilling to have baby's blood drawn
Mother unwilling to have samples drawn
Infant received any vaccines other than BCG before start of study
Infant has history of seizures or other apparent neurologic disorders
Parents are planning to enroll child into another competing/conflicting clinical study in the next two years
Infant has siblings currently or previously enrolled in the study, including a twin

Study Arms: The study screened pregnant women for eligibility and enrolled 700 consenting infant-mother pairs soon after birth and randomized to vaccine interventions in a 2 x 2 factorial design. The four study groups were:

Dose 4 IPV + No Rotavirus
Dose 4 IPV + Rotavirus
Dose 4 tOPV + No Rotavirus
Dose 4 tOPV + Rotavirus

Data Collection: For evaluation of environmental enteropathy, a lactulose-mannitol solution was given to all children at four time points during the study: 12, 24, 40 and 104 weeks. The mother-infant pair were followed at 15 visits (refer to workplan table below) for anthropometry, phlebotomy, and vaccinations. Comprehensive primary care was provided to the families. Biweekly diarrheal surveillance was conducted in the homes of the participants by trained field research assistants using a structured questionnaire to obtain history and frequency of diarrhea and vomiting, body temperature at visit, feeding history and use of antibiotics and oral rehydration solution. During follow-up malnourished infants were treated according to icddr, b guidelines including: 1) promotion of exclusive breast feeding and lactation counseling for mothers of children with low WAZ or HAZ scores in the first six months of life; and 2) referral to specialized nutrition centers for malnutrition management in cases of WAZ < -3SD after six months. Adverse events occurring for 48 hr post-phlebotomy, post-vaccination, and post-ingestion of lactulose-mannitol solution and severe adverse events were recorded during the protocol period until the final day 25 fecal excretion sample at 52 weeks of age. Adverse events were reported to ethics boards or committees per local requirements.

Study Documentation: Currently only available to those who have requested and been granted access to the data. Case report forms and data dictionaries are available as zip files through the download section.

ClinEpiDB Data Integration: Data files were provided to ClinEpiDB as flat txt files. These datasets were merged by unique ID and redundant or administrative columns were dropped from presentation on ClinEpiDB.org. All dates were obfuscated per participant through the application of a random number algorithm that shifted dates no more than seven days to comply with the ethical conduct of human subjects research.

Acknowledgements: The study team thanks the families of Mirpur for their participation in and support for the study, the entire PROVIDE study staff; R. Bradley Sack, Johns Hopkins University, Independent Medical Monitor; The Gates Foundation, and the PROVIDE external advisory board.

Financial Support: Bill and Melinda Gates Foundation.

Ethics Statement: This study was conducted in compliance with the Declaration of Helsinki and in full conformity with the principles of the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR 46, 21 CFR 312, and/or ICH E6; 62 Federal Regulations 25691 (1997). Each participating institution's Research Review and Ethical Review Committees or Institutional Review Boards reviewed and approved the protocol and associated informed consent documents. Any amendments to the protocol or consent materials was approved before they were implemented.

Last Updated: March 10, 2021The Performance of Rotavirus and Oral Polio Vaccines in Developing Countries (PROVIDE) study was a randomized controlled trial evaluating oral vaccine efficacy in Bangladesh. Infants aged 0-7 days old with no congenital abnormalities or birth defects and no abnormal stools since birth were enrolled with their mothers and assiged to one of 4 intervention arms in a 2 x 2 factorial trial design. Participants were followed for two years. A visual depiction of collection timpoints for various data types can be found below.